The phase II CheckMate 714 randomised clinical trial was the first study to evaluate nivolumab plus ipilimumab versus nivolumab monotherapy as first-line treatment for recurrent or metastatic squamous cell carcinoma of head and neck (SCCHN) and the largest study designed to specifically assess dual immunotherapy in patients with platinum-refractory SCCHN, a population with high unmet need. The study did not meet its primary endpoint of objective response rate (ORR) in the platinum-refractory population. No ORR benefit with nivolumab plus ipilimumab versus nivolumab was reported in the population with platinum-eligible recurrent or metastatic SCCHN either.
There was a modest increase in the incidence of grade 3 or 4 side effects in the nivolumab plus ipilimumab arm of the population with platinum-eligible recurrent or metastatic SCCHN. However, the combination regimen had a manageable safety profile in both populations. Patient subpopulations that would benefit from nivolumab plus ipilimumab over nivolumab for recurrent or metastatic SCCHN are yet to be identified, and further research to identify biomarkers to optimise patient selection and improve patient outcomes is warranted according to Kevin J. Harrington, MBBS, PhD of The Institute of Cancer Research in London, UK and colleagues who published the findings on 6 April 2023 in the JAMA Oncology.
The authors wrote in the background that despite recent advances, there is an unmet need for efficacious therapies and novel biomarkers for predicting response to immunotherapy in patients with recurrent or metastatic SCCHN. Nivolumab and ipilimumab are immune checkpoint inhibitors with distinct, but complementary mechanisms of action. Nivolumab plus ipilimumab at various doses and/or schedules has shown long-term, durable survival benefit for several cancer types, including non–small cell lung cancer, melanoma, renal cell carcinoma, oesophageal squamous cell carcinoma, and malignant pleural mesothelioma. However, first-line nivolumab plus ipilimumab did not result in a statistically significant improvement in overall survival (OS) versus the EXTREME regimen for recurrent or metastatic SCCHN in the phase III CheckMate 651 study.
In the latest article published in the JAMA Oncology, the CheckMate 714 study team reports results from this randomised phase II clinical study, which evaluated nivolumab plus ipilimumab versus nivolumab monotherapy, thereby assessing the contribution of each component of dual immunotherapy as first-line treatment for patients with platinum-refractory or platinum-eligible recurrent or metastatic SCCHN. They also report an exploratory analysis of efficacy outcomes by tumour immune assessment gene expression profile (TIA-GEP), a measure of tumour inflammation.
The study was conducted at 83 sites in 21 countries. Eligible patients were aged 18 years or older and had platinum-refractory or platinum-eligible recurrent or metastatic SCCHN and no prior systemic treatment for recurrent or metastatic disease. Patients were randomised 2:1 to receive nivolumab (3 mg/kg intravenously every 2 weeks) plus ipilimumab (1 mg/kg intravenously every 6 weeks) or nivolumab (3 mg/kg intravenously every 2 weeks) plus placebo for up to 2 years or until disease progression, unacceptable side effects, or consent withdrawal. The primary endpoints were ORR and duration of response between treatment arms by blinded independent central review in the population with platinum-refractory recurrent or metastatic SCCHN. Exploratory endpoints included safety.
Of 425 included patients, 241 had platinum-refractory disease and from these patients 159 received nivolumab plus ipilimumab and 82 received nivolumab, while 184 patients had platinum-eligible disease and from these 123 patients received nivolumab plus ipilimumab and 61 patients received nivolumab. At primary database lock, the ORR in the population with platinum-refractory disease was 13.2% (95% confidence interval [CI] 8.4%-19.5%) with nivolumab plus ipilimumab versus 18.3% (95% CI 10.6%-28.4%) with nivolumab (odds ratio [OR] 0.68; 95.5% CI 0.33-1.43; p = 0.29). Median duration of response for nivolumab plus ipilimumab was not reached (NR) (95% CI 11.0 months to NR) versus 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 versus 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 versus nivolumab were 15.8% versus 14.6% in the population with platinum-refractory disease and 24.6% versus 13.1% in the population with platinum-eligible disease.
With a minimum follow-up of over 20 months, there was no OS or progression-free survival (PFS) benefit in either population. Subgroup analyses of OS by baseline characteristics were exploratory; patient numbers were small, and the analyses lacked statistical power, preventing definitive conclusions about OS benefit with nivolumab plus ipilimumab versus nivolumab in patient subgroups.
In CheckMate 714, no clinical benefit with nivolumab plus ipilimumab versus nivolumab was observed in patients with tumour PD-L1 expression less than 1% or 1% or greater; however, analysis by combined positive score (CPS) was not protocol defined. Treatment effect by CPS could not be analyzed in Checkmate 714 due to lack of a validated CPS assay at the time of histologic analyses.
In an exploratory analysis of efficacy by the 16-gene signature TIA-GEP score in CheckMate 714, patients with a TIA-GEP score of 10 or higher showed numerically better survival outcomes than those with a TIA-GEP score lower than 10, suggesting that efficacy benefit with immunotherapy was associated with higher tumour inflammation. However, within TIA-GEP subgroups, no notable differences were observed between treatment arms in either the population with platinum-refractory recurrent or metastatic SCCHN or the population with platinum-eligible recurrent or metastatic SCCHN.
In the population with platinum-refractory disease, the TIA-GEP score was balanced between arms; however, in the population with platinum-eligible disease, there was an imbalance in TIA-GEP scores, with a higher proportion of patients with a TIA-GEP score of 10 or higher in the nivolumab arm (47.5%) versus the nivolumab plus ipilimumab arm (30.1%). The authors commented while exploratory efficacy analyses by the TIA-GEP score were promising, it should be noted that these subgroups were small, and these results should be interpreted with caution due to potential imbalances in treatment arms, as TIA-GEP was not a stratification factor in the study.
In an accompanied editorial article, Dr. Marshall Posner of the Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai in New York, NY, US wrote that from the results of the CheckMate 651 and CheckMate 714 studies, we know that nivolumab alone is an effective first-line treatment and probably is more effective than EXTREME in patients with CPS-positive disease. These results are also in line with the results of KN-048 with pembrolizumab, a comparable PD1 inhibitor.
What we do not know is whether the addition of ipilimumab after progression on PD1 will salvage a fraction of the patients experiencing disease progression while receiving a PD1 inhibitor. Because crossover to the experimental immunotherapy or combination therapy was not permitted on either study, ability to fully understand the population responsive to a crossover agent, the appropriate timing for the introduction of the crossover agent, and the impact of crossover treatment on the second PFS and OS outcomes could not be robustly investigated or reported in either study. It is possible that a small subset of patients who experience disease progression while receiving nivolumab or pembrolizumab may respond to a combination. We do not know who those patients might be, nor do we have a biomarker to help identify this population.