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Merkel cell carcinoma responds to immunotherapy


 

AT THE EUROPEAN CANCER CONGRESS 2015

References

VIENNA – High response rates to pembrolizumab and to intratumoral delivery of plasmid interleukin-12 (IL-12) were observed among patients with advanced Merkel cell carcinoma (MCC), based on studies presented at the 2015 European Cancer Congress.

There is strong rationale for immunotherapy in MCC. For one thing, the Merkel cell polyomavirus, which is expressed in 80% of tumors, serves as a powerful antigen for stimulating an immune response. Secondly, MCC tumors often express the ligand for the programmed death protein (PD-1), creating an opportunity for PD-1 pathway blockade with PD-1 inhibitors such as pembrolizumab, according to the investigators.

Responses in 10 of 14 given pembrolizumab

Dr. Paul Nghiem of the University of Washington in Seattle, led an open-label, single-arm, multicenter phase II trial of pembrolizumab, which is approved for metastatic melanoma and which could become the first systemic therapy for unresectable or metastatic MCC (Abstract 22LBA).

Dr. Paul Nghiem

Dr. Paul Nghiem

In the study, which opened in January 2015, there are 24 evaluable patients treated with pembrolizumab 2 mg/kg every 3 weeks for up to 2 years. Fourteen had at least one posttreatment scan; 10 of these 14 patients (71%) have responded, 2 had complete responses. One patient had stable disease and three progressed.

“Responses were rapid, and appear more durable than we see with chemotherapy,” Dr. Nghiem said.

The drug was generally well tolerated, with an adverse event profile similar to what has been seen in melanoma. One patient experienced grade 4 myocarditis after one dose and one developed grade 4 transaminase elevation after two doses. Both improved after discontinuing pembrolizumab and starting corticosteroids.

“Strikingly, despite receiving only one or two doses, both patients had profound and ongoing responses to pembrolizumab,” Dr. Nghiem observed.

Many subjects had “profound shrinkage of tumor that has not rebounded,” he noted. “Pembrolizumab looks to be very favorable in terms of durability of response. With chemotherapy, at 90 days half of our patients have gone off treatment.”

The researchers are considering expanding the study population, and may include a chemotherapy-relapsed cohort. They are also analyzing biomarkers, and hope to evaluate response according to virus-positive versus virus-negative status.

Dr. Caroline Robert ©2015 AACR/Todd Buchanan

Dr. Caroline Robert

Dr. Caroline Robert of the Institut Gustave Roussy in Villejuif, France, commented on the findings, first noting the difficulty of treating patients for whom there are no approved therapies. Median overall survival is less than 10 months, she said, and clinicians have lacked clinical trials to enroll patients.

“MCC patients represent a high medical need,” she said. Although the results with pembrolizumab are early, “they are very promising.”

Intratumoral plasmid IL-12

Dr. Shailender Bhatia of the University of Washington in Seattle, described a different immunotherapeutic approach in an MCC population (Abstract 504).

Dr. Shailender Bhatia

Dr. Shailender Bhatia

IL-12, which regulates adaptive type-1 immunity, has demonstrated antitumor efficacy in MCC but is associated with severe toxicities when administered systemically. Local IL-12 delivery to the tumor microenvironment “may provide adequate cytokine concentration in the vicinity of tumor antigens, and therefore improve efficacy while sparing systemic toxicity,” he said.

Intratumoral IL-12 plasmid DNA (pIL-12) injection with electroporation (which uses pulsed electricity to open pores in cell membranes) has shown antitumor activity in melanoma, and might also work in MCC, Dr. Bhatia and his colleagues hypothesized. The concept is one of promoting tumor inflammation and thereby a systemic antitumor immune response. This would be reflected, and measured, by increased IL-12 protein expression in the tumor microenvironment, which became this study’s primary endpoint.

“To the best of our knowledge, this study represents the first prospective clinical trial of immunotherapy in advanced MCC,” Dr. Bhatia noted.

Beginning in January 2012, the study enrolled 15 patients with MCC and superficial injectable tumors. Patients received injections of pIL-12 on days 1, 5, and 8; 2 weeks later, on day 22, their lesions were biopsied. The 3-person cohort with localized MCC (stage IIIb) then underwent definitive surgery and/or radiation therapy starting in week 4, while the 12 with distant metastatic disease (stage IV) could receive additional treatment cycles (maximum of 4) at least 6 weeks apart.

The treatment was well tolerated, with most adverse events – primarily pain and local inflammatory reaction – being mild and transient. No patients discontinued because of toxicity.

The primary endpoint, sustained local expression of IL-12 protein on day 22, was observed in 79% of patients. In paired biopsy samples, comparing baseline to day 22 levels, IL-12 protein expression increased by almost 2-fold to more than 3,000-fold.

In addition, enrichment of Merkel cell polyomavirus-specific CD8-positive T cells were found in the tumor infiltrating lymphocytes (TILs) of treated and distant tumors in some patients.

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