Published Results Affirm Efficacy of Fixed-Dose Pembrolizumab in HNSCC

Laura Quan Man Chow, MD

The FDA-approved fixed dose of 200 mg of pembrolizumab administered once every 3 weeks yielded durable responses in patients with recurrent and/or metastatic head and neck squamous cell carcinoma (HNSCC), according to results from an expansion cohort of the phase Ib KEYNOTE-012 trial reported in the Journal of Clinical Oncology (JCO).

The KEYNOTE-012 trial included 192 total patients with recurrent/metastatic HNSCC who received 1 of 2 doses of pembrolizumab. In the initial treatment group, 60 patients with PD-L1—positive HNSCC received the PD-1 inhibitor at 10 mg/kg. In the expansion cohort, 132 patients received pembrolizumab at 200 mg every 3 weeks, regardless of PD-L1 status.

The expansion cohort data published in JCO showed that at a median follow-up of 9 months, the overall response rate (ORR) was 18% (95% CI, 12%-26%) by central imaging vendor review and 20% (95% CI, 13%-28%) by investigator review. The median duration of response was not reached (range, ≥2 to ≥11 months).

A statistically significant increase in ORR was observed for PD-L1—positive (22%) versus PD-L1–negative (4%) patients (P = .021). ORR was 32% among patients with HPV-associated HNSCC compared with 14% among patients with non—HPV-associated HNSCC.

The 6-month progression-free survival (PFS) rate was 23% and the median PFS was 2 months (95% CI, 2.0-2.2). The 6-month OS rate was 59% and the median overall survival (OS) was 8 months (95% CI, 6-10).

Previously reported data for the 10 mg/kg, PD-L1—positive initial cohort showed an ORR of 18% by central imaging review, with a median PFS of 2 months, and a median OS of 13 months.

“Results from the current study indicate that the less frequent, fixed dose of pembrolizumab is tolerable and provides comparable antitumor activity with pembrolizumab administered in a body weight—based dosing regimen. Patients responded to pembrolizumab regardless of HPV status, and PD-L1 expression on tumor and immune cells was found to be associated with response,” first study author Laura QM Chow, MD, department of Medical Oncology, University of Washington, and coauthors wrote.

The patients in the expansion cohort were accrued between June 12 and October 8, 2014. The median patient age was 60 years (range, 25-84 years), 83% were male, and all had an ECOG performance status of 0 or 1. Patients were heavily pretreated, with 57% having received 2 or more prior therapies for recurrent/metastatic disease.

Patients received pembrolizumab for a median of 88 days (range, 1-411). Eighty percent (106/132) of patients discontinued therapy because of progressive disease (n = 78), an adverse event (AE; n = 15), physician or patient decision (n = 8), death (n = 3), need for medication exclusion (n = 1), and protocol violation (n = 1).

All-grade AEs occurred in 62% (n = 82) of patients. The most common all-grade AEs included fatigue (n = 28), hypothyroidism (n = 14), and decreased appetite (n = 11). Grade3/4 AEs occurred in 9% (n = 12) of patients, with the most frequent being decreased appetite, facial swelling, and pneumonitis, all reported in 2 patients each.

Grade 3 immune-related AEs in the expansion cohort included pneumonitis (n = 2), diabetes mellitus (n = 1), decubitus ulcer (n = 1), colitis (n = 1), and drug-induced liver injury (n = 1). Diabetic ketoacidosis was the one grade 4 immune-related AE reported. There were no treatment-related deaths.

“[The study] findings support ongoing phase II (KEYNOTE-055) and phase III (KEYNOTE-040 and KEYNOTE-048) studies of the fixed-dose regimen in patients with advanced HNSCC,” Chow, et al, wrote in their conclusion.

In August 2016, the FDA approved pembrolizumab at the the fixed 200-mg dose for the treatment of patients with recurrent or metastatic HNSCC following progression on a platinum-based chemotherapy. The approval was based on data from a cohort of 174 patients from KEYNOTE-012 who were treated with either the 200-mg or 10-mg/kg dose after previously receiving a platinum-based regimen. In these patients, the ORR was 16%, including a complete response rate of 5%.

Chow L, Haddad R, Gupta S, et al. Antitumor activity of pembrolizumab in biomarker-unselected patients with recurrent and/or metastatic head and neck squamous cell carcinoma: results from the phase Ib KEYNOTE-012 expansion cohort [published online September 19, 2016]. J Clin Oncol. doi:10.1200/JCO.2016.68.1478.