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Pembrolizumab Demonstrates Robust Activity in Advanced and Recurrent/Metastatic CSCC


Single-agent pembrolizumab yielded robust antitumor activity in patients with locally advanced or recurrent/metastatic cutaneous squamous cell carcinoma.

Single-agent pembrolizumab (Keytruda) yielded robust antitumor activity in patients with locally advanced or recurrent/metastatic cutaneous squamous cell carcinoma (CSCC), according to the data from the second interim analysis of the phase 2 KEYNOTE-629 study (NCT03284424) presented during the AACR Annual Meeting 2021.

“Pembrolizumab has demonstrated robust durable anti-tumor activity and promising survival in both the locally advanced and recurrent metastatic cutaneous SCC cohorts,” Brett G.M. Hughes, MD, Royal Brisbane and Women’s Hospital, said during a presentation of the data. “… This data establish pembrolizumab as a promising treatment option for those with locally advanced, recurrent/metastatic cutaneous SCC.”

In the multicenter, open-label, nonrandomized, phase 2 KEYNOTE-629 trial, patients with locally advanced disease demonstrated an objective response rate (ORR) of 50.0% (95% CI, 36.1-63.9), while the recurrent/metastatic cohort showed an ORR of 35.2% (95% CI, 26.2-45.2). ORR in the total population was 40.3% (95% CI, 32.6-48.3).

Disease control rate (DCR), defined as stable disease (SD) for 12 weeks or more plus ORR, in the locally advanced and recurrent/metastatic cohorts were 64.8% (95% CI, 50.6-77.3) and 52.4% (95% CI, 42.4-62.2), respectively. DCR in the entire patient population was 56.6% (95% CI, 48.5-64.4).

“From the subgroup analysis, overall response was generally consistent across most subgroups analyzed in both cohorts,” Hughes added. “In the recurrent/metastatic cohort, there was a slightly higher response rate observed in patients who received pembrolizumab in the first line. This was more in the range of 50% versus 33% for those that have had prior treatment. Although responses were observed, regardless of PDL1 expression, an increase in objective response was observed in those who had a CPS of 1 or greater, or a TPS score of more than 50%.”

In the locally advanced and recurrent/metastatic cohorts, 9 (16.7%) and 11 (10.5%), respectively, had a complete response (CR), 18 (33.3%) and 26 (24.8%) with a partial response (PR), 13 (24.1%) and 30 (28.6%) with SD, 8 (14.8%) and 18 (17.1%) with SD for 12 weeks or more, and 9 (16.7%) and 28 (26.7%) with progressive disease (PD). Amongst the entire patient population, 20 (12.6%) patients experienced a CR, 44 (27.7%) had a PR, 43 (27.0%) had SD, 26 (16.4%) had SD for 12 weeks or more, and 37 (23.3%) had PD.

“Most responses were quite deep and significant in the local advanced cohort,” Hughes noted. “… Notably for the first two interim analyses, despite similar overall response and disease control rates being observed, more patients are now achieving a complete response that have improved from a partial response, with 7 patients now added to the complete response cohort.”

The 12-month progression-free survival (PFS) rates in the locally advanced and recurrent/metastatic cohorts were 54% and 36.4%, respectively. Median PFS was not reached (NR) in the locally advanced cohort (95% CI, 5.5-NR). In the recurrent/metastatic group, median PFS was 5.7 months (95% CI, 3.1-8.5).

The 12-month overall survival (OS) rates in the locally advanced and recurrent/metastatic cohorts were 73.6% and 61.0%, respectively. Median OS was not reached in the locally advanced group (95% CI, NR-NR). Median OS in the recurrent/metastatic group was 23.8 months (95% CI, 13.4-29.8).

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

“CSCC is the second most common non-melanoma skin cancer in the world representing approximately 20% of all non-melanoma skin cancers and 20% of all skin cancer-related mortality,” Hughes said. “In the first interim analysis of this study, we demonstrated that pembrolizumab monotherapy had a clinically meaningful and durable anti-tumor activity with manageable safety profile for recurrent and metastatic disease.”

At the meeting, Hughes reported initial efficacy and safety data from the locally advanced cohort of patients after a median follow-up of 13.4 months, and updated data from the recurrent/metastatic cohort after a median follow-up of 23.8 months.

Patients with locally advanced (n = 54) or recurrent/metastatic (n = 105) CSCC received 200 mg pembrolizumab once every 3 weeks for up to 35 cycles, or approximately 2 years, or until protocol-specified treatment discontinuation criteria were met.

To be eligible for the trial, patients must have been 18 years or older, had histologically confirmed CSCC with measurable disease per RECIST 1.1 by blinded independent central review (BICR), an ECOG PS score of 0 or 1, and adequate organ function. “Of note patients in the recurrent metastatic disease [cohort] at initial design of the study, all had to have prior systemic therapy,” Hughes said.

ORR per RECIST 1.1 by BICR served as the primary end point of the study. Secondary end points included DOR, DCR, and PFS (all per RECIST 1.1 by BICR), OS, and safety/tolerability.

Median age was 74 years (IQR, 62-82). The majority of patients were male (74.8%) and had an ECOG PS of 1 (63.5%). “Most patients had a PDL1 combined proportion score of more than 1 in the locally advanced cohort; 22% of the 54 were treated with prior systemic therapy with curative intent. Most commonly this was platinum-based chemotherapy with radiation,” Hughes said. “In the metastatic cohort, 91 of the 105, or 86.7% had received prior systemic therapy. A small number of patients after a protocol modification received treatment as their first recurrent metastatic line of therapy.”

The median time from the first dose to data cutoff on July 29, 2020, was 14.9 months (range, 10.1-19.4) for the locally advanced cohort and 27.2 months (range, 24.6-32.0) for the recurrent/metastatic cohort.

This article was initially published by our sister publication ONC Live.


1. Hughes BG, Munoz-Couselo E, Mortier L, et al. Phase 2 study of pembrolizumab (pembro) for locally advanced (LA) or recurrent/metastatic (R/M) cutaneous squamous cell carcinoma (cSCC): KEYNOTE-629. Presented at: AACR Annual Meeting; April 10

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