PD-L1 blockade with avelumab: A new paradigm for treating Merkel cell carcinoma

ABSTRACT

Merkel cell carcinoma (MCC) is a rare and aggressive neuroendocrine skin cancer. Until recently, no durable treatment options were available for patients with advanced disease. As an immunogenic cancer, MCC was hypothesized to be a candidate for PD-L1/PD-1 targeted therapy. On March 23, 2017 the US Food and Drug Administration granted accelerated approval for avelumab, an anti-PD-L1 monoclonal antibody, for the treatment of metastatic MCC on the basis of the JAVELIN Merkel 200 trial. Here we examine the results and implications of this pivotal study, published in Lancet Oncology by Kaufman et al., as well as current developments in the use of immune-checkpoint therapies for treating patients with MCC.

KEYWORDS:

• Merkel cell carcinoma
• avelumab
• immunotherapy
• PD-L1, PD-1

Merkel cell carcinoma (MCC) is a highly aggressive neuroendocrine skin cancer. MCC is a rare cancer with an annual incidence rate of 0.79 per 100,000 people in the US (∼2000 cases/year), however on a case by case basis it is more deadly than melanoma.¹ Until recently, the standard treatment for metastatic MCC was chemotherapy, but responses were not durable with a mean progression-free survival of only 3 months.² With a rising incidence rate and a disease-specific mortality of 46%, new therapies were needed for MCC.^1,3 In March of 2017 avelumab, an anti-PD-L1 monoclonal antibody, became the first FDA approved treatment for metastatic MCC on the basis of the results of the JAVELIN Merkel 200 trial published by Kaufman et al. in Lancet Oncology in September of 2016.¹

The emergence of checkpoint inhibitors and other immunotherapeutics has revolutionized the cancer treatment field in recent years. MCC was thought to be a good target for this therapeutic approach for a variety of reasons. First, MCC has a higher incidence rate in elderly and immunosuppressed populations, and has a worse prognosis in both populations.³ Moreover, 80% of Merkel cell carcinomas are associated with integration of the Merkel cell polyomavirus, while the other 20% are associated with a high number of UV-induced mutations.¹ It was thought that viral antigens or neoantigens produced as a result of UV-signature mutations would provide good epitopes for the body's cellular immune response.^3,4 Indeed, MCC survival has been shown to correlate with high levels of intratumoral CD8+ T cells.⁵ Despite the evidence that immune responses are important for controlling MCC, some tumors are still able to evade immune detection and cause disease in patients.

The PD-L1/PD-1 checkpoint is frequently used by cancers to evade the body's immune system by inducing “immune exhaustion” of infiltrating T lymphocytes.² When the programmed death 1 (PD-1) receptor on antigen-specific T cells is bound by its ligand (PD-L1 or PD-L2), T effector cells become inactivated and undergo apoptosis.^6,7 MCC tumors and tumor associated myeloid cells frequently express PD-L1, promoting immune protection of the tumor cells.⁸ Most MCC tumor infiltrating lymphocytes (TILs) express PD-1, with virus-specific T cells expressing particularly high levels of the receptor,⁹ suggesting that these cells have been inhibited. These observations led to the hypothesis that drugs targeting this pathway would disinhibit and increase the number of anti-tumor lymphocytes and be highly effective at treating MCC. This approach built upon the success of anti-PD-1 therapies in non-small cell lung cancer and metastatic melanoma.²

As reported by Kaufman et al., the JAVELIN Merkel 200 trial was a single-arm, open-label, phase II trial that enrolled and treated 88 patients with MCC at treatment centers world-wide. The trial enrolled patients with stage IV disease that had progressed after cytotoxic chemotherapy. Patients were treated with avelumab, a fully human anti-PD-L1 IgG1 monoclonal antibody, at a dose of 10 mg/kg intravenously every 2 weeks.¹ In addition to blocking PD-L1 signaling to PD-1, avelumab possesses an intact F_c region.¹⁰ This native functional region is capable of interacting with the innate immune system, and was shown to activate antibody-dependent cell-mediated cytotoxicity (ADCC).^10,11 This dual function is unique among clinical antibodies targeting the PD-L1/PD-1 immune checkpoint. The theoretical combination of checkpoint blockade with ADCC killing of PD-L1 expressing tumor cells coupled with a favorable safety profile made avelumab a promising therapeutic agent.¹

Patients received treatment every 2 weeks until confirmed progression, toxicity, or other adverse events that warranted study withdrawal. An independent review committee utilized RECIST version 1.1 to determine tumor responses. At the time of primary analysis, the study team had followed patients for a median of 10.4 months, with follow-up ongoing for many of the patients. The confirmed objective response rate to avelumab was 31.8%, with 20 patients experiencing partial responses and 8 patients having complete responses. At the time of analysis, responses were ongoing in 82% of patients who had exhibited responses to avelumab treatment. Additionally, 10% of patients achieved stable disease. Post-hoc analysis showed that 29% of patients exhibited durable responses, defined as those lasting at least 6 months. Median duration of response had still not been met at the time of initial analysis. 33% of patients showed tumor regression of at least 30%, including one case that showed initial pseudoprogression before shrinkage. Median progression-free survival for the patient group was 2.7 months.¹

In terms of safety, avelumab was generally well tolerated. Grade 3 adverse events were seen in 4 out of 88 patients, and no grade 4 or grade 5 treatment-related events occurred. The most common adverse events related to treatment were fatigue and infusion-related reactions. Patients were pre-treated with acetaminophen and antihistamine prior to drug infusion to avoid infusion-related reactions.¹

Patient enrollment was not based on Merkel cell polyomavirus status or PD-L1 expression levels in the tumor. Strikingly, responses to avelumab occurred irrespective of tumor viral or PD-L1 expression status. In evaluable tumors, 34.5% of PD-L1 positive and 19% of PD-L1 negative tumors responded to avelumab. Similarly, 26% of virus positive and 35.5% of virus negative tumors responded to treatment.¹ These results suggest avelumab can have meaningful clinical benefits in patients regardless of the etiology of their MCC.

The results of the JAVELIN Merkel 200 trial were remarkable. Avelumab achieved a 6-month durable response rate of 29% in MCC patients compared to the 6.7% historically achieved with second-line chemotherapy.¹ The study results, bolstered by reports of treatment success with anti-PD-1 therapies including pembrolizumab and nivolumab,^2,12 proved the PD-L1/PD-1 pathway to be a viable and valuable target for the treatment of MCC. Based on the JAVELIN Merkel 200 trial, the US Food and Drug Administration granted accelerated approval to avelumab (Bavencio) on March 23, 2017, making it the first approved treatment for metastatic Merkel cell carcinoma.

Although the initial cohort of patients had all failed chemotherapy, avelumab was approved for treating both chemotherapy-naïve and chemotherapy-resistant MCC. To confirm the efficacy of avelumab in the first-line setting, the JAVELIN Merkel 200 trial was expanded (Part B) and is currently enrolling MCC patients who have not been treated with chemotherapy. Preliminary results for first-line avelumab were reported at the 2017 American Society of Clinical Oncology annual meeting with 64.0% of 29 patients showing an objective response.¹³ The high response rates to single-agent checkpoint inhibition make MCC one of the most responsive solid tumors to immunotherapy.^2,12,13

Extended follow-up data for Part A of the JAVELIN Merkel 200 trial were presented at the American Association for Cancer Research 2017 Annual Meeting. After a median follow-up time of 16.4 months, the overall response rate rose to 33%. Responses were ongoing in 22% of patients, and 2 new complete responses were recorded since the initial analysis cutoff point. Of those patients that responded to treatment with avelumab, 74% had a durable response of at least one year.¹⁴ These results further underscore the clinical efficacy of MCC treatment with avelumab. The success of the JAVELIN Merkel 200 trial paves the way for continued use of anti-PD-L1/PD-1 agents in MCC and other immune-responsive malignancies.

Acknowledgment

The opinions expressed in this article are the authors' own and do not reflect the view of the National Institutes of Health, the Department of Health and Human Services, or the United States government.

Disclosure Statement

The authors have nothing to disclose. Savannah Barkdull, Dermatology Branch, Center for Cancer Research, National Cancer Institute, NIH, Building 10 Room 12S239, 10 Center Drive, Bethesda, MD 20892, Email: [email protected]