Non-Small Cell Lung Cancer, part 2

The phase III PACIFIC trial (NCT02125461) enrolled 713 patients with stage III NSCLC whose disease had not progressed after two or more cycles of platinum-based chemoradiation therapy. Patients were randomly assigned in a 2:1 ratio to receive durvalumab (10 mg/kg intravenously) or placebo (every 2 weeks for up to 12 months).[16] The coprimary end points were PFS assessed by blinded independent central review and OS (unplanned for the interim analysis).

Sources: PACIFIC · 16

The phase III PACIFIC trial (NCT02125461) enrolled 713 patients with stage III NSCLC whose disease had not progressed after two or more cycles of platinum-based chemoradiation therapy. Patients were randomly assigned in a 2:1 ratio to receive durvalumab (10 mg/kg intravenously) or placebo (every 2 weeks for up to 12 months).[16] The coprimary end points were PFS assessed by blinded independent central review and OS (unplanned for the interim analysis).

At the interim analysis, the coprimary end point of PFS was met. The median PFS was 16.8 months with durvalumab versus 5.6 months with placebo (HR, 0.52; 95% CI, 0.42–0.65; P < .001).[16][Level of evidence B1] The 18-month PFS rate was 44.2% with durvalumab versus 27% with placebo.

Sources: 16 · Level of evidence B1

PFS benefit was seen across all prespecified subgroups and was irrespective of PD-L1 expression before chemoradiation therapy or smoking status. EGFR variants were observed in 6% of patients (29 treated with durvalumab vs. 14 treated with placebo). The unstratified HR for the subgroup with EGFR variants was 0.76 (95% CI, 0.35–1.64).

Grade 3 or 4 adverse events occurred in 29.9% of patients treated with durvalumab and in 26.1% of patients treated with placebo. The most common adverse event of grade 3 or 4 was pneumonia in 4.4% of patients treated with durvalumab and in 3.8% of patients treated with placebo.

OS was not assessed at the interim analysis.

The phase III, double-blind, placebo-controlled LAURA trial (NCT03521154) included patients with unresectable stage III NSCLC and EGFR variants . Patients had not progressed during or after definitive chemoradiation therapy. A total of 216 patients who had undergone chemoradiation therapy were randomly assigned to receive either osimertinib (n = 143) or placebo (n = 73). The primary end point was PFS as assessed by blinded independent central review.[17]

Sources: LAURA · 17

The phase III, double-blind, placebo-controlled LAURA trial (NCT03521154) included patients with unresectable stage III NSCLC and EGFR variants . Patients had not progressed during or after definitive chemoradiation therapy. A total of 216 patients who had undergone chemoradiation therapy were randomly assigned to receive either osimertinib (n = 143) or placebo (n = 73). The primary end point was PFS as assessed by blinded independent central review.[17]

The median PFS was 39.1 months with osimertinib and 5.6 months with placebo (HRdisease progression or death, 0.16; 95% CI, 0.10–0.24; P < .001).

At 36 months, the OS rate was 84% for patients in the osimertinib group (95% CI, 75%–89%) and 74% for patients in the placebo group (95% CI, 57%–85%) (HRdeath, 0.81; 95% CI, 0.42–1.56; P = .53) (at 20% data maturity).[17][Level of evidence A1]

Sources: 17 · Level of evidence A1

Grade 3 or higher adverse events occurred in 35% of patients in the osimertinib group and 12% of patients in the placebo group. Radiation pneumonitis was reported in 48% of patients in the osimertinib group and 38% of patients in the placebo group.

One prospective randomized clinical study showed the following:

One prospective randomized clinical study showed the following:

Radiation therapy given as three daily fractions improved OS compared with radiation therapy given as one daily fraction.[23][Level of evidence A1]

Sources: 23 · Level of evidence A1

Patterns of failure for patients treated with radiation therapy alone included both locoregional and distant failures.

Tracheal, esophageal, or bronchial compression.

Pain.

Vocal cord paralysis.

Hemoptysis.

Superior vena cava syndrome.

A systematic review identified six randomized trials of high-dose rate endobronchial brachytherapy (HDREB) alone or with external-beam radiation therapy (EBRT) or laser therapy.[25]

Sources: 25

A systematic review identified six randomized trials of high-dose rate endobronchial brachytherapy (HDREB) alone or with external-beam radiation therapy (EBRT) or laser therapy.[25]

Better overall symptom palliation and fewer re-treatments were required in previously untreated patients using EBRT alone.[25][Level of evidence A3]

Sources: 25 · Level of evidence A3

HDREB provided palliation of symptomatic patients with recurrent endobronchial obstruction previously treated by EBRT, when it was technically feasible.

Although EBRT is frequently prescribed for symptom palliation, there is no consensus about when the fractionation scheme should be used.

Although different multifraction regimens appear to provide similar symptom relief,[26-31] single-fraction radiation may be insufficient for symptom relief compared with hypofractionated or standard regimens, as shown in the National Cancer Institute of Canada Clinical Trials Group trial (NCT00003685).[28][Level of evidence A3]

Sources: 26 · 31 · NCT00003685 · 28 · Level of evidence A3

Evidence of a modest increase in survival in patients with better performance status given high-dose radiation therapy is available.[26,27][Level of evidence A1]

Sources: 26 · 27 · Level of evidence A1

History and molecular features.

Sources: History and molecular features

Age and comorbidity.

Sources: Age and comorbidity

Performance status.

Sources: Performance status

Platinum-containing combination chemotherapy regimens provide clinical benefit when compared with supportive care or single-agent therapy; however, such treatment may be contraindicated in some older patients because of the age-related reduction in the functional reserve of many organs and/or comorbid conditions. Approximately two-thirds of patients with NSCLC are aged 65 years or older, and approximately 40% are aged 70 years or older.[7] Surveillance, Epidemiology, and End Results (SEER) Program data suggest that the percentage of patients older than 70 years is closer to 50%.

Sources: 7

A review of the SEER Medicare data from 1994 to 1999 found a much lower rate of chemotherapy use than expected for the overall population.[8] The same data suggested that older patients may have more comorbidities or a higher rate of functional compromise that would make study participation difficult, if not contraindicated; lack of clinical trial data may influence decisions to treat individual patients with standard chemotherapy.

Sources: 8

Single-agent chemotherapy and combination chemotherapy clearly benefit at least some older patients. In the Elderly Lung Cancer Vinorelbine Italian Study, 154 patients who were older than 70 years were randomly assigned to vinorelbine or supportive care.[9]

Sources: 9

Single-agent chemotherapy and combination chemotherapy clearly benefit at least some older patients. In the Elderly Lung Cancer Vinorelbine Italian Study, 154 patients who were older than 70 years were randomly assigned to vinorelbine or supportive care.[9]

Patients who were treated with vinorelbine had a 1-year survival rate of 32%, compared with 14% for those who were treated with supportive care alone. Quality-of-life parameters were also significantly improved in the chemotherapy arm, and toxic effects were acceptable.

A trial from Japan compared single-agent docetaxel with vinorelbine in 180 patients older than 70 years with good performance status.[10]

Sources: 10

A trial from Japan compared single-agent docetaxel with vinorelbine in 180 patients older than 70 years with good performance status.[10]

Response rates (22% vs. 10%) and progression-free survival (PFS) (5.4 months vs. 3.1 months) were significantly better with docetaxel, but median survival (14.3 months vs. 9.9 months) and 1-year survival rates (59% vs. 37%) did not reach statistical significance.

Retrospective data analyzing and comparing younger (age <70 years) patients with older (age ≥70 years) patients who participated in large randomized trials of doublet combinations have also shown that older patients may derive the same survival benefit, but with a higher risk of toxic effects in the bone marrow.[5,6,11-14]

Sources: 5 · 6 · 11 · 14

The Cancer and Leukemia Group B trial (CLB-9730 [NCT00003117]), which compared carboplatin and paclitaxel with single-agent paclitaxel, enrolled 99 patients with a performance status of 2 (18% of the study's population).[13]

Sources: CLB-9730 · 13

The Cancer and Leukemia Group B trial (CLB-9730 [NCT00003117]), which compared carboplatin and paclitaxel with single-agent paclitaxel, enrolled 99 patients with a performance status of 2 (18% of the study's population).[13]

When compared with patients with a performance status of 0 to 1, who had a median survival of 8.8 months and a 1-year survival rate of 38%, the corresponding median survival figures for patients with a performance status of 2 were 3.0 months and a 1-year survival rate of 14%; this demonstrates the poor prognosis conferred by a lower performance status. These differences were statistically significant.

When patients with a performance status of 2 were analyzed by treatment arm, those who received combination chemotherapy had a significantly higher response rate (24% vs. 10%), longer median survival (4.7 months vs. 2.4 months), and a superior 1-year survival rate (18% vs. 10%), compared with those who were treated with single-agent paclitaxel.[13]

Sources: 13

A phase III trial compared single-agent pemetrexed with the combination of carboplatin and pemetrexed in 205 patients with a performance status of 2 who had not had any previous chemotherapy.[16][Level of evidence A1]This study, which was performed in eight centers in Brazil and one center in the United States, reported rates of OS and PFS that were higher than has historically been noted in most, although not all, other published studies. This may indicate differences in patient selection.

Sources: 16 · Level of evidence A1

A phase III trial compared single-agent pemetrexed with the combination of carboplatin and pemetrexed in 205 patients with a performance status of 2 who had not had any previous chemotherapy.[16][Level of evidence A1]This study, which was performed in eight centers in Brazil and one center in the United States, reported rates of OS and PFS that were higher than has historically been noted in most, although not all, other published studies. This may indicate differences in patient selection.

Median OS was 5.3 months for the pemetrexed-alone group and 9.3 months for the carboplatin-and-pemetrexed group (hazard ratio [HR], 0.62; 95% confidence interval [CI], 0.46–0.83; P = .001).

Median PFS was 2.8 months for the pemetrexed-alone group and 5.8 months for the carboplatin-and-pemetrexed group (P < .001).

The response rates were 10.3% for the pemetrexed-alone group and 23.8% for the carboplatin-and-pemetrexed group (P = .032).

Side effects were more frequent in the combination arm, as expected.

A subset analysis of 68 patients with a performance status of 2 from a trial that randomly assigned more than 1,200 patients to four platinum-based regimens has been published.

A subset analysis of 68 patients with a performance status of 2 from a trial that randomly assigned more than 1,200 patients to four platinum-based regimens has been published.

Despite a high incidence of adverse events, including five deaths, the final analysis showed that the overall toxic effects experienced by patients with a performance status of 2 was not significantly different from that experienced by patients with a performance status of 0 to 1.

An efficacy analysis demonstrated an overall response rate of 14%, median survival time of 4.1 months, and a 1-year survival rate of 19%; all were substantially inferior to the patients with performance status of 0 to 1.

A phase II randomized trial (E-1599 [NCT00006004]) of attenuated dosages of cisplatin plus gemcitabine and carboplatin plus paclitaxel included 102 patients with a performance status of 2.[17]

Sources: E-1599 · 17

A phase II randomized trial (E-1599 [NCT00006004]) of attenuated dosages of cisplatin plus gemcitabine and carboplatin plus paclitaxel included 102 patients with a performance status of 2.[17]

Response rates were 25% in the cisplatin-plus-gemcitabine arm and 16% in the carboplatin-plus-paclitaxel arm; median survival times were 6.8 months in the cisplatin-plus-gemcitabine arm and 6.1 months in the carboplatin-plus-paclitaxel arm; 1-year survival rates were 25% in the cisplatin-plus-gemcitabine arm and 19% in the carboplatin-plus-paclitaxel arm. None of these differences was statistically significant, but the survival figures were longer than expected, based on historical controls.

Results from two trials suggest that patients with a performance status of 2 may experience symptom improvement.[18,19]

Sources: 18 · 19

Cytotoxic combination chemotherapy with platinum (cisplatin or carboplatin) and paclitaxel, gemcitabine, docetaxel, vinorelbine, irinotecan, protein-bound paclitaxel, or pemetrexed.

Sources: Cytotoxic combination chemotherapy

Cytotoxic combination chemotherapy with platinum (cisplatin or carboplatin) and paclitaxel, gemcitabine, docetaxel, vinorelbine, irinotecan, protein-bound paclitaxel, or pemetrexed.

Combination chemotherapy.

Sources: Combination chemotherapy

Drug and dose schedule.

Sources: Drug and dose schedule

Combination chemotherapy with monoclonal antibodies.

Sources: Combination chemotherapy with monoclonal antibodies

Combination chemotherapy with monoclonal antibodies.

Bevacizumab.

Sources: Bevacizumab

Cetuximab.

Sources: Cetuximab

Necitumumab.

Sources: Necitumumab

Maintenance therapy after first-line chemotherapy (for patients with stable or responding disease after four cycles of platinum-based combination chemotherapy).

Sources: Maintenance therapy after first-line chemotherapy

Maintenance therapy after first-line chemotherapy (for patients with stable or responding disease after four cycles of platinum-based combination chemotherapy).

Maintenance therapy following first-line chemotherapy.

Pemetrexed following first-line platinum-based combination chemotherapy.

EGFR tyrosine kinase inhibitors (TKIs) with or without chemotherapy (for patients with EGFR variants).

Sources: EGFR tyrosine kinase inhibitors (TKIs) with or without chemotherapy

EGFR tyrosine kinase inhibitors (TKIs) with or without chemotherapy (for patients with EGFR variants).

Osimertinib alone.

Sources: Osimertinib alone

Osimertinib plus chemotherapy.

Sources: Osimertinib plus chemotherapy

Amivantamab plus lazertinib.

Sources: Amivantamab plus lazertinib

Dacomitinib.

Sources: Dacomitinib

Gefitinib.

Sources: Gefitinib

Erlotinib.

Sources: Erlotinib

Afatinib.

Sources: Afatinib

EGFR-directed therapy (for patients with EGFR exon 20 insertions).

Sources: EGFR-directed therapy

EGFR-directed therapy (for patients with EGFR exon 20 insertions).

Amivantamab.

Sources: Amivantamab

ALK inhibitors (for patients with ALK translocations).

Sources: ALK inhibitors

ALK inhibitors (for patients with ALK translocations).

Alectinib.

Sources: Alectinib

Lorlatinib.

Sources: Lorlatinib

Crizotinib.

Sources: Crizotinib

Ceritinib.

Sources: Ceritinib

Brigatinib.

Sources: Brigatinib

BRAF V600E and MEK inhibitors (for patients with BRAF V600E variants).

Sources: BRAF V600E and MEK inhibitors

BRAF V600E and MEK inhibitors (for patients with BRAF V600E variants).

Dabrafenib and trametinib.

Sources: Dabrafenib and trametinib

ROS1 inhibitors (for patients with ROS1 rearrangements).

Sources: ROS1 inhibitors

ROS1 inhibitors (for patients with ROS1 rearrangements).

Entrectinib.

Sources: Entrectinib

Crizotinib.

Sources: Crizotinib

Repotrectinib (for both ROS1 TKI-naïve and ROS1 TKI-treated patients).

Sources: Repotrectinib

NTRK inhibitors (for patients with NTRK fusions).

Sources: NTRK inhibitors

NTRK inhibitors (for patients with NTRK fusions).

Larotrectinib.

Sources: Larotrectinib

Entrectinib.

Sources: Entrectinib

RET inhibitors (for patients with RET fusions).

Sources: RET inhibitors

RET inhibitors (for patients with RET fusions).

Selpercatinib.

Sources: Selpercatinib

Pralsetinib.

Sources: Pralsetinib

MET inhibitors (for patients with MET exon 14-skipping variants).

Sources: MET inhibitors

MET inhibitors (for patients with MET exon 14-skipping variants).

Tepotinib.

Sources: Tepotinib

Capmatinib.

Sources: Capmatinib

Immune checkpoint inhibitors with or without chemotherapy.

Sources: Immune checkpoint inhibitors with or without chemotherapy

Immune checkpoint inhibitors with or without chemotherapy.

Pembrolizumab plus chemotherapy.

Sources: Pembrolizumab plus chemotherapy

Pembrolizumab alone.

Sources: Pembrolizumab alone

Cemiplimab-rwlc plus chemotherapy.

Sources: Cemiplimab-rwlc plus chemotherapy

Cemiplimab-rwlc alone.

Sources: Cemiplimab-rwlc alone

Tremelimumab.

Sources: Tremelimumab

Atezolizumab alone.

Sources: Atezolizumab alone

Atezolizumab plus chemotherapy.

Sources: Atezolizumab plus chemotherapy

Atezolizumab plus bevacizumab plus chemotherapy.

Sources: Atezolizumab plus bevacizumab plus chemotherapy

Nivolumab plus ipilimumab.

Sources: Nivolumab plus ipilimumab

mTOR inhibitors (for patients with unresectable, locally advanced or metastatic, progressive, well-differentiated, nonfunctional, neuroendocrine tumors).

Sources: mTOR inhibitors

mTOR inhibitors (for patients with unresectable, locally advanced or metastatic, progressive, well-differentiated, nonfunctional, neuroendocrine tumors).

Everolimus.

Sources: Everolimus

Local therapies and special considerations.

Sources: Local therapies and special considerations

Local therapies and special considerations.

Endobronchial laser therapy and/or brachytherapy (for obstructing lesions).[20]

Sources: Endobronchial laser therapy and/or brachytherapy · 20

External-beam radiation therapy (EBRT) (primarily for palliation of local symptomatic tumor growth).[21-23]

Sources: External-beam radiation therapy (EBRT) · 21 · 23

Treatment of second primary tumor.

Sources: Treatment of second primary tumor.

Treatment of brain metastases.

Sources: Treatment of brain metastases.

Clinical trials can be considered as first-line therapy.

Certain three-drug combinations that add so-called targeted agents may result in superior survival.

EGFR inhibitors may benefit selected patients with EGFR variants.

Maintenance chemotherapy after four cycles of platinum combination chemotherapy may improve PFS and OS.

Platinum combinations with vinorelbine, paclitaxel, docetaxel, gemcitabine, irinotecan, protein-bound paclitaxel, and pemetrexed yield similar improvements in survival. Types and frequencies of toxic effects differ, and these may determine the preferred regimen for an individual patient. Patients with adenocarcinoma may benefit from pemetrexed.

Cisplatin and carboplatin yield similar improvements in outcome with different toxic effects. Some, but not all, trials and meta-analyses of trials suggest that outcomes with cisplatin may be superior, although with a higher risk of certain toxicities such as nausea and vomiting.

Nonplatinum combinations offer no advantage to platinum-based chemotherapy, and some studies demonstrate inferiority.

Three-drug combinations of the commonly used chemotherapy drugs do not result in superior survival and are more toxic than two-drug combinations.

The Cochrane Collaboration reviewed data from all randomized controlled trials published between January 1980 and June 2006, comparing a doublet regimen with a single-agent regimen or comparing a triplet regimen with a doublet regimen in patients with advanced NSCLC.[24] Sixty-five trials (13,601 patients) were identified.

Sources: 24

The Cochrane Collaboration reviewed data from all randomized controlled trials published between January 1980 and June 2006, comparing a doublet regimen with a single-agent regimen or comparing a triplet regimen with a doublet regimen in patients with advanced NSCLC.[24] Sixty-five trials (13,601 patients) were identified.

In the trials that compared a doublet regimen with a single-agent regimen, a significant increase was observed in tumor response (odds ratio [OR], 0.42; 95% CI, 0.37–0.47; P < .001) and 1-year survival (OR, 0.80; 95% CI, 0.70–0.91; P < .001) in favor of the doublet regimen. The absolute benefit in 1-year survival was 5%, which corresponds to an increase in 1-year survival from 30% with a single-agent regimen to 35% with a doublet regimen. The rates of grades 3 and 4 toxic effects caused by doublet regimens were statistically increased compared with rates after single-agent therapy, with ORs ranging from 1.2 to 6.2. Infection rates did not increase in doublet regimens.

There was no increase in 1-year survival (OR, 1.01; 95% CI, 0.85–1.21; P = .88) for triplet regimens versus doublet regimens. The median survival ratio was 1.00 (95% CI, 0.94–1.06; P = .97).

Several meta-analyses have evaluated whether cisplatin or carboplatin regimens are superior, with variable results.[25-27] One meta-analysis reported individual patient data for 2,968 patients entered in nine randomized trials.[25]

Sources: 25 · 27 · 25

Several meta-analyses have evaluated whether cisplatin or carboplatin regimens are superior, with variable results.[25-27] One meta-analysis reported individual patient data for 2,968 patients entered in nine randomized trials.[25]

The objective response rate was higher for patients treated with cisplatin (30%) than for patients treated with carboplatin (24%); (OR, 1.37; 95% CI, 1.16–1.61; P < .001).

Carboplatin treatment was associated with a nonstatistically significant increase in the hazard of mortality relative to treatment with cisplatin (HR, 1.07; 95% CI, 0.99–1.15; P = .100).

In patients with nonsquamous cell tumors and in patients treated with third-generation chemotherapy, carboplatin-based chemotherapy was associated with a statistically significant increase in mortality (HR, 1.12; 95% CI, 1.01–1.23 in patients with nonsquamous cell tumors and HR, 1.11; 95% CI, 1.01–1.21 in patients treated with third-generation chemotherapy).

Treatment-related toxic effects were also assessed in the meta-analysis. More thrombocytopenia was seen with carboplatin than with cisplatin (12% vs. 6%; OR, 2.27; 95% CI, 1.71–3.01; P < .001), but cisplatin caused more nausea and vomiting (8% vs. 18%; OR, 0.42; 95% CI, 0.33–0.53; P < .001) and renal toxic effects (0.5% vs. 1.5%; OR, 0.37; 95% CI, 0.15–0.88; P = .018).

The authors concluded that treatment with cisplatin was not associated with a substantial increase in the overall risk of severe toxic effects. This comprehensive individual-patient meta-analysis is consistent with the conclusions of other meta-analyses that were based on essentially the same clinical trials, but which used only published data.

Three literature-based meta-analyses have trials that compared platinum with nonplatinum combinations.[28-30]

Sources: 28 · 30

Three literature-based meta-analyses have trials that compared platinum with nonplatinum combinations.[28-30]

The first meta-analysis identified 37 assessable trials that included 7,633 patients.[28]

Sources: 28

Three literature-based meta-analyses have trials that compared platinum with nonplatinum combinations.[28-30] › The first meta-analysis identified 37 assessable trials that included 7,633 patients.[28]

A 62% increase in the OR for response was attributable to platinum-based therapy (OR, 1.62; 95% CI, 1.46–1.8; P < .001). The 1-year survival rate was increased by 5% with platinum-based regimens (34% vs. 29%; OR, 1.21; 95% CI, 1.09–1.35; P = .003).

No statistically significant increase in 1-year survival was found when platinum therapies were compared with third-generation-based combination regimens (OR, 1.11; 95% CI, 0.96–1.28; P = .17).

The toxic effects of platinum-based regimens was significantly higher for hematologic toxic effects, nephrotoxic effects, and nausea and vomiting but not for neurological toxic effects, febrile neutropenia rate, or toxic death rate. These results are consistent with the second literature-based meta-analysis.

Three literature-based meta-analyses have trials that compared platinum with nonplatinum combinations.[28-30]

The second meta-analysis identified 17 trials that included 4,920 patients.[29]

Sources: 29

Three literature-based meta-analyses have trials that compared platinum with nonplatinum combinations.[28-30] › The second meta-analysis identified 17 trials that included 4,920 patients.[29]

The use of platinum-based doublet regimens was associated with a slightly higher survival at 1 year (relative risk [RR], 1.08; 95% CI, 1.01%–1.16%; P = .03) and a better partial response (RR, 1.11; 95% CI, 1.02–1.21; P = .02), with a higher risk of anemia, nausea, and neurological toxic effects.

In subanalyses, cisplatin-based doublet regimens improved survival at 1 year (RR, 1.16%; 95% CI, 1.06–1.27; P = .001), complete response (RR, 2.29; 95% CI, 1.08–4.88; P = .03), and partial response (RR, 1.19; 95% CI, 1.07–1.32; P = .002), with an increased risk of anemia, neutropenia, neurological toxic effects, and nausea.

Conversely, carboplatin-based doublet regimens did not increase survival at 1 year (RR, 0.95; 95% CI, 0.85–1.07; P = .43).

Three literature-based meta-analyses have trials that compared platinum with nonplatinum combinations.[28-30]

The third meta-analysis of phase III trials randomizing platinum-based versus nonplatinum combinations as first-line chemotherapy identified 14 trials.[30] Experimental arms were gemcitabine and vinorelbine (n = 4), gemcitabine and taxane (n = 7), gemcitabine and epirubicin (n = 1), paclitaxel and vinorelbine (n = 1), and gemcitabine and ifosfamide (n = 1). This meta-analysis was limited to the set of 11 phase III studies that used a platinum-based doublet (2,298 patients in the platinum-based arm and 2,304 patients in the nonplatinum arm).

Sources: 30

Three literature-based meta-analyses have trials that compared platinum with nonplatinum combinations.[28-30] › The third meta-analysis of phase III trials randomizing platinum-based versus nonplatinum combinations as first-line chemotherapy identified 14 trials.[30] Experimental arms were gemcitabine and vinorelbine (n = 4), gemcitabine and taxane (n = 7), gemcitabine and epirubicin (n = 1), paclitaxel and vinorelbine (n = 1), and gemcitabine and ifosfamide (n = 1). This meta-analysis was limited to the set of 11 phase III studies that used a platinum-based doublet (2,298 patients in the platinum-based arm and 2,304 patients in the nonplatinum arm).

Patients treated with a platinum-based regimen benefited from a statistically significant reduction in the risk of death at 1 year (OR, 0.88; 95% CI, 0.78–0.99; P = .044) and a lower risk of being refractory to chemotherapy (OR, 0.87; CI, 0.73–0.99; P = .049).

Forty-four (1.9%) toxic-related deaths were reported for platinum-based regimens and 29 (1.3%) toxic-related deaths were reported for nonplatinum regimens (OR, 1.53; CI, 0.96–2.49; P = .08). An increased risk of grade 3 to 4 gastrointestinal and hematologic toxic effects for patients treated with platinum-based chemotherapy was statistically demonstrated. There was no statistically significant increase in the risk of febrile neutropenia (OR, 1.23; CI, 0.94–1.60; P = .063).

One meta-analysis of seven trials that included 2,867 patients assessed the benefit of docetaxel versus vinorelbine.[31] Docetaxel was administered with a platinum agent in three trials, with gemcitabine in two trials, or as monotherapy in two trials. Vinca alkaloid (vinorelbine in six trials and vindesine in one trial) was administered with cisplatin in six trials or alone in one trial.

Sources: 31

One meta-analysis of seven trials that included 2,867 patients assessed the benefit of docetaxel versus vinorelbine.[31] Docetaxel was administered with a platinum agent in three trials, with gemcitabine in two trials, or as monotherapy in two trials. Vinca alkaloid (vinorelbine in six trials and vindesine in one trial) was administered with cisplatin in six trials or alone in one trial.

The pooled estimate for OS showed an 11% improvement in favor of docetaxel (HR, 0.89; 95% CI, 0.82–0.96; P = .004). Sensitivity analyses that considered only vinorelbine as a comparator or only the doublet regimens showed similar improvements.

Grade 3 to 4 neutropenia and grade 3 to 4 serious adverse events were less frequent with docetaxel-based regimens (OR, 0.59; 95% CI, 0.38–0.89; P = .013) versus vinca alkaloid-based regimens (OR, 0.68; 95% CI, 0.55–0.84; P < .001).

Two randomized trials compared weekly versus every-3-week dosing of paclitaxel and carboplatin, which reported no significant difference in efficacy and better tolerability for weekly administration.[32,33] Although meta-analyses of randomized controlled trials suggest that cisplatin combinations may be superior to carboplatin or nonplatinum combinations, the clinical relevance of the differences in efficacy must be balanced against the anticipated tolerability, logistics of administration, and familiarity of the medical staff in making treatment decisions for individual patients.

Sources: 32 · 33

A large, noninferiority, phase III randomized study compared the OS in 1,725 chemotherapy-naïve patients with stage IIIB/IV NSCLC and a performance status of 0 to 1.[4] Patients received cisplatin 75 mg/m2 on day 1 and gemcitabine 1,250 mg/m2 on days 1 and 8 (n = 863) or cisplatin 75 mg/m2 and pemetrexed 500 mg/m2 on day 1 (n = 862) every 3 weeks for up to six cycles.

Sources: 4

A large, noninferiority, phase III randomized study compared the OS in 1,725 chemotherapy-naïve patients with stage IIIB/IV NSCLC and a performance status of 0 to 1.[4] Patients received cisplatin 75 mg/m2 on day 1 and gemcitabine 1,250 mg/m2 on days 1 and 8 (n = 863) or cisplatin 75 mg/m2 and pemetrexed 500 mg/m2 on day 1 (n = 862) every 3 weeks for up to six cycles.

OS for cisplatin and pemetrexed (median survival, 10.3 months) was noninferior to cisplatin and gemcitabine (median survival, 10.3 months; HR, 0.94; 95% CI, 0.84%–1.05%).

In patients with adenocarcinoma (n = 847), OS was statistically superior for cisplatin and pemetrexed (12.6 months) versus cisplatin and gemcitabine (10.9 months); in patients with large cell carcinoma (n = 153), OS was statistically superior for cisplatin and pemetrexed (10.4 months) versus cisplatin and gemcitabine (6.7 months).

In contrast, in patients with squamous cell histology (n = 473), there was a significant improvement in survival with cisplatin and gemcitabine (10.8 months) versus cisplatin and pemetrexed (9.4 months). For cisplatin and pemetrexed, rates of grade 3 or 4 neutropenia, anemia, and thrombocytopenia (P ≤ .001); febrile neutropenia (P = .002); and alopecia (P < .001) were significantly lower, whereas grade 3 or 4 nausea (P = .004) was more common.

The results of this study suggested that the cisplatin and pemetrexed doublet is another alternative doublet for first-line chemotherapy for advanced NSCLC. The results also suggested that there may be differences in outcome depending on histology.

Two randomized trials have evaluated the addition of bevacizumab, an antibody targeting vascular endothelial growth factor, to standard first-line combination chemotherapy.

Two randomized trials have evaluated the addition of bevacizumab, an antibody targeting vascular endothelial growth factor, to standard first-line combination chemotherapy.

In a randomized study of 878 patients with recurrent or advanced stage IIIB/IV NSCLC, 444 patients received paclitaxel and carboplatin alone, and 434 patients received paclitaxel and carboplatin plus bevacizumab.[34] Chemotherapy was administered every 3 weeks for six cycles, and bevacizumab was administered every 3 weeks until disease progression was evident or toxic effects were intolerable. Patients with squamous cell tumors, brain metastases, clinically significant hemoptysis, or inadequate organ function or performance status (ECOG performance status >1) were excluded.

Sources: 34

Two randomized trials have evaluated the addition of bevacizumab, an antibody targeting vascular endothelial growth factor, to standard first-line combination chemotherapy. › In a randomized study of 878 patients with recurrent or advanced stage IIIB/IV NSCLC, 444 patients received paclitaxel and carboplatin alone, and 434 patients received paclitaxel and carboplatin plus bevacizumab.[34] Chemotherapy was administered every 3 weeks for six cycles, and bevacizumab was administered every 3 weeks until disease progression was evident or toxic effects were intolerable. Patients with squamous cell tumors, brain metastases, clinically significant hemoptysis, or inadequate organ function or performance status (ECOG performance status >1) were excluded.

Median survival was 12.3 months in the group assigned to chemotherapy plus bevacizumab, as compared with 10.3 months in the chemotherapy-alone group (HRdeath, 0.79; P = .003).

Median PFS was 6.2 months in the group assigned to chemotherapy plus bevacizumab (HRdisease progression, 0.66; P < .001), with a 35% response rate (P < .001), and 4.5 months in the chemotherapy-alone group (HRdisease progression, 0.66; P < .001), with a 15% response rate (P < .001).

Rates of clinically significant bleeding were 4.4% in the group assigned to chemotherapy plus bevacizumab and 0.7% in the chemotherapy-alone group (P < .001). There were 15 treatment-related deaths in the chemotherapy-plus-bevacizumab group, including five from pulmonary hemorrhage.

For this subgroup of patients with NSCLC, the addition of bevacizumab to paclitaxel and carboplatin may provide survival benefit.[34][Level of evidence A1]

Sources: 34 · Level of evidence A1

Two randomized trials have evaluated the addition of bevacizumab, an antibody targeting vascular endothelial growth factor, to standard first-line combination chemotherapy.

Another randomized, phase III trial investigated the efficacy and safety of cisplatin-gemcitabine plus bevacizumab.[35] Patients were randomly assigned to receive cisplatin (80 mg/m2) and gemcitabine (1,250 mg/m2) for up to six cycles, plus low-dose bevacizumab (7.5 mg/kg), high-dose bevacizumab (15 mg/kg), or placebo every 3 weeks until disease progression. The primary end point was amended from OS to PFS during the course of the study. A total of 1,043 patients were accrued (placebo group, n = 347; low-dose group, n = 345; high-dose group, n = 351).

Sources: 35

Two randomized trials have evaluated the addition of bevacizumab, an antibody targeting vascular endothelial growth factor, to standard first-line combination chemotherapy. › Another randomized, phase III trial investigated the efficacy and safety of cisplatin-gemcitabine plus bevacizumab.[35] Patients were randomly assigned to receive cisplatin (80 mg/m2) and gemcitabine (1,250 mg/m2) for up to six cycles, plus low-dose bevacizumab (7.5 mg/kg), high-dose bevacizumab (15 mg/kg), or placebo every 3 weeks until disease progression. The primary end point was amended from OS to PFS during the course of the study. A total of 1,043 patients were accrued (placebo group, n = 347; low-dose group, n = 345; high-dose group, n = 351).

PFS was significantly prolonged with the addition of bevacizumab; the HRs for PFS were 0.75 in the low-dose group (median PFS, 6.7 months vs. 6.1 months for the placebo group; P = .03) and 0.82 in the high-dose group compared with the placebo group (median PFS, 6.5 months vs. 6.1 months for the placebo group; P = .03).[35][Level of evidence A1]

Sources: 35 · Level of evidence A1

Objective response rates were also improved with the addition of bevacizumab, and they were 20.1% for placebo, 34.1% for low-dose bevacizumab, and 30.4% for high-dose bevacizumab plus cisplatin/gemcitabine.

Incidence of grade 3 or greater adverse events was similar across arms.

Grade 3 or greater pulmonary hemorrhage rates were 1.5% or less for all arms, despite 9% of patients receiving therapeutic anticoagulation.

These results support the addition of bevacizumab to platinum-containing chemotherapy, but the results are far less impressive than when the carboplatin-paclitaxel combination was used.

Furthermore, no significant difference in survival was shown in this study, as reported in abstract form.

Altogether, these findings may suggest that the backbone of chemotherapy may be important when bevacizumab is added.

Two trials have evaluated the addition of cetuximab to first-line combination chemotherapy.[36,37]

Sources: 36 · 37

Two trials have evaluated the addition of cetuximab to first-line combination chemotherapy.[36,37]

In the first trial, 676 chemotherapy-naïve patients with stage IIIB (pleural effusion) or stage IV NSCLC, without restrictions by histology or EGFR expression, received cetuximab with taxane (paclitaxel or docetaxel with carboplatin) or combination chemotherapy.[36]

Sources: 36

Two trials have evaluated the addition of cetuximab to first-line combination chemotherapy.[36,37] › In the first trial, 676 chemotherapy-naïve patients with stage IIIB (pleural effusion) or stage IV NSCLC, without restrictions by histology or EGFR expression, received cetuximab with taxane (paclitaxel or docetaxel with carboplatin) or combination chemotherapy.[36]

The addition of cetuximab did not result in a statistically significant improvement in PFS, the primary study end point, or OS.

Median PFS was 4.40 months for patients in the cetuximab-chemotherapy arm versus 4.24 months for patients in the taxane-carboplatin arm (HR, 0.902; 95% CI, 0.761–1.069; P = .236).

Median OS was 9.69 months for patients in the cetuximab-chemotherapy arm versus 8.38 months for patients in the chemotherapy-alone arm (HR, 0.890; 95% CI, 0.754–1.051; P = .169).

In treatment-specific analyses, PFS, OS, and response were not significantly associated with EGFR expression, EGFR variants, EGFR copy number, or KRAS variants.[38]

Sources: 38

Two trials have evaluated the addition of cetuximab to first-line combination chemotherapy.[36,37]

The second trial was composed of 1,125 chemotherapy-naïve patients with advanced EGFR-expressing stage IIIB/IV NSCLC treated with cisplatin-vinorelbine chemotherapy plus cetuximab or chemotherapy alone.[37]

Sources: 37

Two trials have evaluated the addition of cetuximab to first-line combination chemotherapy.[36,37] › The second trial was composed of 1,125 chemotherapy-naïve patients with advanced EGFR-expressing stage IIIB/IV NSCLC treated with cisplatin-vinorelbine chemotherapy plus cetuximab or chemotherapy alone.[37]

The primary study end point, OS, was longer for patients treated with cetuximab and chemotherapy (median 11.3 months vs. 10.1 months; HRdeath, 0.871; 95% CI, 0.762–0.996; P = .044).

A survival benefit was seen in all histological subgroups; however, survival benefit was not seen in non-White or Asian patients. Only the interaction between the treatment and the ethnic origin was significant (P = .011).

The main cetuximab-related adverse event was acne-like rash (grade 3, 10%).

Two trials have evaluated the addition of cetuximab to first-line combination chemotherapy.[36,37]

It is not clear whether the differences in outcome in these two studies are the result of differences in the study populations, tumor characterization for EGFR expression, or chemotherapy regimens.

Two phase III trials have evaluated the addition of the second-generation, recombinant, human immunoglobulin G1 EGFR antibody, necitumumab, to platinum-doublet chemotherapy in the first-line treatment of patients with advanced nonsquamous cell and squamous cell NSCLC.[39,40]

Sources: 39 · 40

Two phase III trials have evaluated the addition of the second-generation, recombinant, human immunoglobulin G1 EGFR antibody, necitumumab, to platinum-doublet chemotherapy in the first-line treatment of patients with advanced nonsquamous cell and squamous cell NSCLC.[39,40]

The SQUIRE trial (NCT00981058) randomly assigned 1,093 patients with advanced squamous NSCLC to receive either first-line chemotherapy with cisplatin and gemcitabine or the same regimen with the addition of necitumumab (800 mg on day 1 and day 8 of each cycle).[40]

Sources: SQUIRE · 40

Two phase III trials have evaluated the addition of the second-generation, recombinant, human immunoglobulin G1 EGFR antibody, necitumumab, to platinum-doublet chemotherapy in the first-line treatment of patients with advanced nonsquamous cell and squamous cell NSCLC.[39,40] › The SQUIRE trial (NCT00981058) randomly assigned 1,093 patients with advanced squamous NSCLC to receive either first-line chemotherapy with cisplatin and gemcitabine or the same regimen with the addition of necitumumab (800 mg on day 1 and day 8 of each cycle).[40]

Median OS was prolonged with the addition of necitumumab (11.5 months vs. 9.9 months; P = .01).

PFS was also prolonged with the addition of necitumumab (5.7 months vs. 5.5 months); however, the overall response rate was similar in both groups (31% vs. 28%).

Grades 3 and 4 adverse events were higher in the necitumumab-containing arm (72% vs. 62%).

Necitumumab is associated with higher toxicity and relatively modest benefit.

Two phase III trials have evaluated the addition of the second-generation, recombinant, human immunoglobulin G1 EGFR antibody, necitumumab, to platinum-doublet chemotherapy in the first-line treatment of patients with advanced nonsquamous cell and squamous cell NSCLC.[39,40]

The INSPIRE trial (NCT00982111) randomly assigned 633 patients with advanced nonsquamous NSCLC to receive either first-line chemotherapy with cisplatin and pemetrexed or to cisplatin and pemetrexed with the addition of necitumumab (800 mg on day 1 and day 8 of each cycle).[39]

Sources: INSPIRE · 39

Two phase III trials have evaluated the addition of the second-generation, recombinant, human immunoglobulin G1 EGFR antibody, necitumumab, to platinum-doublet chemotherapy in the first-line treatment of patients with advanced nonsquamous cell and squamous cell NSCLC.[39,40] › The INSPIRE trial (NCT00982111) randomly assigned 633 patients with advanced nonsquamous NSCLC to receive either first-line chemotherapy with cisplatin and pemetrexed or to cisplatin and pemetrexed with the addition of necitumumab (800 mg on day 1 and day 8 of each cycle).[39]

This study showed no benefit from the addition of necitumumab to standard first-line chemotherapy for advanced nonsquamous NSCLC.

OS was 11.3 months (95% CI, 9.5–13.4) for patients in the necitumumab-containing arm versus 11.5 months (95% CI, 10.1–13.1) for patients in the chemotherapy alone arm; P = .96. Similarly, there was no difference between the arms in terms of objective response or PFS.

Serious adverse events and rates of grades 3 and 4 adverse events, including thromboembolic events, were higher in patients in the necitumumab-containing arm; the incidence of treatment-related deaths was also higher (5% vs. 3%).

On the basis of these results, necitumumab is not recommended as combination therapy with standard first-line chemotherapy for patients with advanced nonsquamous NSCLC.

Continuing the initial combination chemotherapy regimen.

Continuing only single-agent chemotherapy.

Introducing a new agent as maintenance.

None of the trials of continued cytotoxic combinations showed a significant OS advantage with additional or longer durations beyond four cycles. For patients with nonsquamous NSCLC, two studies have demonstrated improved PFS and OS with either switch or continuous maintenance chemotherapy (e.g., maintenance pemetrexed after initial cisplatin and gemcitabine or maintenance pemetrexed after initial cisplatin and pemetrexed).[41]

Sources: 41

Three trials found statistically significantly improved PFS or time to progression with additional chemotherapy.[42-44]

Sources: 42 · 44

No consistent improvement in quality of life was reported.[43,45,46]

Sources: 43 · 45 · 46

Chemotherapy-related toxicities were greater with prolonged chemotherapy.[45,46]

Sources: 45 · 46

In the first trial, 663 patients with stage IIIB/IV disease who had not progressed during four cycles of nonpemetrexed platinum–based chemotherapy were randomly assigned (in a 2:1 ratio) to receive pemetrexed or placebo until disease progression.[47]

Sources: 47

In the first trial, 663 patients with stage IIIB/IV disease who had not progressed during four cycles of nonpemetrexed platinum–based chemotherapy were randomly assigned (in a 2:1 ratio) to receive pemetrexed or placebo until disease progression.[47]

Both the primary end point of PFS and the secondary end point of OS were statistically significantly prolonged with the addition of maintenance pemetrexed (median PFS, 4.3 months vs. 2.6 months; HR, 0.50; 95% CI, 0.42–0.61; P < .0001; median OS, 13.4 months vs. 10.6 months; HR, 0.79; 95% CI, 0.65–0.95; P = .012).

Benefit was not seen in patients with squamous histology.

Higher than grade 3 toxicity and treatment discontinuations that resulted from drug-related toxic effects were higher in the pemetrexed group than in the placebo group.

No pemetrexed-related deaths occurred.

Relatively fewer patients in the pemetrexed group than in the placebo group received systemic postdiscontinuation therapy (227 [51%] vs. 149 [67%]; P = .0001).

Quality of life during maintenance therapy with pemetrexed was similar to placebo, except for a small increase in loss of appetite and significantly delayed worsening of pain and hemoptysis as assessed using the Lung Cancer Symptom Scale.[48] The quality-of-life results require cautious evaluation because there was a high degree of censoring (>50%) with the primary quality-of-life end point, which was time to worsening of symptoms.

Sources: 48

Trials have not evaluated maintenance pemetrexed versus pemetrexed at progression.

In the second trial, 539 patients with nonsquamous NSCLC with nonprogression after treatment with pemetrexed and cisplatin were randomly assigned to continued pemetrexed or placebo.[44]

Sources: 44

In the second trial, 539 patients with nonsquamous NSCLC with nonprogression after treatment with pemetrexed and cisplatin were randomly assigned to continued pemetrexed or placebo.[44]

There was a statistically significant improvement in the primary end point of PFS (4.1 months vs. 2.8 months, HR, 0.62; 95% CI, 0.49–0.79) and in the secondary end point of OS (13.9 months vs. 11 months, HR, 0.78; 95% CI, 0.64–0.96).[41,44][Level of evidence B1]

Sources: 41 · 44 · Level of evidence B1

A phase III, multicenter, randomized, double-blind, controlled trial (FLAURA [NCT02296125]) compared osimertinib, an oral, third-generation, irreversible EGFR TKI that inhibits both EGFR-TKI–sensitizing variants and the EGFR T790M resistance variant, with standard of care EGFR TKIs (gefitinib or erlotinib) as first-line treatment of patients with previously untreated, EGFR-positive (exon 19 deletion or L858R), advanced NSCLC, as detected by a U.S. Food and Drug Administration (FDA)-approved test.[49] The 556 patients were randomly assigned in a 1:1 ratio.

Sources: FLAURA · 49

A phase III, multicenter, randomized, double-blind, controlled trial (FLAURA [NCT02296125]) compared osimertinib, an oral, third-generation, irreversible EGFR TKI that inhibits both EGFR-TKI–sensitizing variants and the EGFR T790M resistance variant, with standard of care EGFR TKIs (gefitinib or erlotinib) as first-line treatment of patients with previously untreated, EGFR-positive (exon 19 deletion or L858R), advanced NSCLC, as detected by a U.S. Food and Drug Administration (FDA)-approved test.[49] The 556 patients were randomly assigned in a 1:1 ratio.

The primary end point of PFS was significantly longer with osimertinib (18.9 months vs. 10.2 months; HR, 0.46; 95% CI, 0.37–0.57, P < .001).[49][Level of evidence B1]

Sources: 49 · Level of evidence B1

The objective response rate was similar for both groups (80% for the osimertinib group vs. 76% for the standard EGFR TKI group).

Central nervous system (CNS) progression was observed less often in the osimertinib group compared with the standard EGFR TKI group (6% vs. 15%).

The median duration of response (DOR) was 17.2 months (95% CI, 13.8–22.0) with osimertinib versus 8.5 months (95% CI, 7.3–9.8) with standard EGFR TKIs.

OS was a key secondary end point. With a follow-up of at least 39 months in each group, the median OS was 38.6 months (95% CI, 34.5–41.8) in the osimertinib group and 31.8 months (95% CI, 26.6–36.0) in the standard EGFR TKI group (HRdeath 0.80; 95.05% CI, 0.64–1.00; P = .046).[50][Level of evidence A1]

Sources: 50 · Level of evidence A1

The crossover rate from the standard EGFR TKI group to the osimertinib group was 31% (85 of 277) among patients assigned to the standard EGFR TKI group and 47% (85 of 180) among patients discontinuing the EGFR TKI. The authors noted that this crossover probably contributed to the duration of OS in the EGFR TKI (31.8 months).

No new safety signals were observed. Rates of adverse events of grade 3 or higher and adverse events leading treatment discontinuations were similar between groups. Adverse events leading to dose interruptions, reductions, or permanent discontinuations were 43%, 5%, and 15%, respectively, in the osimertinib group and 41%, 4%, and 18%, respectively, in the EGFR TKI group.

A multicenter, randomized, open-label, phase III trial (FLAURA2 [NCT04035486]) compared osimertinib plus chemotherapy with osimertinib alone in patients with advanced NSCLC and EGFR variants (EGFR exon 19 deletion or EGFR L858R variant). Patients had not previously received treatment for advanced disease. Patients received osimertinib (80 mg once daily) with chemotherapy (pemetrexed [500 mg/m2 of body-surface area] plus either cisplatin [75 mg/m2] or carboplatin [pharmacologically guided dose, area under the curve (AUC) = 5]) or osimertinib monotherapy (80 mg once daily). Chemotherapy in the combination arm was given for four 21-day cycles and was followed by osimertinib and pemetrexed (500 mg/m2) maintenance every 3 weeks. A total of 557 eligible patients were randomly assigned in a 1:1 ratio. The primary end point was investigator-assessed PFS.[51]Analysis of OS, a secondary end point, requires further follow-up (data maturity, 27%).

Sources: FLAURA2 · 51

A multicenter, randomized, open-label, phase III trial (FLAURA2 [NCT04035486]) compared osimertinib plus chemotherapy with osimertinib alone in patients with advanced NSCLC and EGFR variants (EGFR exon 19 deletion or EGFR L858R variant). Patients had not previously received treatment for advanced disease. Patients received osimertinib (80 mg once daily) with chemotherapy (pemetrexed [500 mg/m2 of body-surface area] plus either cisplatin [75 mg/m2] or carboplatin [pharmacologically guided dose, area under the curve (AUC) = 5]) or osimertinib monotherapy (80 mg once daily). Chemotherapy in the combination arm was given for four 21-day cycles and was followed by osimertinib and pemetrexed (500 mg/m2) maintenance every 3 weeks. A total of 557 eligible patients were randomly assigned in a 1:1 ratio. The primary end point was investigator-assessed PFS.[51]Analysis of OS, a secondary end point, requires further follow-up (data maturity, 27%).

PFS was 25.5 months (24.7–not calculable) for patients in the osimertinib-plus-chemotherapy group and 16.7 months (14.1–21.3) for patients in the osimertinib-monotherapy group (HR, 0.62; 95% CI, 0.49–0.79; P < .001).[51][Level of evidence B1] PFS was assessed according to blinded independent central review and was consistent with the primary analysis (HR, 0.62; 95% CI, 0.48–0.80).

Sources: 51 · Level of evidence B1

At 24 months, 57% (95% CI, 50%–63%) of the patients in the osimertinib-plus-chemotherapy group and 41% (95% CI, 35%–47%) of those in the osimertinib-alone group were alive and progression-free.

An objective response (complete or partial) occurred in 83% of patients who received osimertinib plus chemotherapy and 76% of patients who received osimertinib alone.

The median DOR was 24.0 months (95% CI, 20.9–27.8) in the osimertinib-plus-chemotherapy group and 15.3 months (95% CI, 12.7–19.4), in the osimertinib-alone group.

Grade 3 or higher adverse events from any cause were more common with the combination (64%) than with monotherapy (27%); this is consistent with known chemotherapy-related adverse events. Osimertinib plus pemetrexed with a platinum-based agent had a safety profile that was consistent with the established profiles of these agents.

The international phase III MARIPOSA trial (NCT04487080) included 1,074 patients with untreated advanced or metastatic NSCLC and EGFR variants (EGFR exon 19 deletion or EGFR L858R). Patients were randomly assigned in a 2:2:1 ratio to receive amivantamab plus lazertinib (429 patients, in an open-label fashion), osimertinib (429 patients, in a blinded fashion), or lazertinib (216 patients, in a blinded fashion). The primary end point of the study was PFS for the amivantamab-lazertinib group compared with the osimertinib group, as assessed by blinded independent central review. At a median follow-up of 22.0 months, the median duration of treatment was 18.5 months (range, 0.2–31.4) in the amivantamab-lazertinib group and 18.0 months (range, 0.2–32.7) in the osimertinib group.[52]

Sources: MARIPOSA · 52

The international phase III MARIPOSA trial (NCT04487080) included 1,074 patients with untreated advanced or metastatic NSCLC and EGFR variants (EGFR exon 19 deletion or EGFR L858R). Patients were randomly assigned in a 2:2:1 ratio to receive amivantamab plus lazertinib (429 patients, in an open-label fashion), osimertinib (429 patients, in a blinded fashion), or lazertinib (216 patients, in a blinded fashion). The primary end point of the study was PFS for the amivantamab-lazertinib group compared with the osimertinib group, as assessed by blinded independent central review. At a median follow-up of 22.0 months, the median duration of treatment was 18.5 months (range, 0.2–31.4) in the amivantamab-lazertinib group and 18.0 months (range, 0.2–32.7) in the osimertinib group.[52]

The median PFS was 23.7 months in the amivantamab-lazertinib group and 16.6 months in the osimertinib group (HRdisease progression or death, 0.70; 95% CI, 0.58–0.85; P < .001).[52][Level of evidence B1]

Sources: 52 · Level of evidence B1

The objective response rate was 86% in the amivantamab-lazertinib group (95% CI, 83%–89%) and 85% in the osimertinib group (95% CI, 81%–88%).

The median DOR was 25.8 months (95% CI, 20.1–not estimable [NE]) in the amivantamab-lazertinib group and 16.8 months (95% CI, 14.8-18.5) in the osimertinib group.

The HRdeath was 0.80 (95% CI, 0.61–1.05).

The treatment discontinuation rate due to adverse events was 10% in the amivantamab-lazertinib group and 3% in the osimertinib group.

A multicenter open-label, phase III trial (ARCHER 1050 [NCT01774721]) compared dacomitinib, a second-generation, irreversible EGFR TKI, administered orally at a dose of 45 mg per day with gefitinib administered orally at a dose of 250 mg per day, as first-line therapy in patients with newly diagnosed advanced NSCLC and the following EGFR variants: EGFR exon 19 deletion or EGFR L858R variants, as detected by an FDA-approved test.[53] Four hundred and fifty-two eligible patients were randomly assigned in a 1:1 ratio. The primary end point was PFS assessed by masked independent review in the intention-to-treat (ITT) population.

Sources: ARCHER 1050 · 53

A multicenter open-label, phase III trial (ARCHER 1050 [NCT01774721]) compared dacomitinib, a second-generation, irreversible EGFR TKI, administered orally at a dose of 45 mg per day with gefitinib administered orally at a dose of 250 mg per day, as first-line therapy in patients with newly diagnosed advanced NSCLC and the following EGFR variants: EGFR exon 19 deletion or EGFR L858R variants, as detected by an FDA-approved test.[53] Four hundred and fifty-two eligible patients were randomly assigned in a 1:1 ratio. The primary end point was PFS assessed by masked independent review in the intention-to-treat (ITT) population.

Median PFS was 14.7 months in the dacomitinib group and 9.2 months in the gefitinib group (HR, 0.59; 95% CI, 0.47−0.74; P < .0001).[53][Level of evidence B1]

Sources: 53 · Level of evidence B1

The objective response rate was similar between the two groups (75% for the dacomitinib group vs. 72% for the gefitinib group; P = 0.42).

The median DOR was longer in the dacomitinib group (14.8 months vs. 8.3 months; HR, 0.4; 95% CI, 0.31−0.53; P < .0001).

The median OS was 34.1 months with dacomitinib vs. 26.8 months with gefitinib (HR, 0.76; 95% CI, 0.58−0.99; P = .44).[53]

Sources: 53

Grade 3 or higher adverse events of any cause occurred in 63% of patients who received dacomitinib and 41% of patients who received gefitinib. The most common grade 3 or 4 adverse events were dermatitis acneiform (14% in the dacomitinib group vs. none in the gefitinib group), diarrhea (8% vs. 1%), and raised alanine aminotransferase (ALT) levels (1% vs. 8%). Serious treatment-related adverse events were more frequent in the dacomitinib group (9% vs. 4%). Permanent discontinuation of the study drug because of treatment-related adverse events occurred more often in the dacomitinib group (10% vs. 7%). Dose reductions were also more frequent in the dacomitinib group (66% vs. 8%).

A phase III, multicenter, randomized trial compared gefitinib with carboplatin plus paclitaxel as first-line treatment in clinically selected patients in East Asia who had advanced adenocarcinoma of the lung and had never smoked or were former light smokers.[54]

Sources: 54

A phase III, multicenter, randomized trial compared gefitinib with carboplatin plus paclitaxel as first-line treatment in clinically selected patients in East Asia who had advanced adenocarcinoma of the lung and had never smoked or were former light smokers.[54]

The study met its primary objective of demonstrating the superiority of gefitinib compared with the carboplatin-paclitaxel combination for PFS (HRprogression or death, 0.74; 95% CI, 0.65–0.85; P < .001).

The median PFS was 5.7 months in the gefitinib group and 5.8 months in the carboplatin-paclitaxel group.[54][Level of evidence B1]

Sources: 54 · Level of evidence B1

Following the time that chemotherapy was discontinued and while gefitinib was continued, the PFS curves clearly separated and favored gefitinib.

The 12-month PFS rates were 24.9% with the gefitinib group and 6.7% with the carboplatin-paclitaxel group.

More than 90% of the patients in the trial with variants had either EGFR del19 or L858R variants, which have been shown to be sensitive to EGFR inhibitors. In the subgroup of patients with these variants, PFS was significantly longer among those who received gefitinib (HR, 0.48; 95% CI, 0.36–0.64; P < .001); however, in the subgroup of patients who were negative for EGFR variants, PFS was significantly longer in those who received the carboplatin-paclitaxel combination (HR with gefitinib, 2.85; 95% CI, 2.05–3.98; P < .001). There was a significant interaction between treatment and EGFR variants with respect to PFS (P < .001).[54]

Sources: 54

OS was similar for patients who received gefitinib and carboplatin-paclitaxel, with no significant difference in treatments (HR, 0.90; 95% CI, 0.79–1.02; P = .109) or in EGFR variant–positive (HR, 1.00; 95% CI, 0.76–1.33; P = .990) or EGFR variant–negative (HR, 1.18; 95% CI, 0.86–1.63; P = .309; treatment by EGFR variant interaction P = .480) subgroups. A high proportion (64.3%) of EGFR variant–positive patients randomly assigned to the carboplatin-paclitaxel regimen received subsequent EGFR TKIs. PFS was significantly longer with gefitinib for patients who had both high EGFR gene copy number and EGFR variants (HR, 0.48; 95% CI, 0.34–0.67) but significantly shorter when high EGFR gene copy number was not accompanied by an EGFR variant (HR, 3.85; 95% CI, 2.09–7.09).

A phase III trial from Japan prospectively confirmed that patients with NSCLC and EGFR variants have improved PFS but not OS when treated with gefitinib. The trial included 230 chemotherapy-naïve patients with metastatic NSCLC and EGFR variants who were randomly assigned to receive gefitinib or carboplatin-paclitaxel.[55]

Sources: 55

A phase III trial from Japan prospectively confirmed that patients with NSCLC and EGFR variants have improved PFS but not OS when treated with gefitinib. The trial included 230 chemotherapy-naïve patients with metastatic NSCLC and EGFR variants who were randomly assigned to receive gefitinib or carboplatin-paclitaxel.[55]

In the planned interim analysis of data for the first 200 patients, PFS was significantly longer in the gefitinib group than in the standard-chemotherapy group (HRdeath or disease progression with gefitinib, 0.36; P < .001), resulting in early termination of the study.

The gefitinib group had a significantly longer median PFS (10.8 months vs. 5.4 months in the chemotherapy group; HR, 0.30; 95% CI, 0.22–0.41; P < .001).[55][Level of evidence B1] The median OS was 30.5 months in the gefitinib group and 23.6 months in the standard chemotherapy group (P = .31).

Sources: 55 · Level of evidence B1

Another phase III trial from Japan also prospectively confirmed that patients with NSCLC and EGFR variants have improved PFS but not OS when treated with gefitinib. In the second trial, the West Japanese Oncology Group conducted a phase III study (WJTOG3405) in 177 chemotherapy-naïve patients aged 75 years or younger and diagnosed with stage IIIB/IV NSCLC or postoperative recurrence and EGFR variants (either the EGFR exon 19 deletion or EGFR L858R single nucleotide variant). Patients were randomly assigned to receive either gefitinib or cisplatin plus docetaxel (given every 21 days for three to six cycles). The primary end point was PFS.[56]

Sources: 56

Another phase III trial from Japan also prospectively confirmed that patients with NSCLC and EGFR variants have improved PFS but not OS when treated with gefitinib. In the second trial, the West Japanese Oncology Group conducted a phase III study (WJTOG3405) in 177 chemotherapy-naïve patients aged 75 years or younger and diagnosed with stage IIIB/IV NSCLC or postoperative recurrence and EGFR variants (either the EGFR exon 19 deletion or EGFR L858R single nucleotide variant). Patients were randomly assigned to receive either gefitinib or cisplatin plus docetaxel (given every 21 days for three to six cycles). The primary end point was PFS.[56]

The gefitinib group had significantly longer PFS than the cisplatin-plus-docetaxel group, with a median PFS of 9.2 months (95% CI, 8.0–13.9) versus 6.3 months (range, 5.8–7.8 months; HR, 0.489; 95% CI, 0.336–0.710; log-rank P < .0001).[56][Level of evidence B1]

Sources: 56 · Level of evidence B1

An open-label phase III trial (NCT00874419) from China included 165 patients older than 18 years with histologically confirmed stage IIIB/IV NSCLC and confirmed activating EGFR variants (i.e., EGFR exon 19 deletion or EGFR L858R single nucleotide variant). Patients were randomly assigned to receive either oral erlotinib (150 mg/day) until they experienced disease progression or unacceptable toxic effects, or up to four cycles of gemcitabine plus carboplatin.[57]

Sources: NCT00874419 · 57

An open-label phase III trial (NCT00874419) from China included 165 patients older than 18 years with histologically confirmed stage IIIB/IV NSCLC and confirmed activating EGFR variants (i.e., EGFR exon 19 deletion or EGFR L858R single nucleotide variant). Patients were randomly assigned to receive either oral erlotinib (150 mg/day) until they experienced disease progression or unacceptable toxic effects, or up to four cycles of gemcitabine plus carboplatin.[57]

The median PFS was significantly longer in patients who received erlotinib than in patients who received chemotherapy (13.1 months [95% CI, 10.58–16.53] vs. 4.6 months [range, 4.21–5.42 months]; HR, 0.16; 95% CI, 0.10–0.26; P < .0001).[57][Level of evidence B1]

Sources: 57 · Level of evidence B1

In a European study (EURTAC [NCT00446225]), 1,227 patients with advanced NSCLC were screened for EGFR variants. Of these, 174 patients with EGFR variants were randomly assigned to receive erlotinib or platinum-based chemotherapy.[58] The primary end point was PFS.

Sources: EURTAC · 58

In a European study (EURTAC [NCT00446225]), 1,227 patients with advanced NSCLC were screened for EGFR variants. Of these, 174 patients with EGFR variants were randomly assigned to receive erlotinib or platinum-based chemotherapy.[58] The primary end point was PFS.

In an interim analysis of the first 153 patients, PFS in the chemotherapy arm was 5.2 months (95% CI, 4.5–5.8) compared with 9.7 months (95% CI, 8.4–12.3) in the erlotinib arm (HR, 0.37; P < .0001). Median survival was 19.3 months in patients in the chemotherapy arm and 19.5 months in patients in the erlotinib arm (HR, 0.80; P = .42).[59][Level of evidence B1]

Sources: 59 · Level of evidence B1

An open-label, randomized, phase III study (LUX-Lung 3 [NCT00949650]) included 345 Asian (72%) and White (26%) patients with stage IIIB/IV NSCLC and confirmed EGFR variants (i.e., EGFR exon 19 deletion, EGFR L858R variant, or other [38 of 345 patients had other less-common EGFR variants]). Patients were screened, and 340 patients received at least one dose of study medication, which was either 40 mg of oral afatinib, an irreversible EGFR/human epidermal receptor TKI, daily or up to six cycles of cisplatin and pemetrexed for first-line treatment.[60]

Sources: LUX-Lung 3 · 60

An open-label, randomized, phase III study (LUX-Lung 3 [NCT00949650]) included 345 Asian (72%) and White (26%) patients with stage IIIB/IV NSCLC and confirmed EGFR variants (i.e., EGFR exon 19 deletion, EGFR L858R variant, or other [38 of 345 patients had other less-common EGFR variants]). Patients were screened, and 340 patients received at least one dose of study medication, which was either 40 mg of oral afatinib, an irreversible EGFR/human epidermal receptor TKI, daily or up to six cycles of cisplatin and pemetrexed for first-line treatment.[60]

The primary end point was PFS. In this study, the afatinib group had significantly longer PFS than the cisplatin-plus-pemetrexed group, with a median PFS of 11.1 months for afatinib and 6.9 months for chemotherapy (HR, 0.58; 95% CI, 0.43–0.78; P = .001).[60][Level of evidence B1]

Sources: 60 · Level of evidence B1

Assessment of OS was a secondary end point and was reported separately.[61] Similar to the PFS analysis, OS was stratified based on EGFR variant type and the patient's ethnic origin.

Sources: 61

An open-label, randomized, phase III study (LUX-Lung 3 [NCT00949650]) included 345 Asian (72%) and White (26%) patients with stage IIIB/IV NSCLC and confirmed EGFR variants (i.e., EGFR exon 19 deletion, EGFR L858R variant, or other [38 of 345 patients had other less-common EGFR variants]). Patients were screened, and 340 patients received at least one dose of study medication, which was either 40 mg of oral afatinib, an irreversible EGFR/human epidermal receptor TKI, daily or up to six cycles of cisplatin and pemetrexed for first-line treatment.[60] › Assessment of OS was a secondary end point and was reported separately.[61] Similar to the PFS analysis, OS was stratified based on EGFR variant type and the patient's ethnic origin.

With a median follow-up of 41 months, median OS was 28.2 months in patients in both arms (HR, 0.88; 95% CI, 0.66–1.17; P = .39).

In patients with common EGFR variants (i.e., EGFR exon 19 deletion or EGFR L858R variant), survival did not differ significantly between treatment arms (HR, 0.78; 95% CI, 0.58–1.06; P = .11). However, prespecified subgroup analyses demonstrated a survival advantage with afatinib compared with chemotherapy in patients with EGFR del19 variants (median OS, 33.3 months vs. 21.1 months; HR, 0.54; 95% CI, 0.36–0.79; P = .0015) but no significant difference between treatment arms in patients with EGFR L858R variants (median OS, 27.6 months vs. 40.3 months; HR, 1.30; 95% CI, 0.80–2.11; P = .29).

First-line afatinib was associated with a significant survival advantage compared with chemotherapy in patients with NSCLC and EGFR del19 variants, but not in patients with EGFR L858R variants or in the overall EGFR-positive patient population.[61][Level of evidence A1]

Sources: 61 · Level of evidence A1

An open-label phase III study (LUX-Lung 6 [NCT01121393]) included 364 East Asian patients with stage IIIB/IV NSCLC and confirmed EGFR variants (i.e., EGFR exon 19 deletion, EGFR L858R variant, or other EGFR variants). Patients were randomly assigned in a 2:1 ratio to receive 40 mg of afatinib daily or gemcitabine and cisplatin for up to six cycles for first-line treatment.[62]

Sources: LUX-Lung 6 · 62

An open-label phase III study (LUX-Lung 6 [NCT01121393]) included 364 East Asian patients with stage IIIB/IV NSCLC and confirmed EGFR variants (i.e., EGFR exon 19 deletion, EGFR L858R variant, or other EGFR variants). Patients were randomly assigned in a 2:1 ratio to receive 40 mg of afatinib daily or gemcitabine and cisplatin for up to six cycles for first-line treatment.[62]

The primary end point was PFS. Median PFS was significantly longer in the afatinib group (11.0 months; 95% CI, 9.7–13.7) than in the gemcitabine and cisplatin group (5.6 months, [range, 5.1–6.7 months]; HR, 0.28; 95% CI, 0.20–0.39; P < .0001).[62][Level of evidence B1]

Sources: 62 · Level of evidence B1

Assessment of OS was a prespecified secondary end point and was reported separately.[61] Similar to the PFS analysis, OS was stratified on the basis of EGFR variant type and the patient's ethnic origin.

Sources: 61

An open-label phase III study (LUX-Lung 6 [NCT01121393]) included 364 East Asian patients with stage IIIB/IV NSCLC and confirmed EGFR variants (i.e., EGFR exon 19 deletion, EGFR L858R variant, or other EGFR variants). Patients were randomly assigned in a 2:1 ratio to receive 40 mg of afatinib daily or gemcitabine and cisplatin for up to six cycles for first-line treatment.[62] › Assessment of OS was a prespecified secondary end point and was reported separately.[61] Similar to the PFS analysis, OS was stratified on the basis of EGFR variant type and the patient's ethnic origin.

With a median follow-up of 33 months, median OS was 23.1 months in patients in the afatinib arm and 23.5 months in patients in the chemotherapy arm (HR, 0.93; 95% CI, 0.72–1.22; P = .61).

In patients with common EGFR variants (i.e., EGFR exon 19 deletion or EGFR L858R variant), survival did not differ significantly between treatment arms (HR, 0.83; 95% CI, 0.62–1.09; P = .18). However, prespecified subgroup analyses demonstrated a survival advantage with afatinib compared with chemotherapy in patients with EGFR del19 variants (median OS, 31.4 months vs. 18.4 months; HR, 0.64; 95% CI, 0.44–0.94; P = .023), but no significant difference between treatment arms was seen in patients with EGFR L858R variants (median OS, 19.6 months vs. 24.3 months; HR, 1.22; 95% CI, 0.81–1.83; P = .34).

First-line afatinib was associated with a significant survival advantage compared with chemotherapy in patients with NSCLC and EGFR del19 variants but not in patients with EGFR L858R variants or in the overall EGFR-positive patient population.[61][Level of evidence A1]

Sources: 61 · Level of evidence A1

PAPILLON (NCT04538664) was a phase III randomized trial that compared amivantamab plus chemotherapy with chemotherapy alone as first-line treatment for patients with advanced NSCLC and EGFR exon 20 insertions. Patients in the chemotherapy-alone group who had disease progression were allowed to cross over to receive amivantamab monotherapy. A total of 308 patients were randomly assigned 1:1 to receive either amivantamab plus carboplatin and pemetrexed or carboplatin plus pemetrexed. The primary end point was PFS according to blinded independent central review. The median follow-up was 14.9 months.[63][Level of evidence B1] The study supports amivantamab plus chemotherapy as an effective first-line treatment option for patients with NSCLC and EGFR exon 20 insertions based on superior PFS when compared with chemotherapy alone.[63]

Sources: PAPILLON · 63 · Level of evidence B1 · 63

PAPILLON (NCT04538664) was a phase III randomized trial that compared amivantamab plus chemotherapy with chemotherapy alone as first-line treatment for patients with advanced NSCLC and EGFR exon 20 insertions. Patients in the chemotherapy-alone group who had disease progression were allowed to cross over to receive amivantamab monotherapy. A total of 308 patients were randomly assigned 1:1 to receive either amivantamab plus carboplatin and pemetrexed or carboplatin plus pemetrexed. The primary end point was PFS according to blinded independent central review. The median follow-up was 14.9 months.[63][Level of evidence B1] The study supports amivantamab plus chemotherapy as an effective first-line treatment option for patients with NSCLC and EGFR exon 20 insertions based on superior PFS when compared with chemotherapy alone.[63]

At 18 months, the PFS rate was 31% for patients who received amivantamab plus chemotherapy, and 3% for patients who received chemotherapy alone.

The objective response rate was higher in the amivantamab-plus-chemotherapy group (73%) than the chemotherapy-alone group (47%).

In an interim OS analysis, there was no statistically significant difference.

The most common adverse events with amivantamab plus chemotherapy were hematologic toxicities, rash, and paronychia. Infusion reactions occurred in 42% of patients.

In an open-label, randomized, phase III study (the ALEX trial [NCT02075840]), 303 patients with previously untreated, advanced ALK-rearranged NSCLC received either alectinib (600 mg twice a day) or crizotinib (250 mg twice a day).[64] The primary end point was investigator-assessed PFS.

Sources: ALEX · 64

In an open-label, randomized, phase III study (the ALEX trial [NCT02075840]), 303 patients with previously untreated, advanced ALK-rearranged NSCLC received either alectinib (600 mg twice a day) or crizotinib (250 mg twice a day).[64] The primary end point was investigator-assessed PFS.

The rate of PFS was significantly higher with alectinib than crizotinib; the 12-month event-free survival rate was 68.4% for the alectinib group (95% CI, 61.0%–75.9%) compared with 48.7% for the crizotinib group (95% CI, 40.4%–56.9%) (HR, 0.47; 95% CI, 0.34–0.65; P < .001). The median PFS was not reached with alectinib. The results of independent review committee-assessed PFS were consistent.[64][Level of evidence B1]

Sources: 64 · Level of evidence B1

CNS progression events were less frequent with alectinib (12%) than with crizotinib (45%) (HR, 0.16; 95% CI, 0.10–0.28; P <.001).

The response rate was similar for both groups, 82.9% for the alectinib group compared with 75.5% for the crizotinib group (P = .09).

Grade 3 to 5 adverse events were less frequent with alectinib (41%) than with crizotinib (50%).

A second, open-label, randomized, phase III trial (J-ALEX) recruited 207 ALK-inhibitor–naïve Japanese patients with ALK-positive NSCLC who were chemotherapy-naïve or had received one previous chemotherapy regimen. Patients were randomly assigned in a 1:1 ratio to receive alectinib (300 mg twice daily, which is the dose approved in Japan and is lower than the 600 mg twice daily dose approved elsewhere) versus crizotinib (250 mg twice daily).[65] The primary end point was PFS-assessed by an independent review committee.

Sources: 65

A second, open-label, randomized, phase III trial (J-ALEX) recruited 207 ALK-inhibitor–naïve Japanese patients with ALK-positive NSCLC who were chemotherapy-naïve or had received one previous chemotherapy regimen. Patients were randomly assigned in a 1:1 ratio to receive alectinib (300 mg twice daily, which is the dose approved in Japan and is lower than the 600 mg twice daily dose approved elsewhere) versus crizotinib (250 mg twice daily).[65] The primary end point was PFS-assessed by an independent review committee.

At data cutoff for the second primary interim analysis, the independent data monitoring committee determined that the primary end point was met (HR, 0.34; 99.7% CI, 0.17–0.71; P <.0001) and recommended immediate release of the data. Median PFS had not been reached with alectinib but was reached at 10.2 months with crizotinib.

Grade 3 or 4 adverse events occurred less frequently with alectinib (26% occurrence rate) than with crizotinib (52% occurrence rate).

The phase III CROWN trial (NCT03052608) included patients with advanced ALK-rearranged NSCLC who had received no prior systemic therapy for metastatic disease. The trial randomly assigned 296 patients to receive either lorlatinib (100 mg daily) or crizotinib (250 mg twice daily). The primary end point was PFS as determined by blinded independent central review.[66][Level of evidence B1]

Sources: CROWN · 66 · Level of evidence B1

The phase III CROWN trial (NCT03052608) included patients with advanced ALK-rearranged NSCLC who had received no prior systemic therapy for metastatic disease. The trial randomly assigned 296 patients to receive either lorlatinib (100 mg daily) or crizotinib (250 mg twice daily). The primary end point was PFS as determined by blinded independent central review.[66][Level of evidence B1]

With a median follow-up of 60.2 months, the median PFS was not reached (NR) (95% CI, 64.3–NR) in patients who received lorlatinib. With a median follow-up of 55.1 months, the median PFS was 9.1 months (95% CI, 7.4–10.9) in patients who received crizotinib (HR, 0.19; 95% CI, 0.13–0.27).[67]

Sources: 67

The 5-year PFS rate was 60% (95% CI, 51%–68%) in patients who received lorlatinib and 8% (95% CI, 3%–14%) in patients who received crizotinib.

The median time to intracranial progression was not reached (95% CI, NR–NR) in the lorlatinib group and was 16.4 months (95% CI, 12.7–21.9) in the crizotinib group (HR, 0.06; 95% CI, 0.03–0.12).

Lorlatinib was associated with more grade 3 to 4 adverse events than crizotinib (72% vs. 56%), the most common being altered lipid levels. Treatment discontinuation occurred in 7% of patients who received lorlatinib and 9% of patients who received crizotinib.[66]

Sources: 66

In an open-label, randomized, phase III study, 343 patients with stage IIIB/IV NSCLC harboring translocations in ALK received either 250 mg of crizotinib orally twice a day or the combination of pemetrexed and cisplatin or carboplatin for up to six cycles.[68] At the time of disease progression, patients on the chemotherapy arm were allowed to cross over to crizotinib; 60% of patients in the chemotherapy arm subsequently received crizotinib. The primary end point of this study was PFS.

Sources: 68

In an open-label, randomized, phase III study, 343 patients with stage IIIB/IV NSCLC harboring translocations in ALK received either 250 mg of crizotinib orally twice a day or the combination of pemetrexed and cisplatin or carboplatin for up to six cycles.[68] At the time of disease progression, patients on the chemotherapy arm were allowed to cross over to crizotinib; 60% of patients in the chemotherapy arm subsequently received crizotinib. The primary end point of this study was PFS.

The study met its primary end point and demonstrated that crizotinib is superior to chemotherapy in prolonging PFS (median, 10.9 months vs. 7.0 months; HR, 0.454; 95% CI, 0.346–0.596; P < .0001).[69][Level of evidence B1]

Sources: 69 · Level of evidence B1

In an open-label, randomized, phase III study, 376 patients with stage IIIB/IV ALK-rearranged nonsquamous NSCLC received either oral ceritinib 750 mg daily or platinum-based chemotherapy (cisplatin or carboplatin and pemetrexed) every 3 weeks for four cycles, followed by maintenance pemetrexed.[70] The primary end point was PFS and crossover from chemotherapy to ceritinib was allowed upon documented progression.

Sources: 70

In an open-label, randomized, phase III study, 376 patients with stage IIIB/IV ALK-rearranged nonsquamous NSCLC received either oral ceritinib 750 mg daily or platinum-based chemotherapy (cisplatin or carboplatin and pemetrexed) every 3 weeks for four cycles, followed by maintenance pemetrexed.[70] The primary end point was PFS and crossover from chemotherapy to ceritinib was allowed upon documented progression.

Median PFS, assessed by blinded independent review, was 16.6 months in the ceritinib group and 8.1 months in the chemotherapy group (HR, 0.55; 95% CI, 0.42–0.73; P < .00001).

The median OS was not reached with ceritinib, and it was 26.2 months with chemotherapy (HR, 0.73; 95% CI, 0.50–1.08; P = .056).[70][Level of evidence B1]

Sources: 70 · Level of evidence B1

A phase II, open-label trial (NCT02094573) enrolled 222 patients with ALK-translocated locally advanced or metastatic NSCLC who had disease progression after crizotinib treatment. Patients were randomly assigned to receive 90 mg every day (n = 112; 109 treated) or 180 mg every day with a 7-day lead-in at 90 mg every day (n = 110).[71]

Sources: NCT02094573 · 71

A phase II, open-label trial (NCT02094573) enrolled 222 patients with ALK-translocated locally advanced or metastatic NSCLC who had disease progression after crizotinib treatment. Patients were randomly assigned to receive 90 mg every day (n = 112; 109 treated) or 180 mg every day with a 7-day lead-in at 90 mg every day (n = 110).[71]

The primary end point assessed by the investigators was objective response rate. The objective response rate was 45% (97.5% CI, 34%–56%) for patients who received the 90 mg dose and 54% (97.5% CI, 43%–65%) for patients who received the 180 mg dose.

Median PFS was 9.2 months (95% CI, 7.4–15.6) for patients who received the 90 mg dose and 12.9 months (95% CI, 11.1–NR) for patients who received the 180 mg dose.

At data cutoff, the median DOR was 13.8 months (95% CI, 5.6–13.8) for patients who received the 90 mg dose and 11.1 months (95% CI, 9.2–13.8) for patients who received the 180 mg dose.[71][Level of evidence B3]

Sources: 71 · Level of evidence B3

The CNS objective response rate in patients with measurable CNS lesions was 42% in patients who received 90 mg every day (n = 26) and 67% in patients who received 180 mg every day (n = 18).

Common adverse events, which were mainly grade 1 or 2 and occurred in 27% to 38% of patients at the higher dose, were nausea, diarrhea, headache, and cough. A subset of pulmonary adverse events with early onset (median onset, day 2) occurred in 14 of 219 treated patients (all grades, 6%; grade ≥3, 3%); none occurred after escalation to 180 mg. These events included dyspnea, hypoxia, cough, pneumonia, or pneumonitis. They were managed with dose interruption. Seven of the 14 patients were successfully retreated with brigatinib.

The FDA-approved dose of brigatinib is 90 mg every day for 7 days; if tolerated, the dose is increased to 180 mg every day.

In a phase II, multicenter, nonrandomized, open-label study (NCT01336634), 36 patients with previously untreated metastatic NSCLC who tested positive for BRAF V600E variants were treated with dabrafenib (a BRAF inhibitor) 150 mg twice a day and trametinib (a MEK inhibitor) 2 mg every day.[72] BRAF V600E variants were identified by the Oncomine Dx Target Test (ThermoFisher Scientific). The primary end point was investigator-assessed overall response.

Sources: NCT01336634 · 72

In a phase II, multicenter, nonrandomized, open-label study (NCT01336634), 36 patients with previously untreated metastatic NSCLC who tested positive for BRAF V600E variants were treated with dabrafenib (a BRAF inhibitor) 150 mg twice a day and trametinib (a MEK inhibitor) 2 mg every day.[72] BRAF V600E variants were identified by the Oncomine Dx Target Test (ThermoFisher Scientific). The primary end point was investigator-assessed overall response.

The overall response rate was 64% (95% CI, 46%–79%). Six percent of patients had a complete response, and 58% of patients had a partial response.

The median investigator-assessed PFS was 10.9 months (95% CI, 7.0–16.6). The estimated median DOR was 10.4 months (95% CI, 8.3–17.9). At data cutoff, 47% of patients had died, and the median OS was 24.6 months (95% CI, 12.3–NE).

Sixty-nine percent of patients had at least one grade 3 or 4 adverse event, of which the most common were pyrexia, ALT increase, hypertension, or vomiting. Adverse events led to permanent discontinuation in 22% of patients, dose interruption or delay in 75% of patients, and dose reduction in 39% of patients.[72][Level of evidence C3]

Sources: 72 · Level of evidence C3

The safety and clinical activity of entrectinib in ROS1 fusion–positive metastatic NSCLC was determined by integrated analysis of three multicenter, single-arm, open-label clinical trials (ALKA-372-001/EudraCT, 2012-000148-88, STARTRK-1 [NCT02097810], and STARTRK-2 [NCT02568267]).[74] Entrectinib was given orally at a dose of at least 600 mg once daily. Primary end points were objective response rate and the DOR determined by blinded independent central review. Of note, time-to-event end points are difficult to interpret in the absence of a control arm. Evaluation of tumor samples for the ROS1 gene fusion was conducted prospectively in local laboratories using either a FISH or next-generation sequencing (NGS) laboratory-developed test. Seventeen (32%) patients had received no previous systemic therapy, 23 (43%) had received one previous therapy, and 13 (25%) had received two or more lines of treatment. CNS disease was present in 23 (43%) patients at baseline. Thirty-one (59%) patients were never-smokers and 52 (98%) patients had adenocarcinoma histology.

Sources: STARTRK-1 · STARTRK-2 · 74

The safety and clinical activity of entrectinib in ROS1 fusion–positive metastatic NSCLC was determined by integrated analysis of three multicenter, single-arm, open-label clinical trials (ALKA-372-001/EudraCT, 2012-000148-88, STARTRK-1 [NCT02097810], and STARTRK-2 [NCT02568267]).[74] Entrectinib was given orally at a dose of at least 600 mg once daily. Primary end points were objective response rate and the DOR determined by blinded independent central review. Of note, time-to-event end points are difficult to interpret in the absence of a control arm. Evaluation of tumor samples for the ROS1 gene fusion was conducted prospectively in local laboratories using either a FISH or next-generation sequencing (NGS) laboratory-developed test. Seventeen (32%) patients had received no previous systemic therapy, 23 (43%) had received one previous therapy, and 13 (25%) had received two or more lines of treatment. CNS disease was present in 23 (43%) patients at baseline. Thirty-one (59%) patients were never-smokers and 52 (98%) patients had adenocarcinoma histology.

The objective response rate in 53 efficacy-evaluable patients was 77% (95% CI, 64%−88%). Six percent of patients had a complete response and 72% had a partial response. Among patients with CNS disease at baseline, the objective response rate was 74% (95% CI, 52%−90%) and all patients had a partial response. Among patients without CNS disease at baseline, the overall response rate was 80% (95% CI, 61%−92%) (10% had a complete response and 70% had a partial response).[74][Level of evidence C3]

Sources: 74 · Level of evidence C3

The median DOR was 24.6 months (95% CI, 11.4−34.8) in efficacy-evaluable patients; 12.6 months (95% CI, 6.5−NE) in patients with baseline CNS disease, and 24.6 months (95% CI, 11.4−34.8) in those without CNS disease at baseline.

Treatment-related adverse events were assessed in 134 patients in the safety-evaluable population. Grade 1 or 2 treatment-related adverse events were observed in 79 patients (59%). Grade 3 or 4 treatment-related adverse events were observed in 46 patients (34%). Fifteen patients (11%) had serious treatment-related adverse events. There were no treatment-related deaths.

The median PFS was 19 months (95% CI, 12.2−36.6) in efficacy-evaluable patients; 13.6 months (95% CI, 4.5−NE) in patients with baseline CNS disease, and 26.3 months (95% CI, 15.7−36.6) in patients with no baseline CNS disease.

In an expansion cohort of a phase I study of crizotinib, 50 patients with advanced NSCLC who tested positive for ROS1 rearrangement were treated with oral crizotinib 250 mg twice daily.[75] ROS1 rearrangements were identified using break-apart FISH or reverse transcriptase−polymerase chain reaction assay. Seven patients (14%) had not had any previous treatment for advanced disease, 21 patients (42%) had one prior treatment, and 22 patients (44%) had more than one prior treatment. The primary end point was response rate.

Sources: 75

In an expansion cohort of a phase I study of crizotinib, 50 patients with advanced NSCLC who tested positive for ROS1 rearrangement were treated with oral crizotinib 250 mg twice daily.[75] ROS1 rearrangements were identified using break-apart FISH or reverse transcriptase−polymerase chain reaction assay. Seven patients (14%) had not had any previous treatment for advanced disease, 21 patients (42%) had one prior treatment, and 22 patients (44%) had more than one prior treatment. The primary end point was response rate.

The overall response rate was 72% (95% CI, 58%–84%). Six percent of patients had a complete response, 66% had a partial response, and 18% had stable disease as their best response.

Median PFS was 19.2 months (95% CI, 14.4–NR). The estimated DOR was 17.6 months (95% CI, 14.5–NR).[75][Level of evidence C3]

Sources: 75 · Level of evidence C3

In a phase II, open-label, single-arm trial, 127 East Asian patients with ROS1-positive NSCLC were treated with crizotinib 250 mg twice daily.[76] Twenty-four patients (18.9%) had not had any previous treatment for advanced disease, 53 patients (41.7%) had one previous treatment, and 50 patients (39%) had two or three previous treatments. The primary end point was objective response rate by independent review.

Sources: 76

In a phase II, open-label, single-arm trial, 127 East Asian patients with ROS1-positive NSCLC were treated with crizotinib 250 mg twice daily.[76] Twenty-four patients (18.9%) had not had any previous treatment for advanced disease, 53 patients (41.7%) had one previous treatment, and 50 patients (39%) had two or three previous treatments. The primary end point was objective response rate by independent review.

The objective response rate was 71.7% (95% CI, 63.0%–79.3%). Response rates were similar, irrespective of the number of previous therapies. Complete responses occurred in 13.4% of patients, while 58.3% of patients had partial responses, and 16.5% of patients had stable disease as their best response.[76][Level of evidence C3]

Sources: 76 · Level of evidence C3

Median PFS was 15.9 months (95% CI, 12.9–24). The DOR was 19.7 months (95% CI, 14.1–NR).

OS was 32.5 months (95% CI, 32.5–NR).

The phase I/II, single-arm TRIDENT-1 trial (NCT03093116) evaluated the safety and efficacy of repotrectinib in patients with advanced solid tumors with ALK, ROS1, NTRK1, NTRK2, or NTRK3 rearrangements. In total, 352 patients with ROS1 fusion–positive NSCLC were assigned to one of four cohorts based on previous exposure to a ROS1 TKI (yes vs. no) and/or to chemotherapy or immunotherapy (yes vs. no). The primary efficacy end point was objective response rate in two cohorts (n = 127): patients who had not previously received either a ROS1 TKI or chemotherapy/immunotherapy and patients who had previously received one ROS1 TKI but had not received chemotherapy/immunotherapy. Secondary end points included PFS, DOR, OS, and intracranial response.[78]

Sources: TRIDENT-1 · 78

The phase I/II, single-arm TRIDENT-1 trial (NCT03093116) evaluated the safety and efficacy of repotrectinib in patients with advanced solid tumors with ALK, ROS1, NTRK1, NTRK2, or NTRK3 rearrangements. In total, 352 patients with ROS1 fusion–positive NSCLC were assigned to one of four cohorts based on previous exposure to a ROS1 TKI (yes vs. no) and/or to chemotherapy or immunotherapy (yes vs. no). The primary efficacy end point was objective response rate in two cohorts (n = 127): patients who had not previously received either a ROS1 TKI or chemotherapy/immunotherapy and patients who had previously received one ROS1 TKI but had not received chemotherapy/immunotherapy. Secondary end points included PFS, DOR, OS, and intracranial response.[78]

Among ROS1 TKI-naïve patients (n = 71), the objective response rate was 79% (95% CI, 68%–88%). Among patients who had received one prior ROS1 TKI and never received chemotherapy/immunotherapy (n = 56), the objective response rate was 38% (95% CI, 25%–52%). Responses were seen in six of eight pretreated patients with detectable TKI-resistance variants.[78][Level of evidence C3]

Sources: 78 · Level of evidence C3

Among ROS1 TKI-naïve patients, the median PFS was 35.7 months (95% CI, 27.4–NE), and the median DOR was 34.1 months (95% CI, 26–NE). Among ROS1 TKI-treated patients, the median PFS was 9.0 months (95% CI, 6.8–19.6) and the median DOR was 14.8 months (95% CI, 7.6–NE). The median time to response was 1.8 months in both cohorts.

Among all patients with advanced solid tumors treated at the phase II recommended dose (n = 426), adverse events of grade 3 or higher occurred in 29% of patients. The most common grade 3 or higher adverse events were anemia (4%) and increased blood creatine kinase (4%). Adverse events led to dose reductions in 38% of patients, dose interruptions in 50% of patients, and treatment discontinuation in 7% of patients.

Larotrectinib was studied in three protocols: a phase I study involving adults, a phase I/II study involving children, and a phase II study involving adolescents and adults.[81] Fusions were confirmed in the tumors using either FISH or NGS methods. The primary end point for the combined analysis was objective response rate by independent review and was conducted with input from regulators with the goal of excluding a lower bound of less than 30% for response rate. In total, 55 patients with a median age of 45 years (range, 4 months‒76 years) were enrolled across 17 different NTRK fusion-positive tumor types. All patients had either metastatic disease (82%) or locally advanced unresectable disease (18%). Enrolled patients had received a median of two previous systemic therapies.

Sources: 81

Larotrectinib was studied in three protocols: a phase I study involving adults, a phase I/II study involving children, and a phase II study involving adolescents and adults.[81] Fusions were confirmed in the tumors using either FISH or NGS methods. The primary end point for the combined analysis was objective response rate by independent review and was conducted with input from regulators with the goal of excluding a lower bound of less than 30% for response rate. In total, 55 patients with a median age of 45 years (range, 4 months‒76 years) were enrolled across 17 different NTRK fusion-positive tumor types. All patients had either metastatic disease (82%) or locally advanced unresectable disease (18%). Enrolled patients had received a median of two previous systemic therapies.

The objective response rate was 75% (95% CI, 61%‒75%) and 73% of these responses lasted at least 6 months.[81][Level of evidence C3]

Sources: 81 · Level of evidence C3

Treatment was well tolerated with 93% of adverse events being grade 1 to 2; the most common grade 3 to 4 adverse events were anemia (11% of patients), transaminitis (7%), and neutropenia (7%).

The safety and clinical activity of entrectinib in NTRK inhibitor-naïve patients with metastatic or locally-advanced solid tumors (including NSCLC) and NTRK1, NTRK2, or NTRK3 gene fusions was determined by integrated analysis of three early-phase, multicenter, single-arm, open-label clinical trials (ALKA-372-001/EudraCT, 2012-000148-88, STARTRK-1 [NCT02097810], and STARTRK-2 [NCT02568267]).[82] Treatment consisted of entrectinib administered orally at a dose of at least 600 mg once per day. The primary end points were objective response rate and median DOR, which were assessed by blinded independent central review. Of note, time-to-event end points are difficult to interpret in the absence of a control arm. Identification of positive NTRK gene fusion status was conducted prospectively in local laboratories or a central laboratory using various nucleic acid–based tests. Of 54 patients in the NTRK gene fusion–positive efficacy-evaluable population, 20 (37%) had received no previous systemic therapy, 11 (20%) had received one previous systemic therapy, and 23 (43%) had received two or more systemic therapies. Twelve (22%) patients had CNS disease at baseline. Ten (19%) patients had NSCLC. Fifty-two (96%) patients had NTRK gene fusions detected by NGS and 2 (4%) had NTRK gene fusions detected by other nucleic acid–based tests.

Sources: 82

The safety and clinical activity of entrectinib in NTRK inhibitor-naïve patients with metastatic or locally-advanced solid tumors (including NSCLC) and NTRK1, NTRK2, or NTRK3 gene fusions was determined by integrated analysis of three early-phase, multicenter, single-arm, open-label clinical trials (ALKA-372-001/EudraCT, 2012-000148-88, STARTRK-1 [NCT02097810], and STARTRK-2 [NCT02568267]).[82] Treatment consisted of entrectinib administered orally at a dose of at least 600 mg once per day. The primary end points were objective response rate and median DOR, which were assessed by blinded independent central review. Of note, time-to-event end points are difficult to interpret in the absence of a control arm. Identification of positive NTRK gene fusion status was conducted prospectively in local laboratories or a central laboratory using various nucleic acid–based tests. Of 54 patients in the NTRK gene fusion–positive efficacy-evaluable population, 20 (37%) had received no previous systemic therapy, 11 (20%) had received one previous systemic therapy, and 23 (43%) had received two or more systemic therapies. Twelve (22%) patients had CNS disease at baseline. Ten (19%) patients had NSCLC. Fifty-two (96%) patients had NTRK gene fusions detected by NGS and 2 (4%) had NTRK gene fusions detected by other nucleic acid–based tests.

The objective response rate in 54 patients was 57% (95% CI, 43.2%−70.8%). Seven percent of patients had a complete response and 50% had a partial response. In patients with baseline CNS disease, 50% achieved a response (all partial responses), whereas in patients without baseline CNS disease, 60% achieved a response (10% complete response; 50% partial response).[82][Level of evidence C3]

Sources: 82 · Level of evidence C3

The median DOR in efficacy-evaluable patients was 10.4 months (95% CI, 7.1−NE). In patients with baseline CNS disease DOR was not estimable, and in patients with no baseline CNS disease it was 12.9 months (95% CI, 7.1−NE).

Among 10 patients with NSCLC, the response rate was 70% (95% CI, 35%−93%) and DOR ranged between 1.9 months and 20.1 months. For more information, see the prescribing information.

Sources: prescribing information

The safety-evaluable population consisted of 68 patients with NTRK fusion–positive tumors. Most treatment-related adverse events were grade 1 or 2 and reversible. The most frequent grade 3 or 4 treatment-related adverse events were increased weight gain (10%) and anemia (12%). Serious treatment-related adverse events were reported in 7 (10%) patients. Three (4%) patients had dose interruptions and 27 (40%) patients had dose reductions due to treatment-related adverse events. There were no treatment-related deaths.

Median PFS was 11.2 months (95% CI, 8.0−14.9). In patients with baseline CNS disease, median PFS was 7.7 months (95% CI, 4.7−NE), and it was 12 months (95% CI, 8.7−15.7) in patients with no baseline CNS disease.

A phase I/II study (LIBRETTO-001 [NCT03157128]) enrolled patients with RET fusion−positive solid tumors. RET fusion status was determined by local molecular testing (NGS, FISH, or polymerase chain reaction assay) without central confirmation. The primary end point was objective response.[84][Level of evidence C3]

Sources: LIBRETTO-001 · 84 · Level of evidence C3

A phase I/II study (LIBRETTO-001 [NCT03157128]) enrolled patients with RET fusion−positive solid tumors. RET fusion status was determined by local molecular testing (NGS, FISH, or polymerase chain reaction assay) without central confirmation. The primary end point was objective response.[84][Level of evidence C3]

Updated analysis was conducted in 316 patients with RET fusion–positive NSCLC.[84]

Sources: 84

Among the 69 treatment-naïve patients, the objective response rate was 84% (95% CI, 73%–92%), and 6% achieved complete responses. The median DOR was 20.2 months (95% CI, 13.0–could not be evaluated); 40% of responses were ongoing at the data cutoff (median follow-up, 20.3 months). The median PFS was 22.0 months; 35% of patients were alive and progression-free at the data cutoff (median follow-up, 21.9 months).

Among the 247 patients who had received prior platinum-based chemotherapy, the objective response rate was 61% (95% CI, 55%–67%), and 7% achieved complete responses. The median DOR was 28.6 months (95% CI, 20.4–could not be evaluated); 49% of responses were ongoing (median follow-up, 21.2 months). The median PFS was 24.9 months; 38% of patients were alive and progression-free at the data cutoff (median follow-up, 24.7 months).

Among the 26 patients with measurable baseline CNS metastasis by the independent review committee, the intracranial objective response rate was 85% (95% CI, 65%–96%), and 27% had complete responses.

In the full safety population (n = 796), the median treatment duration was 36.1 months.

There was no significant change in the safety profile. Most adverse events were grade 1 to 2. The most common adverse events were edema, diarrhea, fatigue, dry mouth, hypertension, increased ALT and aspartate aminotransferase (AST), and rash.

A phase I/II study (ARROW [NCT03037385]) enrolled patients with RET fusion−positive solid tumors. Two hundred thirty-three patients had RET fusion−positive NSCLC. RET fusion status was determined by local molecular testing of tumor or circulating tumor nucleic acid (ctDNA) in blood, without central confirmation. The primary end point was objective response.[85][Level of evidence C3]

Sources: ARROW · 85 · Level of evidence C3

A phase I/II study (ARROW [NCT03037385]) enrolled patients with RET fusion−positive solid tumors. Two hundred thirty-three patients had RET fusion−positive NSCLC. RET fusion status was determined by local molecular testing of tumor or circulating tumor nucleic acid (ctDNA) in blood, without central confirmation. The primary end point was objective response.[85][Level of evidence C3]

Ninety-two patients who had received platinum-based chemotherapy and 29 patients who were treatment-naïve (and not candidates for standard platinum-based treatment) received pralsetinib before the efficacy enrollment cutoff (July 11, 2019). Eighty-seven previously treated patients and 27 treatment-naïve patients had centrally adjudicated baseline measurable disease, and thus formed the efficacy cohort.

The overall response rate was 61% (95% CI, 50%–71%) in the 87 patients who had received platinum-based chemotherapy, including complete responses in 6%. The median DOR was not reached (15.2 months–NE).

The overall response rate was 70% (95% CI, 50%–86%) in the 27 treatment-naïve patients, including complete responses in 11%. The median DOR was 9.0 months (6.3–NE).

In the 233-patient safety cohort, 93% had treatment-related adverse events, including 48% with grade 3 or worse events. The most common grade 3 or worse treatment-related adverse events were neutropenia (18%), hypertension (11%), and anemia (10%). Dose reductions occurred in 38% of patients, and 6% discontinued treatment because of adverse events.

An open-label phase II study (VISION [NCT02864992]) enrolled patients with MET exon 14-skipping variants. The trial included 152 patients who received tepotinib (500 mg orally once daily). MET status was determined centrally, either via liquid biopsy (from circulating free DNA obtained from plasma; n = 66) or via tissue biopsy (n = 60). Twenty-seven patients had positive results from both methods. The primary end point was objective response.[87][Level of evidence C3]

Sources: VISION · 87 · Level of evidence C3

An open-label phase II study (VISION [NCT02864992]) enrolled patients with MET exon 14-skipping variants. The trial included 152 patients who received tepotinib (500 mg orally once daily). MET status was determined centrally, either via liquid biopsy (from circulating free DNA obtained from plasma; n = 66) or via tissue biopsy (n = 60). Twenty-seven patients had positive results from both methods. The primary end point was objective response.[87][Level of evidence C3]

Among the 99 patients who had been followed for at least 9 months (i.e., the efficacy population), the objective response rate as assessed by independent review was 46% (95% CI, 36%–57%), with a median DOR of 11.1 months (95% CI, 7.2–NE). Response rates were similar in the liquid biopsy and tissue biopsy groups.

Responses were similar regardless of prior therapy.

Grade 3 or higher adverse events occurred in 28% of patients, including peripheral edema in 7% of patients. Adverse events led to therapy discontinuation in 11% of patients.

A phase II study (GEOMETRY [NCT02414139]) evaluated capmatinib (400 mg orally twice daily) in patients with MET exon 14-skipping variants or MET amplification. MET status was performed centrally. A total of 373 patients were enrolled and treated. Of those patients, 160 had NSCLC with MET exon 14-skipping variants. Patients were assigned to cohorts based on MET status and previous treatments (cohorts 1a–7). There were 60 treatment-naïve patients (cohorts 5b and 7) and 100 previously treated patients (cohorts 4 and 6). The primary end point was overall response rate.[88][Level of evidence B3] The FDA approved capmatinib for patients with metastatic NSCLC and MET exon 14-skipping variants.

Sources: GEOMETRY · 88 · Level of evidence B3

A phase II study (GEOMETRY [NCT02414139]) evaluated capmatinib (400 mg orally twice daily) in patients with MET exon 14-skipping variants or MET amplification. MET status was performed centrally. A total of 373 patients were enrolled and treated. Of those patients, 160 had NSCLC with MET exon 14-skipping variants. Patients were assigned to cohorts based on MET status and previous treatments (cohorts 1a–7). There were 60 treatment-naïve patients (cohorts 5b and 7) and 100 previously treated patients (cohorts 4 and 6). The primary end point was overall response rate.[88][Level of evidence B3] The FDA approved capmatinib for patients with metastatic NSCLC and MET exon 14-skipping variants.

The overall median follow-up was 46.4 months (interquartile range [IQR], 41.8–65.4) for treatment-naïve patients and 66.9 months (IQR, 56.7–73.9) for previously treated patients.

The overall response rate was 68% (95% CI, 55.0%–79.7%) in treatment-naïve patients and 44% (95% CI, 34.1%–54.3%) in previously treated patients.

The most common treatment-related adverse events were peripheral edema (n = 174; 47%), nausea (n = 130; 35%), increased blood creatinine (n = 78; 21%), and vomiting (n = 74; 20%). Grade 3 to 4 serious adverse events occurred in 44% of patients, with dyspnea as the most common (occurring in 5% of patients).

A phase III double-blind trial (KEYNOTE-189 [NCT02578680]) randomly assigned, in a 2:1 ratio, 616 patients with metastatic nonsquamous NSCLC without sensitizing EGFR variants or ALK rearrangements who had received no previous treatment for metastatic disease. Patients received pemetrexed and a platinum-based drug plus either 200 mg of pembrolizumab or placebo every 3 weeks for 4 cycles, followed by pembrolizumab or placebo for up to a total of 35 cycles plus pemetrexed maintenance.[1] Crossover to pembrolizumab monotherapy was permitted after verified progression among patients in the placebo-containing combination group. The primary end points were OS and PFS as assessed by blinded independent central committee radiological review.

Sources: KEYNOTE-189 · 1

A phase III double-blind trial (KEYNOTE-189 [NCT02578680]) randomly assigned, in a 2:1 ratio, 616 patients with metastatic nonsquamous NSCLC without sensitizing EGFR variants or ALK rearrangements who had received no previous treatment for metastatic disease. Patients received pemetrexed and a platinum-based drug plus either 200 mg of pembrolizumab or placebo every 3 weeks for 4 cycles, followed by pembrolizumab or placebo for up to a total of 35 cycles plus pemetrexed maintenance.[1] Crossover to pembrolizumab monotherapy was permitted after verified progression among patients in the placebo-containing combination group. The primary end points were OS and PFS as assessed by blinded independent central committee radiological review.

In the 5-year updated analysis, the median time from random assignment to data cutoff was 64.6 months (range, 60.1–72.4).[90]

Sources: 90

After 5 years, pembrolizumab plus pemetrexed-platinum was associated with improved OS and PFS, compared with placebo plus pemetrexed-platinum in patients with metastatic nonsquamous NSCLC, regardless of PD-L1 expression. In the ITT population, 5-year OS rates were 19.4% in the pembrolizumab plus pemetrexed-platinum group, compared with 11.3% in the placebo plus pemetrexed-platinum group.

Survival was higher in patients with a higher PD-L1 tumor proportion score (TPS), especially in the TPS >50% subgroup (29.6% vs. 21.4%).

There were 57 patients who completed 35 cycles of pembrolizumab. For these patients, the objective response rate was 86.0% and the 3-year OS rate after completing 35 cycles (approximately 5 years after random assignment) was 71.9%.[90]

Sources: 90

Immune-mediated adverse events and infusion reactions occurred in 113 (27.9%) and 27 (13.4%) patients.

Adverse events of grade 3 or higher occurred with similar frequency in both treatment groups (71.9% in the pembrolizumab combination group vs. 66.8% in the placebo combination group).

A phase III, randomized, double-blind study (KEYNOTE-407 [NCT02775435]) included previously untreated patients with metastatic squamous cell NSCLC. Patients were randomly assigned 1:1 to receive pembrolizumab 200 mg or placebo plus carboplatin and paclitaxel/nab-paclitaxel once every 3 weeks for four cycles, followed by pembrolizumab or placebo for up to 35 cycles (pembrolizumab-plus-chemotherapy, n = 5,278; placebo-plus-chemotherapy, n = 5,281). Primary end points were OS and PFS per RECIST version 1.1 by blinded independent central review.[91]

Sources: KEYNOTE-407 · 91

A phase III, randomized, double-blind study (KEYNOTE-407 [NCT02775435]) included previously untreated patients with metastatic squamous cell NSCLC. Patients were randomly assigned 1:1 to receive pembrolizumab 200 mg or placebo plus carboplatin and paclitaxel/nab-paclitaxel once every 3 weeks for four cycles, followed by pembrolizumab or placebo for up to 35 cycles (pembrolizumab-plus-chemotherapy, n = 5,278; placebo-plus-chemotherapy, n = 5,281). Primary end points were OS and PFS per RECIST version 1.1 by blinded independent central review.[91]

The median time from random assignment to data cutoff was 56.9 months (range, 49.9–66.2). OS and PFS were improved with pembrolizumab-plus-chemotherapy versus placebo-plus-chemotherapy (HR, 0.71 [0.59–0.85] and 0.62 [0.52–0.74]), respectively; 95% CI). The 5-year OS rates were 18.4% and 9.7%, respectively.[91][Level of evidence A1]

Sources: 91 · Level of evidence A1

A total of 55 patients completed 35 cycles of pembrolizumab. The objective response rate was 90.9% and the 3-year OS rate after completion of 35 cycles (approximately 5 years after random assignment) was 69.5%.

A phase III open-label study (KEYNOTE-024) randomly assigned 305 patients with previously untreated, advanced NSCLC with PD-L1 expression on 50% or more tumor cells and no sensitizing EGFR variants or ALK translocations to either intravenous pembrolizumab (200 mg every 3 weeks for up to 35 cycles) or platinum-based chemotherapy (four to six cycles, investigator’s choice; pemetrexed maintenance was allowed for nonsquamous tumors).[89] The primary end point was PFS.

Sources: KEYNOTE-024 · 89

A phase III open-label study (KEYNOTE-024) randomly assigned 305 patients with previously untreated, advanced NSCLC with PD-L1 expression on 50% or more tumor cells and no sensitizing EGFR variants or ALK translocations to either intravenous pembrolizumab (200 mg every 3 weeks for up to 35 cycles) or platinum-based chemotherapy (four to six cycles, investigator’s choice; pemetrexed maintenance was allowed for nonsquamous tumors).[89] The primary end point was PFS.

PD-L1 expression was centrally assessed using the PD-L1 immunohistochemistry 22C3 pharmDx assay. PD-L1 tumor expression of 50% or more was found in 30.2% of 1,653 patient samples that were examined.

Pembrolizumab demonstrated significant improvement in median PFS (10.3 months vs. 6.0 months; HR, 0.50; 95% CI, 0.37–0.68; P < .001). The overall response rate (44.8% vs. 27.8%), the median DOR (NR, [range, 1.9–14.5 months] vs. 6.3 months [range, 2.1–12.6 months]), and the estimated rate of OS at 6 months (80.2% vs. 72.4%; HR, 0.60; 95% CI, 0.41–0.89; P = .005) were all higher with pembrolizumab than with chemotherapy.

Further follow-up of this study confirmed an OS advantage in favor of pembrolizumab; the median OS for patients who received pembrolizumab was 30 months (95% CI, 18.3 months–NR) versus 14.2 months for patients who received chemotherapy, with a 75% crossover to immunotherapy afterwards, suggesting the crossover did not impact survival.[92]

Sources: 92

Adverse events (any grade) were less frequent with pembrolizumab than with chemotherapy (73.4% vs. 90.0%).

A phase III open-label study (KEYNOTE-024) randomly assigned 305 patients with previously untreated, advanced NSCLC with PD-L1 expression on 50% or more tumor cells and no sensitizing EGFR variants or ALK translocations to either intravenous pembrolizumab (200 mg every 3 weeks for up to 35 cycles) or platinum-based chemotherapy (four to six cycles, investigator’s choice; pemetrexed maintenance was allowed for nonsquamous tumors).[89] The primary end point was PFS. › Adverse events (any grade) were less frequent with pembrolizumab than with chemotherapy (73.4% vs. 90.0%).

Grade 3 to 5 adverse events occurred in 26.6% of patients treated with pembrolizumab and 53.3% of patients treated with chemotherapy.

Grade 3 or 4 immune-related events occurred in 9.7% of patients treated with pembrolizumab and 0.7% of patients treated with chemotherapy.

The most common grade 3 or 4 immune-related events associated with pembrolizumab were severe skin reactions (3.9%), pneumonitis (2.6%), and colitis (1.3%).

There were no grade 5 immune-related events.

A phase III open-label study (KEYNOTE-024) randomly assigned 305 patients with previously untreated, advanced NSCLC with PD-L1 expression on 50% or more tumor cells and no sensitizing EGFR variants or ALK translocations to either intravenous pembrolizumab (200 mg every 3 weeks for up to 35 cycles) or platinum-based chemotherapy (four to six cycles, investigator’s choice; pemetrexed maintenance was allowed for nonsquamous tumors).[89] The primary end point was PFS.

Pembrolizumab treatment demonstrated significant improvement in PFS, OS, and DOR with less frequent adverse events compared with chemotherapy treatment.[89][Level of evidence B1]

Sources: 89 · Level of evidence B1

A phase III open-label study (KEYNOTE-042 [NCT02220894]) included patients with locally advanced or metastatic NSCLC without EGFR or ALK alterations and with a PD-L1 TPS score of greater than 1%. Patients were randomly assigned to receive either pembrolizumab 200 mg once every 3 weeks for 35 cycles or chemotherapy (carboplatin plus paclitaxel or pemetrexed) for four to six cycles with optional maintenance pemetrexed (pembrolizumab, n = 637; chemotherapy, n = 637). The primary end points were OS in the populations with a PD-L1 TPS greater than 50%, greater than 20%, and greater than 1%.[93]

Sources: KEYNOTE-042 · 93

A phase III open-label study (KEYNOTE-042 [NCT02220894]) included patients with locally advanced or metastatic NSCLC without EGFR or ALK alterations and with a PD-L1 TPS score of greater than 1%. Patients were randomly assigned to receive either pembrolizumab 200 mg once every 3 weeks for 35 cycles or chemotherapy (carboplatin plus paclitaxel or pemetrexed) for four to six cycles with optional maintenance pemetrexed (pembrolizumab, n = 637; chemotherapy, n = 637). The primary end points were OS in the populations with a PD-L1 TPS greater than 50%, greater than 20%, and greater than 1%.[93]

The median follow-up was 61.1 months (range, 50.0–76.3).

OS outcomes favored pembrolizumab versus chemotherapy, regardless of the PD-L1 TPS.

A phase III open-label study (KEYNOTE-042 [NCT02220894]) included patients with locally advanced or metastatic NSCLC without EGFR or ALK alterations and with a PD-L1 TPS score of greater than 1%. Patients were randomly assigned to receive either pembrolizumab 200 mg once every 3 weeks for 35 cycles or chemotherapy (carboplatin plus paclitaxel or pemetrexed) for four to six cycles with optional maintenance pemetrexed (pembrolizumab, n = 637; chemotherapy, n = 637). The primary end points were OS in the populations with a PD-L1 TPS greater than 50%, greater than 20%, and greater than 1%.[93] › OS outcomes favored pembrolizumab versus chemotherapy, regardless of the PD-L1 TPS.

The HR was 0.68 (95% CI, 0.57–0.81) for the TPS >50% group, 0.75 (95% CI, 0.64–0.87) for the TPS >20% group, and 0.79 (95% CI, 0.70–0.89) for the TPS >1% group.

The OS rates for patients who received pembrolizumab were 21.9% (TPS >50%), 19.4% (TPS >1%), and 16.6% (TPS >1%).

A phase III open-label study (KEYNOTE-042 [NCT02220894]) included patients with locally advanced or metastatic NSCLC without EGFR or ALK alterations and with a PD-L1 TPS score of greater than 1%. Patients were randomly assigned to receive either pembrolizumab 200 mg once every 3 weeks for 35 cycles or chemotherapy (carboplatin plus paclitaxel or pemetrexed) for four to six cycles with optional maintenance pemetrexed (pembrolizumab, n = 637; chemotherapy, n = 637). The primary end points were OS in the populations with a PD-L1 TPS greater than 50%, greater than 20%, and greater than 1%.[93]

The most common adverse reactions reported in at least 10% of patients who received pembrolizumab as a single agent in KEYNOTE-042 included fatigue, decreased appetite, dyspnea, cough, rash, constipation, diarrhea, nausea, hypothyroidism, pneumonia, pyrexia, and weight loss.

A phase III, double-blind, placebo-controlled trial (EMPOWER-Lung 3 [NCT03409614]) examined cemiplimab-rwlc plus platinum-doublet chemotherapy in 466 patients with stage III or IV advanced NSCLC. Patients had not received previous chemotherapy and had no EGFR, ALK, or ROS1 genomic tumor aberrations. Patients were randomly assigned (2:1) to receive cemiplimab-rwlc 350 mg (n = 312) or placebo (n = 154) every 3 weeks for up to 108 weeks along with four cycles of platinum-doublet chemotherapy. Patients also received pemetrexed maintenance as indicated. The primary end point was OS. The trial met preset OS efficacy criteria and was stopped early on the recommendation of the independent data monitoring committee.[94][Level of evidence A1]

Sources: EMPOWER-Lung 3 · 94 · Level of evidence A1

A phase III, double-blind, placebo-controlled trial (EMPOWER-Lung 3 [NCT03409614]) examined cemiplimab-rwlc plus platinum-doublet chemotherapy in 466 patients with stage III or IV advanced NSCLC. Patients had not received previous chemotherapy and had no EGFR, ALK, or ROS1 genomic tumor aberrations. Patients were randomly assigned (2:1) to receive cemiplimab-rwlc 350 mg (n = 312) or placebo (n = 154) every 3 weeks for up to 108 weeks along with four cycles of platinum-doublet chemotherapy. Patients also received pemetrexed maintenance as indicated. The primary end point was OS. The trial met preset OS efficacy criteria and was stopped early on the recommendation of the independent data monitoring committee.[94][Level of evidence A1]

The median OS was 21.9 months (95% CI, 15.5–not evaluable [NE]) in the cemiplimab-rwlc-plus-chemotherapy group and 13 months (95% CI, 11.9–16.1) in the placebo-plus-chemotherapy group (HR, 0.71; 95% CI, 0.53–0.93; P = .014).

The secondary end point of median PFS was 8.2 months (95% CI, 6.4–9.3) in the cemiplimab-rwlc-plus-chemotherapy group and 5.0 months (95% CI, 4.3–6.2) in the placebo-plus-chemotherapy group (HR, 0.56; 95% CI, 0.44–0.70; P < .0001).

Another secondary end point, the estimated proportion of patients alive at 12 months, was 65.7% (95% CI, 59.9%–70.9%) in the cemiplimab-rwlc-plus-chemotherapy group and 56.1% (95% CI, 47.5%–63.8%) in the placebo-plus-chemotherapy group.

Grade 3 or greater adverse events occurred in 43.6% (136 of 312) of patients who received cemiplimab-rwlc plus chemotherapy and 31.4% (48 of 153) of patients who received placebo plus chemotherapy.

The most common (≥15%) adverse reactions were alopecia, musculoskeletal pain, nausea, fatigue, peripheral neuropathy, and decreased appetite.

A phase III open-label study (EMPOWER-Lung 1 [NCT03088540]) enrolled 710 patients with advanced NSCLC and PD-L1 tumor expression of at least 50%. Patients were randomly assigned (1:1) to receive cemiplimab-rwlc 350mg every 3 weeks for up to 108 weeks or platinum-doublet chemotherapy. Patients could cross over from chemotherapy to cemiplimab-rwlc in the event of disease progression. There was also the option to cross over to continue cemiplimab-rwlc plus four cycles of chemotherapy in the event of progression with cemiplimab alone. Primary end points were OS and PFS per blinded independent central review. The median follow-up was 37 months for the ITT population.[95,96][Level of evidence A1]

Sources: EMPOWER-Lung 1 · 95 · 96 · Level of evidence A1

A phase III open-label study (EMPOWER-Lung 1 [NCT03088540]) enrolled 710 patients with advanced NSCLC and PD-L1 tumor expression of at least 50%. Patients were randomly assigned (1:1) to receive cemiplimab-rwlc 350mg every 3 weeks for up to 108 weeks or platinum-doublet chemotherapy. Patients could cross over from chemotherapy to cemiplimab-rwlc in the event of disease progression. There was also the option to cross over to continue cemiplimab-rwlc plus four cycles of chemotherapy in the event of progression with cemiplimab alone. Primary end points were OS and PFS per blinded independent central review. The median follow-up was 37 months for the ITT population.[95,96][Level of evidence A1]

At 35 months of follow-up, in patients with PD-L1 expression ≥50%, the median OS was 26.1 months with cemiplimab-rwlc and 13.3 months with chemotherapy (HR, 0.57; P < .0001).

The median PFS was 8.1 months for patients who received cemiplimab-rwlc and 5.3 months for patients who received chemotherapy (HR, 0.51; P < .0001).

The objective response rate was 46% for patients who received cemiplimab-rwlc and 21% for patients who received chemotherapy (OR, 3.264; P < .0001).

Benefits were greater in patients with PD-L1 expression ≥90% versus 50% to 89%.

Among 64 patients who received cemiplimab-rwlc plus chemotherapy after initial progression while receiving cemiplimab-rwlc alone, the median PFS was 6.6 months, the objective response rate was 31%, and the OS was 15.1 months.

The most common adverse reactions (>10%) with cemiplimab-rwlc were musculoskeletal pain, rash, anemia, fatigue, decreased appetite, pneumonia, and cough. The safety profile of cemiplimab-rwlc was consistent over longer follow-up.

POSEIDON (NCT03164616), a phase III open-label trial, studied tremelimumab plus durvalumab and chemotherapy, durvalumab plus chemotherapy, and chemotherapy alone as first-line therapy in patients with metastatic NSCLC. The primary end points were PFS and OS for durvalumab plus chemotherapy versus chemotherapy. Key alpha-controlled secondary end points were PFS and OS for tremelimumab plus durvalumab and chemotherapy versus chemotherapy. Patients were randomly assigned (1:1:1) to one of the following three arms:[97][Level of evidence B1]The following results were observed:

Sources: POSEIDON · 97 · Level of evidence B1

POSEIDON (NCT03164616), a phase III open-label trial, studied tremelimumab plus durvalumab and chemotherapy, durvalumab plus chemotherapy, and chemotherapy alone as first-line therapy in patients with metastatic NSCLC. The primary end points were PFS and OS for durvalumab plus chemotherapy versus chemotherapy. Key alpha-controlled secondary end points were PFS and OS for tremelimumab plus durvalumab and chemotherapy versus chemotherapy. Patients were randomly assigned (1:1:1) to one of the following three arms:[97][Level of evidence B1]The following results were observed:

Arm 1: Tremelimumab 75 mg plus durvalumab 1,500 mg with platinum-based chemotherapy for up to four 21-day cycles followed by durvalumab once every 4 weeks until progression and one additional tremelimumab dose at week 16.

Arm 2: Durvalumab plus chemotherapy for up to four 21-day cycles followed by durvalumab once every 4 weeks until progression.

Arm 3: Platinum-based chemotherapy for up to six 21-day cycles (with or without maintenance pemetrexed).

Treatment with durvalumab significantly improved PFS compared with chemotherapy alone. The median PFS was 5.5 months for patients who received durvalumab plus chemotherapy and 4.8 months for patients who received chemotherapy alone (HR, 0.74; 95% CI, 0.62–0.89; P = .0009).

A trend for improved OS did not reach statistical significance for patients in arms 2 and 3. The median OS was 13.3 months for patients who received durvalumab plus chemotherapy and 11.7 months for patients who received chemotherapy alone. (HR, 0.86; 95% CI, 0.72–1.02; P = .0758). The 24-month OS rate was 29.6% in the durvalumab-plus-chemotherapy arm and 22.1% in the chemotherapy-alone arm.

Both PFS and OS were significantly improved when tremelimumab therapy was added to durvalumab and chemotherapy compared with chemotherapy alone. The median PFS was 6.2 months for patients who received tremelimumab plus durvalumab and chemotherapy and 4.8 months for patients who received chemotherapy alone (HR, 0.72; 95% CI, 0.60–0.86; P = .0003). The median OS was 14.0 months in the tremelimumab arm and 11.7 months in the chemotherapy-alone arm (HR, 0.77; 95% CI, 0.65–0.92; P = .0030). The 24-month OS rate was 32.9% in the tremelimumab-plus durvalumab-and-chemotherapy arm and 22.1% in the chemotherapy-alone arm. In addition, this combination demonstrated consistent OS results across levels of PD-L1 expression.

Grade 3 to 4 treatment-related events occurred in 51.8% of patients who received tremelimumab plus durvalumab and chemotherapy, 14.1% of patients who received durvalumab and chemotherapy, and 9.9% of patients who received chemotherapy alone.

A phase III open-label study (IMpower110 [NCT02409342]) included 572 patients with previously untreated metastatic nonsquamous or squamous NSCLC. Patients had PD-L1 expression on at least 1% of tumor cells or on at least 1% of tumor-infiltrating immune cells. Patients were randomly assigned to receive either atezolizumab (1,200 mg intravenously) or platinum-based chemotherapy (4 or 6 cycles) once every 3 weeks. The primary end point was OS in the PD-L1–selected population that excluded sensitizing EGFR variants or ALK translocations.[98][Level of evidence A1]

Sources: IMpower110 · 98 · Level of evidence A1

A phase III open-label study (IMpower110 [NCT02409342]) included 572 patients with previously untreated metastatic nonsquamous or squamous NSCLC. Patients had PD-L1 expression on at least 1% of tumor cells or on at least 1% of tumor-infiltrating immune cells. Patients were randomly assigned to receive either atezolizumab (1,200 mg intravenously) or platinum-based chemotherapy (4 or 6 cycles) once every 3 weeks. The primary end point was OS in the PD-L1–selected population that excluded sensitizing EGFR variants or ALK translocations.[98][Level of evidence A1]

PD-L1 expression was assessed by the SP142 immunohistochemical assay. High expression was defined as more than 50% of tumor cells or more than 10% of tumor-infiltrating immune cells expressing PD-L1.

In the 205 patients with high PD-L1 expression, the median OS was 20.2 months for patients who received atezolizumab and 13.1 months for patients who received chemotherapy (HRdeath, 0.59; P = .01).

Grade 3 to 4 adverse events occurred in 30.1% of patients who received atezolizumab and 52.5% of patients who received chemotherapy.

A phase III open-label study (IMpower130 [NCT02367781]) included 724 patients with previously untreated, stage IV, nonsquamous NSCLC. Patients were randomly assigned 2:1 to receive atezolizumab (1,200 mg intravenously every 3 weeks) plus chemotherapy (carboplatin, AUC 6 mg/mL per minute every 3 weeks with nab-paclitaxel 100 mg/m2 intravenously every week), or chemotherapy alone given once every 3 weeks for four or six cycles. All patients received maintenance therapy as follows: (1) patients in the atezolizumab-plus-chemotherapy group received atezolizumab 1,200 mg intravenously every 3 weeks until investigator-assessed loss of clinical benefit or toxicity, and (2) patients in the chemotherapy-alone group received best supportive care or pemetrexed switch maintenance therapy until disease progression or toxicity. Coprimary end points were investigator-assessed PFS and OS in the ITT population with EGFR wild-type and ALK wild-type tumors.[99][Level of evidence A1]

Sources: IMpower130 · 99 · Level of evidence A1

A phase III open-label study (IMpower130 [NCT02367781]) included 724 patients with previously untreated, stage IV, nonsquamous NSCLC. Patients were randomly assigned 2:1 to receive atezolizumab (1,200 mg intravenously every 3 weeks) plus chemotherapy (carboplatin, AUC 6 mg/mL per minute every 3 weeks with nab-paclitaxel 100 mg/m2 intravenously every week), or chemotherapy alone given once every 3 weeks for four or six cycles. All patients received maintenance therapy as follows: (1) patients in the atezolizumab-plus-chemotherapy group received atezolizumab 1,200 mg intravenously every 3 weeks until investigator-assessed loss of clinical benefit or toxicity, and (2) patients in the chemotherapy-alone group received best supportive care or pemetrexed switch maintenance therapy until disease progression or toxicity. Coprimary end points were investigator-assessed PFS and OS in the ITT population with EGFR wild-type and ALK wild-type tumors.[99][Level of evidence A1]

In the ITT wild-type population, the median OS was 18.6 months (95% CI, 16.0–21.2) in the atezolizumab-plus-chemotherapy group and 13.9 months (95% CI, 12.0–18.7) in the chemotherapy group (stratified HR, 0.79; 95% CI, 0.64–0.98; P = .033).

The median PFS was 7 months (95% CI, 6.2–7.3) in the atezolizumab-plus-chemotherapy group and 5.5 months (95% CI, 4.4–5.9) in the chemotherapy group (stratified HR, 0.64; 95% CI, 0.54–0.77; P < .0001).

Subgroup analyses showed OS and PFS benefit with atezolizumab across several clinical subgroups, with the exception of patients with liver metastases where the additional of atezolizumab did not improve OS versus chemotherapy alone, and for patients with EGFR and ALK genomic alterations.

OS and PFS benefit with atezolizumab was also observed in the ITT wild-type population independent of PD-L1 expression.

Grade 3 or 4 adverse events occurred in 81% of patients who received atezolizumab plus chemotherapy versus 71% of patients who received chemotherapy alone. Immune-related adverse events occurred in 45% of patients treated with atezolizumab plus chemotherapy and most were grade 1 or 2 in severity. The most common immune-related adverse events were rash (24%), hypothyroidism (15%), and hepatitis (10%).

In a phase III open-label study (IMpower150 [NCT02366143]),1,202 patients with stage IV or recurrent metastatic nonsquamous NSCLC were randomly assigned in a 1:1:1 ratio to receive either atezolizumab plus carboplatin plus paclitaxel (ACP group), atezolizumab plus bevacizumab plus carboplatin plus paclitaxel (ABCP group), or bevacizumab plus carboplatin plus paclitaxel (BCP group). Treatment consisted of four or six 21-day cycles. Atezolizumab was given intravenously at a dose of 1,200 mg, bevacizumab at a dose of 15 mg per kilogram of body weight, carboplatin at an area under the concentration-time curve of 6 mg/mL per minute and paclitaxel at a dose of 200 mg/m2 (175 mg/m2 for Asian patients). Patients continued to receive atezolizumab, bevacizumab, or both until disease progression or development of intolerable toxicity. Coprimary end points were PFS, both in the ITT population with EGFR wild-type and ALK wild-type tumors and among patients with wild-type tumors who had high expression of an effector T-cell (Teff) gene signature in the tumor, and OS in the wild-type population.[100][Level of evidence A1]

Sources: IMpower150 · 100 · Level of evidence A1

In a phase III open-label study (IMpower150 [NCT02366143]),1,202 patients with stage IV or recurrent metastatic nonsquamous NSCLC were randomly assigned in a 1:1:1 ratio to receive either atezolizumab plus carboplatin plus paclitaxel (ACP group), atezolizumab plus bevacizumab plus carboplatin plus paclitaxel (ABCP group), or bevacizumab plus carboplatin plus paclitaxel (BCP group). Treatment consisted of four or six 21-day cycles. Atezolizumab was given intravenously at a dose of 1,200 mg, bevacizumab at a dose of 15 mg per kilogram of body weight, carboplatin at an area under the concentration-time curve of 6 mg/mL per minute and paclitaxel at a dose of 200 mg/m2 (175 mg/m2 for Asian patients). Patients continued to receive atezolizumab, bevacizumab, or both until disease progression or development of intolerable toxicity. Coprimary end points were PFS, both in the ITT population with EGFR wild-type and ALK wild-type tumors and among patients with wild-type tumors who had high expression of an effector T-cell (Teff) gene signature in the tumor, and OS in the wild-type population.[100][Level of evidence A1]

Median PFS was longer in the ABCP group (8.3 months) than the BCP group (6.8 months) (HR, 0.62; 95% CI, 0.52–0.74; P < .001). In the Teff-high wild-type population, PFS was 11.3 months versus 6.8 months (HR, 0.51; 95% CI, 0.38–0.68; P .001). PFS was also longer in the ABCP group versus the BCP group in the ITT population with EGFR and ALK genomic alterations, among patients with low or negative PD-L1 expression, low Teff gene-signature expression, and in patients with liver metastases.

Median OS among patients with wild-type tumors was longer in the ABCP group (19.2 months), compared with the BCP group (14.7 months) (HR, 0.78; 95% CI, 0.64–0.96; P = .02).

Grade 3 or 4 treatment-related adverse events occurred in 56% of patients in the ABCP group versus 48% of patients in the BCP group. Most immune-related adverse events in the ABCP group were grade 1 or 2, and rash, hypothyroidism, hyperthyroidism, hepatitis, pneumonitis, and colitis were most common. Treatment-related deaths occurred in 11 patients (2.8%) in the ABCP group and 9 patients (2.3%) in the BCP group. Five deaths in the ABCP group were caused by pulmonary hemorrhage or hemoptysis, and four of five occurred in patients with high-risk features, including tumors infiltrating great vessels or tumor cavitation.

A phase III open-label study (CheckMate 227 [NCT02477826]) evaluated nivolumab in combination with ipilimumab versus chemotherapy as first-line treatment for stage IV or recurrent NSCLC without sensitizing EGFR variants or ALK translocations. Patients (n = 1,739) were grouped by PD-L1 tumor status (either ≥1% or <1%). Patients with PD-L1 expression of at least 1% were randomly assigned to receive either nivolumab (3 mg/kg every 2 weeks) plus ipilimumab (1 mg/kg every 6 weeks), nivolumab (240 mg every 2 weeks) alone, or platinum-doublet chemotherapy every 3 weeks for up to four cycles. Patients with PD-L1 expression less than 1% were randomly assigned to receive nivolumab with ipilimumab, nivolumab with platinum-doublet chemotherapy, or platinum-doublet chemotherapy (every 3 weeks). Patients were treated until disease progression or unacceptable toxicity or up to 2 years for immunotherapy. Coprimary end points were OS with nivolumab-plus-ipilimumab compared with chemotherapy in patients with tumor PD-L1 expression of at least 1%, and PFS with nivolumab-plus-ipilimumab compared with chemotherapy in patients with high tumor mutational burden (TMB) (≥10 mutations per megabase).[2,102][Level of evidence A1]

Sources: CheckMate 227 · 2 · 102 · Level of evidence A1

A phase III open-label study (CheckMate 227 [NCT02477826]) evaluated nivolumab in combination with ipilimumab versus chemotherapy as first-line treatment for stage IV or recurrent NSCLC without sensitizing EGFR variants or ALK translocations. Patients (n = 1,739) were grouped by PD-L1 tumor status (either ≥1% or <1%). Patients with PD-L1 expression of at least 1% were randomly assigned to receive either nivolumab (3 mg/kg every 2 weeks) plus ipilimumab (1 mg/kg every 6 weeks), nivolumab (240 mg every 2 weeks) alone, or platinum-doublet chemotherapy every 3 weeks for up to four cycles. Patients with PD-L1 expression less than 1% were randomly assigned to receive nivolumab with ipilimumab, nivolumab with platinum-doublet chemotherapy, or platinum-doublet chemotherapy (every 3 weeks). Patients were treated until disease progression or unacceptable toxicity or up to 2 years for immunotherapy. Coprimary end points were OS with nivolumab-plus-ipilimumab compared with chemotherapy in patients with tumor PD-L1 expression of at least 1%, and PFS with nivolumab-plus-ipilimumab compared with chemotherapy in patients with high tumor mutational burden (TMB) (≥10 mutations per megabase).[2,102][Level of evidence A1]

Among patients with tumor PD-L1 ≥1% (n = 1,189), the median OS was 17.1 months (95% CI, 15.0–20.2) with nivolumab-plus-ipilimumab and 14.9 months (95% CI, 12.7–16.7) with chemotherapy (HR, 0.77; 95% CI, 0.66–0.91; P = .007). Five-year outcomes with nivolumab-plus-ipilimumab versus chemotherapy showed durable clinical benefit, with an OS rate of 24% with nivolumab-plus-ipilimumab and 14% for chemotherapy alone.[101]

Sources: 101

In patients with TMB-high NSCLC, the median PFS was 7.2 months (95% CI, 5.5–13.2) with nivolumab-plus-ipilimumab, versus 5.5 months (95% CI, 4.4–5.8) with chemotherapy alone (HR, 0.58; 97.5% CI, 0.41–0.81; P < .001).

Among patients with tumor PD-L1 <1% (n = 550), the median OS was 17.4 months (95% CI, 13.2–22.0) with nivolumab-plus-ipilimumab, and 12.2 months (95% CI, 9.2–14.3) with chemotherapy alone (HR, 0.65; 95% CI, 0.52–0.81). Five-year outcomes with nivolumab-plus-ipilimumab versus chemotherapy alone showed durable clinical benefit, with an OS rate of 19% for nivolumab-plus-ipilimumab and 7% for chemotherapy alone.[101]

Sources: 101

The frequency of grade 3 to 4 treatment-related adverse events was similar in both groups (32.8% with nivolumab-plus-ipilimumab vs. 36.0% with chemotherapy alone). Treatment-related adverse events leading to therapy discontinuation were more common with nivolumab-plus-ipilimumab than with chemotherapy alone (24.5% vs. 13.9%).

Treatment-related deaths occurred in eight patients who received nivolumab-plus-ipilimumab (pneumonitis in four patients; shock, myocarditis, acute tubular necrosis, and cardiac tamponade in one patient each) and in six patients who received chemotherapy (sepsis in two patients; febrile neutropenia, multifocal brain infarctions, interstitial lung disease, and thrombocytopenia in one patient each).

A randomized, double-blind, placebo-controlled, phase III trial (RADIANT-4 [NCT01524783]) evaluated everolimus in patients older than 18 years with advanced, progressive, well-differentiated, nonfunctional neuroendocrine tumors of lung or gastrointestinal origin.[103] Eligible patients were randomly assigned in a 2:1 ratio to received everolimus 10 mg daily orally or placebo, both with best supportive care. A total of 302 patients were enrolled (205 in the everolimus arm and 97 in the placebo arm), including 90 patients with neuroendocrine tumors of lung origin (63 in the everolimus arm and 27 in the placebo arm). The primary end point was PFS assessed by central radiology review in the ITT population.

Sources: RADIANT-4 · 103

A randomized, double-blind, placebo-controlled, phase III trial (RADIANT-4 [NCT01524783]) evaluated everolimus in patients older than 18 years with advanced, progressive, well-differentiated, nonfunctional neuroendocrine tumors of lung or gastrointestinal origin.[103] Eligible patients were randomly assigned in a 2:1 ratio to received everolimus 10 mg daily orally or placebo, both with best supportive care. A total of 302 patients were enrolled (205 in the everolimus arm and 97 in the placebo arm), including 90 patients with neuroendocrine tumors of lung origin (63 in the everolimus arm and 27 in the placebo arm). The primary end point was PFS assessed by central radiology review in the ITT population.

Median PFS was 11.0 months in the everolimus arm and 3.9 months in the placebo group (HR, 0.48; 95% CI, 0.35−0.67; P < .00001).[103][Level of evidence B1]

Sources: 103 · Level of evidence B1

In a post hoc analysis of the lung subgroup, median PFS by central review was 9.2 months in the everolimus arm and 3.6 months in the placebo arm (HR, 0.50; 95% CI, 0.28−0.88).[103]

Sources: 103

The objective response rate was 2% in patients who received everolimus and 1% in patients who received placebo. Disease stabilization was observed in 81% of patients in the everolimus arm and 64% of patients in the placebo arm.

The median duration of treatment was longer in the patients who received everolimus compared with those who received placebo (40.4 weeks vs. 19.6 weeks).

A planned interim analysis of OS showed a 36% reduction in the estimated risk of death with everolimus relative to placebo (HR, 0.64; 95% CI, 0.40−1.05). These results were not statistically significant.

The most common treatment-related adverse events were stomatitis, diarrhea, fatigue, infections, rash, and peripheral edema. The most common drug-related grade 3 or 4 adverse events were stomatitis, diarrhea, infections, anemia, and fatigue. Grade 3 or 4 adverse events resulted in treatment discontinuation in 12% of patients in the everolimus group and 3% of patients in the placebo group.

Tracheal, esophageal, or bronchial compression.

Pain.

Vocal cord paralysis.

Hemoptysis.

Superior vena cava syndrome.

A systematic review identified six randomized trials of high-dose rate endobronchial brachytherapy (HDREB) alone or with EBRT or laser therapy.[111]

Sources: 111

A systematic review identified six randomized trials of high-dose rate endobronchial brachytherapy (HDREB) alone or with EBRT or laser therapy.[111]

Better overall symptom palliation and fewer re-treatments were required in previously untreated patients using EBRT alone.[111][Level of evidence A3]

Sources: 111 · Level of evidence A3

HDREB provided palliation of symptomatic patients with recurrent endobronchial obstruction previously treated by EBRT, when it was technically feasible.