There continues to be an unmet need for effective and tolerable frontline treatments for patients with squamous cell carcinoma of the head and neck, according to investigators.
Nivolumab (Opdivo) plus ipilimumab (Yervoy) did not significantly improve overall survival (OS) compared with 6 cycles of cetuximab (Erbitux) plus cisplatin/carboplatin plus fluorouracil followed by cetuximab maintenance (EXTREME regimen) in patients with recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC), missing the primary end point of the CheckMate 651 trial (NCT02741570). Nivolumab/ipilimumab did, however, demonstrate a more tolerable safety profile than EXTREME, according to findings published in the Journal of Clinical Oncology.1
In the all-patient population (n = 947), the median OS with the immunotherapy combination (n = 472) and EXTREME (n = 475) was 13.9 months (95% CI, 12.1-15.8) vs 13.5 months (95% CI, 12.6-15.2), respectively. The HR was 0.95 (97.9% CI, 0.80-1.13; P = .4951). The median OS for patients with a combined positive score (CPS) of at least 20 was 17.6 months (95% CI, 13.8-22.0) with nivolumab/ipilimumab (n = 185) vs 17.6 months (95% CI, 12.3-16.0) with EXTREME (n = 178; HR, 0.78; 97.5% CI, 0.59-1.03; P = .0469).1
Among those with a CPS score of at least 1, the median OS was 15.7 months with the immunotherapy combination (n = 355) vs 13.2 months with EXTREME (n = 372; HR, 0.82; 95% CI, 0.69-0.97).1
The dual immunotherapy also inspired a shorter median progression-free survival (PFS) vs EXTREME among all-treated patients (3.3 months vs 6.7 months, respectively), in the CPS greater than or equal to 20 population (5.4 months vs 7.0 months), and in the CPS of at least 1 population (4.2 months vs 6.1 months).1
Of note, the rate of the grade 3/4 treatment-related adverse events (TRAE) with nivolumab/ipilimumab was 28.2% among all-treated patients, whereas the rate observed with EXTREME was 70.7%.1
“First-line nivolumab plus ipilimumab did not result in a statistically significant improvement in OS vs EXTREME in platinum-eligible R/M HNSCC in the all randomly assigned or CPS [of at least] 20 populations,” wrote Robert I. Haddad, MD, of the Dana-Farber Cancer Institute and co-investigators, in the study. “Safety with nivolumab plus ipilimumab was favorable compared with EXTREME.”1
Study authors explained that HNSCC is common worldwide, and many patients initially present with advanced disease.2 Over 50% of patients with locally advanced HNSCC who receive multimodal approached develop recurrent or metastatic disease within 3 years of the completing curative-intent treatments. These patients go on to face a poor prognosis with high levels of morbidity and deterioration in the quality of life.3 To that end, this study sought to see if a treatment regimen of nivolumab/ipilimumab could improve survival outcomes in this setting.1
The study included 947 patients with R/M HNSCC who were naïve to systemic treatments. Participants were randomly assigned 1:1 to receive either nivolumab plus ipilimumab for up to 2 years or the EXTREME regimen. The median age was 61 years (range, 24-86) in the dual immunotherapy arm and 62 years (range, 29-86) in the EXTREME arm. Between the 2 arms, 80.5% and 83.6% were male, 76.3% and 77.7% were current or former smokers, 39.2% and 37.5% had CPS of at least 20, and 57.2% and 57.7% had tumor PD-L1 expression of at least 1%, respectively.1
OS was a dual primary end point in the all-patient and CPS of at least 20 populations. OS in the PD-L1 CPS of at least 1 population, along with PFS, overall response rate (ORR), and duration of response (DOR) in all randomly assigned and CPS of at least 20 populations were secondary end points.1
The minimum follow-up was 27.3 months, and the median follow-up was 39.1 months. At database lock, no patients remained on treatment on the nivolumab/ipilimumab arm and 40 patients (8.5%) had completed the full 2 years of treatment. At data cutoff, treatment was ongoing for 1.6% of patients in the EXTREME arm.
The median duration of therapy was 3.8 months vs 5.0 months with nivolumab/ipilimumab vs EXTREME in the all-patient population, respectively. A median of 8 doses of nivolumab and 3 doses of ipilimumab were administered.
In the EXTREME arm, 24% of patients received cisplatin, 54% received carboplatin, and 11% received both cisplatin and carboplatin during treatment. The median dose of cisplatin and carboplatin administered during treatments was 4 and 5 doses, respectively. A total of 52.8% of patients received cetuximab (Erbitux) maintenance.
Moreover, subsequent systemic therapy was administered to 29.2% and 60.2% of patients on the dual immunotherapy and EXTREME regimens, respectively, with 8.5% and 46.3% of patients receiving subsequent immunotherapy, most of whom went on to nivolumab. Additional treatments included receiving platinum-based chemotherapy (42.2% vs 16.2%, respectively), and cetuximab (27.3% vs 12.8%).
To account for number of patients in the EXTREME arm receiving subsequent immunotherapy was much greater than the experimental arm (46% vs 9%). Following this adjustment, the median OS in the all-patient population was 12.4 months with dual immunotherapy compared with 10.8 months with EXTREME (HR, 0.80; 95% CI, 0.68-0.92). In the CPS of at least 20 population the median OS was 14.1 months vs 11.7 months (HR, 0.71; 95% CI, 0.55-0.99).
The rate of any-grade TRAEs were 72.2% vs 97.5% with nivolumab/ipilimumab vs EXTREME. The most common any-grade TRAES with nivolumab plus ipilimumab were fatigue (18.2%), pruritus (15.0%), and hypothyroidism (14.1%). With EXTREME, the most common any-grade TRAEs were nausea (44.7%), rash (38.3%), and anemia (34.9%).
For patients who experienced any-grade immune-related adverse events, the most common were hypothyroidism/thyroiditis (16.0%), rash (12.6%), and hyperthyroidism (6.8%). Grade 3/4 events were uncommon, and most events occurred within the first 5 months of treatment.
“Use of immunotherapy in the treatment of [HNSCC] is still evolving, with a continued unmet need for first-line regimens that provide durable clinical benefit with tolerable safety,” Gary K. Schwartz, MD, a medical oncologist with Colombia University Medical Center and associate editor with the Journal of Clinical Oncology, wrote in an analysis of the findings. “Further research is needed to determine the utility of dual immunotherapy as a treatment option for [HNSCC] and identify novel biomarkers to predict benefit with immunotherapy.”