Jean-Jacques Grob, MD, PhD
As reported in the Journal of Clinical Oncology by Jean-Jacques Grob, MD, PhD, of Aix-Marseille University, France, and colleagues, the first interim analysis of the phase II KEYNOTE-629 trial has shown the achievement of durable responses with pembrolizumab treatment of recurrent or metastatic cutaneous squamous cell carcinoma.1 The study supported the June 2020 approval of pembrolizumab in recurrent or metastatic cutaneous squamous cell carcinoma that is not curable by surgery or radiation.
In the single-arm trial, 105 patients with recurrent or metastatic disease who were not amenable to surgery or radiation were enrolled from sites in nine countries between October 2017 and June 2018 and were treated with pembrolizumab at 200 mg every 3 weeks for 35 doses (approximately 2 years) or until disease progression or unacceptable toxicity. The primary endpoint was an objective response rate upon blinded independent central review using Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 criteria. Secondary endpoints were duration of response, disease control rate, progression-free survival, overall survival, and safety.
Median patient age was 72 years, 80% were male, and all had an Eastern Cooperative Oncology Group performance status of 0 (34%) or 1. PD-L1 status was a combined positive score of at least 1 in 66% of patients, less than 1 in 10%, and not available in 25%. Overall, 83% had stage IV disease and 64% had nodal involvement. Disease status was locoregional alone in 45%, distant metastatic alone in 24%, and both in 31%; 74% had received radiation and 80% oncologic surgery, 45% had received carboplatin and 33% cetuximab as prior treatments, and 91% were receiving pembrolizumab as second- or later-line therapy.
At data cutoff in April 2019, median follow-up was at 11.4 months (range = 0.4–6.3 months). An objective response was observed in 36 patients (34.3%, 95% confidence interval [CI] = 25.3%–44.2%), including a complete response in 4 (3.8%). An additional 31 patients (29.5%) had stable disease, with 19 (18.1%) having stable disease for at least 12 weeks; the disease control rate (including stable disease ≥ 12 weeks) was 52.4% (95% CI = 42.4%–62.2%). Median duration of response was not reached (range = 2.7 to 13.1+ months). Median time to response was 1.5 months (range = 1.2–5.7 months). Median progression-free survival was 6.9 months (95% CI = 3.1–8.5 months), with 6- and 12-month rates of 50.4% and 32.4%. Median overall survival was not reached (95% CI = 10.7 months to not reached), with 6- and 12-month rates of 79.0% and 60.3%.
Among 28 patients who received pembrolizumab beyond disease progression, 1 achieved complete response and 7 had partial response on immune-related RECIST criteria, with ongoing responses in 4 patients at data cutoff.
Among the 14 patients receiving pembrolizumab as first-line treatment, an objective response was observed in 7 (50%), including a complete response in 2. Median progression-free survival was 8.3 months and median overall survival was not reached. Among 91 patients receiving pembrolizumab as second-line or later treatment, an objective response was observed in 29 (31.9%), with a complete response in 2. Median progression-free survival was 5.4 months and median overall survival was not reached.
Among 69 patients with a PD-L1 combined positive score of at least 1, an objective response was observed in 23 (33.3%), with complete response in 2. Median progression-free survival was 5.4 months and median overall survival was not reached. Among the 10 patients with a PD-L1 combined positive score of less than 1, an objective response was observed in 2 (10.0%), median progression-free survival was 4.2 months, and median overall survival was not reached.
In other subgroups, objective response rates were 36.2% in patients with locoregional-only disease, 32.8% in those with distant metastatic disease, 42.6% in 47 patients with cutaneous squamous cell carcinoma tumors with primary head and neck location, and 27.6% in 58 patients with tumors at other primary locations.
Treatment-related adverse events of any grade occurred in 70 patients (66.7%), the most common being pruritus (14.3%), asthenia (13.3%), and fatigue (12.4%). Grade ≥ 3 treatment-related adverse events occurred in six patients (5.7%) and consisted of elevated creatine phosphokinase, dementia, generalized exfoliative dermatitis, increased gamma-glutamyltransferase, oral lichen planus, peripheral sensory neuropathy, rash, increased transaminases, and cranial nerve neuropathy in one patient each.
Treatment-related serious adverse events occurred in seven patients (6.7%) and consisted of lymphocytic hypophysitis, increased transaminase, cranial nerve neuropathy, dementia, peripheral sensory neuropathy, acute kidney injury, pneumonitis, and rash in one patient each. Adverse events irrespective of causality attribution led to treatment interruption in 28 patients (26.7%) and to treatment discontinuation in 13 (12.4%). One patient died from treatment-related cranial nerve neuropathy.
Immune-mediated adverse events were reported in 23 patients (21.9%), the most common being hypothyroidism (9.5%), severe skin reactions (grade ≥ 3; 4.8%), pneumonitis (3.8%), adrenal insufficiency (2.9%), and hyperthyroidism (2.9%). No grade ≥ 4 immune-mediated adverse events were reported.
The investigators concluded: “Pembrolizumab demonstrated effective antitumor activity; clinically meaningful, durable responses; and acceptable safety in primarily elderly patients with [relapsed or metastatic] cutaneous squamous cell carcinoma, supporting its use in clinical practice. Pembrolizumab adverse events in this study were consistent with its established safety profile.”
DISCLOSURE: The study was funded by Merck Sharp & Dohme, a subsidiary of Merck & Co. Dr. Grob has served in a consulting or advisory role for Amgen, BMS, Merck KGaA, MSD Oncology, Novartis, Pierre Fabre, Roche/Genentech, and Sunpharma; has participated in a speakers’ bureau for Novartis; and has been reimbursed for travel, accommodations, or other expenses by BMS, MSD Oncology, Novartis, and Pierre Fabre.
1. Grob J-J, MD, Gonzalez R, Basset-Seguin N, et al: Pembrolizumab monotherapy for recurrent or metastatic cutaneous squamous cell carcinoma: A single-arm phase II trial (KEYNOTE-629). J Clin Oncol. July 16, 2020 (early release online).