CheckMate 714 Trial of Nivolumab and Ipilimumab Misses Primary End Point in R/M SCCHN

Robert L. Ferris, MD, PhD, FACS

The primary end point of overall response rate (ORR) benefit was not met with first-line nivolumab (Opdivo) plus ipilimumab (Yervoy) vs nivolumab alone among patients with platinum-refractory recurrent or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN) in the CheckMate 714 trial (NCT02823574).¹

While nivolumab plus ipilimumab demonstrated an acceptable safety profile, further research to identify patient subpopulations in R/M SCCHN that would derive benefit from the combination of nivolumab plus ipilimumab vs nivolumab alone is warranted.

“Our conclusion from the CheckMate 714 trial was that in patients with first-line recurrent or metastatic head and neck cancer who were cisplatin refractory or not, the addition of ipilimumab to standard of care nivolumab was not better in terms of overall response rate vs nivolumab alone, which received FDA approval in 2016 for cisplatin refractory, recurrent or metastatic HNSCC patients as a monotherapy,” Robert L. Ferris, MD, PhD, FACS, director, UPMC Hillman Cancer Center; Hillman Professor of Oncology; associate vice chancellor for cancer research; co-director for the Tumor Microenvironment Center; professor of otolaryngology, immunology, and radiation oncology, University of Pittsburgh; and co-physician editor in chief of Targeted Therapies in Oncology™, told Targeted Oncology^TM.

In the double-blind, randomized, phase 2 The CheckMate 714 trial, patients aged 18 years and older with platinum-refractory or platinum-eligible R/M SCCHN and no prior systemic therapy for R/M disease were enrolled. The study was conducted at 83 sites across 21 countries between October 20, 2016, and January 23, 2019.

Patients included in the trial were also required to have an ECOG performance status of 0 or 1, measurable disease per RECIST V1.1, documentation of tumor PD-L1 expression, and documentation of human papillomavirus.

The patient population with platinum-refractory R/M SCCHN included patients with SCCHN who had recurring disease less than 6 months after completion of platinum-based chemotherapy, and the population with platinum-eligible R/M SCCHN included patients who were platinum-based chemotherapy naive or had disease recurrence 6 or more months after completion of platinum-based chemotherapy. Patients in both populations could have received prior platinum-based chemotherapy for locally advanced disease but not for R/M disease.

Those enrolled in were randomized in a 2:1 fashion to receive nivolumab at a dose of 3 mg/kg intravenously (IV) every 2 weeks plus ipilimumab at 1 mg/kg IV every 6 weeks, or nivolumab 3 mg/kg IV every 2 weeks plus placebo for up to 2 years or until disease progression, unacceptable toxic effects, or consent withdrawal.

The primary end points assessed were ORR, duration of response (DOR), and time to response (TTR). Secondary end points of the study included ORR, DOR, progression-free survival, and overall survival, and exploratory end points of the study included safety.²

A total of 425 patients were included in the study. The 241 patients (56.7%) with platinum-refractory R/M SCCHN had a median age of 59 (range, 24-82) years, 194 were males (80.5%), and159 were assigned to receive nivolumab plus ipilimumab and 82 to nivolumab and placebo. A total of 184 had platinum-eligible disease (43.3%), had a median age of 62 (range, 33-88) years, 152 were male (82.6%), and 123 were given nivolumab plus ipilimumab while 61 were given nivolumab. Overall, baseline characteristics were well balanced between treatment arms in both populations.1

At primary database lock of March 8, 2019, the ORR among patients with platinum-refractory disease was 13.2% (95% CI, 8.4%-19.5%) with nivolumab plus ipilimumab vs 18.3% (95% CI, 10.6%-28.4%) with nivolumab alone (odds ratio [OR], 0.68; 95.5% CI, 0.33-1.43; P = .29). The median duration of response with the combination of nivolumab plus ipilimumab was not reached (NR; 95% CI, 11.0 months to NR) compared with 11.1 months (95% CI, 4.1 months to NR) for nivolumab. Between treatment arms, the ORR difference was estimated to be −5.1% (95.5% CI, −15.0 to 4.8) and the median TTR was 2.6 months (range, 1.1-6.6 months) with nivolumab plus ipilimumab and 1.5 months (range, 1.2-7.7 months) with nivolumab.

Among patients with platinum-eligible disease, the ORR was 20.3% (95% CI, 13.6%-28.5%) with the nivolumab plus ipilimumab combination vs 29.5% (95% CI, 18.5%-42.6%) with nivolumab alone. The median TTR was 2.7 months (range, 1.2-6.9 months) with the nivolumab and ipilimumab combination vs 2.6 months (range, 1.1-11.1 months) for nivolumab. Additionally, the median DOR was 27.0 months (95% CI, 11.1 months to NR) in the nivolumab plus ipilimumab arm vs 24.6 months in the nivolumab alone arm (95% CI, 5.5 months to NR).

Regarding safety, rates of grade 3 or 4 treatment-related adverse events with nivolumab plus ipilimumab vs nivolumab were generally similar for patients with platinum-eligible R/M SCCHN. Rates of any grade and grade 3 or 4 serious treatment-related adverse events (TRAEs) were 8.2% (13 of 158 patients) and 5.7% (9 of 158), respectively, with nivolumab plus ipilimumab vs 9.8% (8 of 82) and 3.7% (3 of 82), respectively, with nivolumab in the population with platinum-refractory R/M SCCHN. Any grade and grade 3 or 4 TRAEs which led to discontinuation of any part of the treatment regimen included 5.1% (8 of 158) and 2.5% (4 of 158), respectively, with nivolumab plus ipilimumab vs 1.2% (1 of 82) and 0% (0 of 82), respectively, with nivolumab.

Among patients with platinum-eligible R/M SCCHN, rates of any grade and grade 3 or 4 serious TRAEs with nivolumab plus ipilimumab were 14.8% (18 of 122) and 13.1% (16 of 122), respectively, vs 4.9% (3 of 61) and 3.3% (2 of 61), respectively, with nivolumab. Rates of any grade and grade 3 or 4 which led to discontinuation of any component of the regimen were 9.8% (12 of 122) and 8.2% (10 of 122), respectively, with nivolumab plus ipilimumab vs 3.3% (2 of 61) and 3.3% (2 of 61), respectively, with nivolumab. Moreover, no treatment-related deaths were reported in either population.

“This trial indicates that response rates were not significantly better with the combination of nivolumab plus ipilimumab. Thus, there remains a persistent, unmet need to find immuno oncology doublets, which are better than PD-1 inhibitors alone for recurrent or metastatic head and neck cancer,” added Ferris.

REFERENCES:

1. Harrington KJ, Ferris RL, Gillison M, et al. Efficacy and safety of nivolumab plus ipilimumab vs nivolumab alone for treatment of recurrent or metastatic squamous cell carcinoma of the head and neck: The phase 2 CheckMate 714 randomized clinical trial [published online ahead of print, 2023 Apr 6]. JAMA Oncol. 2023;e230147. doi:10.1001/jamaoncol.2023.0147

2. Study of nivolumab in combination with ipilimumab versus nivolumab in combination with ipilimumab placebo in patients with recurrent or metastatic squamous cell carcinoma of the head and neck (CheckMate 714). ClinicalTrials.gov. Updated May 2, 2023. Accessed May 3, 2023. https://clinicaltrials.gov/ct2/show/NCT02823574