Avelumab in patients with chemotherapy-refractory metastatic Merkel cell carcinoma: a multicentre, single-group, open-label, phase 2 trial

Abstract

Background: Merkel cell carcinoma is a rare, aggressive skin cancer with poor prognosis in patients with advanced disease. Current standard care uses various cytotoxic chemotherapy regimens, but responses are seldom durable. Tumour oncogenesis is linked to Merkel cell polyomavirus integration and ultraviolet-radiation-induced mutations, providing rationale for treatment with immunotherapy antibodies that target the PD-L1/PD-1 pathway. We assessed treatment with avelumab, an anti-PD-L1 monoclonal antibody, in patients with stage IV Merkel cell carcinoma that had progressed after cytotoxic chemotherapy.

Methods: In this multicentre, international, prospective, single-group, open-label, phase 2 trial, patients with stage IV chemotherapy-refractory, histologically confirmed Merkel cell carcinoma (aged ≥18 years) were enrolled from 35 cancer treatment centres and academic hospitals in North America, Europe, Australia, and Asia. Key eligibility criteria were an ECOG performance status of 0 or 1, measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, adequate haematological, hepatic, and renal function, and immune-competent status (patients with HIV, immunosuppression, haematological malignancies, and previous organ transplantation were excluded). Patient selection was not based on PD-L1 expression or Merkel cell polyomavirus status. Collection of biopsy material or use of archival tissue for these assessments was mandatory. Avelumab was given intravenously at a dose of 10 mg/kg every 2 weeks. The primary endpoint was confirmed objective response (complete response or partial response) assessed according to RECIST version 1.1 by an independent review committee. Safety and clinical activity were assessed in all patients who received at least one dose of study drug (the modified intention-to-treat population). This trial is registered with ClinicalTrials.gov as NCT02155647.

Findings: Between July 25, 2014, and Sept 3, 2015, 88 patients were enrolled and received at least one dose of avelumab. Patients were followed up for a median of 10·4 months (IQR 8·6-13·1). The proportion of patients who achieved an objective response was 28 (31·8% [95·9% CI 21·9-43·1]) of 88 patients, including eight complete responses and 20 partial responses. Responses were ongoing in 23 (82%) of 28 patients at the time of analysis. Five grade 3 treatment-related adverse events occurred in four (5%) patients: lymphopenia in two patients, blood creatine phosphokinase increase in one patient, aminotransferase increase in one patient, and blood cholesterol increase in one patient; there were no treatment-related grade 4 adverse events or treatment-related deaths. Serious treatment-related adverse events were reported in five patients (6%): enterocolitis, infusion-related reaction, aminotransferases increased, chondrocalcinosis, synovitis, and interstitial nephritis (n=1 each).

Interpretation: Avelumab was associated with durable responses, most of which are still ongoing, and was well tolerated; hence, avelumab represents a new therapeutic option for advanced Merkel cell carcinoma.

Funding: Merck KGaA, Darmstadt, Germany.

Conflict of interest statement

Declaration of interests

HLK reports personal fees from Alkermes, Amgen, EMD Serono, Prometheus, and Sanofi; non-financial support from Merck; grants from Bristol-Myers Squibb, outside the submitted work. OH reports personal fees from Merck, outside the submitted work. PT reports personal fees from Merck Sharp & Dohme, Bristol-Myers Squibb, Roche, Novartis, and GlaxoSmithKline, outside the submitted work. SPD’A reports personal fees from EMD Serono and Amgen, outside the submitted work. CL reports personal fees from Novartis, Bristol-Myers Squibb, Roche Glycart, Amgen, and Merck Sharp & Dohme, outside the submitted work. MM reports personal fees from AstraZeneca, Novartis, Pfizer, Celgene, and NeoPharm, outside the submitted work. KDL reports institutional research funding from EMD Serono, outside the submitted work. KC is an employee of EMD Serono and holds stock in Bristol-Myers Squibb. LM is an employee of EMD Serono. AvH is an employee and stockholder at Merck KGaA. J-MC is an employee of EMD Serono. PN has been reimbursed for travel, accommodation, or expenses from EMD Serono, outside the submitted work. All other authors declare no competing interests.

Copyright © 2016 Elsevier Ltd. All rights reserved.

Figures

Figure 1

Trial profile

Figure 2. Clinical activity of avelumab

(A) Time to response, the duration of treatment, and the duration of response to avelumab in 28 patients with a confirmed response. (B) Percentage change in sum of target lesion diameters from baseline over time for all assessable patients (n=65), defined as those patients with baseline tumour assessments and at least one post-baseline assessment. A patient with pseudoprogression is indicated by an asterisk. Upper dotted line represents progression at 20% and lower dotted line represents the RECIST boundary for complete response or partial response at 30%. (C) Plot of tumour regression from baseline as measured by RECIST version 1.1 in all assessable patients (n=65). Upper dotted line represents progression at 20% and lower dotted line represents the RECIST boundary for complete response or partial response at 30%. (D) Kaplan-Meier estimate of progression-free survival in the modified intention-to-treat population (n=88). Vertical lines show censored events. RECIST=Response Evaluation Criteria in Solid Tumors.

Figure 3. Objective response by subgroup for select patient characteristics

Error bars show 95% CI. Disease burden was defined by SLD. SLD=sum of target lesion diameters. ECOG PS=Eastern Cooperative Oncology Group performance status. MCPyV=Merkel cell polyomavirus.