For the past decade, the standard first-line treatment for patients with recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC) has been the combination of cetuximab, platinum chemotherapy, and 5-FU followed by cetuximab maintenance, commonly referred to as the “EXTREME regimen.” However, while this regimen results in a 10.1-month overall survival (OS), it is associated with substantial toxicity, making it unsuitable for many patients. In recent years, immunotherapy with PD-1 inhibitors has become a viable treatment option for patients with R/M HNSCC progressing on the EXTREME regimen. The randomized, open-label, phase III KEYNOTE-048 trial (N = 882) was designed to test the safety and efficacy of pembrolizumab monotherapy and pembrolizumab in combination with platinum and 5-FU chemotherapy to EXTREME in previously untreated patients with R/M HNSCC. At the second interim analysis, presented in 2018, pembrolizumab was found to result in significant improvements in OS compared to EXTREME both as a monotherapy in PD-L1-positive patients and in combination with chemotherapy in the entire trial population.
At the 2019 American Society of Clinical Oncology (ASCO) Annual Meeting, Danny Rischin, MD (Peter MacCallum Cancer Center, Melbourne, Australia), presented the protocol-specified final results of the KEYNOTE-048 trial (Abstract 6000). Compared to the EXTREME regimen, pembrolizumab plus chemotherapy was associated with a significant improvement in OS in PD-L1-positive patients. In patients with a PD-L1 combined positive score (CPS) ³20, the median OS was 14.7 months with pembrolizumab plus chemotherapy, compared to 11.0 months with EXTREME (HR 0.60, P = .0004). Similar improvement was seen in patients with a CPS ³1 (13.6 months vs 10.4 months; HR 0.65, P<.0001). The OS benefit for pembrolizumab plus chemotherapy in PD-L1-positve patients was consistent across all prespecified patient subgroups. There was also an OS benefit with pembrolizumab plus chemotherapy in the total population (13.0 months vs 10.7 months; HR 0.72), with a 36-month survival rate of 22.6% with the pembrolizumab-based regimen, compared to 10% with EXTREME. There was no improvement in PFS or ORR compared to EXTREME, but the duration of response was longer in patients receiving pembrolizumab plus chemotherapy (7.1 months vs 4.2 months for CPS ³20 and 6.7 months vs 4.3 months for CPS ³1). The safety of the two regimens was comparable. Grade 3-5 adverse events (AEs) occurred in 85.1% of patients receiving pembrolizumab plus chemotherapy, compared to 83.3% of patients receiving EXTREME.
A similar trend was seen in patients treated with pembrolizumab monotherapy. While there was no OS benefit compared to EXTREME in the total population (11.5 months vs 10.7 months; HR 0.83, P = .0199), the duration of response was much longer with pembrolizumab (22.6 months vs 4.5 months). Furthermore, OS was improved with pembrolizumab monotherapy in both the CPS ³20 population (14.9 months vs 10.7 months; HR 0.61) and the CPS ³1 population (12.3 months vs 10.3 months; HR 0.74). Pembrolizumab monotherapy has favorable safety profile compared to EXTREME. Grade 3-5 AEs occurred in 54.7% of patients receiving pembrolizumab, compared to 83.3% of patients receiving the EXTREME regimen.
Dr Rischin concluded that these data support pembrolizumab plus platinum-based chemotherapy and pembrolizumab monotherapy (CPS ³20) as a new first-line standard of care for R/M HNSCC. The discussant of this abstract, Vanita Noronha, MD (Tata Memorial Hospital, Mumbai, India), agreed that these results are practice changing, but indicated that patients who are symptomatic due to disease burden and require rapid response should receive chemotherapy, with or without pembrolizumab. She also highlighted that several important questions remain to more thoroughly define the role of pembrolizumab in first-line R/M HNSCC, including which patients should receive pembrolizumab monotherapy versus pembrolizumab plus chemotherapy, how to identify patients who are most likely to respond to immunotherapy, and the optimal sequence for treatments in the R/M setting.