Single-agent pembrolizumab achieved durable responses and promising survival in patients with locally advanced or recurrent/metastatic cutaneous squamous cell carcinoma, according to the second interim analysis of the phase II ­KEYNOTE-629 study, which was presented at the virtual American Association for Cancer Research (AACR) Annual Meeting 2021.¹

Objective response rates were 50% for locally advanced cutaneous squamous cell carcinoma and 35.2% for recurrent and/or metastatic cutaneous squamous cell carcinoma. Disease control rates (defined as stable disease for 12 weeks or more plus objective response rates) were 64.8% in the cohort with locally advanced disease and 52.4% in the cohort with recurrent/metastatic disease.

‘Robust, Durable Activity’

“Pembrolizumab has demonstrated robust, durable antitumor activity and promising survival rates in both the locally advanced and recurrent metastatic cutaneous squamous cell carcinoma cohorts,” said lead author Brett G.M. Hughes, MD, of Royal Brisbane and Women’s Hospital, Queensland, Australia. “These data establish pembrolizumab as a promising treatment option for those with locally advanced, recurrent/metastatic cutaneous squamous cell carcinoma.”

“Cutaneous squamous cell carcinoma is the second most common nonmelanoma skin cancer in the world, representing about 20% of all nonmelanoma skin cancers and 20% of all skin cancer–related mortalities,” Dr. Hughes told listeners.

Pembrolizumab has demonstrated robust durable antitumor activity and promising survival in both the locally advanced and recurrent metastatic cutaneous squamous cell carcinoma cohorts.

— Brett G.M. Hughes, MD

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“In the first interim analysis of this study, we demonstrated that pembrolizumab monotherapy had clinically meaningful and durable antitumor activity, with a manageable safety profile for recurrent and metastatic disease.” The first interim analysis focused on the cohort with recurrent/metastatic disease at a median follow-up of 11.4 months. The objective response rate was 34.3%, complete response rate was 4%, and disease control rate was 52.4% in that cohort.²

At the AACR meeting, Dr. Hughes reported initial efficacy and safety data from the cohort of patients with locally advanced disease, based on a median follow-up of 13.4 months, as well as updated data from the recurrent/metastatic disease cohort, with median follow-up of 23.8 months.

Study Details

The multicenter, open-label, nonrandomized phase II KEYNOTE-629 study was conducted at 59 sites in 10 countries and had two cohorts: locally advanced cutaneous squamous cell carcinoma (n = 54) and recurrent/metastatic cutaneous squamous cell carcinoma (n = 105). All patients were treated with pembrolizumab at 200 mg once every 3 weeks for up to 35 cycles (approximately 2 years) or until protocol-specified treatment discontinuation criteria were met.

Patients eligible for the trial were 18 years or older, had histologically confirmed cutaneous squamous cell carcinoma with measurable disease per Response Evaluation Criteria in Solid Tumors ­(RECIST) version 1.1 by blinded independent central review, an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and adequate organ function. Patients in the recurrent/metastatic disease cohort had to have received prior systemic therapy.

In the locally advanced cohort with unresectable disease, 54 patients were enrolled and 30 discontinued therapy. In the recurrent/metastatic disease cohort, 105 patients enrolled and 83 discontinued therapy. Objective response rate per RECIST version 1.1 by blinded review was the primary endpoint of the study. Secondary endpoints included duration of response, disease control rate, progression-free survival, overall survival, and safety/tolerability.

At baseline, the median age of patients was 74 years. The majority of patients were male (74.8%) and had an ECOG performance status of 1 (63.5%).

“In the locally advanced cohort, most patients had a PD-L1 combined proportion score of more than 1%, and 22% of the 54 patients were treated with prior systemic therapy with curative intent. Most commonly, this was platinum-based chemotherapy with radiation,” Dr. Hughes said.

“In the recurrent/metastatic cohort, 91 of the 105, or 86.7%, received prior systemic therapy. After a protocol modification, a small number of patients received treatment as their first line of therapy for recurrent/metastatic disease,” Dr. Hughes noted.

The median time from the first dose to data cutoff on July 29, 2020, was 14.9 months for the locally advanced disease cohort and 27.2 months for the recurrent/metastatic disease cohort.

Subgroup Analyses

In a subgroup analysis of objective response rate, overall response was generally consistent across most subgroups analyzed in both cohorts. In the recurrent/metastatic disease cohort, there was a slightly higher response rate observed in patients who received pembrolizumab as first-line therapy: approximately 50% vs 33% for those with prior treatment. Although responses were observed regardless of PD-L1 expression, an increase in objective response was observed among those who had a combined proportion score of 1 or greater or a tumor proportion score of more than 50%.

In the locally advanced and recurrent/metastatic disease cohorts, 9 patients (16.7%) and 11 patients (10.5%), respectively, had a complete response. A partial response was observed in 18 (33.3%) and 26 (24.8%), respectively; stable disease was observed in 13 (24.1%) and 30 (28.6%), respectively; and stable disease for 12 weeks or more was seen in 8 (14.8%) and 18 (17.1%), respectively. Progressive disease was observed in 9 (16.7%) and 28 (26.7%), respectively.

In the overall study population, 20 patients (12.6%) experienced a complete response, 44 (27.7%) had a partial response, 43 (27.0%) had stable disease, 26 (16.4%) had stable disease for 12 weeks or more, and 37 (23.3%) had progressive disease.

“Most responses were deep and significant in the locally advanced disease cohort,” Dr. Hughes said. “Notably, for the first two interim analyses, despite similar overall response and disease control rates, seven patients went from partial response to complete response.”

The 12-month progression-free survival rates in the locally advanced and recurrent/metastatic cohorts were 54% and 36.4%, respectively. Median progression-free survival was not reached in the locally advanced disease cohort and was 5.7 months in the recurrent/metastatic disease group.

The 12-month overall survival rates in the locally advanced and recurrent/metastatic disease cohorts were 73.6% and 61.0%, respectively. Median overall survival was not reached in the group with locally advanced disease and was 23.8 months in those with recurrent/metastatic disease.

Any-grade treatment-related adverse events occurred in 69.2% of patients, including grades 3 to 5 in 11.9% of patients. Treatment-related adverse events led to treatment discontinuation in 8.8% of patients and death in 1.3% of patients. The most common treatment-related adverse events of any grade were pruritus (18.2%), fatigue (14.5%), asthenia (12.6%), rash (10.7%), diarrhea (9.4%), hypothyroidism (8.8%), arthralgia (6.3%), and nausea (5.7%). 

DISCLOSURE: Dr. Hughes has served as a consultant or advisor to AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Eisai, MSD Oncology, Pfizer, Roche, and Sanofi/Regeneron; has received institutional research funding from Amgen; and has been reimbursed for travel, accommodations, or other expenses by AstraZeneca and Bristol Myers Squibb.

REFERENCES

1. Hughes BG, Munoz-Couselo E, Mortier L, et al: Phase 2 study of pembrolizumab for locally advanced or recurrent/metastatic cutaneous squamous cell carcinoma: KEYNOTE-629. AACR Annual Meeting 2021. Abstract CT006. Presented April 10, 2021. 

2. Grob JJ, 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 38:2916-2925, 2020.