Pembrolizumab Alone or With Chemotherapy for Recurrent/Metastatic Head and Neck Squamous Cell Carcinoma in KEYNOTE-048: Subgroup Analysis by Programmed Death Ligand-1 Combined Positive Score

Abstract

PURPOSE The phase III KEYNOTE-048 (ClinicalTrials.gov identifier: NCT02358031 ) trial of pembrolizumab in recurrent or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) included planned efficacy analyses in the total population and in participants with programmed death ligand-1 (PD-L1) combined positive score (CPS) ≥ 1 and CPS ≥ 20. To further characterize the predictive value of PD-L1 expression on outcome, we conducted efficacy analyses in the PD-L1 CPS < 1 and CPS 1-19 subgroups in KEYNOTE-048. METHODS Participants with R/M HNSCC and no prior systemic therapy for R/M disease were randomly assigned 1:1:1 to pembrolizumab, pembrolizumab-chemotherapy, or cetuximab-chemotherapy. Post hoc efficacy analyses of the PD-L1 CPS < 1 and CPS 1-19 subgroups were performed. RESULTS Of 882 participants enrolled, 128 had PD-L1 CPS < 1 and 373 had CPS 1-19. For pembrolizumab versus cetuximab-chemotherapy, the median overall survival was 7.9 versus 11.3 months in the PD-L1 CPS < 1 subgroup (hazard ratio [HR], 1.51 [95% CI, 0.96 to 2.37]) and 10.8 versus 10.1 months in the CPS 1-19 subgroup (HR, 0.86 [95% CI, 0.66 to 1.12]). For pembrolizumab-chemotherapy versus cetuximab-chemotherapy, the median overall survival was 11.3 versus 10.7 months in the PD-L1 CPS < 1 subgroup (HR, 1.21 [95% CI, 0.76 to 1.94]) and 12.7 versus 9.9 months in the CPS 1-19 subgroup (HR, 0.71 [95% CI, 0.54 to 0.94]). CONCLUSION Increased efficacy of pembrolizumab or pembrolizumab-chemotherapy was observed with increasing PD-L1 expression. PD-L1 CPS < 1 subgroup analysis was limited by small participant numbers. Results from the PD-L1 CPS 1-19 subgroup support previous findings of treatment benefit with pembrolizumab monotherapy and pembrolizumab-chemotherapy in patients with PD-L1 CPS ≥ 1 tumors. Although PD-L1 expression is informative, exploration of additional predictive biomarkers is needed for low PD-L1–expressing HNSCC.

Current Therapy for Metastatic Head and Neck Cancer: Evidence, Opportunities, and Challenges

“…Patients with PD-L1-expressing metastatic head and neck squamous cell carcinoma should be treated with pembrolizumab or the combination of pembrolizumab and chemotherapy in the first line. 6 Therapeutic effects were not significantly different for those with locoregional recurrence, distant metastases, or both. 13 In the CheckMate 651 trial, the combination of nivolumab plus ipilimumab was compared against the same control arm as employed in the KN-048 trial, that is the combination of chemotherapy and cetuximab known as the EXTREME regimen.…”

“…New drug development in metastatic HNSCC now takes place in the context of a clear role for first-line PD-1 inhibitor therapy when the cancer expresses PD-L1. 5,6 The biologic properties that foster metastasis in HNSCC are under study, and differences have emerged between HPV1 and HPVÀ forms of HNSCC. Among the multiple processes that support metastasis are production of matrix metalloproteases that can degrade and remodel the tumor microenvironment; partial or complete epithelial-mesenchymal transition with their resultant reduction of cell adhesion and enhancement of cell migration; and expression of markers of stemness.…”

Novel Systemic Treatment Modalities Including Immunotherapy and Molecular Targeted Therapy for Recurrent and Metastatic Head and Neck Squamous Cell Carcinoma

“…A recent post-hoc analysis compared the CPS <1 (n = 128) and CPS 1–19 (n = 373) subgroups [ 165 ]. In the CPS < 1 subgroup, the median OS duration of patients treated with pembrolizumab was shorter than in patients treated with chemotherapy plus cetuximab (7.9 vs. 11.3 months; HR, 1.51; 95% CI, 0.96 to 2.37).…”

Current perspectives on recurrent HPV-mediated oropharyngeal cancer

“…For patients with resectable recurrence after prior radiation treatment, there is strong evidence that adjuvant therapy following salvage surgery reduces progression free survival and is recommended by NCCN guidelines ( 19 , 82 ). OPSCC patients who experience recurrence are at high risk for developing second recurrence ( 68 ), and use of postoperative radiation is associated with improved survival after surgical salvage ( 72 ).…”