Non-Small Cell Lung Cancer, part 3

Chemotherapy.

Sources: Chemotherapy

Chemotherapy.

Docetaxel.

Sources: Docetaxel

Docetaxel plus ramucirumab.

Sources: Docetaxel plus ramucirumab

Datopotamab deruxtecan.

Sources: Datopotamab deruxtecan

Pemetrexed.

Sources: Pemetrexed

EGFR-directed therapy.

Sources: EGFR-directed therapy

EGFR-directed therapy.

EGFR-directed therapy after first-line chemotherapy (for patients with EGFR-sensitizing variants).

Sources: EGFR-directed therapy after first-line chemotherapy

EGFR-directed therapy. › EGFR-directed therapy after first-line chemotherapy (for patients with EGFR-sensitizing variants).

Erlotinib.

Sources: Erlotinib

Gefitinib.

Sources: Gefitinib

Afatinib.

Sources: Afatinib

EGFR-directed therapy.

EGFR-directed therapy (for patients with acquired EGFR T790M variants after previous EGFR-directed therapy).

Sources: EGFR-directed therapy

EGFR-directed therapy. › EGFR-directed therapy (for patients with acquired EGFR T790M variants after previous EGFR-directed therapy).

Osimertinib.

Sources: Osimertinib

EGFR-directed therapy.

EGFR-directed therapy after first-line chemotherapy (for patients with EGFR exon 20 insertions).

Sources: EGFR-directed therapy after first-line chemotherapy

EGFR-directed therapy. › EGFR-directed therapy after first-line chemotherapy (for patients with EGFR exon 20 insertions).

Amivantamab.

Sources: Amivantamab

Amivantamab plus chemotherapy.

Sources: Amivantamab plus chemotherapy

Subcutaneous amivantamab-lazertinib.

Sources: Subcutaneous amivantamab-lazertinib

ALK-directed tyrosine kinase inhibitors (TKIs).

Sources: ALK-directed tyrosine kinase inhibitors (TKIs)

ALK-directed tyrosine kinase inhibitors (TKIs).

ALK-directed TKIs after first-line chemotherapy.

Sources: ALK-directed TKIs after first-line chemotherapy

ALK-directed tyrosine kinase inhibitors (TKIs). › ALK-directed TKIs after first-line chemotherapy.

Crizotinib.

Sources: Crizotinib

ALK-directed tyrosine kinase inhibitors (TKIs).

ALK-directed TKIs after prior ALK TKI therapy.

Sources: ALK-directed TKIs after prior ALK TKI therapy

ALK-directed tyrosine kinase inhibitors (TKIs). › ALK-directed TKIs after prior ALK TKI therapy.

Ceritinib.

Sources: Ceritinib

Alectinib.

Sources: Alectinib

Brigatinib.

Sources: Brigatinib

Lorlatinib.

Sources: Lorlatinib

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-directed therapy.

Sources: ROS1-directed therapy

ROS1-directed therapy.

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

KRAS G12C inhibitors (for patients with KRAS G12C variants).

Sources: KRAS G12C inhibitors

KRAS G12C inhibitors (for patients with KRAS G12C variants).

Adagrasib.

Sources: Adagrasib

Sotorasib.

Sources: Sotorasib

HER2-targeted therapy (for patients with HER2 variants).

Sources: HER2-targeted therapy

HER2-targeted therapy (for patients with HER2 variants).

Trastuzumab deruxtecan.

Sources: Trastuzumab deruxtecan

Immunotherapy.

Sources: Immunotherapy

Immunotherapy.

Nivolumab.

Sources: Nivolumab

Pembrolizumab.

Sources: Pembrolizumab

Atezolizumab.

Sources: Atezolizumab

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

Clinical trials can be considered as second-line therapy.

Two prospective randomized studies have shown an improvement in survival with the use of docetaxel compared with vinorelbine, ifosfamide, or best supportive care;[4,5] however, criteria for the selection of appropriate patients for second-line treatment are not well defined.[6]

Sources: 4 · 5 · 6

A meta-analysis of five trials of 865 patients assessing the efficacy and safety of docetaxel administered weekly or every 3 weeks has been reported.[7] In that analysis, the following was shown:

Sources: 7

A meta-analysis of five trials of 865 patients assessing the efficacy and safety of docetaxel administered weekly or every 3 weeks has been reported.[7] In that analysis, the following was shown:

Median survival was 27.4 weeks for patients treated every 3 weeks and 26.1 weeks for patients treated weekly (log-rank P = .24).

Significantly less severe neutropenia and febrile neutropenia were reported with weekly docetaxel (P < .001 for both); however, no significant differences were observed for anemia, thrombocytopenia, and nonhematologic toxic effects.

In a double-blind, placebo-controlled, phase III study, 1,253 patients with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1 who had progressive disease after first-line chemotherapy were randomly assigned to receive docetaxel and placebo or docetaxel and ramucirumab.[8][Level of evidence A1] Ramucirumab is a human immunoglobulin G1 monoclonal antibody that targets the extracellular domain of vascular endothelial growth factor receptor 2. The primary end point of the study was overall survival (OS), with secondary end points of progression-free survival (PFS) and objective response rate. The study enrolled patients with either nonsquamous or squamous NSCLC; however, patients with poorly controlled hypertension, gastrointestinal perforation or fistulae, arterial thromboembolic event within 6 months (before random assignment), gross hemoptysis within 2 months, or grade 3 to 4 gastrointestinal bleeding within 3 months were excluded. In addition, the trial did not include patients with tumors that had major blood vessel involvement or intratumor cavitation.

Sources: 8 · Level of evidence A1

In a double-blind, placebo-controlled, phase III study, 1,253 patients with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1 who had progressive disease after first-line chemotherapy were randomly assigned to receive docetaxel and placebo or docetaxel and ramucirumab.[8][Level of evidence A1] Ramucirumab is a human immunoglobulin G1 monoclonal antibody that targets the extracellular domain of vascular endothelial growth factor receptor 2. The primary end point of the study was overall survival (OS), with secondary end points of progression-free survival (PFS) and objective response rate. The study enrolled patients with either nonsquamous or squamous NSCLC; however, patients with poorly controlled hypertension, gastrointestinal perforation or fistulae, arterial thromboembolic event within 6 months (before random assignment), gross hemoptysis within 2 months, or grade 3 to 4 gastrointestinal bleeding within 3 months were excluded. In addition, the trial did not include patients with tumors that had major blood vessel involvement or intratumor cavitation.

The addition of ramucirumab to docetaxel compared with placebo plus docetaxel led to an increase in median OS (10.5 months vs. 9.1 months; hazard ratio [HR], 0.86; 95% confidence interval [CI], 0.75–0.98), objective response rate (23% vs. 14%), and PFS (4.5 months vs. 3 months). The improvement in OS from the addition of ramucirumab appeared consistent across subgroups including squamous and nonsquamous histologies.

Grade 3 to 4 treatment-related adverse events occurred in 79% of patients who received docetaxel and ramucirumab as compared with 71% of patients who received docetaxel and placebo. Febrile neutropenia, fatigue, and hypertension were among the toxicities that were more common with the addition of ramucirumab to docetaxel. There was no significant difference in the incidence of grades 3 to 4 hemorrhage between the groups.

On the basis of this study, the addition of ramucirumab to docetaxel chemotherapy can be considered for patients with good performance status with advanced NSCLC who have progressive disease after first-line chemotherapy.

The randomized, open-label, global phase III TROPION-Lung01 study (NCT04656652) compared the efficacy and safety of Dato-DXd with docetaxel in patients with pretreated advanced or metastatic NSCLC. Patients received Dato-DXd (6 mg/kg) (n = 299) or docetaxel (75 mg/m2) (n = 305) once every 3 weeks. Dual primary end points were PFS and OS. Objective response rate, duration of response (DOR), and safety were secondary end points.[9]

Sources: TROPION-Lung01 · 9

The randomized, open-label, global phase III TROPION-Lung01 study (NCT04656652) compared the efficacy and safety of Dato-DXd with docetaxel in patients with pretreated advanced or metastatic NSCLC. Patients received Dato-DXd (6 mg/kg) (n = 299) or docetaxel (75 mg/m2) (n = 305) once every 3 weeks. Dual primary end points were PFS and OS. Objective response rate, duration of response (DOR), and safety were secondary end points.[9]

The median PFS was 4.4 months (95% CI, 4.2–5.6) in the Dato-DXd group and 3.7 months (95% CI, 2.9–4.2) in the docetaxel group (HR, 0.75; 95% CI, 0.62–0.91; P = .004).[9][Level of evidence B2]

Sources: 9 · Level of evidence B2

The median OS was 12.9 months (95% CI, 11.0–13.9) with Dato-DXd and 11.8 months (95% CI, 10.1–12.8) with docetaxel (HR, 0.94; 95% CI, 0.78–1.14; P = .530).

In the nonsquamous histology subgroup, the median PFS was 5.5 months with Dato-DXd versus 3.6 months with docetaxel (HR, 0.63; 95% CI, 0.51–0.79). The median OS was 14.6 months with Dato-DXd versus 12.3 months with docetaxel (HR, 0.84; 95% CI, 0.68–1.05).

In the squamous histology subgroup, the median PFS was 2.8 months with Dato-DXd versus 3.9 months with docetaxel (HR, 1.41; 95% CI, 0.95–2.08). The median OS was 7.6 months with Dato-DXd versus 9.4 months with docetaxel (HR, 1.32; 95% CI, 0.91–1.92).

Grade 3 or higher treatment-related adverse events occurred in 25.6% of patients who received Dato-DXd and 2.1% of patients who received docetaxel. Interstitial lung disease/pneumonitis occurred in 8.8% of patients in Dato-DXd group and 4.1% of patients in the docetaxel group.

The single-arm, open-label, phase II TROPION-Lung05 (NCT04484142) study enrolled adult patients with stage IIIB, IIIC, or IV NSCLC. Patients had at least one documented activating EGFR, ALK, ROS1, NTRK, BRAF, MET exon 14-skipping, or RET genomic alteration. All patients received Dato-DXd at a dose of 6.0 mg/kg once every 3 weeks. The primary end point was objective response rate by blinded independent central review. Secondary end points included DOR, PFS, OS, pharmacokinetics, and safety. Overall, 56.9% of patients had EGFR pathogenic variants and 24.8% of patients had ALK rearrangements.[10]

Sources: TROPION-Lung05 · 10

The single-arm, open-label, phase II TROPION-Lung05 (NCT04484142) study enrolled adult patients with stage IIIB, IIIC, or IV NSCLC. Patients had at least one documented activating EGFR, ALK, ROS1, NTRK, BRAF, MET exon 14-skipping, or RET genomic alteration. All patients received Dato-DXd at a dose of 6.0 mg/kg once every 3 weeks. The primary end point was objective response rate by blinded independent central review. Secondary end points included DOR, PFS, OS, pharmacokinetics, and safety. Overall, 56.9% of patients had EGFR pathogenic variants and 24.8% of patients had ALK rearrangements.[10]

The median treatment duration was 4.4 months (range, 0.7–20.6). The median DOR was 7.0 months (95% CI, 4.2–9.8), and the overall disease control rate was 78.8% (95% CI, 71.0%–85.3%).[10][Level of evidence C3]

Sources: 10 · Level of evidence C3

The confirmed objective response rate was 35.8% (95% CI, 27.8%–44.4%) overall. The rate was 43.6% (95% CI, 32.4%–55.3%) in patients with EGFR pathogenic variants and 23.5% (95% CI, 10.7%–41.2%) in patients with ALK rearrangements.

Grade 3 or higher treatment-related adverse events occurred in 28.5% of patients. The most common treatment-related adverse event was stomatitis (any grade, 56.2%; grade ≥3, 9.5%).

A pooled analysis of patients with EGFR-altered NSCLC (n = 117) who received Dato-DXd in TROPION-Lung05 (n = 78) or TROPION-Lung01 (n = 39) was completed and findings were published in abstract form.[11]The U.S. Food and Drug Administration (FDA) has granted breakthrough therapy designation to Dato-DXd for the treatment of adult patients with locally advanced or metastatic, EGFR-altered NSCLC with disease progression during or after treatment with an EGFR TKI and platinum-based chemotherapy.

Sources: TROPION-Lung05 · TROPION-Lung01 · 11

A pooled analysis of patients with EGFR-altered NSCLC (n = 117) who received Dato-DXd in TROPION-Lung05 (n = 78) or TROPION-Lung01 (n = 39) was completed and findings were published in abstract form.[11]The U.S. Food and Drug Administration (FDA) has granted breakthrough therapy designation to Dato-DXd for the treatment of adult patients with locally advanced or metastatic, EGFR-altered NSCLC with disease progression during or after treatment with an EGFR TKI and platinum-based chemotherapy.

The objective response rate was 42.7% (95% CI, 33.6%–52.2%) in patients who received Dato-DXd per blinded independent central review, including a complete response rate of 4.3% and a partial response rate of 38.5%.

The percentage of patients with stable disease was 41.0%, and the disease control rate was 86.3% (95% CI, 78.7%–92.0%).

The median DOR was 7.0 months (95% CI, 4.2–9.8). The median PFS was 5.8 months (95% CI, 5.4–8.2), and the median OS was 15.6 months (95% CI, 13.1–19.0).

Patients previously treated with osimertinib (n = 96) had an objective response rate of 44.8% (95% CI, 34.6%–55.3%), including a complete response rate of 4.2%, a partial response rate of 40.6%, and a stable disease rate of 38.5%. The median DOR was 6.9 months (95% CI, 4.2–9.8), and the disease control rate was 85.4% (95% CI, 76.7%–91.8%). The median PFS was 5.7 months (95% CI, 5.4–7.9), and the median OS was 14.7 months (95% CI, 13.0–18.3).

A randomized phase III trial of 571 patients was designed to demonstrate the noninferiority of pemetrexed compared with docetaxel.

A randomized phase III trial of 571 patients was designed to demonstrate the noninferiority of pemetrexed compared with docetaxel.

The trial showed no difference in response rates, PFS, or OS between treatments.[12][Level of evidence A1]

Sources: 12 · Level of evidence A1

Of note, patients with squamous histology benefited from docetaxel, and those with nonsquamous histologies appeared to benefit more from pemetrexed.[13]

Sources: 13

A trial of erlotinib versus best supportive care included 731 patients; 49% had received two previous chemotherapy regimens, and 93% had received platinum-based chemotherapy.

A trial of erlotinib versus best supportive care included 731 patients; 49% had received two previous chemotherapy regimens, and 93% had received platinum-based chemotherapy.

OS was 6.7 months among those who had received two previous chemotherapy regimens and 4.7 months among those who had received platinum-based chemotherapy. The HR was 0.70 (P < .001) in favor of erlotinib.[14][Level of evidence A1]

Sources: 14 · Level of evidence A1

In a second trial (NCT00556322), which was designed to show the superiority of erlotinib versus standard second-line chemotherapy after disease progression during first-line platinum combination therapy, 424 patients were randomly assigned.

Sources: NCT00556322

In a second trial (NCT00556322), which was designed to show the superiority of erlotinib versus standard second-line chemotherapy after disease progression during first-line platinum combination therapy, 424 patients were randomly assigned.

There was no difference in the primary end point of OS (median OS, 5.3 months vs. 5.5 months; HR, 0.96; 95% CI, 0.78–1.19).[16][Level of evidence A1]

Sources: 16 · Level of evidence A1

A randomized phase III trial evaluated gefitinib versus placebo in 1,692 patients with previously treated NSCLC and showed the following:

A randomized phase III trial evaluated gefitinib versus placebo in 1,692 patients with previously treated NSCLC and showed the following:

Gefitinib did not improve OS.

Median survival did not differ significantly between the groups in the overall population (5.6 months for gefitinib and 5.1 months for placebo; HR, 0.89; 95% CI, 0.77–1.02; P = .087) or among the 812 patients with adenocarcinoma (6.3 months vs. 5.4 months; HR, 0.84; CI, 0.68–1.03; P = .089).

Preplanned subgroup analyses showed significantly longer survival in the gefitinib group than in the placebo group for never-smokers (n = 375; 95% CI, 0.67 [0.49–0.92]; P = .012; median survival, 8.9 months vs. 6.1 months) and for patients of Asian origin (n = 342; 95% CI, 0.66 [0.48–0.91]; P = .01; median survival, 9.5 months vs. 5.5 months).[17][Level of evidence A1]

Sources: 17 · Level of evidence A1

In a large randomized trial, gefitinib was compared with docetaxel in patients with locally advanced or metastatic NSCLC who had been pretreated with platinum-based chemotherapy.[18] The primary objective was to compare OS between the groups with coprimary analyses to assess noninferiority in the overall population and superiority in patients with high EGFR gene copy number in the intention-to-treat population. The 1,466 patients were randomly assigned to receive gefitinib (250 mg per day by mouth; n = 733) or docetaxel (75 mg/m2 intravenously [IV] every 3 weeks; n = 733).

Sources: 18

In a large randomized trial, gefitinib was compared with docetaxel in patients with locally advanced or metastatic NSCLC who had been pretreated with platinum-based chemotherapy.[18] The primary objective was to compare OS between the groups with coprimary analyses to assess noninferiority in the overall population and superiority in patients with high EGFR gene copy number in the intention-to-treat population. The 1,466 patients were randomly assigned to receive gefitinib (250 mg per day by mouth; n = 733) or docetaxel (75 mg/m2 intravenously [IV] every 3 weeks; n = 733).

Noninferiority of gefitinib compared with docetaxel was confirmed for OS (HR, 1.020; 95% CI, 0.905–1.150). However, superiority of gefitinib in patients with high EGFR gene copy number (85 patients vs. 89 patients) was not proven (HR, 1.09; 95% CI, 0.78–1.51; P = .62).

In the gefitinib group, the most common adverse events were rash or acne (49% vs. 10%) and diarrhea (35% vs. 25%). In the docetaxel group, neutropenia (5% vs. 74%), asthenia (25% vs. 47%), and alopecia (3% vs. 36%) were most common.

This trial established noninferior survival of patients treated with gefitinib compared with docetaxel, suggesting that gefitinib is a valid treatment for pretreated patients with advanced NSCLC.

Afatinib, an irreversible inhibitor of the ErbB-family of receptors, has been compared with erlotinib as second-line treatment in patients with advanced squamous cell carcinoma. In a randomized, controlled, phase III trial (LUX-Lung 8 [NCT01523587]), patients with stage IIIB/IV squamous cell NSCLC with disease progression after frontline platinum-based chemotherapy were randomly assigned in a 1:1 ratio to receive afatinib (398 patients, 40 mg by mouth every day) or erlotinib (397 patients, 150 mg by mouth every day).[27][Level of evidence B1] The primary end point was PFS. Secondary end points included OS and response rate.

Sources: LUX-Lung 8 · 27 · Level of evidence B1

Afatinib, an irreversible inhibitor of the ErbB-family of receptors, has been compared with erlotinib as second-line treatment in patients with advanced squamous cell carcinoma. In a randomized, controlled, phase III trial (LUX-Lung 8 [NCT01523587]), patients with stage IIIB/IV squamous cell NSCLC with disease progression after frontline platinum-based chemotherapy were randomly assigned in a 1:1 ratio to receive afatinib (398 patients, 40 mg by mouth every day) or erlotinib (397 patients, 150 mg by mouth every day).[27][Level of evidence B1] The primary end point was PFS. Secondary end points included OS and response rate.

After a median follow-up of 6.7 months, the PFS was 2.4 months versus 1.9 months (HR, 0.82; 95% CI, 0.68–1.00).

After a median follow-up of 18.4 months, the median OS was significantly longer in the afatinib arm (7.9 months vs. 6.8 months; HR, 0.81; 95% CI, 0.69–0.95; P = .007). Survival at 6 months (63.6% vs. 54.6%; P = .009), 12 months (36.4% vs. 28.2%; P = .015), and 18 months (22% vs. 14.4%; P = .013) were all significantly better in patients who received afatinib.

There was no significant difference in response rate between the two arms (6% vs. 3%; P = .551).

The frequency of adverse events was similar between the two groups with 57% of the patients experiencing a rate of grade 3 or higher adverse events. Grade 3 treatment-related diarrhea and stomatitis occurred more frequently with afatinib; however, grade 3 rash or acne were more common in patients who received erlotinib.

Afatinib, as compared with erlotinib, represents another option for the second-line treatment of patients with stage IV squamous cell NSCLC.

An open-label phase III trial (AURA 3 [NCT02151981]) studied osimertinib in patients with NSCLC and EGFR-sensitizing variants whose disease had progressed after first-line EGFR inhibitors. These patients had EGFR T790M resistance variants as determined by the cobas® EGFR Mutation Test.[28] The trial randomly assigned 419 patients (in a 2:1 ratio) to receive either osimertinib 80 mg by mouth every day or pemetrexed plus carboplatin or cisplatin IV every 3 weeks for up to six cycles; maintenance pemetrexed was allowed for the chemotherapy group. The primary end point was PFS.

Sources: AURA 3 · 28

An open-label phase III trial (AURA 3 [NCT02151981]) studied osimertinib in patients with NSCLC and EGFR-sensitizing variants whose disease had progressed after first-line EGFR inhibitors. These patients had EGFR T790M resistance variants as determined by the cobas® EGFR Mutation Test.[28] The trial randomly assigned 419 patients (in a 2:1 ratio) to receive either osimertinib 80 mg by mouth every day or pemetrexed plus carboplatin or cisplatin IV every 3 weeks for up to six cycles; maintenance pemetrexed was allowed for the chemotherapy group. The primary end point was PFS.

Osimertinib was superior to chemotherapy in prolonging median PFS (10.1 months vs. 4.4 months; HR, 0.30; 95% CI, 0.23–0.41; P < .001).

The objective response was 71% with osimertinib versus 31% with platinum therapy (odds ratio for objective response, 5.39; 95% CI, 3.47–8.48; P < .001).

Among 144 patients with central nervous system (CNS) metastases, median PFS duration was 8.5 months with osimertinib versus 4.2 months with platinum therapy (HR, 0.32; 95% CI, 0.21–0.49).

Adverse events of grade 3 or greater occurred in 23% of osimertinib-treated patients versus 47% of platinum-treated patients.[28][Level of evidence B1]

Sources: 28 · Level of evidence B1

A phase I, open-label, dose-escalation, and dose-expansion study (CHRYSALIS [NCT02609776]) investigated amivantamab, an EGFR-MET bispecific antibody, in several different patient groups. A total of 114 patients with EGFR exon 20 insertions who had received previous platinum-based chemotherapy received the recommended phase II dose of amivantamab (1,050 mg [1,400 mg if >80 kg] IV) once weekly for the first 4 weeks and then once every 2 weeks starting at week 5. The primary end point for the dose-expansion group was overall response rate.[29][Level of evidence C3]

Sources: CHRYSALIS · 29 · Level of evidence C3

A phase I, open-label, dose-escalation, and dose-expansion study (CHRYSALIS [NCT02609776]) investigated amivantamab, an EGFR-MET bispecific antibody, in several different patient groups. A total of 114 patients with EGFR exon 20 insertions who had received previous platinum-based chemotherapy received the recommended phase II dose of amivantamab (1,050 mg [1,400 mg if >80 kg] IV) once weekly for the first 4 weeks and then once every 2 weeks starting at week 5. The primary end point for the dose-expansion group was overall response rate.[29][Level of evidence C3]

At the time of clinical data cutoff, 81 patients were evaluable with at least three disease assessments. The overall response rate was 40% (95% CI, 29%–51%), including three complete responses. The median DOR was 11.1 months (95% CI, 6.9–not reached [NR]). The clinical benefit rate (including patients with stable disease) was 74% (95% CI, 63%–83%).

The median PFS was 8.3 months (95% CI, 6.5–10.9); OS data are not mature.

The most common adverse events were rash (86%), infusion-related reactions (66%), and paronychia (45%). Patients experienced adverse events related to both EGFR inhibition (rash, paronychia, stomatitis, pruritus, diarrhea) and MET inhibition (hypoalbuminemia, peripheral edema). Grade 3 or greater adverse events occurred in 35% of patients, with rash (4%) and infusion reactions (3%) as the most common.

The infusion reactions occurred primarily with the first exposure to amivantamab. The administration of the first dose was split over 2 days to minimize this toxicity.

The global phase III MARIPOSA-2 trial (NCT04988295) included 657 patients with locally advanced or metastatic NSCLC and EGFR variants (EGFR exon 19 deletions or EGFR L858R variants). Patients had disease progression after receiving prior osimertinib. Patients were randomly assigned in a 2:2:1 ratio to receive amivantamab plus lazertinib plus chemotherapy, chemotherapy alone, or amivantamab and chemotherapy. Patients with brain metastases were eligible if their intracranial disease was clinically stable and they were asymptomatic and receiving stable doses of steroids. The dual primary end points were (1) PFS in patients who received amivantamab plus chemotherapy versus chemotherapy alone and (2) in patients who received amivantamab plus lazertinib and chemotherapy versus chemotherapy alone. Key secondary end points included objective response rate per blinded independent central review and OS.[30]

Sources: MARIPOSA-2 · 30

The global phase III MARIPOSA-2 trial (NCT04988295) included 657 patients with locally advanced or metastatic NSCLC and EGFR variants (EGFR exon 19 deletions or EGFR L858R variants). Patients had disease progression after receiving prior osimertinib. Patients were randomly assigned in a 2:2:1 ratio to receive amivantamab plus lazertinib plus chemotherapy, chemotherapy alone, or amivantamab and chemotherapy. Patients with brain metastases were eligible if their intracranial disease was clinically stable and they were asymptomatic and receiving stable doses of steroids. The dual primary end points were (1) PFS in patients who received amivantamab plus chemotherapy versus chemotherapy alone and (2) in patients who received amivantamab plus lazertinib and chemotherapy versus chemotherapy alone. Key secondary end points included objective response rate per blinded independent central review and OS.[30]

The median follow-up was 8.7 months.

The median PFS was 6.3 months (95% CI, 5.6–8.4) in the amivantamab-plus-chemotherapy arm, 8.3 months (95% CI, 6.8–9.1) in the amivantamab-plus-lazertinib-plus-chemotherapy arm and 4.2 months (95% CI, 4.0–4.4) in the chemotherapy-alone arm (HR, 0.48; 95% CI, 0.36–0.64; P < .0001).[30][Level of evidence B1]

Sources: 30 · Level of evidence B1

The confirmed objective response rate was 64% (95% CI, 55%–72%) in the amivantamab-plus-chemotherapy arm, 63% (95% CI, 57%–69%) in the amivantamab-plus-lazertinib-plus-chemotherapy arm, and 36% (95% CI, 30%–42%) in the chemotherapy-alone arm (P < .0001).

At the time of this first interim OS analysis, the HRdeath was 0.77 (95% CI, 0.49–1.21) for amivantamab plus chemotherapy versus chemotherapy alone, and 0.96 (95% CI, 0.67–1.35) for amivantamab plus lazertinib and chemotherapy versus chemotherapy alone.

Patients in the amivantamab-plus-chemotherapy arm had lower rates of hematologic adverse events than those in the amivantamab-plus-lazertinib-plus-chemotherapy arm. Hematologic toxicities were observed in the patients in the amivantamab-plus-lazertinib-plus-chemotherapy arm that necessitated a regimen change to start lazertinib therapy after carboplatin completion.

The phase III PALOMA-3 study (NCT05388669) enrolled 418 patients with EGFR-altered advanced NSCLC who progressed after receiving osimertinib and platinum-based chemotherapy. Patients were randomly assigned in a 1:1 ratio to receive either subcutaneous or IV amivantamab. Patients in both groups also received lazertinib.[31]

Sources: PALOMA-3 · 31

The phase III PALOMA-3 study (NCT05388669) enrolled 418 patients with EGFR-altered advanced NSCLC who progressed after receiving osimertinib and platinum-based chemotherapy. Patients were randomly assigned in a 1:1 ratio to receive either subcutaneous or IV amivantamab. Patients in both groups also received lazertinib.[31]

The objective response rate was 30% (95% CI, 24%–37%) in the subcutaneous amivantamab group and 33% (95% CI, 26%–39%) in the IV amivantamab group. The median PFS was 6.1 months (95% CI, 4.3–8.1) in the subcutaneous amivantamab group and 4.3 months (95% CI, 4.1–5.7) in the IV amivantamab group.[31][Level of evidence A1]

Sources: 31 · Level of evidence A1

The OS was significantly longer in the subcutaneous amivantamab group than the IV amivantamab group (HRdeath, 0.62; 95% CI, 0.42–0.92; nominal P = .02).

Infusion-related reactions occurred in 13% of patients in the subcutaneous amivantamab group and 66% of patients in the IV amivantamab group. Venous thromboembolism occurred in 9% of patients in the subcutaneous amivantamab group and 14% of patients in the IV amivantamab group.

The median administration time for the first infusion was 4.8 minutes (range, 0–18) in patients who received subcutaneous amivantamab and 5 hours (range, 0.2–9.9) in patients who received IV amivantamab.

A study (NCT00585195) screened 1,500 patients with NSCLC for ALK rearrangements and identified 82 patients with advanced ALK-positive disease. Those 82 patients were enrolled in an expanded cohort study instituted after phase I dose escalation had established a recommended dose of crizotinib (250 mg twice a day in 28-day cycles).[32] Most of the patients had received previous treatment.

Sources: NCT00585195 · 32

A study (NCT00585195) screened 1,500 patients with NSCLC for ALK rearrangements and identified 82 patients with advanced ALK-positive disease. Those 82 patients were enrolled in an expanded cohort study instituted after phase I dose escalation had established a recommended dose of crizotinib (250 mg twice a day in 28-day cycles).[32] Most of the patients had received previous treatment.

At a mean treatment duration of 6.4 months, the overall response rate was 57% (47 of 82 patients, with 46 confirmed partial responses, and one confirmed complete response); 27 patients (33%) had stable disease.[32][Level of evidence C2]

Sources: 32 · Level of evidence C2

The estimated probability of 6-month PFS was 72%.

The 1-year OS rate was 74% (95% CI, 63%–82%), and the 2-year OS rate was 54% (40%–66%).

Survival in 30 patients with ALK variants who were given crizotinib in the second-line or third-line setting was significantly longer than in 23 ALK-positive controls identified from a different cohort given any second-line therapy (median OS, NR [95% CI, 14 months–NR] vs. 6 months [95% CI, 4–17], 1-year OS rate, 70% [95% CI, 50%–83%] vs. 44% [95% CI, 23%–64%], and 2-year OS rate, 55% [33%–72%] vs. 12% [2%–30%]; HR, 0.36; 95% CI, 0.17–0.75; P = .004).[33][Level of evidence C2]

Sources: 33 · Level of evidence C2

Common toxicities were grade 1 or 2 (mild) gastrointestinal side effects.

Patients with ALK rearrangements tended to be younger than those without the rearrangements; most of the patients had little or no exposure to tobacco; and the patients had adenocarcinomas.

In an open-label, randomized, phase III study, 347 patients with stage IIIB/IV NSCLC and translocations in ALK, who had received one previous regimen of platinum-based chemotherapy, received either crizotinib (250 mg by mouth twice a day) or chemotherapy (pemetrexed 500 mg/m2 if pemetrexed-naïve or docetaxel 75 mg/m2 IV every 21 days). The primary end point was PFS.[34]

Sources: 34

In an open-label, randomized, phase III study, 347 patients with stage IIIB/IV NSCLC and translocations in ALK, who had received one previous regimen of platinum-based chemotherapy, received either crizotinib (250 mg by mouth twice a day) or chemotherapy (pemetrexed 500 mg/m2 if pemetrexed-naïve or docetaxel 75 mg/m2 IV every 21 days). The primary end point was PFS.[34]

Median PFS was significantly longer in favor of crizotinib (7.7 months vs. 3.0 months, P < .001).[34][Level of evidence B1]

Sources: 34 · Level of evidence B1

OS, a secondary end point, was not significantly different, but there was significant crossover in the design.

A single-arm open-label trial enrolled 163 patients with ALK-translocated stage IIIB/IV NSCLC who had disease progression while receiving crizotinib or were intolerant to the drug.[35] The primary end point was objective response rate according to Response Evaluation Criteria In Solid Tumors (RECIST, version 1.0) with a secondary end point of DOR.

Sources: 35

A single-arm open-label trial enrolled 163 patients with ALK-translocated stage IIIB/IV NSCLC who had disease progression while receiving crizotinib or were intolerant to the drug.[35] The primary end point was objective response rate according to Response Evaluation Criteria In Solid Tumors (RECIST, version 1.0) with a secondary end point of DOR.

The objective response rate by blinded independent review was 43.6% (95% CI, 36%–52%), and the median DOR was 7.1 months (range, 5.6–not estimable [NE]).[35][Level of evidence C3]

Sources: 35 · Level of evidence C3

Of note, 38% of patients required dose modification because of gastrointestinal toxicity; elevation of alanine transaminase to more than five times the upper limit of normal occurred in 27% of patients.

A phase II open-label trial (NCT01871805) enrolled 87 patients with ALK-translocated stage IIIB/IV NSCLC who had disease progression after crizotinib treatment. The primary end point was objective response according to RECIST (version 1.1).[36]

Sources: NCT01871805 · 36

A phase II open-label trial (NCT01871805) enrolled 87 patients with ALK-translocated stage IIIB/IV NSCLC who had disease progression after crizotinib treatment. The primary end point was objective response according to RECIST (version 1.1).[36]

At the time of primary end point analysis, 48% of patients (95% CI, 36%–60%) had a confirmed partial response, and 32% had stable disease by blinded independent review. The median DOR was 13.5 months (95% CI, 6.7–NE). The estimated median PFS was 8.1 months (95% CI, 6.2–12.6).[36][Level of evidence C3]

Sources: 36 · Level of evidence C3

Sixteen patients had measurable CNS disease at baseline, of whom 11 had received prior radiation therapy. The CNS overall response rate was 75% (95% CI, 48%–93%), with 25% of the patients attaining complete response and 50% of the patients attaining partial response.

The most common side effects were grade 1 or 2 in severity; the most frequent adverse events, occurring in 23% to 36% of patients, were constipation, fatigue, myalgia, and peripheral edema. Dose interruption was needed in 36% of patients, and dose reduction occurred in 16%.

A second phase II, open-label trial enrolled 138 patients with stage IIIB/IV NSCLC and ALK variants who had disease progression while receiving crizotinib. The primary end point was objective response rate by independent central review.[37]

Sources: 37

A second phase II, open-label trial enrolled 138 patients with stage IIIB/IV NSCLC and ALK variants who had disease progression while receiving crizotinib. The primary end point was objective response rate by independent central review.[37]

The objective response rate was 50% (95% CI, 41%–59%). Median DOR was 11.2 months (95% CI, 9.6–NR). Median PFS was 8.9 months (95% CI, 5.6–11.3).[37][Level of evidence C3]

Sources: 37 · Level of evidence C3

CNS objective response rate in 35 patients with measurable CNS lesions was 57% (95% CI, 39%–74%).

Common adverse events that were mainly grade 1 or 2, which occurred in 25% to 33% of patients, were constipation, fatigue, and peripheral edema.

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). The primary end point was investigator-assessed objective response rate.[38]

Sources: NCT02094573 · 38

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). The primary end point was investigator-assessed objective response rate.[38]

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.[38][Level of evidence B3]

Sources: 38 · 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.

In an open-label ongoing phase II study with multiple cohorts, patients with metastatic ALK-rearranged NSCLC were enrolled into six ALK expansion (EXP) cohorts on the basis of their ALK status and treatment history.[39] They received lorlatinib 100 mg once daily continuously in 21-day cycles. The primary end point was overall and intracranial tumor response by independent central review, as assessed in key pooled subgroups.[39][Level of evidence C3]

Sources: 39 · 39 · Level of evidence C3

In an open-label ongoing phase II study with multiple cohorts, patients with metastatic ALK-rearranged NSCLC were enrolled into six ALK expansion (EXP) cohorts on the basis of their ALK status and treatment history.[39] They received lorlatinib 100 mg once daily continuously in 21-day cycles. The primary end point was overall and intracranial tumor response by independent central review, as assessed in key pooled subgroups.[39][Level of evidence C3]

The number of patients treated, the objective response, and the intracranial response rates in each cohort or pooled cohorts are as follows:

In an open-label ongoing phase II study with multiple cohorts, patients with metastatic ALK-rearranged NSCLC were enrolled into six ALK expansion (EXP) cohorts on the basis of their ALK status and treatment history.[39] They received lorlatinib 100 mg once daily continuously in 21-day cycles. The primary end point was overall and intracranial tumor response by independent central review, as assessed in key pooled subgroups.[39][Level of evidence C3] › The number of patients treated, the objective response, and the intracranial response rates in each cohort or pooled cohorts are as follows:

EXP1 (n = 30, treatment naïve).

In an open-label ongoing phase II study with multiple cohorts, patients with metastatic ALK-rearranged NSCLC were enrolled into six ALK expansion (EXP) cohorts on the basis of their ALK status and treatment history.[39] They received lorlatinib 100 mg once daily continuously in 21-day cycles. The primary end point was overall and intracranial tumor response by independent central review, as assessed in key pooled subgroups.[39][Level of evidence C3] › The number of patients treated, the objective response, and the intracranial response rates in each cohort or pooled cohorts are as follows: › EXP1 (n = 30, treatment naïve).

Objective response rate, 90.0% (95% CI, 73.5%‒97.9%).

Intracranial response rate (n = 3), 66.7% (95% CI, 9.4%‒99.2%).

In an open-label ongoing phase II study with multiple cohorts, patients with metastatic ALK-rearranged NSCLC were enrolled into six ALK expansion (EXP) cohorts on the basis of their ALK status and treatment history.[39] They received lorlatinib 100 mg once daily continuously in 21-day cycles. The primary end point was overall and intracranial tumor response by independent central review, as assessed in key pooled subgroups.[39][Level of evidence C3] › The number of patients treated, the objective response, and the intracranial response rates in each cohort or pooled cohorts are as follows:

EXP2 (n = 27, previous crizotinib only) and EXP3A (n = 32, previous crizotinib and chemotherapy).

In an open-label ongoing phase II study with multiple cohorts, patients with metastatic ALK-rearranged NSCLC were enrolled into six ALK expansion (EXP) cohorts on the basis of their ALK status and treatment history.[39] They received lorlatinib 100 mg once daily continuously in 21-day cycles. The primary end point was overall and intracranial tumor response by independent central review, as assessed in key pooled subgroups.[39][Level of evidence C3] › The number of patients treated, the objective response, and the intracranial response rates in each cohort or pooled cohorts are as follows: › EXP2 (n = 27, previous crizotinib only) and EXP3A (n = 32, previous crizotinib and chemotherapy).

Objective response rate, 69.5% (95% CI, 56.1%‒80.8%).

Intracranial response rate (n = 23), 87.0% (95% CI, 66.4%‒97.2%).

In an open-label ongoing phase II study with multiple cohorts, patients with metastatic ALK-rearranged NSCLC were enrolled into six ALK expansion (EXP) cohorts on the basis of their ALK status and treatment history.[39] They received lorlatinib 100 mg once daily continuously in 21-day cycles. The primary end point was overall and intracranial tumor response by independent central review, as assessed in key pooled subgroups.[39][Level of evidence C3] › The number of patients treated, the objective response, and the intracranial response rates in each cohort or pooled cohorts are as follows:

EXP3B (n = 28, one previous second-generation ALK inhibitor with or without chemotherapy).

In an open-label ongoing phase II study with multiple cohorts, patients with metastatic ALK-rearranged NSCLC were enrolled into six ALK expansion (EXP) cohorts on the basis of their ALK status and treatment history.[39] They received lorlatinib 100 mg once daily continuously in 21-day cycles. The primary end point was overall and intracranial tumor response by independent central review, as assessed in key pooled subgroups.[39][Level of evidence C3] › The number of patients treated, the objective response, and the intracranial response rates in each cohort or pooled cohorts are as follows: › EXP3B (n = 28, one previous second-generation ALK inhibitor with or without chemotherapy).

Objective response rate, 32.1% (95% CI, 15.9%‒52.4%).

Intracranial response rate (n = 9), 55.6% (95% CI, 21.2%‒86.3%).

In an open-label ongoing phase II study with multiple cohorts, patients with metastatic ALK-rearranged NSCLC were enrolled into six ALK expansion (EXP) cohorts on the basis of their ALK status and treatment history.[39] They received lorlatinib 100 mg once daily continuously in 21-day cycles. The primary end point was overall and intracranial tumor response by independent central review, as assessed in key pooled subgroups.[39][Level of evidence C3] › The number of patients treated, the objective response, and the intracranial response rates in each cohort or pooled cohorts are as follows:

EXP4 (n = 65, two previous ALK inhibitors with or without chemotherapy) and EXP5 (n = 46, three previous lines of ALK inhibitors, with or without chemotherapy).

In an open-label ongoing phase II study with multiple cohorts, patients with metastatic ALK-rearranged NSCLC were enrolled into six ALK expansion (EXP) cohorts on the basis of their ALK status and treatment history.[39] They received lorlatinib 100 mg once daily continuously in 21-day cycles. The primary end point was overall and intracranial tumor response by independent central review, as assessed in key pooled subgroups.[39][Level of evidence C3] › The number of patients treated, the objective response, and the intracranial response rates in each cohort or pooled cohorts are as follows: › EXP4 (n = 65, two previous ALK inhibitors with or without chemotherapy) and EXP5 (n = 46, three previous lines of ALK inhibitors, with or without chemotherapy).

Objective response rate, 38.7% (95% CI, 29.6%‒48.5%).

Intracranial response rate (n = 49), 53.1% (95% CI, 38.3%‒67.5%).

In an open-label ongoing phase II study with multiple cohorts, patients with metastatic ALK-rearranged NSCLC were enrolled into six ALK expansion (EXP) cohorts on the basis of their ALK status and treatment history.[39] They received lorlatinib 100 mg once daily continuously in 21-day cycles. The primary end point was overall and intracranial tumor response by independent central review, as assessed in key pooled subgroups.[39][Level of evidence C3]

The median DOR has not been reached for any of the pooled cohorts.

The most common adverse event was hypercholesterolemia (16% grade 3–4), and 3% of patients discontinued treatment due to adverse events.

In a phase II, multicenter, nonrandomized, open-label study (NCT01336634), 57 patients with progression after at least one to three previous platinum-containing regimens for treatment of 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.[40] BRAF V600E variants were ascertained by local testing. The primary end point was investigator-assessed overall response.

Sources: NCT01336634 · 40

In a phase II, multicenter, nonrandomized, open-label study (NCT01336634), 57 patients with progression after at least one to three previous platinum-containing regimens for treatment of 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.[40] BRAF V600E variants were ascertained by local testing. The primary end point was investigator-assessed overall response.

The overall response rate was 63.2% (95% CI, 49.3%–75.6%), as determined independently by investigator and independent review committee assessments. There were 2 out of 36 complete responses by investigator assessment; all responses were deemed partial by the independent review committee.

The median investigator-assessed PFS was 9.7 months (95% CI, 6.9–19.6 months). The estimated median DOR was 9.0 months (95% CI, 6.9–18.3). The OS data are immature.

Forty-nine percent of patients had at least one grade 3 or 4 adverse event, the most common of which were neutropenia, hyponatremia, and anemia.[40][Level of evidence C3]

Sources: 40 · 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]).[42] Entrectinib was given orally at a dose of at least 600 mg once daily. Primary end points were the overall 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 · 42

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]).[42] Entrectinib was given orally at a dose of at least 600 mg once daily. Primary end points were the overall 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 overall 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 overall response rate was 74% and all patients had a partial response. Among patients without CNS disease at baseline, the overall response rate was 80% (10% complete response rate; 70% partial response rate).[42][Level of evidence C3]

Sources: 42 · Level of evidence C3

The median DOR was 24.6 months (95% CI, 11.4−34.8); 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 (59%) patients. Grade 3 or 4 treatment-related adverse events were observed in 46 (34%) patients. Fifteen (11%) patients had serious treatment-related adverse events. There were no treatment-related deaths.

The median PFS was 19 months (95% CI, 12.2−36.6); 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 rearrangements were treated with oral crizotinib 250 mg twice daily.[43] 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 previous treatment, and 22 patients (44%) had more than one previous treatment. The primary end point was response rate.

Sources: 43

In an expansion cohort of a phase I study of crizotinib, 50 patients with advanced NSCLC who tested positive for ROS1 rearrangements were treated with oral crizotinib 250 mg twice daily.[43] 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 previous treatment, and 22 patients (44%) had more than one previous 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).[43][Level of evidence C3]

Sources: 43 · Level of evidence C3

In a phase II, open-label, single-arm trial, 127 East Asian patients with NSCLC and ROS1 variants were treated with crizotinib 250 mg twice daily.[44] 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: 44

In a phase II, open-label, single-arm trial, 127 East Asian patients with NSCLC and ROS1 variants were treated with crizotinib 250 mg twice daily.[44] 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.[44][Level of evidence C3]

Sources: 44 · 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.[46]

Sources: TRIDENT-1 · 46

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.[46]

Among ROS1 TKI-naïve patients (n = 71), the objective response rate was 79% (95% CI, 68%–88%). In 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.[46][Level of evidence C3]

Sources: 46 · 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.[49] 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: 49

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.[49] 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.[49][Level of evidence C3]

Sources: 49 · 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]).[50] Treatment consisted of entrectinib administered orally at a dose of at least 600 mg once per day. The primary end points were objective response 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 two (4%) had NTRK gene fusions detected by other nucleic acid–based tests.

Sources: STARTRK-1 · STARTRK-2 · 50

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]).[50] Treatment consisted of entrectinib administered orally at a dose of at least 600 mg once per day. The primary end points were objective response 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 two (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 the overall response rate was 50% (all partial responses), whereas in patients without baseline CNS disease, the overall response rate was 60% (10% complete response; 50% partial response).[50][Level of evidence C3]

Sources: 50 · Level of evidence C3

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

Among 10 patients with NSCLC, the overall response rate was 70% (95% CI, 35%−93%) and the 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.[52][Level of evidence C3]

Sources: LIBRETTO-001 · 52 · 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.[52][Level of evidence C3]

Updated analysis was conducted in 316 patients with RET fusion–positive NSCLC.[52]

Sources: 52

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 alanine aminotransferase (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.[53][Level of evidence C3]

Sources: ARROW · 53 · 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.[53][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.[55][Level of evidence C3]

Sources: VISION · 55 · 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.[55][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 determined centrally. A total of 364 patients were enrolled. The primary end point was overall response.[56][Level of evidence C3]

Sources: GEOMETRY · 56 · Level of evidence C3

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 determined centrally. A total of 364 patients were enrolled. The primary end point was overall response.[56][Level of evidence C3]

Of the 69 patients with MET exon 14-skipping variants who had received one or two prior lines of therapy, the overall response rate was 41% (95% CI, 29%–53%). The median DOR was 9.7 months (95% CI, 5.6–13.0).

Of the 28 patients with MET exon 14-skipping variants who had not received any prior treatment, the overall response rate was 68% (95% CI, 48%–84%). The median DOR was 12.6 months (95% CI, 5.6–NE).

Response rates in patients with MET amplification without exon 14-skipping variants did not meet the prespecified threshold for clinically relevant activity.

Grade 3 to 4 adverse events occurred in 67% of patients. The most common events, regardless of causality, were peripheral edema, nausea, vomiting, and increased creatinine. Adverse events led to therapy discontinuation in 11% of patients.

KRYSTAL-1 (NCT03785249) was a phase I/II multiple expansion cohort clinical trial that investigated adagrasib (600 mg orally twice daily) in patients with advanced solid tumors. A phase II cohort of the trial included patients with NSCLC and KRAS G12C variants who were previously treated with platinum-based chemotherapy and anti–programmed death 1 (PD-1) or anti–programmed death-ligand 1 (PD-L1) therapy. The cohort enrolled 116 patients; 98.3% had previously received both chemotherapy and immunotherapy. The primary end point was objective response assessed by blinded independent central review.[58][Level of evidence C3]

Sources: KRYSTAL-1 · 58 · Level of evidence C3

KRYSTAL-1 (NCT03785249) was a phase I/II multiple expansion cohort clinical trial that investigated adagrasib (600 mg orally twice daily) in patients with advanced solid tumors. A phase II cohort of the trial included patients with NSCLC and KRAS G12C variants who were previously treated with platinum-based chemotherapy and anti–programmed death 1 (PD-1) or anti–programmed death-ligand 1 (PD-L1) therapy. The cohort enrolled 116 patients; 98.3% had previously received both chemotherapy and immunotherapy. The primary end point was objective response assessed by blinded independent central review.[58][Level of evidence C3]

Among 112 evaluable patients, the confirmed objective response rate was 42.9% (95% CI, 33.5%–52.6%), including one complete response (0.9%). The median DOR was 8.5 months (95% CI, 6.2–13.8). Disease control occurred in 79.5% of patients (95% CI, 70.8%–86.5%).

The median PFS was 6.5 months (95% CI, 4.7–8.4), and the median OS was 12.6 months (95% CI, 9.2–19.2).

Among 33 patients with previously treated stable CNS metastases, the intracranial confirmed objective response rate was 33.3% (95% CI, 18.0%–51.8%).

Grade 3 or higher adverse events occurred in 44.8% of patients and included two deaths. The most common adverse events were diarrhea, nausea, fatigue, vomiting, dyspnea, increased creatinine, increased ALT, increased AST, and decreased appetite. Adverse events led to therapy discontinuation in 6.9% of patients.

A phase II clinical trial (CodeBreaK 100 [NCT03600883]) evaluated sotorasib (960 mg orally once daily) in patients with KRAS G12C variants who were previously treated with standard therapies. A total of 126 patients were enrolled. Of 124 evaluable patients, most (81%) received prior platinum-based therapy and inhibitors of PD-1 or PD-L1. The primary end point was overall response according to independent central review.[57][Level of evidence C3]

Sources: CodeBreaK 100 · 57 · Level of evidence C3

A phase II clinical trial (CodeBreaK 100 [NCT03600883]) evaluated sotorasib (960 mg orally once daily) in patients with KRAS G12C variants who were previously treated with standard therapies. A total of 126 patients were enrolled. Of 124 evaluable patients, most (81%) received prior platinum-based therapy and inhibitors of PD-1 or PD-L1. The primary end point was overall response according to independent central review.[57][Level of evidence C3]

For the 124 evaluable patients, the overall response rate was 37.1% (95% CI, 28.6%–46.2%), including complete responses in 3.2%. The median DOR was 11.1 months (95% CI, 6.9–could not be evaluated). Disease control occurred in 80.6% of patients (95% CI, 72.6%–87.2%).

Median PFS was 6.8 months (95% CI, 5.1–8.2) and median OS was 12.5 months (95% CI, 10.0–could not be evaluated).

Grade 3 to 4 adverse events occurred in 20.6% of patients. The most common adverse events that were considered treatment related were diarrhea, nausea, increases in ALT or AST, and fatigue. Adverse events led to therapy discontinuation in 7.1% of patients.

DESTINY-Lung01 (NCT03505710) was a multicenter, open-label, two-cohort, phase II clinical trial that investigated trastuzumab deruxtecan at a dose of 6.4 mg/kg of body weight. Enrolled patients had unresectable or metastatic nonsquamous NSCLC with disease relapse during standard treatment or with disease that was refractory to standard treatment. Patients had HER2 variants or HER2-overexpressing disease. Patients who had previously received a HER2 antibody or an antibody-drug conjugate were ineligible. However, those who had received a HER2 TKI were eligible. The primary end point was objective response as assessed by independent central review. Ninety-one patients with NSCLC and HER2 variants were enrolled; 95% had received previous platinum-based therapy, and 66% had received anti-PD-1 or anti-PD-L1 immunotherapy.[61][Level of evidence C3]

Sources: DESTINY-Lung01 · 61 · Level of evidence C3

DESTINY-Lung01 (NCT03505710) was a multicenter, open-label, two-cohort, phase II clinical trial that investigated trastuzumab deruxtecan at a dose of 6.4 mg/kg of body weight. Enrolled patients had unresectable or metastatic nonsquamous NSCLC with disease relapse during standard treatment or with disease that was refractory to standard treatment. Patients had HER2 variants or HER2-overexpressing disease. Patients who had previously received a HER2 antibody or an antibody-drug conjugate were ineligible. However, those who had received a HER2 TKI were eligible. The primary end point was objective response as assessed by independent central review. Ninety-one patients with NSCLC and HER2 variants were enrolled; 95% had received previous platinum-based therapy, and 66% had received anti-PD-1 or anti-PD-L1 immunotherapy.[61][Level of evidence C3]

All 91 patients were evaluable for response. The confirmed objective response rate was 55% (95% CI, 44%–65%), including one complete response (1%). The median DOR was 9.3 months (95% CI, 5.7–14.7). Disease control was observed in 92% of patients (95% CI, 85%–97%).

The median PFS was 8.2 months (95% CI, 6.0–11.9), and the median OS was 17.8 months (95% CI, 13.8–22.1).

Among 33 patients with CNS metastases at baseline, 14 had previously received radiation therapy to the brain, and 19 had not. Of these patients, 8 (57%) and 10 (53%), respectively, had a partial response. The median PFS for patients with CNS metastases at baseline was 7.1 months (95% CI, 5.5–9.8), and the median OS was 13.8 months (95% CI, 9.8–20.9).

Grade 3 or higher drug-related adverse events occurred in 46% of patients. The most common adverse events were nausea, fatigue, alopecia, vomiting, neutropenia, anemia, diarrhea, decreased appetite, leukopenia, and constipation. The most common grade 3 or higher drug-related adverse events were neutropenia (19%) and anemia (10%).

Drug-related adverse events led to treatment discontinuation in 23 patients (25%) and included pneumonitis in 12 patients (13%) and interstitial lung disease in 5 patients (5%).

There were two drug-related deaths caused by interstitial lung disease.

A randomized, open-label, phase III trial randomly assigned 272 patients with advanced squamous cell NSCLC who had received one regimen of platinum-containing chemotherapy to receive either nivolumab (3 mg/kg every 2 weeks) or docetaxel (75 mg/m2 every 3 weeks), administered until disease progression.[62] The primary end point of this study was OS.

Sources: 62

A randomized, open-label, phase III trial randomly assigned 272 patients with advanced squamous cell NSCLC who had received one regimen of platinum-containing chemotherapy to receive either nivolumab (3 mg/kg every 2 weeks) or docetaxel (75 mg/m2 every 3 weeks), administered until disease progression.[62] The primary end point of this study was OS.

Nivolumab demonstrated a significant improvement in median OS compared with docetaxel (9.2 months vs. 6 months; P < .001). In addition, the response rate (20% vs. 9%; P = .008) and median PFS (3.5 months vs. 2.8 months; P < .001) favored nivolumab.

Rates of treatment-related toxicity were significantly lower with nivolumab than with docetaxel (all grades, 58% for nivolumab vs. 86% for docetaxel; grades 3–4, 7% for nivolumab vs. 55% for docetaxel).

A randomized, open-label, phase III trial included 582 patients with advanced nonsquamous NSCLC who had received one regimen of platinum-containing chemotherapy. Patients were randomly assigned to receive either nivolumab (3 mg/kg every 2 weeks) or docetaxel (75 mg/m2 every 3 weeks), administered until disease progression.[63] Previous maintenance chemotherapy after first-line platinum-doublet was allowed; patients with EGFR variants or ALK translocations were allowed to have received an additional regimen of therapy with a TKI. The primary end point of this study was OS.

Sources: 63

A randomized, open-label, phase III trial included 582 patients with advanced nonsquamous NSCLC who had received one regimen of platinum-containing chemotherapy. Patients were randomly assigned to receive either nivolumab (3 mg/kg every 2 weeks) or docetaxel (75 mg/m2 every 3 weeks), administered until disease progression.[63] Previous maintenance chemotherapy after first-line platinum-doublet was allowed; patients with EGFR variants or ALK translocations were allowed to have received an additional regimen of therapy with a TKI. The primary end point of this study was OS.

Patients who received nivolumab had a significant improvement in median OS compared with patients who received docetaxel (12.2 months vs. 9.4 months; HR, 0.73; 96% CI, 0.59–0.89; P = .002). In this study, the response rate (19% vs. 12%; P = .02) but not median PFS (2.3 months for nivolumab vs. 4.2 months for docetaxel) favored nivolumab. The median DOR in patients was 17.2 months for nivolumab and 5.6 months for docetaxel.

Rates of treatment-related toxicity were significantly lower with nivolumab than with docetaxel (all grades, 69% for nivolumab vs. 88% for docetaxel; grades 3–4, 10% for nivolumab vs. 54% for docetaxel).

In a phase I study with multiple expansion cohorts, pembrolizumab demonstrated significant activity with respect to response rate and DOR.[64][Level of evidence C3]

Sources: 64 · Level of evidence C3

In a phase I study with multiple expansion cohorts, pembrolizumab demonstrated significant activity with respect to response rate and DOR.[64][Level of evidence C3]

In the study, 495 patients received either pembrolizumab 2 mg/kg every 3 weeks, 10 mg/kg every 3 weeks, or 10 mg/kg every 2 weeks. No significant differences were seen among the different treatment schedules. Key exclusion criteria were autoimmune disease, history of pneumonitis, requirement for systemic immunosuppressive therapy, and a performance status higher than 1. The objective response rate was 19.4% (95% CI, 16.0%–23.2%), which included a response rate of 18.0% (95% CI, 14.4%–22.2%) in 394 previously treated patients and 24.8% (95% CI, 16.7%–34.3%) in 101 previously untreated patients. Median PFS was 3.7 months (95% CI, 2.9–4.1) for all patients, 3.0 months (95% CI, 2.2–4.0) for previously treated patients, and 6.0 months (95% CI, 4.1–8.6) for previously untreated patients. The median DOR was 12.5 months (range, 1.0–23.3 months) in all patients.

The study evaluated the efficacy of pembrolizumab in patients with high levels of PD-L1, as assessed by the anti-PD-L1 antibody clone 22C3. Using the cutoff of membranous staining in at least 50% of tumor cells in a validation group of 73 patients, the response rate was 45.2% (95% CI, 33.5%–57.3%), and the median PFS in this group was 6.3 months (95% CI, 2.9–12.5). Median OS was not reached at the time of publication.

The estimated prevalence of PD-L1 tumor staining from 1,143 screened patients, of whom 824 had evaluable samples, is as follows: 23.2% had 50% or more tumor cells with staining; 37.6% had between 1% and 49% tumor cells with staining; and 39.2% had less than 1% of tumor cells with staining.

The most common adverse events were fatigue, pruritus, and decreased appetite. Grade 3 or higher adverse events were reported in 9.5% of patients. Inflammatory and immune-mediated adverse events that occurred in more than 2% of patients were infusion-related reactions (3.0%), hypothyroidism (6.9%), and pneumonitis (3.6%).

In a phase II/III randomized clinical trial, patients with previously treated NSCLC with PD-L1 expression on at least 1% of tumor cells were randomly assigned (1:1:1) to receive pembrolizumab (2 mg/kg), pembrolizumab (10 mg/kg), or docetaxel (75 mg/m2) every 3 weeks.[66][Level of evidence A1] The primary end points were OS and PFS in the total population and in patients with PD-L1 expression on at least 50% of tumor cells. This study enrolled 1,034 patients; 345 of them were allocated to pembrolizumab (2 mg/kg); 346 were allocated to pembrolizumab (10 mg/kg); and 343 were allocated to docetaxel.

Sources: 66 · Level of evidence A1

In a phase II/III randomized clinical trial, patients with previously treated NSCLC with PD-L1 expression on at least 1% of tumor cells were randomly assigned (1:1:1) to receive pembrolizumab (2 mg/kg), pembrolizumab (10 mg/kg), or docetaxel (75 mg/m2) every 3 weeks.[66][Level of evidence A1] The primary end points were OS and PFS in the total population and in patients with PD-L1 expression on at least 50% of tumor cells. This study enrolled 1,034 patients; 345 of them were allocated to pembrolizumab (2 mg/kg); 346 were allocated to pembrolizumab (10 mg/kg); and 343 were allocated to docetaxel.

In the total population, median OS was 10.4 months with pembrolizumab (2 mg/kg), 12.7 months with pembrolizumab (10 mg/kg), and 8.5 months with docetaxel. OS was significantly longer for pembrolizumab (2 mg/kg) versus docetaxel (HR 0.71; 95% CI, 0.58–0.88; P = .0008) and for pembrolizumab (10 mg/kg) versus docetaxel (HR, 0.61; CI, 0.49–0.75; P < .0001).

In the total population, PFS was not prolonged in the pembrolizumab groups compared with the docetaxel group.

Among patients with at least 50% of tumor cells expressing PD-L1, OS was significantly longer with pembrolizumab (2 mg/kg) than with docetaxel (median, 14.9 months vs. 8.2 months; HR, 0.54; 95% CI, 0.38–0.77; P = .0002) and with pembrolizumab (10 mg/kg) than with docetaxel (median, 17.3 months vs. 8.2 months; HR, 0.50; CI, 0.36–0.70; P < .0001).

In the group of patients with at least 50% of tumor cells expressing PD-L1, PFS was significantly longer with pembrolizumab (2 mg/kg) than with docetaxel (median, 5.0 months vs. 4.1 months; HR, 0.59; 95% CI, 0.44–0.78; P = .0001) and with pembrolizumab (10 mg/kg) than with docetaxel (median, 5.2 months vs. 4.1 months; HR, 0.59; CI, 0.45–0.78; P < .0001).

Grade 3 to 5 treatment-related adverse events were less common with pembrolizumab than with docetaxel (43 [13%] of 339 patients given pembrolizumab (2 mg/kg), 55 [16%] of 343 patients given pembrolizumab (10 mg/kg), and 109 [35%] of 309 patients given docetaxel).

Two international, randomized, open-label clinical trials (OAK [NCT02008227] and POPLAR [NCT01903993]) demonstrated efficacy and safety in a total of 1,137 patients with NSCLC who previously received platinum chemotherapy.[67,68][Level of evidence A1] Compared with docetaxel, treatment with atezolizumab in the intended patient population resulted in improved OS rates of 4.2 months in the OAK study and 2.9 months in the POPLAR study.

Sources: OAK · POPLAR · 67 · 68 · Level of evidence A1

Two international, randomized, open-label clinical trials (OAK [NCT02008227] and POPLAR [NCT01903993]) demonstrated efficacy and safety in a total of 1,137 patients with NSCLC who previously received platinum chemotherapy.[67,68][Level of evidence A1] Compared with docetaxel, treatment with atezolizumab in the intended patient population resulted in improved OS rates of 4.2 months in the OAK study and 2.9 months in the POPLAR study.

In the OAK trial, the median OS was 13.8 months in the atezolizumab arm (95% CI, 11.8–15.7) compared with 9.6 months in the docetaxel arm (95% CI, 8.6–11.2) (HR, 0.74; 95% CI, 0.63–0.87; P = .0004).

The median OS in the POPLAR trial was 12.6 months in the atezolizumab arm (95% CI, 9.7–16.0) and 9.7 months in the docetaxel arm (95% CI, 8.6–12.0) (HR, 0.69; 95% CI, 0.52–0.92).

Although the magnitude of improvement correlated with PD-L1 immunohistochemistry expression on tumor cells and tumor-infiltrating immune cells, survival benefit with atezolizumab was seen in patients with tumors with and without PD-L1 expression.

In the POPLAR trial, the most common (≥20%) adverse reactions were in patients treated with atezolizumab and included fatigue, decreased appetite, dyspnea, cough, nausea, musculoskeletal pain, and constipation.

The most common (≥2%) grade 3 to 4 adverse events in patients treated with atezolizumab were dyspnea, pneumonia, hypoxia, hyponatremia, fatigue, anemia, musculoskeletal pain, ALT and AST increase, dysphagia, and arthralgia.

Clinically significant immune-related adverse events for patients who received atezolizumab included pneumonitis, hepatitis, colitis, and thyroid disease.

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.[69] Eligible patients were randomly assigned in a 2:1 ratio to receive 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 intention-to-treat population.

Sources: RADIANT-4 · 69

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.[69] Eligible patients were randomly assigned in a 2:1 ratio to receive 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 intention-to-treat 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).[69][Level of evidence B1]

Sources: 69 · 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).[69]

Sources: 69

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.

the stage of the cancer (the size of the tumor and whether it is in the lung only or has spread to other places in the body)

the type of lung cancer

whether the cancer has mutations (changes) in certain genes, such as the epidermal growth factor receptor (EGFR) gene or the anaplastic lymphoma kinase (ALK) gene

Sources: mutations · epidermal growth factor receptor (EGFR) gene · anaplastic lymphoma kinase (ALK) gene

whether there are signs and symptoms such as coughing or trouble breathing

your general health

There are different types of treatment for people with non-small cell lung cancer.

The following types of treatment are used:

The following types of treatment are used:

Surgery

Radiation therapy

Chemotherapy

Targeted therapy

Immunotherapy

Laser therapy

Photodynamic therapy (PDT)

Cryosurgery

Electrocautery

New types of treatment are being tested in clinical trials.

Treatment for non-small cell lung cancer may cause side effects.

Follow-up care may be needed.

Wedge resection is surgery to remove a tumor and some of the normal tissue around it. When a slightly larger amount of tissue is taken, it is called a segmental resection.

Sources: segmental resection

Lobectomy is surgery to remove a whole lobe (section) of the lung.

Pneumonectomy is surgery to remove one whole lung.

Sleeve resection is surgery to remove part of the bronchus.

Sources: bronchus

External radiation therapy uses a machine outside the body to send radiation toward the area of the body with cancer. Certain ways of giving external radiation therapy can help keep radiation from damaging nearby healthy tissue:

Sources: External radiation therapy

External radiation therapy uses a machine outside the body to send radiation toward the area of the body with cancer. Certain ways of giving external radiation therapy can help keep radiation from damaging nearby healthy tissue:

Stereotactic body radiation therapy uses special equipment to ensure you are in the same position for each radiation treatment. Once a day for several days, a radiation machine aims a larger than usual dose of radiation directly at the tumor. By having you in the same position for each treatment, there is less damage to nearby healthy tissue. This procedure is also called stereotactic external beam radiation therapy and stereotaxic radiation therapy.

Sources: Stereotactic body radiation therapy · dose

Stereotactic radiosurgery is used to treat lung cancer that has spread to the brain. A rigid head frame is attached to the skull to keep the head still during the radiation treatment. A machine aims a single large dose of radiation directly at the tumor in the brain. This procedure does not involve surgery. It is also called stereotaxic radiosurgery, radiosurgery, and radiation surgery.

Sources: Stereotactic radiosurgery · skull

Internal radiation therapy uses a radioactive substance sealed in needles, seeds, wires, or catheters that are placed directly into or near the cancer.

Sources: Internal radiation therapy · radioactive · seeds · catheters

carboplatin

Sources: carboplatin

cisplatin

Sources: cisplatin

docetaxel

Sources: docetaxel

doxorubicin

Sources: doxorubicin

etoposide

Sources: etoposide

gemcitabine

Sources: gemcitabine

paclitaxel

Sources: paclitaxel

pemetrexed

Sources: pemetrexed

vinorelbine

Sources: vinorelbine

adagrasib

Sources: adagrasib

afatinib

Sources: afatinib

alectinib

Sources: alectinib

amivantamab

Sources: amivantamab

bevacizumab

Sources: bevacizumab

brigatinib

Sources: brigatinib

capmatinib

Sources: capmatinib

ceritinib

Sources: ceritinib

cetuximab

Sources: cetuximab

crizotinib

Sources: crizotinib

dabrafenib

Sources: dabrafenib

dacomitinib

Sources: dacomitinib

entrectinib

Sources: entrectinib

erlotinib

Sources: erlotinib

everolimus

Sources: everolimus

gefitinib

Sources: gefitinib

larotrectinib

Sources: larotrectinib

lazertinib

Sources: lazertinib

lorlatinib

Sources: lorlatinib

necitumumab

Sources: necitumumab

osimertinib

Sources: osimertinib

pralsetinib

Sources: pralsetinib

ramucirumab

Sources: ramucirumab

repotrectinib

Sources: repotrectinib

selpercatinib

Sources: selpercatinib

sotorasib

Sources: sotorasib

tepotinib

Sources: tepotinib

trametinib

Sources: trametinib

atezolizumab

Sources: atezolizumab

cemiplimab-rwlc

Sources: cemiplimab-rwlc

durvalumab

Sources: durvalumab

ipilimumab

Sources: ipilimumab

nivolumab

Sources: nivolumab

pembrolizumab

Sources: pembrolizumab

tremelimumab

Sources: tremelimumab

surgery (wedge resection or segmental resection)

Sources: wedge resection · segmental resection

photodynamic therapy, electrocautery, cryosurgery, or laser surgery for tumors in or near the bronchus

Sources: photodynamic therapy · electrocautery · cryosurgery · laser surgery · bronchus

surgery (wedge resection, segmental resection, sleeve resection, or lobectomy)

Sources: wedge resection · segmental resection · sleeve resection · lobectomy

surgery followed by targeted therapy

Sources: targeted therapy

surgery followed by chemotherapy and immunotherapy

external radiation therapy, including stereotactic body radiation therapy for people who cannot have surgery or choose not to have surgery

Sources: external radiation therapy · stereotactic body radiation therapy

surgery (wedge resection, segmental resection, sleeve resection, lobectomy, or pneumonectomy)

Sources: wedge resection · segmental resection · sleeve resection · lobectomy · pneumonectomy

surgery followed by chemotherapy

Sources: chemotherapy

surgery followed by targeted therapy

Sources: targeted therapy

surgery followed by chemotherapy and immunotherapy

surgery followed by immunotherapy

Sources: immunotherapy

surgery followed by radiation therapy

Sources: radiation therapy

chemotherapy followed by surgery

immunotherapy and chemotherapy followed by surgery

immunotherapy and chemotherapy followed by surgery and more immunotherapy

external radiation therapy for people who cannot have surgery

Sources: external radiation therapy

chemotherapy followed by surgery

Sources: chemotherapy

chemotherapy and radiation therapy followed by surgery

Sources: radiation therapy

immunotherapy and chemotherapy followed by surgery

Sources: immunotherapy

immunotherapy and chemotherapy followed by surgery and more immunotherapy

surgery followed by chemotherapy

surgery followed by targeted therapy

Sources: targeted therapy

surgery followed by chemotherapy and immunotherapy

surgery followed by immunotherapy

surgery followed by chemotherapy and radiation therapy

surgery followed by radiation therapy

chemotherapy and radiation therapy

chemotherapy and radiation therapy followed by immunotherapy

external radiation therapy alone

Sources: external radiation therapy

internal radiation therapy or laser surgery as palliative treatment to relieve symptoms and improve quality of life

Sources: internal radiation therapy · laser surgery · palliative treatment · symptoms · quality of life

surgery

chemotherapy and radiation therapy followed by surgery

radiation therapy alone

surgery

surgery and radiation therapy

radiation therapy alone

chemotherapy combined with radiation therapy and/or surgery

chemotherapy followed by external radiation therapy

Sources: chemotherapy · external radiation therapy

chemotherapy with radiation therapy

Sources: radiation therapy

immunotherapy and chemotherapy followed by surgery and more immunotherapy

Sources: immunotherapy

immunotherapy before or after chemotherapy and radiation therapy

targeted therapy before or after chemotherapy and radiation therapy

Sources: targeted therapy

external radiation therapy alone for people who cannot have chemotherapy

external radiation therapy as palliative therapy to relieve symptoms and improve quality of life

Sources: palliative therapy · symptoms · quality of life

laser therapy and/or internal radiation therapy to relieve symptoms and improve quality of life

Sources: laser therapy · internal radiation therapy

one or more chemotherapy drugs with or without targeted therapy

Sources: chemotherapy · targeted therapy

combination chemotherapy followed by more chemotherapy as maintenance therapy to help keep cancer from progressing

Sources: combination chemotherapy · maintenance therapy · progressing

targeted therapy

one or more immunotherapy drugs

Sources: immunotherapy

chemotherapy

Sources: chemotherapy

targeted therapy with or without chemotherapy

Sources: targeted therapy

immunotherapy

Sources: immunotherapy