Abstract CT009: S1512: High response rate with single agent anti-PD-1 in patients with metastatic desmoplastic melanoma

Abstract

Abstract Background: Desmoplastic melanoma (DM) is a subtype of melanoma with high tumor mutation burden (TMB) due to ultraviolet light damage. A previously published retrospective review of patients with PD-1 blockade treated DM suggested this cancer may be highly responsive to PD-1 blockade (Eroglu et al. Nature 2018). S1512 is the first prospective study investigating PD-1 blockade with pembrolizumab in patients with DM. 1512 Cohort A results were presented and demonstrated a 59% complete pathologic response rate with neoadjuvant pembrolizumab in patients with resectable DM (Kendra et al. ASCO 2022). Herein, we present results from S1512 Cohort B in patients with metastatic DM. Experimental procedures: Patients aged ≥18 with metastatic DM received pembrolizumab 200 mg q3 weeks. Eligibility criteria included: Zubrod PS 0-2, no central nervous system metastases, autoimmune disease, or steroid ≥10 mg of prednisone. The primary endpoint was complete response rate (CR) assessed per RECIST 1.1, with the assumption that CR of 20% or higher indicates that the treatment is of interest. A single stage design with 21 eligible patients would have an alpha of 8.5% (when the true CR is 5%) and a power of 82%. Tumor assessments were performed every 9 weeks. Secondary endpoints included progression free survival (PFS), overall survival (OS), and toxicity assessment. Biopsies were analyzed by whole exome sequencing (WES) for mutational load and oncogenic driver mutations. Summary of data: 27 eligible patients were enrolled in Cohort B. 93% were male, 70% had Zubrod PS 0, median age 75 (range 59-90). Median number of cycles received: 15 (range 1-34). At the time of data cutoff, 3 patients remain on protocol treatment with pembrolizumab. Treatment was discontinued due to: 2 years of therapy (4), adverse event (AE) (8), physician and patient choice (6), progressive disease (4), and under review (2). Objective response rate (including both confirmed and unconfirmed partial and complete responses) was 85% (95% CI: 66%-96%), with 7/27 CR (26%) and 16/27 PR (59%). Grade 3 or higher adverse events were reported in 10 patients. WES analysis was available for 16 patients. Both baseline (N=10) and on-treatment biopsies (N=12) were evaluated for canonical genetic drivers of melanoma; 7 patients had tumors with loss of function (LOF) mutations in NF1, and all had mutations in TP53, with no case having activating mutations in BRAF or NRAS, consistent with the known genetic alterations in DM. The median TMB in baseline biopsies was 79.4 Mut/Mb (range 34.3-159). Conclusion: Patients with metastatic DM are exceptional responders to single agent PD-1 blockade with pembrolizumab. Based on this data, the pathologic subtype of melanoma can be used as a predictive biomarker of response to single agent pembrolizumab. Funding: U10CA180888 and U10CA180819; and in part by Merck Sharp & Dohme LLC., a subsidiary of Merck & Co., Inc., Rahway, NJ, USA Citation Format: Kari Kendra, Shay Bellasea, Zeynep Eroglu, Siwen Hu-Lieskovan, Katie M. Campbell, William Carson, David Wada, Jose A. Plaza, Jeffrey Sosman, Gino K. IN, Alexandra Ikeguchi, John Hyngstrom, Andres Brohl, Nikhil I. Khushalani, Joseph Markowitz, George Negrea, Samer Kasbari, Gary C. Doolittle, Umang Swami, Toni Roberts, Sapna P. Patel, Elad Sharon, James Moon, Michael C. Wu, Antoni Ribas. S1512: High response rate with single agent anti-PD-1 in patients with metastatic desmoplastic melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT009.