Nivolumab Plus Ipilimumab Versus EXTREME Regimen as First-Line Treatment for Recurrent/Metastatic Squamous Cell Carcinoma of the Head and Neck: The Final Results of CheckMate 651

Abstract

Purpose: CheckMate 651 (ClinicalTrials.gov identifier: NCT02741570) evaluated first-line nivolumab plus ipilimumab versus EXTREME (cetuximab plus cisplatin/carboplatin plus fluorouracil ≤ six cycles, then cetuximab maintenance) in recurrent/metastatic squamous cell carcinoma of the head and neck (R/M SCCHN).

Methods: Patients without prior systemic therapy for R/M SCCHN were randomly assigned 1:1 to nivolumab plus ipilimumab or EXTREME. Primary end points were overall survival (OS) in the all randomly assigned and programmed death-ligand 1 combined positive score (CPS) ≥ 20 populations. Secondary end points included OS in the programmed death-ligand 1 CPS ≥ 1 population, and progression-free survival, objective response rate, and duration of response in the all randomly assigned and CPS ≥ 20 populations.

Results: Among 947 patients randomly assigned, 38.3% had CPS ≥ 20. There were no statistically significant differences in OS with nivolumab plus ipilimumab versus EXTREME in the all randomly assigned (median: 13.9 v 13.5 months; hazard ratio [HR], 0.95; 97.9% CI, 0.80 to 1.13; P = .4951) and CPS ≥ 20 (median: 17.6 v 14.6 months; HR, 0.78; 97.51% CI, 0.59 to 1.03; P = .0469) populations. In patients with CPS ≥ 1, the median OS was 15.7 versus 13.2 months (HR, 0.82; 95% CI, 0.69 to 0.97). Among patients with CPS ≥ 20, the median progression-free survival was 5.4 months (nivolumab plus ipilimumab) versus 7.0 months (EXTREME), objective response rate was 34.1% versus 36.0%, and median duration of response was 32.6 versus 7.0 months. Grade 3/4 treatment-related adverse events occurred in 28.2% of patients treated with nivolumab plus ipilimumab versus 70.7% treated with EXTREME.

Conclusion: CheckMate 651 did not meet its primary end points of OS in the all randomly assigned or CPS ≥ 20 populations. Nivolumab plus ipilimumab showed a favorable safety profile compared with EXTREME. There continues to be a need for new therapies in patients with R/M SCCHN.

FIG 1.

CONSORT diagram of patient disposition in all randomly assigned patients. Minimum follow-up: 27.3 months; database lock: June 21, 2021. ^aPatients who were randomly assigned and did not receive nivolumab plus ipilimumab treatment owing to patient no longer meeting study criteria (n = 3) and AEs unrelated to study drug (n = 1). ^bPatients who were randomly assigned and did not receive EXTREME treatment owing to consent withdrawal (n = 18), patient no longer meeting study criteria (n = 6), loss to follow-up (n = 2), patient request (n = 2), disease progression (n = 1), death (n = 1), poor compliance or noncompliance (n = 1), and other (n = 3). ^cData are reported as the number of patients discontinued per reason/number of treated patients in each arm (%). AE, adverse event; DBL, database lock; EXTREME, cetuximab plus cisplatin/carboplatin plus fluorouracil ≤ six cycles, then cetuximab maintenance.

FIG 2.

OS in the (A) all randomly assigned population, (B) PD-L1 CPS ≥ 20 population, and (C) PD-L1 CPS ≥ 1 population. Minimum follow-up: 27.3 months. ^a95% CI, 12.1 to 15.8 (nivolumab plus ipilimumab) and 12.6 to 15.2 (EXTREME). ^bCIs are adjusted on the basis of the final α levels for each primary end point. ^c95% CI, 13.8 to 22.0 (nivolumab plus ipilimumab) and 12.3 to 16.0 (EXTREME). ^d95% CI, 13.7 to 18.8 (nivolumab plus ipilimumab) and 11.1 to 14.6 (EXTREME). CPS, combined positive score; EXTREME, cetuximab plus cisplatin/carboplatin plus fluorouracil ≤ six cycles, then cetuximab maintenance; HR, hazard ratio; OS, overall survival; PD-L1, programmed death-ligand 1.

FIG 3.

OS subgroup analyses in the all randomly assigned population. ^aStratified HR, 0.95. ^bPer interactive response technology. ^cStratified HR, 0.82. ^dStratified HR, 0.78. CPS, combined positive score; ECOG PS, Eastern Cooperative Oncology Group performance status; EXTREME, cetuximab plus cisplatin/carboplatin plus fluorouracil ≤ six cycles, then cetuximab maintenance; HR, hazard ratio; OPC, oropharyngeal cancer; OS, overall survival; PD-L1, programmed death-ligand 1.

FIG 4.

PFS by BICR in the (A) all randomly assigned and (B) PD-L1 CPS ≥ 20 populations; DOR (in patients with complete or partial responses) by BICR in the (C) all randomly assigned and (D) PD-L1 CPS ≥ 20 populations. Minimum follow-up: 27.3 months. ^a95% CI, 2.8 to 4.2 (nivolumab plus ipilimumab) and 5.8 to 7.0 (EXTREME). ^b95% CI, 3.1 to 6.9 (nivolumab plus ipilimumab) and 5.6 to 8.7 (EXTREME). ^c95% CI, 9.7 to 29.4 (nivolumab plus ipilimumab) and 5.4 to 7.0 (EXTREME). ^d95% CI, 12.1 to NR (nivolumab plus ipilimumab) and 5.6 to 10.1 (EXTREME). BICR, blinded independent central review; CPS, combined positive score; DOR, duration of response; EXTREME, cetuximab plus cisplatin/carboplatin plus fluorouracil ≤ six cycles, then cetuximab maintenance; HR, hazard ratio; NR, not reached; PD-L1, programmed death-ligand 1; PFS, progression-free survival.

FIG 5.

(A) Time to symptom deterioration (FHNSI-10)^a and (B) overall self-rated health status (EQ-5D-3L VAS)^b,c in the PD-L1 CPS ≥ 20 population. Minimum follow-up: 27.3 months. ^aTime to symptom deterioration is defined as the time from random assignment to first clinically meaningful decline (reduction of ≥ 3 points) from baseline in FHNSI-10 score. ^bMean (95% CI) change from baseline; horizontal reference line indicates MID = 7-point change on EQ-5D-3L VAS. ^cOnly on-treatment time points with data for ≥ 10 patients in either treatment group are shown, not adjusted for multiplicity. ^d95% CI, 7.4 to 31.6 (nivolumab plus ipilimumab) and 4.3 to 10.9 (EXTREME). CPS, combined positive score; EQ-5D-3L VAS, EQ-5D 3-level version visual analog scale; EXTREME, cetuximab plus cisplatin/carboplatin plus fluorouracil ≤ six cycles, then cetuximab maintenance; FHNSI-10, Functional Assessment of Cancer Therapy Head and Neck Cancer Symptom 10-Item Index; MID, minimally important difference; PD-L1, programmed death-ligand 1; TTSD, time to symptom deterioration.