Novel immune checkpoint blocker to treat Merkel cell carcinoma

Over the past few years, immune checkpoint blockers (ICBs) have literally revolutionized the treatment of multiple tumors, including (but not limited to) melanoma, non-small cell lung carcinoma (NSCLC), Hodgkin's lymphoma and bladder carcinoma.^1-3 Until recently, four different ICBs were approved by the US Food and Drug Administration (FDA) for use in cancer patients, namely, ipilimumab (YERVOY®, from Bristol-Myers Squibb), pembrolizumab (KEYTRUDA®, from Merck and Co.), nivolumab (OPDIVO®, from Bristol-Myers Squibb) and atezolizumab (TECENTRIQ® from Genentech Oncology).^4,5 Ipilimumab specifically targets cytotoxic T lymphocyte-associated protein 4 (CTLA4), pembrolizumab and nivolumab are directed against programmed cell death 1 (PDCD1, best known as PD-1), while atezolizumab blocks CD274 (the main ligand for PD-1, best known as PD-L1).^1,2 On March 23, 2017, the US FDA granted accelerated approval to avelumab (BAVENCIO®, from EMD Serono) for the treatment of patients 12 years and older affected by metastatic Merkel cell carcinoma (MCC) (source https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm547965.htm). This decision raised to five the number of distinct ICBs currently available for use in humans and expanded their indications to an aggressive form of skin cancer other than melanoma.

Similar to atezolizumab (which is currently approved for the treatment of NSCLC and urothelial carcinoma patients progressing upon platinum-containing chemotherapy),^6-8 avelumab (previously known as MSB0010718C) is a fully human monoclonal IgG1 antibody directed against PD-L1.⁹ However, whereas atezolizumab has specifically been developed to avoid antibody-dependent cellular cytotoxicity (ADCC) and consequent depletion of PD-L1-expressing T lymphocytes,¹⁰ avelumab promotes robust ADCC responses.^9,11,12 The approval of avelumab for use in patients with metastatic MCC was based on the results of the JAVELIN Merkel 200 trial, an open-label, single-arm, multi-center Phase II study (NCT02155647).¹³ In this setting, 88 patients with histologically confirmed Stage IV MCC progressing on or after chemotherapy were enrolled and received at least one dose of avelumab. Grade 3 treatment-related adverse effects were documented in 5% of the patients, but no Grade 4 events and treatment-related deaths were observed.¹³ Additional safety data were obtained from 1,738 patients who received 10 mg/kg avelumab every 2 weeks in the context of multiple clinical trials. The most common treatment-related adverse effects were immunological (pneumonitis, colitis, hepatitis, adrenal insufficiency, hypo- and hyperthyroidism, diabetes mellitus and nephritis) or related to infusion (source https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm547965.htm). Of the 88 patients enrolled in the JAVELIN Merkel 200 trial, 33% (95.9%, CI 23.3–43.8) achieved an objective response as per RECIST version 1.1, including 11% complete and 22% partial responses. Of note, response duration ranged from 2.8 to more than 23.3 mo, with 86% of responses lasting >6 mo.¹³

MCC is a rare (< 2,000 new cases per year in the USA) but aggressive neuroendocrine tumor of the skin for which limited therapeutic options are available, which granted MCC the status of orphan disease.¹⁴ At least in part, this explains the accelerated approval of avelumab for use in metastatic MCC patients. Interestingly, sporadic responses to other ICBs, including nivolumab and ipilimumab have also been reported among MCC patients.^15,16 It is tempting to speculate, yet remains to be formally determined, that the superior efficacy of avelumab may rely, at least in part, on its dual ability to block PD-L1 signaling and trigger ADCC. Future studies addressing this possibility may pave the way to an entire new generation of ADCC-competent ICBs for cancer immunotherapy.

Disclosure of potential conflicts of interest

LG provides remunerated consulting to OmniSEQ (Buffalo, NY, US).