Five-Year Survival Outcomes With Nivolumab Plus Ipilimumab Versus Chemotherapy as First-Line Treatment for Metastatic Non-Small-Cell Lung Cancer in CheckMate 227

Abstract

Purpose: We present 5-year results from CheckMate 227 Part 1, in which nivolumab plus ipilimumab improved overall survival (OS) versus chemotherapy in patients with metastatic non-small-cell lung cancer, regardless of tumor programmed death ligand 1 (PD-L1) status.

Methods: Adults with stage IV/recurrent non-small-cell lung cancer without EGFR mutations or ALK alterations and with tumor PD-L1 ≥ 1% or < 1% (n = 1739) were randomly assigned. Patients with tumor PD-L1 ≥ 1% were randomly assigned to first-line nivolumab plus ipilimumab, nivolumab alone, or chemotherapy. Patients with tumor PD-L1 < 1% were randomly assigned to nivolumab plus ipilimumab, nivolumab plus chemotherapy, or chemotherapy. End points included exploratory 5-year results for efficacy, safety, and quality of life.

Results: At a minimum follow-up of 61.3 months, 5-year OS rates were 24% versus 14% for nivolumab plus ipilimumab versus chemotherapy (PD-L1 ≥ 1%) and 19% versus 7% (PD-L1 < 1%). The median duration of response was 24.5 versus 6.7 months (PD-L1 ≥ 1%) and 19.4 versus 4.8 months (PD-L1 < 1%). Among patients surviving 5 years, 66% (PD-L1 ≥ 1%) and 64% (PD-L1 < 1%) were off nivolumab plus ipilimumab without initiating subsequent systemic anticancer treatment by the 5-year time point. Survival benefit continued after nivolumab plus ipilimumab discontinuation because of treatment-related adverse events, with a 5-year OS rate of 39% (combined PD-L1 ≥ 1% and < 1% populations). Quality of life in 5-year survivors treated with nivolumab plus ipilimumab was similar to that in the general US population through the 5-year follow-up. No new safety signals were observed.

Conclusion: With all patients off immunotherapy treatment for ≥ 3 years, nivolumab plus ipilimumab increased 5-year survivorship versus chemotherapy, including long-term, durable clinical benefit regardless of tumor PD-L1 expression. These data support nivolumab plus ipilimumab as an effective first-line treatment for patients with metastatic non-small-cell lung cancer.

Trial registration: ClinicalTrials.gov NCT02477826.

FIG 1.

CheckMate 227 CONSORT diagram. (A) Enrollment and allocation of patients with tumor PD-L1 expression ≥ 1% and < 1%, (B) disposition of patients with tumor PD-L1 expression ≥ 1%, and (C) disposition of patients with tumor PD-L1 expression < 1%. ^aOne patient was enrolled twice in error but not randomly assigned, not having met study criteria; the number of patients enrolled has been corrected here since the original report. AE, adverse event; CONSORT, Consolidated Standards of Reporting Trials; PD-L1, programmed death ligand 1. From the New England Journal of Medicine, Hellmann et al, Nivolumab plus Ipilimumab in Advanced Non–Small-Cell Lung Cancer, 381:2020-2031, 2019 © Massachusetts Medical Society. Reprinted with permission from the Massachusetts Medical Society.

FIG 2.

OS, PFS, and ORR/DOR in randomly assigned patients by tumor PD-L1 expression level. OS in patients with (A) tumor PD-L1 expression ≥ 1% or (B) tumor PD-L1 expression < 1%; PFS in randomly assigned patients with (C) tumor PD-L1 expression ≥ 1% or (D) tumor PD-L1 expression < 1%; ORR and DOR in randomly assigned patients with (E) tumor PD-L1 expression ≥ 1% or (F) tumor PD-L1 expression < 1%. Patients were followed for a minimum of 61.3 months. Ninety-five percent CIs for the nivolumab plus ipilimumab, nivolumab (PD-L1 ≥ 1%) or nivolumab plus chemotherapy (PD-L1 < 1%), and chemotherapy arms at 5-year landmarks, respectively: (A) 20 to 29, 13 to 21, and 11 to 18; (B) 14 to 25, 6 to 15, and 4 to 11; (C) 9 to 16, 6 to 13, and 1 to 5; (D) 5 to 15, 3 to 12, and < 1 to 6; (E) 20 to 37, 15 to 34, and 0 to 11; and (F) 8 to 38, 6 to 24, and NA. DOR, duration of response; HR, hazard ratio; NA, not available; ORR, objective response rate; OS, overall survival; PD-L1, programmed death ligand 1; PFS, progression-free survival.

FIG 3.

Clinical outcomes and treatment status in patients alive at 5 years by tumor PD-L1 expression level. PFS in randomly assigned patients with (A) tumor PD-L1 expression ≥ 1% or (B) tumor PD-L1 expression < 1%; ORR and DOR in randomly assigned patients with (C) tumor PD-L1 expression ≥ 1% or (D) tumor PD-L1 expression < 1%; treatment status at 5 years in treated^a patients with (E) tumor PD-L1 expression ≥ 1% or (F) tumor PD-L1 expression < 1%. Kaplan-Meier curves are not shown for the PD-L1 < 1% chemotherapy arms because of small sample sizes. Ninety-five percent CIs for the nivolumab plus ipilimumab, nivolumab (PD-L1 ≥ 1%) or nivolumab plus chemotherapy (PD-L1 < 1%), and chemotherapy (PD-L1 ≥ 1% only) arms at 5-year landmarks, respectively, (A) 37 to 60, 36 to 64, and 4 to 28; (B) 30 to 68 and 23 to 71; (C) 40 to 66, 39 to 73, and 4 to 36; and (D) 14 to 66 and 23 to 72. ^aOne patient in the PD-L1 ≥ 1% nivolumab arm and 1 patient in the PD-L1 ≥ 1% chemotherapy arm were randomly assigned but not treated and are not included in the analysis of subsequent treatments. DOR, duration of response; HR, hazard ratio; NA, not available; NR, not reached; ORR, objective response rate; PD-L1, programmed death ligand 1; PFS, progression-free survival.

FIG 4.

EQ-5D in 5-year survivors (combined PD-L1 ≥ 1% and < 1% populations). Patients were treated with (A) nivolumab plus ipilimumab (n = 122) or (B) chemotherapy (n = 60). EQ-5D VAS scores range from 0 (worst) to 100 (best), with a minimally important difference cutoff of 7. Weighted averages are represented by solid lines and 95% CIs by dashed lines. PD-L1, programmed death ligand 1; VAS, visual analog scale.

FIG 5.

OS, PFS, and ORR/DOR in patients who completed 2 years of immunotherapy by the tumor PD-L1 expression level. OS in patients with (A) tumor PD-L1 expression ≥ 1% or (B) tumor PD-L1 expression < 1%; PFS in patients with (C) tumor PD-L1 expression ≥ 1% or (D) tumor PD-L1 expression < 1%; ORR and DOR in patients with (E) tumor PD-L1 expression ≥ 1% or (F) tumor PD-L1 expression < 1%. Ninety-five percent CIs for the nivolumab plus ipilimumab and nivolumab (PD-L1 ≥ 1%) or nivolumab plus chemotherapy (PD-L1 < 1%) arms at 5-year landmarks, respectively: (A) 57 to 82 and 56 to 83, (B) 30 to 76 and 41 to 80, (C) 25 to 53 and 24 to 56, (D) 13 to 61 and 15 to 52, (E) 24 to 56 and 16 to 57, and (F) 14 to 64 and 17 to 57. DOR, duration of response; HR, hazard ratio; NA, not available; NR, not reached; ORR, objective response rate; OS, overall survival; PD-L1, programmed death ligand 1; PFS, progression-free survival.