Nivolumab plus ipilimumab

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

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

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

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

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

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

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

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

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

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

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