Predictors of immunotherapy benefit in Merkel cell carcinoma

This is the authors' abstract. We don't add key points for this paper.

// Alec J. Kacew 1 , 2 , * , Harita Dharaneeswaran 1 , 2 , * , Gabriel J. Starrett 1 , 2 , Manisha Thakuria 1 , 2 , Nicole R. LeBoeuf 1 , 2 , Ann W. Silk 1 , 2 , James A. DeCaprio 1 , 2 and Glenn J. Hanna 1 , 2 1 GJS Associated with Laboratory of Cellular Oncology, CCR/NCI, Bethesda, MD, USA 2 Dana-Farber Cancer Institute, Boston, MA, USA * These authors contributed equally to this work Correspondence to: Glenn J. Hanna, email: glenn_hanna@dfci.harvard.edu Keywords: cancer; genomics; immunotherapy; Merkel cell carcinoma; precision medicine Received: August 21, 2020     Accepted: November 12, 2020     Published: November 24, 2020 Copyright: © 2020 Kacew et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. ABSTRACT Merkel cell carcinoma is a rare cancer for which immune checkpoint blockade is standard-of-care for recurrent/metastatic disease. However, not all patients benefit from immunotherapy. A greater understanding of molecular mechanisms and predictive biomarkers are unmet needs. We retrospectively analyzed electronic health records and next-generation sequencing data of 45 patients treated at our institution from 2013 to 2020 to understand clinical and genomic correlates of benefit from immunotherapy. Our cohort predominantly included individuals with stage III disease at primary disease diagnosis and individuals with stage IV disease at recurrent/metastatic disease diagnosis. Most received immunotherapy as first-line treatment. 43% experienced objective response (median duration of response 24.2 months, 95% confidence interval 8.8-not reached). Median overall survival was 15.5 months (95% confidence interval 9.0–28.7) (median follow-up 25.2 months). Less advanced stage at primary disease diagnosis and shorter disease-free interval between completion of initial treatment and recurrence were each associated with greater odds of response (odds ratio of 0.06, p = 0.04 for stage; odds ratio 0.75, p = 0.05 for disease-free interval). Single-nucleotide variants in ARID2 and NTRK1 were associated with response ( p = 0.05, without Bonferroni correction), while none of Merkel cell polyomavirus status, total mutational burden, ultraviolet mutational signatures, and copy-number alterations predicted outcomes. Patients with shorter disease-free interval may be particularly suitable immunotherapy candidates. Our molecular findings point to ARID2 and NTRK1 as potential predictive markers and/or therapeutic targets (e.g., with Trk inhibitors), although this association needs to be confirmed in a larger sample.