Pembrolizumab for advanced basal cell carcinoma: An investigator-initiated, proof-of-concept study
Authors: Anne Lynn S. Chang, Duy C. Tran, John G.D. Cannon, Shufeng Li, Mark Jeng, Roma Patel, Lindsay Van der Bokke, Alana Pague, Richard Brotherton, Kerri E. Rieger, Ansuman T. Satpathy, Kathryn E. Yost, Sunil Reddy, Kavita Sarin, A. Dimitrios Colevas
Journal: Journal of the American Academy of Dermatology (2018)

To the Editor: Case reports1Cannon J.G.D. Russell J.S. Kim J. Chang A.L.S. A case of metastatic basal cell carcinoma treated with continuous PD-1 inhibitor exposure even after subsequent initiation of radiotherapy and surgery.JAAD Case Rep. 2018; 4: 248-250Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar and the high tumor mutational burden2Jayaraman S.S. Rayhan D.J. Hazany S. Kolodney M.S. Mutational landscape of basal cell carcinomas by whole-exome sequencing.J Invest Dermatol. 2014; 134: 213-220Abstract Full Text Full Text PDF PubMed Scopus (146) Google Scholar of basal cell carcinomas (BCCs) compared with other tumor types suggest that programmed death-ligand 1 (PD-L1) inhibitors may be active against advanced BCCs. Many advanced BCCs are refractory to3Sekulic A. Migden M.R. Oro A.E. et al.Efficacy and safety of vismodegib in advanced basal-cell carcinoma.N Engl J Med. 2012; 366: 2171-2179Crossref PubMed Scopus (1043) Google Scholar or are recurrent4Chang A.L. Oro A.E. Initial assessment of tumor regrowth after vismodegib in advanced basal cell carcinoma.Arch Dermatol. 2012; 148: 1324-1325Crossref PubMed Scopus (150) Google Scholar after hedgehog pathway inhibitors, and therefore PD-L1 inhibitors could be a useful therapeutic option. We present a proof-of-principle, nonrandomized, open-label study of pembrolizumab (200 mg intravenously every 3 weeks), with or without vismodegib (150 mg orally daily), for eligible subjects with advanced BCCs. The primary outcome was the overall response rate (ORR) for all evaluable subjects at 18 weeks. Sixteen participants, 9 receiving pembrolizumab monotherapy and 7 receiving pembrolizumab plus vismodegib, were evaluable by the revised Response Evaluation Criteria In Solid Tumors5Eisenhauer E.A. Therasse P. Bogaerts J. et al.New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1).Eur J Cancer. 2009; 45: 228-247Abstract Full Text Full Text PDF PubMed Scopus (18123) Google Scholar (version 1.1) at data cutoff. The ORR for all evaluable subjects was 38% (6/16 patients; 95% confidence interval 15-65%; P = .003) at 18 weeks (Table I, Fig 1). The ORR at 18 weeks for pembrolizumab monotherapy group was 44% (4/9 patients; 95% confidence interval 14-79%; P = .008), and for the dual therapy group was 29% (2/7 patients; 95% confidence interval 4-71%; P = .15).Table IPrimary and secondary outcomesOutcomeAll evaluable participants (N = 16)Pembrolizumab monotherapy (n = 9)Pembrolizumab plus vismodegib (n = 7)Overall response rate (range), n38% (15-65%), 644% (14-79%), 429% (4-71%), 2One-year PFS probability, %706283One-year OS probability, %9489100Median treatment duration, weeks (range)18.5 (5.9-73.0)19.0 (10-73.0)18.0 (5.9-38.6)Median time to response, weeks (range), n10.4 (8.4-17.4), 612.4 (8.4-17.4), 410.3 (8.7-11.9), 2Median duration of response, weeks (range), n67.3 (28.0-82.0), 667.6 (31.4-82.0), 452.8 (28.0-77.6), 2Median time from pembrolizumab start date to next treatment start date, weeks (range), n21.9 (6.1-43.3), 621.9 (15.4-43.3), 419.2 (6.1-32.3), 2Overall response rates were calculated at the 18-week time point. One-year progression-free survival and overall survival probabilities were calculated using the Kaplan–Meier method.OS, Overall survival; PFS, progression-free survival. Open table in a new tab Overall response rates were calculated at the 18-week time point. One-year progression-free survival and overall survival probabilities were calculated using the Kaplan–Meier method. OS, Overall survival; PFS, progression-free survival. The median time to response for all responders (n = 6) was 10.4 weeks (range 8.4-17.4 weeks). The median duration of response for all responders (n = 6) was 67.3 weeks (range 28.0-82.0 weeks; Table I). One-year progression-free survival probability was 70%, and the 1-year overall survival probability was 94% for all evaluable subjects (n = 16; Table I). Before pembrolizumab, 29% (2/7 patients) expressed PD-L1 at ≥1% of tumor cells. There was no significant correlation between prepembrolizumab PD-L1 expression and best percentage change in BCC diameter. There were no life-threatening adverse events (AEs) or deaths during the study. Three severe (grade 3) AEs occurred out of 98 AEs from 16 participants. Only 1 of the severe AEs, hyponatremia, was attributed to pembrolizumab. There were 23 immune-related AEs, with dermatitis and fatigue as the most common (all grade 1 or 2), and only 1 severe immune-related AE (the aforementioned hyponatremia). As a proof-of-principle study, we conclude that pembrolizumab is active against BCCs. Although the 2 groups were not directly compared, the response rate of the pembrolizumab plus vismodegib group was not superior to the monotherapy group. The lack of life-threatening AEs or death suggests that pembrolizumab has a reasonable safety profile in patients with BCC. This study is limited by its sample size, because advanced BCCs are an uncommon disease. Nevertheless, the efficacy and safety data presented here could be used in future meta-analyses and compared with forthcoming multi-institutional studies on PD-L1 inhibitors against advanced BCCs. We thank Alex McMillan, PhD, for biostatistics consultation.