Predictors of immunotherapy benefit in Merkel cell carcinoma

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 firstline 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.

Clinical and molecular characteristics associated with response to therapeutic PD-1/PD-L1 inhibition in advanced Merkel cell carcinoma

“…Clinically applicable predictive biomarkers of ICI therapy response are just starting to emerge: (1) in a trial testing neoadjuvant nivolumab, both pathological complete response (CR) and radiographic tumor regression at the time of surgery were correlated with improved recurrence-free survival, 3 and (2) Kacew et al reported that a limited disease stage at ICI therapy start was associated with a favorable response. 4 However, the study also showed that, unlike in other cancers, neither tumor mutational burden nor copy-number alterations in MCC tumor tissue predicted ICI therapy outcome. Similarly, a recent study by us characterizing 41 MCC patients receiving PD-1/PD-L1 ICI demonstrated that predictive markers of ICI therapy response established in other cancer entities such as neutrophil-to-lymphocyte ratio, metastatic stage and site of the primary were not associated with ICI response in MCC.…”

Expression of Mismatch Repair Proteins in Merkel Cell Carcinoma

“…When compared to previous chemotherapeutic modalities, management of advanced MCC has significantly been improved since the introduction of immune checkpoint inhibitors (ICI) such as anti-programmed cell death protein 1 (PD-1) inhibitors (pembrolizumab, nivolumab) and anti-programmed cell death ligand protein 1 (PD-L1) inhibitors (avelumab) [ 6 , 7 , 8 ]. ICI in the metastatic setting of MCC are frequently associated with durable response rates (≈70%) and the 3-year overall survival of about 65% [ 8 , 9 ]. However, there is a lack of knowledge regarding the molecular predictors of ICI response in MCC.…”

“…However, there is a lack of knowledge regarding the molecular predictors of ICI response in MCC. With respect to tumor cell characteristics, Kacew et al [ 9 ] reported that single-nucleotide variants in ARID2 and NTRK1 genes are associated with response to ICI, whereas the MCPyV status, total mutational burden (TMB), UV mutational signatures, and copy-number alterations did not correlate with treatment response [ 8 , 9 ]. In many cancers, including colorectal, endometrial, prostate, and bladder cancer, small satellite DNA damage results in microsatellite instability (MSI) and consecutive mismatch repair (MMR) deficiency, which may have prognostic consequences.…”

Shaping the Future of Immunotherapy Targets and Biomarkers in Melanoma and Non-Melanoma Cutaneous Cancers

“…High curability with surgery and/or radiation results in a proportionally low death rate, however, due to very high incidence, accounting for 30% of all diagnosed cancer types, the absolute mortality in advanced stages is comparable to melanoma [ 113 ]. NMSCs harbor features predictive of response to immunotherapy, including high tumor mutational burden (TMB) associated with chronic ultraviolet radiation exposure, and other common risk factors like immunosuppression, as well as viral etiology (Merkel cell polyomavirus in MCC) and advanced patients age [ 114 , 115 , 116 ]. In the past decade, multiple clinical trials confirmed the efficacy of ICIs in NMSCs, mainly in SCC and MCC [ 117 , 118 , 119 , 120 , 121 ].…”