Avelumab in patients with previously treated metastatic Merkel cell carcinoma: long-term data and biomarker analyses from the single-arm phase 2 JAVELIN Merkel 200 trial

Abstract

Background: Merkel cell carcinoma (MCC) is a rare, aggressive skin cancer associated with a high risk of metastasis. In 2017, avelumab (anti-programmed death-ligand 1 (PD-L1)) became the first approved treatment for patients with metastatic MCC (mMCC), based on the occurrence of durable responses in a subset of patients. Here, we report long-term efficacy and safety data and exploratory biomarker analyses in patients with mMCC treated with avelumab.

Methods: In a cohort of this single-arm, phase 2 trial (JAVELIN Merkel 200), patients with mMCC and disease progression after prior chemotherapy received avelumab 10 mg/kg intravenously every 2 weeks. The primary endpoint was confirmed objective response rate (ORR) by independent review per Response Evaluation Criteria in Solid Tumors V.1.1. Other assessments included duration of response, progression-free survival, overall survival (OS), safety and biomarker analyses.

Results: As of 14 September 2018, 88 patients had been followed up for a median of 40.8 months (range 36.4-49.7 months). The ORR was 33.0% (95% CI 23.3% to 43.8%), including a complete response in 11.4% (10 patients), and the median duration of response was 40.5 months (95% CI 18.0 months to not estimable). As of 2 May 2019 (≥44 months of follow-up), the median OS was 12.6 months (95% CI 7.5 to 17.1 months) and the 42-month OS rate was 31% (95% CI 22% to 41%). Of long-term survivors (OS >36 months) evaluable for PD-L1 expression status (n=22), 81.8% had PD-L1+ tumors. In exploratory biomarker analyses, high tumor mutational burden (≥2 non-synonymous somatic variants per megabase) and high major histocompatibility complex class I expression (30% of tumors with highest expression) were associated with trends for improved ORR and OS. In long-term safety assessments (≥36 months of follow-up), no new or unexpected adverse events were reported, and no treatment-related deaths occurred.

Conclusions: Avelumab showed continued durable responses and meaningful long-term survival outcomes in patients with mMCC, reinforcing avelumab as a standard-of-care treatment option for this disease.

Trial registration number: NCT02155647.

Keywords: biomarkers, tumor; clinical trials, phase II as topic; immunotherapy; skin neoplasms.

Conflict of interest statement

Competing interests: SPD reports serving as a consultant or advisor for Amgen, EMD Serono (a business of Merck KGaA, Darmstadt, Germany), GlaxoSmithKline, Immunocore, Immune Design, Incyte, Merck & Co, and Nektar; has received research grants from Amgen, Bristol Myers Squibb, Deciphera, EMD Serono, Incyte, Merck & Co, and Nektar; and has received reimbursement for travel and accommodation expenses from Adaptimmune, EMD Serono, Immunocore and Nektar. SB has received honoraria from and served as a consultant or advisor for Bristol Myers Squibb, EMD Serono, Genentech/Roche, and Sanofi/Regeneron; has received institutional research funding from Bristol Myers Squibb, EMD Serono, Exicure, Immune Design, Merck & Co, NantKwest, Novartis, and OncoSec; and has received reimbursement for travel and accommodation expenses from NantKwest. ASB reports serving as a consultant or advisor for Bayer, Deciphera, EMD Serono, and PierianDx. OH reports serving as a consultant or advisor for Amgen, Bristol Myers Squibb, Merck & Co, Novartis, and Roche; has received honoraria from Amgen, Array BioPharma, Bristol Myers Squibb, Genentech/Roche, Novartis, and Sanofi/Regeneron; is a member of a speakers bureau for Amgen, Array BioPharma, Bristol Myers Squibb, Genentech, Novartis, and Sanofi/Regeneron; and has received institutional research funding from Amgen, Arcus Biosciences, Astellas Pharma, AstraZeneca, Bristol Myers Squibb, Celldex, CytomX Therapeutics, Genentech, GlaxoSmithKline, Immunocore, Incyte, Iovance Biotherapeutics, MedImmune, Merck & Co, Merck Serono, Novartis, Parker Institute for Cancer Immunotherapy, Pfizer, Polynoma, Regeneron, and Roche. JMM has received honoraria from EMD Serono and Pfizer; reports serving as a consultant or advisor for Amgen, Array BioPharma, and Boehringer Ingelheim; has received institutional research funding from Amgen, AstraZeneca, Immunocore, Incyte, MacroGenics, Merck & Co, Novartis, Polynoma, and Sanofi; has received reimbursement for travel and accommodation expenses from EMD Serono and Merck & Co; and has other relationships with Amgen, Array BioPharma, Boehringer Ingelheim, EMD Serono, and Merck & Co. PT has received speakers honoraria from Bristol Myers Squibb, CureVac, Merck & Co, Novartis, Pierre Fabre, and Roche; reports serving as a consultant or advisor for Bristol Myers Squibb, Merck KGaA, Novartis, Pierre Fabre, Sanofi, and Roche; and has received travel support from Bristol Myers Squibb and Pierre Fabre. CL has received honoraria from Amgen, Bristol Myers Squibb, Incyte, Merck & Co, Novartis, Pfizer, Pierre Fabre, and Roche; reports serving as a consultant or advisor for Amgen, Bristol Myers Squibb, Merck & Co, Novartis, and Roche; is a member of a speakers bureau for Amgen, Bristol Myers Squibb, Novartis, and Roche; has received research funding from Bristol Myers Squibb and Roche; has received reimbursement for travel and accommodation expenses from Bristol Myers Squibb; and has other relationships with Avantis Medical Systems. KDL has received honoraria from Array BioPharma and Incyte; has served as a consultant or advisor for Array BioPharma, Merck KGaA, Regeneron, and Roche; and has received research funding from Array BioPharma, Bristol Myers Squibb, Incyte, Iovance Biotherapeutics, Merck KGaA, Nektar, and Roche/Genentech. MM has served as a consultant or advisor for Pfizer and Novartis and has received reimbursement for travel and accommodation expenses from Novartis. SG reports employment at EMD Serono Research & Development Institute; a business of Merck KGaA. PS reports employment at EMD Serono Research & Development Institute; a business of Merck KGaA. BE-L reports employment at Merck KGaA. MB reports employment at EMD Serono Research & Development Institute; a business of Merck KGaA. GG reports employment at Merck KGaA. PTN has received honoraria from EMD Serono and Merck & Co; reports serving as a consultant or advisor for EMD Serono and Pfizer; has received research funding from Bristol Myers Squibb and EMD Serono; and reports a pending patent for high-affinity T-cell receptors that target the Merkel cell polyomavirus. KCS, IB and GPL declare that they have no competing interests.

© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY. Published by BMJ.

Figures

Figure 1

Time to and duration of response after ≥36 months of follow-up (n=29).

Figure 2

Overall survival with avelumab after ≥44 months of follow-up. (A) All patients. (B) Subgroups defined by PD-L1 status. PD-L1, programmed death-ligand 1.

Figure 3

TMB in evaluable patients (n=36). (A) Distribution of values. (B) Association with viral and PD-L1 status. (C) OS and PFS by subgroup. The boxes represent IQRs, and the solid horizontal lines inside the boxes are medians. The upper whiskers denote the maximum observation below the upper fence, and the lower whiskers denote the minimum observation above the lower fence. The points outside the boxes are observations. Diamonds within boxes are the tertiles, and diamonds above boxes are the mean. p values were calculated using an exact Wilcoxon two-sample test. MCPyV, Merkel cell polyomavirus; NSSV/Mb, non-synonymous somatic variant per megabase; OS, overall survival; PD-L1, programmed death-ligand 1; PFS, progression-free survival; TMB, tumor mutational burden.

Figure 4

ORR in selected subgroups evaluable for TMB analysis. aCD8+ T cell density data were missing for six patients. IM, invasive margin; MCPyV, Merkel cell polyomavirus; ORR, objective response rate; PD-L1, programmed death-ligand 1; TMB, tumor mutational burden.

Figure 5

Association of MHC class I expression with (A) response, (B) OS (n=37) and (C) CD8+ T cell density expression in evaluable patients (n=31) at the IM (left) and tumor core (right). The boxes represent IQRs, and the horizontal lines are medians. The whiskers denote the lower and upper quartiles, and the circles represent data points. aThe high-expression subgroup was defined as patients in the top 30% of overall MHC expression. BOR, best overall response; CPM, count per million; CR, complete response; IM, invasive margin; MHC, major histocompatibility complex; OS, overall survival; PD, progressive disease; PR, partial response; SD, stable disease.