Efficacy and Safety of Nivolumab Plus Ipilimumab vs Nivolumab Alone for Treatment of Recurrent or Metastatic Squamous Cell Carcinoma of the Head and Neck

Abstract

ImportanceThere remains an unmet need to improve clinical outcomes in patients with recurrent or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN).ObjectiveTo evaluate clinical benefit of first-line nivolumab plus ipilimumab vs nivolumab alone in patients with R/M SCCHN.Design, Setting, and ParticipantsThe CheckMate 714, double-blind, phase 2 randomized clinical trial was conducted at 83 sites in 21 countries between October 20, 2016, and January 23, 2019. Eligible participants were aged 18 years or older and had platinum-refractory or platinum-eligible R/M SCCHN and no prior systemic therapy for R/M disease. Data were analyzed from October 20, 2016 (first patient, first visit), to March 8, 2019 (primary database lock), and April 6, 2020 (overall survival database lock).InterventionsPatients were randomized 2:1 to receive nivolumab (3 mg/kg intravenously [IV] every 2 weeks) plus ipilimumab (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.Main Outcomes and MeasuresThe primary end points were objective response rate (ORR) and duration of response between treatment arms by blinded independent central review in the population with platinum-refractory R/M SCCHN. Exploratory end points included safety.ResultsOf 425 included patients, 241 (56.7%; median age, 59 [range, 24-82] years; 194 males [80.5%]) had platinum-refractory disease (nivolumab plus ipilimumab, n = 159; nivolumab, n = 82) and 184 (43.3%; median age, 62 [range, 33-88] years; 152 males [82.6%]) had platinum-eligible disease (nivolumab plus ipilimumab, n = 123; nivolumab, n = 61). At primary database lock, the ORR in the population 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 (odds ratio [OR], 0.68; 95.5% CI, 0.33-1.43; P = .29). Median duration of response for nivolumab plus ipilimumab was not reached (NR) (95% CI, 11.0 months to NR) vs 11.1 months (95% CI, 4.1 months to NR) for nivolumab. In the population with platinum-eligible disease, the ORR was 20.3% (95% CI, 13.6%-28.5%) with nivolumab plus ipilimumab vs 29.5% (95% CI, 18.5%-42.6%) with nivolumab. The rates of grade 3 or 4 treatment-related adverse events with nivolumab plus ipilimumab vs nivolumab were 15.8% (25 of 158) vs 14.6% (12 of 82) in the population with platinum-refractory disease and 24.6% (30 of 122) vs 13.1% (8 of 61) in the population with platinum-eligible disease.Conclusions and RelevanceThe CheckMate 714 randomized clinical trial did not meet its primary end point of ORR benefit with first-line nivolumab plus ipilimumab vs nivolumab alone in platinum-refractory R/M SCCHN. Nivolumab plus ipilimumab was associated with an acceptable safety profile. Research to identify patient subpopulations in R/M SCCHN that would benefit from nivolumab plus ipilimumab over nivolumab monotherapy is warranted.Trial RegistrationClinicalTrials.gov Identifier: NCT02823574

Assessing Response for Nivolumab Plus Ipilimumab in Squamous Cell Carcinoma of the Head and Neck

“…Severe immune-related toxicity in CheckMate 714 was overall low and did not differ between the combination treatment and nivolumab monotherapy; therefore, the addition of ipilimumab provided no increased immune activation over nivolumab alone. Overall, CheckMate 714 and the above-discussed trials of anti–PD-1/CTLA-4 blockade indicate that a higher ipilimumab dose and/or different scheduling is required to optimally activate an antitumor immune response and achieve superior clinical outcomes compared to anti–PD-1 monotherapy, although this will likely come at the expense of an increased rate of severe immune-related toxicity.…”

Assessing Response for Nivolumab Plus Ipilimumab in Squamous Cell Carcinoma of the Head and Neck

“…To the Editor In their randomized clinical trial published recently in JAMA Oncology , Harrington and colleagues evaluated the efficacy of nivolumab/ipilimumab vs nivolumab alone for treating recurrent or metastatic squamous cell carcinoma of the head and neck . The primary end points were the patient’s objective response and duration of response (DOR).…”

“…Moreover, the reported median DOR was based on the Kaplan-Meier curve constructed with censored observations from the responders . The DOR and its censoring time are likely dependent since they begin accruing at the same time point, which is the time of response.…”

Assessing Response for Nivolumab Plus Ipilimumab in Squamous Cell Carcinoma of the Head and Neck—Reply

“…In Reply We thank Parast et al for commenting on our article reporting the phase 2 CheckMate 714 study outcomes . The study did not meet its primary end point of objective response rate (ORR) benefit with first-line nivolumab and ipilimumab vs nivolumab alone in patients with platinum-refractory recurrent or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN).…”

“…We also thank Klein for taking an interest in our article . While acknowledging that treatment dosage and/or schedule may not be optimum in CheckMate 714, we wish to share background information for selecting the treatment regimen.…”