Advanced Merkel-Cell Carcinoma May Respond To Pembrolizumab Therapy

Pembrolizumab elicits an objective response in Merkel-cell carcinoma patients with advanced disease

medwireNews: Preliminary research suggests that the programmed cell death protein 1 (PD-1) inhibitor pembrolizumab may have potential as front-line systemic treatment for patients with advanced Merkel-cell carcinoma, regardless of disease aetiology.

First-line systemic pembrolizumab, given at a 2 mg/kg dose at 3-week intervals, provoked a RECIST v1.1 objective response in 56% of 25 evaluated patients with stage IIIB or IV disease and an ECOG performance status of 0 or 1, say Suzanne Topalian, from Johns Hopkins University School of Medicine in Baltimore, Maryland, USA, and co-workers.

This included a complete response in four patients and a partial response in 14; response lasted between 2.2 months and up to at least 9.7 months, with just two patients experiencing relapse over a median of 33 weeks of follow-up. At 6 months, progression-free survival was 67%.

The team reports that one patient continues with treatment in the phase II trial following an unconfirmed partial response, another has stable disease and one patient awaits radiological assessment. Nine patients had progressive disease, occurring at pre-existing lesions in four patients, new metastatic sites in two and at both in three.

Response was 62% for the 16 patients with Merkel-cell polyomavirus (MCPyV)-positive tumours and 44% for the nine patients with virus-negative disease.

Fourteen of the 25 patients assessed for tumour expression of programmed death ligand 1 (PD-L1) tested positive for this PD-1 ligand. There was no correlation between PD-L1 expression and tumour response to pembrolizumab therapy but virus-positive tumours were more likely to express PD-L1 than virus-negative disease.

“[P]otentially through distinct mechanisms (viral antigen expression or high tumor mutational load), both virus-positive and virus-negative Merkel-cell carcinomas appear to be immunogenic and susceptible to immune therapy by inhibition of the PD-1 pathway”, the researchers comment.

“Our current understanding of the mechanism of antitumor immunity induced by PD-1 blockade centers on the unleashing of an endogenous repertoire of T cells specific for neo-epitopes generated by a small subset of somatic mutations in the tumor — so-called mutation-associated neoantigens”, they explain.

“However, because the mutational load of MCPyV-positive Merkel-cell carcinoma is so low, our findings, together with previous findings of MCPyV T-antigen– specific T cells in patients with virus-positive Merkel-cell carcinoma, suggest that antigens expressed by oncogenic viruses represent a distinct category of T-cell targets for immune checkpoint blockade”, the team proposes.

The research was reported simultaneously in The New England Journal of Medicine and at the American Association for Cancer Research annual meeting, held in New Orleans, Louisiana, USA.

Reference

Nghiem PT, Bhatia S, Lipson EJ, et al. PD-1 blockade with pembrolizumab in advanced Merkel-cell carcinoma. N Engl J Med 2016; Advance online publication 19 April. DOI: 10.1056/NEJMoa1603702

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