For years, first-line treatment of recurrent/metastatic squamous cell carcinoma of the head and neck (SCCHN) has been the combination of platinum chemotherapy, 5-fluorouracil (5-FU), and cetuximab followed by cetuximab maintenance, commonly known as the EXTREME regimen. This regimen is associated with an overall survival (OS) of about 10 months. It has substantial toxicity but is tolerable for fit patients. Immunotherapy with the PD-1 inhibitors nivolumab and pembrolizumab has recently become standard of care for recurrent/metastatic disease after failure on platinum-based therapy based on durable responses, improved survival, favorable toxicity profile, and improved quality of life.
At the presidential symposium of the 2018 European Society for Medical Oncology (ESMO) Congress, Barbara Burtness, MD (Yale Cancer Center, New Haven, Connecticut), presented late-breaking results from the randomized phase III Keynote-048 trial (N = ), which is comparing first-line pembrolizumab as both monotherapy and in combination with platinum chemotherapy plus 5-FU to the current standard of care (EXTREME) in patients with recurrent/metastatic SCCHN. Primary endpoints for both pembrolizumab-based arms versus EXTREME were progression-free survival (PFS) and OS in the PD-L1 combined positive score (CPS) ≥20, CPS ≥1, and total populations.
Pembrolizumab monotherapy resulted in a 4.2-month improvement in OS compared to the EXTREME regimen in patients with PD-L1 CPS ≥20 (14.9 months vs 10.7 months; HR 0.61, P = .0007). In patients with CPS ≥1, there was a smaller, but still significant, improvement in OS with pembrolizumab monotherapy compared to EXTREME (12.3 months vs 10.3 months; HR 0.78, P = .0086). There was no improvement in median PFS with pembrolizumab monotherapy, regardless of PD-L1 expression, though 2-year PFS favored pembrolizumab. The EXTREME regimen was associated with a higher overall response rate (ORR) than pembrolizumab monotherapy, but the duration of response was longer for pembrolizumab in both the CPS ≥20 group (20.9 months vs 4.2 months) and the CPS ≥1 group (20.9 months vs 4.5 months).
Pembrolizumab monotherapy was well tolerated and associated with fewer adverse events (AEs) than the EXTREME regimen. Grade 3/4 AEs occurred in 16.7% of patients receiving pembrolizumab, compared to 69.0% of patients receiving EXTREME. There were more immune-mediated AEs in the pembrolizumab arm (30.3% vs 23.7%), but these were mild and primarily of grade 1/2. The most common immune-mediated AEs in patients receiving pembrolizumab were hypothyroidism, pneumonitis, hyperthyroidism, and severe skin reactions.
The combination of pembrolizumab and chemotherapy resulted in a significant improvement in OS compared to the EXTREME regimen, regardless of PD-L1 expression (13.0 months vs 10.7 months; HR 0.77, P = .0034). There was no improvement in PFS or ORR, but the duration of response was longer in patients receiving pembrolizumab plus chemotherapy (6.7 months vs 4.3 months). Pembrolizumab plus chemotherapy was associated with an AE profile comparable to the EXTREME regimen, with similar rates of grade 3/4 AEs (71.0% vs 69.0%) and immune-mediated AEs (25.7% vs 23.7%).
Dr Burtness concluded that the impressive OS benefits and manageable toxicity profile seen with pembrolizumab monotherapy support this treatment as the new standard of care for PD-L1-positive recurrent/metastatic SCCHN, while the combination of pembrolizumab plus chemotherapy should be used in patients who do not express PD-L1, or in whom PD-L1 expression status is unknown. The discussant of this abstract, Jean-Pascal Machiels, MD (University College Louvain, Brussels, Belgium), agreed that pembrolizumab should now be considered the first-line standard of care for most patients with recurrent/metastatic SCCHN, but highlighted that in patients who require a more rapid response due to increased disease burden, or those with CPS 0, the EXTREME regimen may still be a viable treatment approach. He pointed out on importance of determining CPS in patients with recurrent/metastatic HNSCC. Additionally, he discussed potential sequencing of subsequent treatments based on the first-line regimen received. While appropriate sequencing for those receiving pembrolizumab monotherapy may be platinum-based therapy, and for patients progressing on EXTREME standard of care is immunotherapy, there is no data how to treat patients who progress on the combination of pembrolizumab and platinum-based chemotherapy.