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.
| Original language | English |
|---|---|
| Journal | The Lancet Oncology |
| Volume | 17 |
| Issue number | 10 |
| Pages (from-to) | 1374-1385 |
| Number of pages | 12 |
| ISSN | 1470-2045 |
| DOIs | |
| Publication status | Published - 01.10.2016 |
Funding
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 cell carcinoma is a rare cancer, the proportion of patients with recurrent disease exceeds 40%, 6 and the incidence of disease-associated mortality is approximately three times that of melanoma. 7,18 Chemotherapy has been shown to produce responses in this population, but they are seldom durable. 3,14,15 In a recent observational study, the proportion of patients with chemotherapy-refractory metastatic disease who responded to chemotherapy in the second-line setting was 23%, with a 6-month durable response rate of 6·7%. 11 Patients in this study all had distant metastases that had been treated with at least one previous line of therapy for metastatic disease, indicating the highest unmet medical need and population with the poorest prognosis among patients with Merkel cell carcinoma. The median duration of response was not reached in this study, and most patients (23 [82%] of 28) had ongoing responses at a median follow-up of 10·4 months (IQR 8·6–13·1). By contrast, responses to chemotherapy reported in the scientific literature are typically short-lived. The response duration and durable response rate reported in this study already exceed what can be achieved with chemotherapy. 11 On the basis of Kaplan-Meier analysis, the 6-month estimate of durability was 92%, and the observed plateau of the Kaplan-Meier curve for progression-free survival was driven by durable responses. The 6-month durable response rate was 29%, and the 6-month progression-free survival rate was 40%. Complete responses occurred in patients who had visceral disease, had a high disease burden based on size of target lesions, and were heavily pretreated. Additionally, a complete response was ongoing in one patient for 9·5 months after this patient had ended treatment with avelumab. These data suggest that meaningful clinical benefit was achieved with avelumab treatment with a median time to response of 6 weeks. Responses to avelumab were observed irrespective of PD-L1 expression or Merkel cell polyomavirus status, suggesting that avelumab might achieve a therapeutic benefit in patients whose disease response and cause are driven by different underlying mechanisms. Specific mechanisms related to the interplay of viral antigen, ultraviolet-based mutagenesis, and PD-L1 expression in the tumour microenvironment are not well understood. However, mutational landscape analyses suggests that Merkel cell polyomavirus-positive and Merkel cell polyomavirus-negative signatures might represent viral-dependent and ultraviolet-induced subtypes, respectively. 19–21 Furthermore, the patterns of responsiveness to anti-PD-L1 treatment with respect to viral status suggest that PD-L1 expression might be driven by mechanisms of immune evasion and by increased mutagenesis and neoantigen expression in patients with viral-negative tumours. 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. A rationale for immune checkpoint inhibition as a promising approach is further supported by evidence of anti-tumour activity with the anti-PD-1 antibody pembrolizumab in first-line metastatic Merkel cell carcinoma. 32 This phase 2 study of 25 assessable patients with Merkel cell carcinoma receiving a first-line systemic therapy for unresectable or metastatic disease and with at least one tumour assessment during treatment reported an objective response of 56% (95% CI 35–76) by RECIST version 1.1. The patients in the first-line pembrolizumab study had stage IIIb and stage IV disease, whereas the patients in this study had only stage IV disease and had been treated in the second-line setting for chemotherapy-refractory disease. Median follow-up time in the first-line study was 7·6 months, compared with 10·4 months in the avelumab second-line study. Because durability of response is an indicator of clinical activity, the longer follow-up time shows a robust signal of benefit with avelumab. Differences observed in response based on PD-L1 expression or Merkel cell polyomavirus status in the two studies might relate to the different patient populations or the number of patients included in the trials; however, both studies reported responses in patients regardless of PD-L1 and Merkel cell polyomavirus status. Although the population in the pembrolizumab study 32 differed from that in the current study of avelumab across several dimensions—less advanced disease and a more heterogeneous patient population, less heavily pretreated in a first-line setting, fewer patients, and shorter follow-up time—the two studies, taken together, reinforce the notion that targeting the PD-L1/PD-1 axis is an effective therapeutic strategy. The safety profile of avelumab was manageable and consistent with anti-PD-L1/PD-1 antibodies in other tumour types. 42 Most adverse events related to avelumab were low grade, consisting mostly of fatigue and infusion-related reactions. In particular, all infusion-related reactions were low grade (CTCAE grade 1 or 2) and, in most cases, resolved on the same day with only supportive medications; none resulted in discontinuation of study treatment. Four patients had grade 3 treatment-related adverse events, one of which led to permanent discontinuation (elevated aminotransferases). The grade 3 treatment-related adverse events were all related to laboratory abnormalities, which is consistent with safety data reported for pembrolizumab in first-line Merkel cell carcinoma. 32 No grade 4 treatment-related events or deaths related to study treatment occurred. The number of potential immune-mediated adverse events related to avelumab was low, and the events were manageable. The patients in this study had completed previous chemotherapy and represent a particularly challenging population. Previous reports in patients with metastatic Merkel cell carcinoma treated with chemotherapy have shown high rates of serious dose-limiting toxicities— including sepsis, neutropenia, and renal toxicity—and treatment-related death, especially in elderly patients. 10,11 The median age of our population was 72·5 years, and no treatment-related deaths were noted. Thus, avelumab was safe in patients with previously treated, metastatic Merkel cell carcinoma. This study does have limitations, which include the non-randomised study design and the small sample size. Merkel cell carcinoma is a rare disease with a rapid natural history in a population with often substantial comorbidities, which makes large randomised clinical trials difficult. To our knowledge, this study is the largest trial of metastatic Merkel cell carcinoma ever reported. Although this trial was not randomised to directly assess anti-PD-L1 therapy compared with chemotherapy in the second-line setting, our findings suggest that treatment with anti-PD-L1 achieves durable disease remission or stabilisation and is well tolerated. Additionally, this trial was designed a priori to assess the clinical activity of avelumab in patients with metastatic Merkel cell carcinoma after progressing on first-line chemotherapy. This study shows a confirmed objective response per RECIST version 1.1 criteria of 31·8% with a 95·9% CI excluding 20%. As a result, the study met its predefined primary objective of clinical activity. We noted objective responses to avelumab in all subgroups analysed. We noted a higher proportion of patients with a response in subgroups who had received fewer lines of previous therapy compared with those who had received more lines of previous therapy. One possible explanation for this observation is that patients who received fewer lines of cytotoxic therapy might be more likely to have fully functioning immune systems than those who had received more lines of therapy, and thus might respond in a more robust way to immunotherapy with a checkpoint inhibitor. Our findings in the second-line and later-line setting, together with the results for pembrolizumab in first-line patients, indicate that anti-PD-L1/PD-1 therapies could become the standard of care in treatment-naive and advanced Merkel cell carcinoma. Additionally, these studies support the clinical activity and safety of anti-PD-L1/PD-1 monotherapy in the treatment framework. Combination approaches with anti-PD-L1/PD-1 antibodies and other immunotherapies have been initiated. Our findings show that avelumab represents a new therapeutic option for advanced Merkel cell carcinoma. Contributors HLK, JHL, KC, AvH, J-MC, and PN conceived and designed the study. HLK, OH, SB, JHL, KC, LM, AvH, J-MC, and PN collected and assembled the data. All authors analysed and interpreted the data, wrote the manuscript, and approved the final version of the manuscript. 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. Acknowledgments We thank the patients and their families, the investigators, co-investigators, and the study teams at each of the participating centres and at Merck KGaA, Darmstadt, Germany; EMD Serono, Billerica, MA, USA; and Quintiles, Durham, NC, USA. This trial was sponsored by Merck KGaA, Darmstadt, Germany, and is part of an alliance between Merck KGaA and Pfizer. Medical writing support was provided by ClinicalThinking, Hamilton, NJ, and funded by Merck KGaA, Darmstadt, Germany and Pfizer.
Research Areas and Centers
- Academic Focus: Center for Infection and Inflammation Research (ZIEL)
