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Background: Pembrolizumab demonstrated clinically meaningful and durable antitumor activity with a manageable safety profile in recurrent/metastatic (R/M) cutaneous squamous cell carcinoma (cSCC). Patients and methods: KEYNOTE-629 was a global, open-label, nonrandomized, phase II trial of patients with locally advanced (LA) or R/M cSCC conducted at 59 centers. Eligible patients received intravenous pembrolizumab 200 mg every 3 weeks for up to 35 cycles. Primary endpoint was objective response rate (ORR), defined as the percentage of patients with a complete (CR) or partial response (PR), by blinded independent central review as per Response Evaluation Criteria in Solid Tumors 1.1. Secondary endpoints included duration of response (DOR), disease control rate, progression-free survival, overall survival, and safety and tolerability. Efficacy and safety were analyzed in patients who were treated with at least one dose of pembrolizumab. Results: Between 29 November 2017 and 25 September 2019, 159 patients were enrolled and treated with pembrolizumab (LA cohort, n ¼ 54; R/M cohort, n ¼ 105). The median time from the first dose to data cut-off date (29 July 2020) was 14.9 [interquartile range (IQR), 12.6-17.2] months for the LA cohort and 27.2 (IQR, 25.6-29.2) months for the R/M cohort. In the LA cohort, ORR was 50.0% [95% confidence interval (CI), 36.1% to 63.9%], including 16.7% of patients with a CR and 33.3% with a PR. In the R/M cohort, ORR was 35.2% (95% CI, 26.2% to 45.2%), including 10.5% of patients with a CR and 24.8% with a PR. Median DOR was not reached in either cohort. Grade 3-5 treatment-related adverse events occurred in 11.9% of patients. Conclusions: The robust antitumor activity of pembrolizumab in both LA and R/M cSCC was confirmed and demonstrated to be durable without unexpected safety signals. Our findings establish pembrolizumab as a promising treatment option for cSCC.

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Background: In the multicenter, open-label, nonrandomized, phase 2 KEYNOTE-629 trial, pembro has demonstrated clinically meaningful and durable antitumor activity with a manageable safety profile for R/M cSCC based on the first interim analysis (IA). Here, we present the second IA of KEYNOTE-629, which reports the initial efficacy and safety data for the LA cohort and updated data for the R/M cohort in cSCC.Methods: Eligible patients (pts) were ≥18 years old, had histologically confirmed cSCC (LA or R/M) 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. Pts received intravenous pembro 200 mg every 3 weeks for up to 35 infusions (~ 2 years) or until protocol-specified treatment discontinuation criteria were met. The primary endpoint was ORR per RECIST 1.1 by BICR. Secondary endpoints were DOR, DCR, and PFS, all per RECIST 1.1 by BICR; OS; and safety and tolerability. Results: A total of 159 pts were enrolled and treated with pembro (LA, n=54; R/M, n=105). The median time from the first dose to data cutoff (July 29, 2020) was 14.9 (range, 10.1-19.4) mo for the LA cohort and 27.2 (range, 24.6-32.0) mo for the R/M cohort. In the LA cohort, 22.2% of pts were treated with prior systemic therapy with curative intent. In the R/M cohort, 86.7% of pts received ≥1 prior systemic therapy. Updated efficacy outcomes are summarized in the table. Across cohorts, grade 3-5 treatment-related AEs occurred in 11.9% of pts. Grade 3-5 immune-related AEs occurred in 8.2% of pts. Conclusions: Pembro confirmed robust and durable antitumor activity, with promising survival in LA and R/M cSCC. AEs with pembro in this study were generally consistent with its established safety profile. These data support the use of pembro for cSCC. LA cSCC(N=54)R/M cSCC(N=105)Total(N=159)ORR, % (95% CI)50.0 (36.1-63.9)35.2 (26.2-45.2)40.3 (32.6-48.3)DCR (SD ≥12 wks + ORR), % (95% CI)64.8 (50.6-77.3)52.4 (42.4-62.2)56.6 (48.5-64.4)Best overall response, n (%)CR9 (16.7)11 (10.5)20 (12.6)PR18 (33.3)26 (24.8)44 (27.7)SD13 (24.1)30 (28.6)43 (27.0)SD≥12 wks8 (14.8)18 (17.1)26 (16.4)PD9 (16.7)28 (26.7)37 (23.3)NE1 (1.9)2 (1.9)3 (1.9)No assessment4 (7.4)8 (7.6)12 (7.5)DOR, median (range), moNR (1.0+-17.2+)NR (2.7-30.4+)NR (1.0+-30.4+)Patients with extended responses≥12 months, n (%)10 (84.1)25 (77.8)35 (80.3)PFS, median (95% CI), moNR (5.5-NR)5.7 (3.1-8.5)7.8 (5.3-12.3)12-mo PFS rate, % (95% CI)54.4 (39.6-67.0)36.4 (27.0- 45.9)42.4 (34.3-50.2)OS, median (95% CI), moNR (NR-NR)23.8 (13.4-29.8)26.4 (19.5-NR)12-mo OS rate, % (95% CI)73.6 (59.5-83.4)61.0 (50.9-69.5)65.1 (57.1-72.0) Citation Format: Brett G.M. Hughes, Eva Munoz-Couselo, Laurent Mortier, Åse Bratland, Ralf Gutzmer, Osama Roshdy, Rene González Mendoza, Jacob Schachter, Ana Arance, Florent Grange, Nicolas Meyer, Abhishek Joshi, Salem Billan, Pingye Zhang, Burak Gumuscu, Ramona F. Swaby, Jean-Jacques Grob. Phase 2 study of pembrolizumab (pembro) for locally advanced (LA) or recurrent/metastatic (R/M) cutaneous squamous cell carcinoma (cSCC): KEYNOTE-629 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT006.