From the Journals

Pembrolizumab extends Merkel cell PFS, OS



Patients with the aggressive skin cancer Merkel cell carcinoma who were treated with the immune checkpoint inhibitor pembrolizumab (Keytruda) in the first line had higher complete response rates, better progression-free survival, and longer overall survival than historical controls treated with cytotoxic chemotherapy.

Among 50 adults with advanced Merkel cell carcinoma (MCC) with no prior systemic therapy who received pembrolizumab 2 mg/kg every 3 weeks for up to 2 years in a phase 2 clinical trial (NCT02267603), 24% had a complete response and 32% a partial response, for an overall response rate of 56%.

The 24-month overall survival rate was 68.7%, with median overall survival not reached after a median follow-up time of 14.9 months. In contrast, a retrospective study of 67 patients with MCC treated with first-line chemotherapy showed an ORR of 29.4%, a median OS of 10.5 months, and a 24-month OS of 24.5% (Future Oncol. 2017 Aug;13(19):1699-1710).

Similarly, a second retrospective study showed that, among 62 patients treated with first-line chemotherapy, the ORR was 55%, median OS was 9.5 months, and 24-month OS was 20% (Cancer Med. 2016 Sep;5(9):2294-2301), reported Paul Nghiem, MD, PhD, from the University of Washington and Fred Hutchinson Cancer Research Center in Seattle, and his colleagues.

The rationale for using a checkpoint inhibitor for advanced MCC is that “[m]ultiple lines of evidence support the notion that MCC is an immunogenic cancer, including the fact that MCC incidence is greater than 10-fold higher in chronically immunosuppressed persons,” they wrote in the Journal of Clinical Oncology.

The current National Comprehensive Cancer Network guideline on Merkel cell carcinoma recommends the use of the programmed death–1/programmed death–ligand 1 (PD-1/PD-L1) inhibitors pembrolizumab, avelumab (Bavencio), or nivolumab (Opdivo) as preferred first-line systemic therapy for patients with disseminated disease, Dr. Nghiem and his colleagues noted.

In the current report, they presented data on the longest follow-up to date of patients with advance MCC who received a PD-1 inhibitor in the first line.

In the multicenter, phase 2 trial, 50 patients with a median age of 70.5 years were treated. Of this group, 64% had tumors positive for the Merkel cell polyomavirus and 49% had PD-L1 expression on tumor cells.

Of the 50 total patients, 28 had an objective response according to Response Evaluation Criteria in Solid Tumors version 1.1, including 12 with a complete response and 16 with a partial response. A total of 5 patients had stable disease, 16 had progressive disease, and 1 patient died before the first on-treatment scan for assessment.

After a median follow-up of 4.9 months, the 24-month progression-free survival rate (PFS) was 48.3% months, with a median PFS of 16.8 months.

As noted before, the 24-month OS rate was 68.7% and the median OS had not been reached at the time of the analysis.

There were no significant differences in PFS or OS between patients with tumors positive or negative for the Merkel polyomavirus, and there was a nonsignificant trend toward better PFS and OS for patients whose tumors had PD-L1 expression greater than 1%.

In all, 48 of the 50 patients had a treatment-related adverse event of any kind, and 14 had grade 3 or greater events. Treatment-related events led to discontinuation of pembrolizumab for seven patients, and one patient, a 73-year-old man with metastatic MCC and atrial fibrillation, developed pericardial and pleural effusions 1 day after receiving a single pembrolizumab infusion. The patient died 10 days after receiving pembrolizumab, and his death was deemed to be related to the drug.

The investigators noted that the drug’s efficacy in patients with both polyomavirus- and UV-induced subtypes of MCC “provides compelling evidence that both the quality and quantity of tumor antigens are important factors driving antitumor immunity and tumor rejection.”

The study was supported by grants from the National Cancer Institute, the Merkel cell carcinoma (MCC) patient gift fund at University of Washington, the Kelsey Dickson MCC Challenge Grant from the Prostate Cancer Foundation, and Merck, which provided pembrolizumab and partial funding. Dr. Nghiem reported receiving honoraria, travel expenses, and a consulting or advisory role from/for Merck and others. Multiple coauthors reported similar relations with Merck and/or other companies.

SOURCE: Nghiem P et al. J Clin Oncol. 2019 Feb 6. doi: 10.1200/JCO.18.01896.

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