SUMMARY: The American Cancer Society estimates that 65,410 people will be diagnosed with Head and Neck cancer in 2019 and 14,620 patients will die of the disease. Patients with Recurrent/Metastatic Squamous Cell Carcinoma of the Head and Neck have a poor prognosis with a short median Overall Survival. The treatment paradigm for Head and Neck cancer has been rapidly evolving with the recognition and better understanding of immune evasion and the role of Immune checkpoints or gate keepers in suppressing antitumor immunity. Blocking the Immune checkpoints unleashes the T cells, resulting in T cell proliferation, activation and a therapeutic response. KEYTRUDA® (Pembrolizumab) is a fully humanized, Immunoglobulin G4, monoclonal antibody, that binds to the PD-1 receptor and blocks its interaction with ligands PD-L1 and PD-L2, thereby undoing PD-1 pathway-mediated inhibition of the immune response and unleashing the tumor-specific effector T cells.
KEYNOTE-048 is an open-label, three arm, randomized, phase III trial, in which KEYTRUDA® monotherapy and KEYTRUDA® plus chemotherapy was compared to ERBITUX® (Cetuximab) plus chemotherapy, as first-line systemic therapy, among patients with Recurrent/Metastatic Head and Neck Squamous Cell Carcinoma. A total 882 patients were randomized in a 1:1:1 ratio to receive either KEYTRUDA® 200 mg IV every 3 weeks for 24 months (N=301), KEYTRUDA® 200 mg IV every 3 weeks for 24 months plus Cisplatin 100 mg/m2 IV or Carboplatin AUC 5 IV (investigator’s choice) on day 1, along with 5-FU 1,000 mg/m2/day IV, days 1-4 of each 3-week cycle, for a maximum of 6 cycles (N=281) or the control arm (EXTREME) consisting of ERBITUX® 400 mg/m2 loading dose followed by 250 mg/m2 weekly, plus Cisplatin 100 mg/m2 or Carboplatin AUC 5 IV on day 1 along with 5-FU 1000 mg/m2/day IV, days 1-4 of each 3-week cycle, for a maximum of 6 cycles (N=300).
Enrolled patients had Recurrent or Metatastic Squamous Cell Carcinoma of the Oral cavity, Oropharynx, Hypopharynx or Larynx, and had not received prior systemic therapy for their recurrent or metastatic disease. Patients were stratified by PD-L1 expression, HPV p16 status, and ECOG Performance Status. PD-L1 expression was measured using the Combined Positive Score (CPS) and Tumor Proportion Score and a CPS of 20 or more indicated high PD-L1 expression, whereas a CPS of 1 or more was the lower threshold of positivity. (CPS measures high PD-L1 expression in the tumor and surrounding immune cells, whereas TPS only captures PD-L1 expression on tumor cells). Approximately 21% of patients were positive for Human Papillomavirus Virus (HPV) p16.
In this analysis, the authors compared the outcomes with KEYTRUDA® alone versus EXTREME (ERBITUX® plus chemo combination) in patients stratified for PD-L1 expression as well as KEYTRUDA® plus chemotherapy versus ERBITUX® plus chemotherapy in all patients with any PD-L1 status. The Primary endpoints were Progression Free Survival (PFS) and Overall Survival (OS) in patients with a PD-L1 CPS of 20 or more and CPS of 1 or more in all enrolled patients. The Secondary endpoints of the study were PFS at 6 months and 12 months, Objective Response Rate (ORR), and time to deterioration in Quality of Life. The minimum follow up was about 17 months.
It was noted that in patients with PD-L1 CPS of 20 or more (high expressors, N=255), single agent KEYTRUDA® was superior to ERBITUX® combination, with a median OS of 14.9 months in patients who received single agent KEYTRUDA® versus 10.7 months in patients who received ERBITUX® with combination chemotherapy (HR=0.61; P=0.0007). There was however no difference in PFS in this PD-L1 subset between the 2 treatment groups (HR=0.99; P=0.5). Similar benefit was seen for patients with a PD-L1 CPS of 1 or more subset (low expressors, N= 512), in which the median OS for KEYTRUDA® monotherapy versus ERBITUX® plus chemotherapy was 12.3 months versus 10.3 months respectively (HR=0.78; P=0.0086). The OS for KEYTRUDA® monotherapy was noninferior to ERBITUX® plus chemotherapy in the total population of patients (N=601). The ORRs were 23% and 36%, with single agent KEYTRUDA® and ERBITUX® combination respectively, in the high expressor subgroup and 19% and 35%, respectively in the low expressor subgroup. However, the median Duration of Response was almost 5 times longer with KEYTRUDA® monotherapy compared to ERBITUX® combination.
When KEYTRUDA® plus chemotherapy was compared with ERBITUX® plus chemotherapy, KEYTRUDA® combination was non-inferior and in fact was superior to ERBITUX® combination for OS in the total population (N = 559), with a median OS of 13.0 versus 10.7 months respectively (HR=0.77; P=0.0034).
It was concluded that among patients with Recurrent/Metastatic Head and Neck Squamous Cell Carcinoma, KEYTRUDA® monotherapy significantly improved Overall Survival compared to ERBITUX® plus chemotherapy in patients with PD-L1 Combined Positive Score of 1 or more. Additionally, KEYTRUDA® plus chemotherapy significantly improved Overall Survival in the total patient population, compared to ERBITUX® plus chemotherapy. Responses associated with single agent KEYTRUDA® and KEYTRUDA® chemotherapy combination, were durable. These data support KEYTRUDA®, as well as KEYTRUDA® plus platinum and 5-FU as the new first-line standards of care for this patient group. KEYNOTE-048: Phase 3 study of first-line pembrolizumab (P) for recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC). Burtness B, Harrington KJ, Greil R, et al. Proceedings from the 2018 ESMO Congress: October 19-23, 2018; Munich, Germany. Abstract LBA8_PR.