Efficacy and Safety of First-line Avelumab Treatment in Patients With Stage IV Metastatic Merkel Cell Carcinoma: A Preplanned Interim Analysis of a Clinical Trial

Abstract

Importance: Merkel cell carcinoma (MCC) is an aggressive skin cancer that is associated with poor survival outcomes in patients with distant metastatic disease. Results of part A of the JAVELIN Merkel 200 trial (avelumab in patients with Merkel cell carcinoma) showed that avelumab, an anti-programmed cell death ligand 1 (PD-L1) antibody, demonstrated efficacy in second-line or later treatment of patients with metastatic MCC (mMCC).

Objective: To evaluate the efficacy and safety of avelumab as first-line treatment for patients with distant mMCC.

Design, setting, and participants: JAVELIN Merkel 200 part B is an international, multicenter, single-arm, open-label clinical trial of first-line avelumab monotherapy. Eligible patients were adults with mMCC who had not received prior systemic treatment for metastatic disease. Patients were not selected for PD-L1 expression or Merkel cell polyomavirus status. Data were collected from April 15, 2016, to March 24, 2017, and enrollment is ongoing.

Interventions: Patients received avelumab, 10 mg/kg, by 1-hour intravenous infusion every 2 weeks until confirmed disease progression, unacceptable toxic effects, or withdrawal occurred.

Main outcomes and measures: Tumor status was assessed every 6 weeks and evaluated by independent review committee per Response Evaluation Criteria in Solid Tumors version 1.1. The primary end point was durable response, defined as an objective response with a duration of at least 6 months. Secondary end points include best overall response, duration of response, progression-free survival, safety, and tolerability.

Results: As of March 24, 2017, 39 patients were enrolled (30 men and 9 women; median age, 75 years [range, 47-88 years]), with a median follow-up of 5.1 months (range, 0.3-11.3 months). In a preplanned analysis, efficacy was assessed in 29 patients with at least 3 months of follow-up; the confirmed objective response rate was 62.1% (95% CI, 42.3%-79.3%), with 14 of 18 responses (77.8%) ongoing at the time of analysis. In responding patients, the estimated proportion with duration of response of at least 3 months was 93% (95% CI, 61%-99%); duration of response of at least 6 months, 83% (95% CI, 46%-96%). First-line avelumab treatment was generally well tolerated, and no treatment-related deaths or grade 4 adverse events occurred.

Conclusions and relevance: High rates of response to first-line avelumab therapy in patients with distant mMCC build on previously reported antitumor activity after second-line or later treatment, and maturing progression-free survival data suggest that responses are durable. These data further support avelumab's approval in the United States and European Union and use as a standard-of-care treatment for mMCC.

Trial registration: clinicaltrials.gov Identifier: NCT02155647.

Conflict of interest statement

Conflict of Interest Disclosures: Dr D’Angelo reports consulting and advisory roles for EMD Serono, Pfizer, Nektar Therapeutics, and Immune Design. Dr Russell reports consulting and advisory roles for EMD Serono and employment by Immunocore Ltd. Dr Lebbé reports consulting and advisory roles and speaker honoraria for Roche, BMS, Novartis, MSD, and Amgen; research grants from Roche and BMS; and travel accommodations and meeting expenses from Roche, BMS, Novartis, and Amgen. Dr Chmielowski reports consulting and advisory roles for EMD Merck Serono. Dr Gambichler reports consulting and advisory roles for Merck, speaker honoraria for NeraCare, and congress travel support from MSD and Novartis. Dr Grob reports consulting and advisory roles for Roche, MSD, Novartis, Amgen, BMS, Merck & Co, Pfizer, and Pierre Fabre and speaker honoraria for Novartis, Amgen, and BMS. Dr Kiecker reports consulting and advisory roles for Merck Serono, MSD, BMS, Roche, Novartis, Incyte, and Pfizer; a research grant from Novartis; and speaker honoraria from Merck Serono, MSD, BMS, Roche, Novartis, and Pfizer. Dr Rabinowits reports consulting and advisory roles for EMD Serono and Pfizer and research support (to the institution) from EMD Serono, Exelixis, and Millennium. Dr Terheyden reports consulting and advisory roles for BMS, Merck & Co, Novartis, and Roche and speaker honoraria from BMS, Novartis, and Roche. Dr Zwiener reports employment by Merck KGaA. Dr Bajars and Ms Hennessy report employment by EMD Serono (a business of Merck KGaA). Dr Kaufman reports consulting and advisory roles for Amgen, Celldex, EMD Serono, Merck, Prometheus, and Turnstone Biologics; research grants from Amgen and Merck; and speaker honoraria from Merck. No other disclosures were reported.

Figures

Figure 1.. Flowchart of Study Population

Figure 2.. Clinical Activity of Avelumab

A, Time to and duration of response and duration of treatment were measured in 18 patients with a confirmed response within the analysis set of patients with at least 3 months of follow-up. B and C, Change in target lesion diameters and percentage of change in target lesion sum diameters from baseline in individual patients were measured in 30 patients with a follow-up tumor assessment available. Parallel broken lines represent Response Evaluation Criteria in Solid Tumors values for progressive disease (≥20% increase in the sum of diameters of target lesions) and partial response (≥30% decrease in the sum of diameters of target lesions).