Five-Year Outcomes From the Randomized, Phase III Trials CheckMate 017 and 057: Nivolumab Versus Docetaxel in Previously Treated Non-Small-Cell Lung Cancer

Abstract

Purpose: Immunotherapy has revolutionized the treatment of advanced non-small-cell lung cancer (NSCLC). In two phase III trials (CheckMate 017 and CheckMate 057), nivolumab showed an improvement in overall survival (OS) and favorable safety versus docetaxel in patients with previously treated, advanced squamous and nonsquamous NSCLC, respectively. We report 5-year pooled efficacy and safety from these trials.

Methods: Patients (N = 854; CheckMate 017/057 pooled) with advanced NSCLC, ECOG PS ≤ 1, and progression during or after first-line platinum-based chemotherapy were randomly assigned 1:1 to nivolumab (3 mg/kg once every 2 weeks) or docetaxel (75 mg/m² once every 3 weeks) until progression or unacceptable toxicity. The primary end point for both trials was OS; secondary end points included progression-free survival (PFS) and safety. Exploratory landmark analyses were investigated.

Results: After the minimum follow-up of 64.2 and 64.5 months for CheckMate 017 and 057, respectively, 50 nivolumab-treated patients and nine docetaxel-treated patients were alive. Five-year pooled OS rates were 13.4% versus 2.6%, respectively; 5-year PFS rates were 8.0% versus 0%, respectively. Nivolumab-treated patients without disease progression at 2 and 3 years had an 82.0% and 93.0% chance of survival, respectively, and a 59.6% and 78.3% chance of remaining progression-free at 5 years, respectively. Treatment-related adverse events (TRAEs) were reported in 8 of 31 (25.8%) nivolumab-treated patients between 3-5 years of follow-up, seven of whom experienced new events; one (3.2%) TRAE was grade 3, and there were no grade 4 TRAEs.

Conclusion: At 5 years, nivolumab continued to demonstrate a survival benefit versus docetaxel, exhibiting a five-fold increase in OS rate, with no new safety signals. These data represent the first report of 5-year outcomes from randomized phase III trials of a programmed death-1 inhibitor in previously treated, advanced NSCLC.

Trial registration: ClinicalTrials.gov NCT01642004 NCT01673867.

FIG 1.

OS of all treated patients: (A) overall, (B) by SQ tumor histology, (C) by NSQ tumor histology, (D) by ≥ 1% PD-L1 expression, and (E) by < 1% PD-L1 expression. Minimum follow-up: CheckMate 017: 64.2 months; CheckMate 057: 64.5 months. HR, hazard ratio; mo, months; No., number; NSQ, nonsquamous; OS, overall survival; PD-L1, programmed death ligand 1; SQ, squamous.

FIG 2.

(A) PFS^a and (B) DOR^a among all treated patients. ^aPer local investigator; minimum follow-up: CheckMate 017: 64.2 months; CheckMate 057: 64.5 months. Since the primary analysis of the CheckMate 057 trial, one patient's response changed from SD to PR and one from PR to CR. DOR for these two patients was determined according to their latest response category. DOR, duration of response; HR, hazard ratio; mo, months; No., number; PFS, progression-free survival.

FIG 3.

PFS and OS landmark analyses by PFS at 2, 3, and 4 years. ^aBased on Kaplan-Meier estimates; ^bNumber of patients at risk. OS, overall survival; PFS, progression-free survival.

FIG 4.

Patients on treatment with first treatment-related select AE by year^a,b. Median (range) nivolumab treatment duration: 2.8 (0-76.2 +) months. ^aIncludes events of any grade reported between the first dose and 30 days after the last dose of trial therapy; ^bSelect AEs were events with a potential immunological cause. AE, adverse event; No., number.

FIG 5.

Treatment status of ≥ 5-year survivors treated with (A) nivolumab and (B) docetaxel. Timing of only the first administered subsequent therapy is noted, patients may have received ≥ 1 subsequent treatment. ^aPatient received radiotherapy prior to discontinuation of nivolumab; ^bPatient received radiotherapy in addition to nivolumab; ^cPatient withdrew consent, and so subsequent treatment status is unknown. ^dPatient response note reported. CR, complete response; No., number; PD, progressive disease; PR, partial response.

FIG A1.

Study design.^{a,b a}NCT01642004; database lock: May 8, 2019; minimum follow-up for OS, 64.2 months; ^bNCT01673867; database lock: May 16, 2019; minimum follow-up for OS, 64.5 months; ^cOptional switch to nivolumab 480 mg every 4 weeks allowed as per the protocol amendment in September 2016; ^dAfter completion of the primary analyses, patients in the docetaxel arms who ended treatment at any time during the trials were allowed to cross over to nivolumab; ^eDefined by RECIST 1.1; patients receiving nivolumab may be treated beyond progression under protocol-defined circumstances; ^fAs assessed by investigator. ALK, anaplastic lymphoma kinase; ECOG PS, Eastern Cooperative Oncology Group performance status; EGFR, epidermal growth factor receptor; IV, intravenous; NSCLC; non–small-cell lung cancer; NSQ, nonsquamous; ORR, objective response rate; OS, overall survival; PD-L1, programmed death ligand 1; PFS, progression-free survival; PROs, patient-reported outcomes; Q2W, every 2 weeks; Q3W, every 3 weeks; R, randomized; SQ, squamous; TKI, tyrosine kinase inhibitor. Reprinted from Annals of Oncology, 29(4), Waterhouse M, Domine M, Garassino LQM, et al, “Nivolumab Versus Docetaxel in Previously Treated Advanced Nonsmall-Cell Lung Cancer (CheckMate 017 and CheckMate 057): 3-Year Update and Outcomes in Patients With Liver Metastases,” 959-965, 2018, with permission from Elsevier.

FIG A2.

CONSORT diagram of patient disposition for (A) CheckMate 017 and (B) CheckMate 057. AE, adverse event.

FIG A3.

Forest plot of OS in predefined subgroups. Hazard ratios were not reported for subgroups with fewer than 10 patients per treatment group. ^aNot reported in two and one patients with nivolumab and docetaxel, respectively. ^bUnknown in seven and four patients with nivolumab and docetaxel, respectively. ^cMedian NLR was 4.80. NLR was not reported in two patients each in nivolumab and docetaxel arms. ^dNot reported in three and two patients with nivolumab and docetaxel, respectively. ECOG PS, Eastern Cooperative Oncology Group performance status; HR, hazard ratio; LDH, lactate dehydrogenase; NLR, neutrophil-to-lymphocyte ratio; OS, overall survival; PD-L1, programmed death ligand 1; PPI, proton pump inhibitor; ULN, upper limit of normal.

FIG A4.

PFS in patients with (A) SQ tumor histology, (B) NSQ tumor histology, (C) ≥ 1% PD-L1 expression, and (D) < 1% PD-L1 expression. ^aPer local investigator; minimum follow-up: CheckMate 017: 64.2 months and CheckMate 057: 64.5 months. HR, hazard ratio; NC, not calculable; No., number; NSQ, nonsquamous; PD-L1, programmed death ligand 1; PFS, progression-free survival; SQ, squamous.

FIG A5.

DOR^a in all treated patients with (A) SQ tumor histology, (B) NSQ tumor histology, (C) ≥ 1% PD-L1 expression, and (D) < 1% PD-L1 expression. ^aPer local investigator. DOR, duration of response; NC, not calculable. No., number; NSQ, nonsquamous; PD-L1, programmed death ligand 1; SQ, squamous.

FIG A6.

Treatment status of survivors at 5 years. ^aMedian (range) nivolumab treatment duration: 36.9 (1.8-76.2 +) months. ^bThe other 3 patients progressed (1.8, 4.5, and 44.2 months, respectively) after discontinuing nivolumab treatment. ^cAfter nivolumab treatment. ^dInformation on subsequent therapy was not available as of database lock. ^eNivolumab treatment durations for individual patients: 8.8, 21.7, 36.6, 43.3, and 43.5 months. ^fMedian (range) nivolumab treatment duration: 68.4 (62.9-76.2 +) months. ^gIncludes two patients treated with nivolumab as first subsequent therapy. ^hBecause of the receipt of subsequent therapy. AE, adverse event; TRAEs, treatment-related adverse events.