Elsevier

The Lancet Oncology

Volume 17, Issue 10, October 2016, Pages 1374-1385
The Lancet Oncology

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

https://doi.org/10.1016/S1470-2045(16)30364-3Get rights and content

Summary

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.

Introduction

Merkel cell carcinoma is an aggressive skin cancer associated with Merkel cell polyomavirus, exposure to ultraviolet irradiation, immunosuppression, and old age.1, 2 Merkel cell carcinoma occurs with an incidence of 0·2–0·4 cases per 100 000 people per year in Europe, 0·79 cases per 100 000 people per year in the USA, and 1·6 cases per 100 000 people per year in Australia.3, 4, 5 Global incidence and mortality from Merkel cell carcinoma have risen substantially over the past 30 years.3, 4 The median age at diagnosis is approximately 75 years, and 5–12% of the patient population present with metastatic disease.1, 4, 6, 7 The 5-year overall survival rate with metastatic Merkel cell carcinoma ranges from 0–18% based on retrospective analyses.6, 8, 9, 10 Prospective studies are uncommon in this tumour type, and no approved therapies exist for non-resectable, recurrent, or metastatic Merkel cell carcinoma.

Although Merkel cell carcinoma is a chemosensitive disease, with response rates of 53–61%8, 10, 11, 12, 13 reported retrospectively for patients with metastatic Merkel cell carcinoma treated in the first-line setting, an overall survival benefit has not been shown.14, 15 Responses to chemotherapy are seldom durable.3, 14, 15 In one report of patients with distant metastatic disease,11 of patients receiving second-line chemotherapy with topotecan (n=7), paclitaxel (n=5), or other regimens (n=18), the objective response was 23% and the median duration of response was 3·3 months.11 In that analysis, median progression-free survival was 2·0 months,11 the progression-free survival rate at 6 months was 13·3% (Nghiem P, unpublished), and the 6-month durable response rate was 6·7% (Nghiem P, unpublished). Chemotherapy is thus considered a treatment option, but not an evidence-based standard of care. Published guidelines recommend enrolment in a clinical trial for patients with metastatic disease.3, 14

Research in context

Evidence before this study

Merkel cell carcinoma is an aggressive skin cancer that is associated with old age, poor prognosis, and lower survival compared with other skin malignancies, including melanoma. No consensus on effective treatment for Merkel cell carcinoma exists. Multiple chemotherapy regimens have been used to treat patients with advanced disease, but responses are short-lived and relapse is common. We searched PubMed on April 7, 2015, and on Jan 27, 2016, for reports published in English since database inception using the search term “Merkel cell carcinoma” combined with “chemotherapy” or the most commonly used chemotherapy drugs. Additionally, we searched congress abstracts published in English from the American Society of Clinical Oncology and the European Society for Medical Oncology from 2010 through 2015 using the term “Merkel cell carcinoma”. Most publications were case reports and retrospective analyses based on institutional or national databases. We identified five cohort studies that assessed patients with distant metastases; of these, only one reported on a confirmed stage IV population. Evidence suggests that Merkel cell carcinoma is a chemosensitive disease but that responses are seldom durable. The reported 5-year overall survival rate is 0–18%. Published guidelines from the National Comprehensive Cancer Network and the European Association of Dermato-Oncology acknowledge the absence of evidence to support chemotherapy as a standard of care and recommend that patients with advanced Merkel cell carcinoma be enrolled in clinical trials of investigative therapies. Additionally, the scientific literature on tumour causes and oncogenesis linked to risk and prognostic factors, including viral infection, ultraviolet-radiation exposure, old age, and immunosuppression, advances the notion that immunotherapy is a promising approach to a crucial unmet medical need.

Added value of this study

This trial investigated avelumab, a fully human IgG1 monoclonal antibody that inhibits PD-L1, in a population of patients with metastatic, chemotherapy-refractory disease. The trial met its primary endpoint, with nearly a third of patients achieving durable objective responses according to Response Evaluation Criteria In Solid Tumors version 1.1 and assessment by an independent review committee. The median duration of response had not been reached after a median follow-up time of 10·4 months. Responses were achieved irrespective of PD-L1 expression or Merkel cell polyomavirus status. Additionally, avelumab was well tolerated, with few grade 3 treatment-related adverse events and no treatment-related grade 4 adverse events or deaths. This is an important advance over chemotherapy, which is associated with a high incidence of toxicity-related morbidity and high disease-related mortality, particularly in patients who are older than 65 years of age with stage IV malignancy. To our knowledge, this is the largest prospective, international, multicentre study of an immune checkpoint inhibitor in Merkel cell carcinoma. On the basis of this study, avelumab received a breakthrough designation, fast-track designation, and orphan drug designation by the US Food and Drug Administration. The European Medicines Agency and the Australian Therapeutic Goods Administration also recognise the orphan drug status of avelumab.

Implications of all the available evidence

Our findings and the results from a phase 2 trial of an anti-PD-1 monoclonal antibody in patients with Merkel cell carcinoma who had not received previous systemic therapy provide evidence that these drugs are efficacious and safely administered in both treatment-naive and chemotherapy-refractory settings. These data add substantial support to changing the therapeutic framework for the treatment of advanced Merkel cell carcinoma. Our results showing clinical activity in both virus-related and ultraviolet-radiation-induced tumours provide an impetus for investigating avelumab in other tumour types with similar causes.

Several lines of evidence indicate mechanistic coupling between immunosuppression and Merkel cell carcinoma oncogenesis and thus support immunotherapy as a promising approach. Merkel cell polyomavirus is present in approximately 80% of patients with Merkel cell carcinoma, with an incidence as high as 97% in samples assessed with PCR.2, 16, 17 The virus integrates into DNA to drive expression of Merkel cell polyomavirus large T antigens, promote tumour proliferation, and disrupt immune responses.2, 18 In virus-negative tumours, a mutational burden signature associated with ultraviolet radiation exposure appears to be important for oncogenesis, leading to increased expression of neoantigens, heightened immunogenicity, and probably an increased requirement for immune evasion by the tumour.19, 20, 21 Active immunosuppression, occurring in relation to HIV infection, some haematological malignancies, and solid-organ transplantation, is associated with an increased risk of Merkel cell carcinoma; however, patients with Merkel cell carcinoma who are immunosuppressed comprise 8–10% of the total Merkel cell carcinoma population.22, 23

PD-L1 is a key therapeutic target in the reactivation of the immune response against multiple cancers.24, 25, 26 PD-L1 is often expressed by tumour cells within the tumour microenvironment and binds to the PD-1 receptor on activated T cells, resulting in the inactivation of the T cell. This process appears to be an important mechanism through which tumours inhibit immune responses. A high concentration of tumour-associated PD-L1 might be prognostic of poor outcome, and in some tumour types, a positive predictive marker of therapeutic response to immunotherapy; however, data have shown that PD-L1 overexpression is not a robust biomarker for response, and investigations of its value as a correlative biomarker are ongoing across multiple tumour types.27, 28 PD-L1 is expressed by Merkel cell carcinoma cells and by adjacent immune cell infiltrates.29, 30 Moreover, tumour-infiltrating CD8-positive and CD4-positive T cells specific to Merkel cell polyomavirus oncoproteins are enriched in some Merkel cell carcinomas in association with enhanced expression of both PD-L1 and the PD-1 receptor.30, 31 These patterns of expression of immune-related inhibitory markers provide a rationale for investigating the therapeutic potential of immune checkpoint inhibitors in Merkel cell carcinoma. Anti-tumour activity of pembrolizumab, an antibody that blocks the PD-1/PD-L1 pathway by targeting PD-1, was shown in a phase 2 study32 of patients with stage IIIb and stage IV Merkel cell carcinoma who were treated in a first-line, systemic, chemotherapy-naive setting. These findings in 25 patients support the potential of anti-PD-1/anti-PD-L1 monoclonal antibodies as a therapeutic option for advanced Merkel cell carcinoma.32

Avelumab (proposed non-proprietary name for MSB0010718C) is a fully human anti-PD-L1 IgG1 monoclonal antibody that inhibits PD-L1/PD-1 interactions but leaves intact the PD-L2/PD-1 pathway.33 Antibody-dependent cellular cytotoxicity might contribute to the activity of avelumab, as shown in preclinical models.34 Promising evidence of clinical activity and an acceptable safety profile has been shown in a phase 1 study33, 35, 36 of avelumab in patients with refractory advanced solid tumours. We aimed to assess the clinical activity and safety of avelumab in patients with metastatic Merkel cell carcinoma progressing after at least one previous line of chemotherapy.

Section snippets

Study design and participants

In this multicentre, international, prospective, open-label, single-group, phase 2 trial done at 35 cancer treatment centres and academic hospitals in North America, Europe, Australia, and Asia (appendix p 5), we enrolled patients with histologically confirmed stage IV Merkel cell carcinoma refractory to chemotherapy, defined as disease progressed after at least one previous line of chemotherapy for metastatic disease. Eligible patients were adults aged at least 18 years who had an ECOG

Results

As of March 3, 2016, the date of data cutoff for the primary analysis, 125 patients were screened and 88 eligible patients were enrolled and treated with avelumab (figure 1). The date of the first dose in the first patient was July 25, 2014, and the last patient received a first dose on Sept 3, 2015. Baseline characteristics of the patient population are shown in table 1. All patients had distant metastatic disease (M1, defined as metastases beyond regional lymph nodes) at the time of study

Discussion

Avelumab monotherapy in patients previously treated for metastatic disease was well tolerated and achieved rapid and sustained responses in 28 (32%) of 88 patients; another nine patients (10%) achieved stable disease. These data provide evidence of therapeutic activity in patients with metastatic, chemotherapy-refractory Merkel cell carcinoma. Merkel cell carcinoma is an aggressive cutaneous malignancy associated with poor survival outcomes in patients with metastatic disease. Although Merkel

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