Better Outcomes in MK-3475-Treated Melanoma Patients With Higher PD-L1 Expression

Advanced melanoma patients treated with the anti–PD-1 inhibitor MK-3475 whose tumors expressed the ligand for the PD-1 receptor, PD-L1, were more likely to have longer survival and more robust immune responses compared with patients with tumors that did not express PD-L1. Patients evaluated were part of a phase I clinical trial that tested three different dosing schedules of MK-3475.

Adil I. Daud, MD, director of melanoma clinical research at the University of California, San Francisco Helen Diller Family Comprehensive Cancer Center, presented the results at a press briefing at the 2014 American Association for Cancer Research (AACR) Annual Meeting, held April 5–9 in San Diego.[1]

Although the frequency of objective responses was higher among patients with PD-L1–positive tumors, the quality of responses was similar among patients with either PD-L1–positive or PD-L1–negative tumors, said Daud during the press briefing.

This is the largest dataset that has analyzed the link between PD-L1 tumor expression and response among metastatic melanoma patients, though the data are still preliminary, according to Daud.

MK-3475 is a humanized monoclonal antibody against PD-1, a checkpoint protein that negatively regulates the immune system. This trial previously demonstrated a 41% overall response rate for all patients treated at all three doses tested. The best objective response was 51% with the 10 mg/kg dose at every 2 weeks. At 1 year, the overall survival rate was 81% in patients treated with the antibody. These results were presented in November 2013 at the 10th International Congress of the Society for Melanoma Research in Philadelphia.

The current analysis found that patients with tumors that expressed PD-L1 had a 46% overall response rate compared with 17% of those patients with tumors that did not express PD-L1. At 6 months, 64% of PD-L1–positive patients had no disease progression compared with 34% of patients with PD-L1–negative tumors. One-year survival was also higher in PD-L1–positive patients: 86% were alive at 1 year compared with 72% of patients with PD-L1–negative tumors. The median progression-free survival was 36 months.

Daud and colleagues analyzed 135 patients’ tumor samples in the trial. Most patients had been previously treated, including with ipilimumab, an anti–CTLA-4 immune checkpoint antibody already approved by the US Food and Drug Administration.

The presence of the PD-L1 protein in the tumor samples was analyzed using immunohistochemistry. A tumor was considered PD-L1–positive if at least one cell per 100 tumor cells stained positive for the protein. Of the 125 patient tumor samples that could be evaluated, 71% (89) were PD-L1–positive and 29% (36) were PD-L1–negative.

Prior treatment with ipilimumab did not appear to impact the response to MK-3475. Overall response rates for the 44% of patients who had not received prior ipilimumab were not different from the response rates of the 47% who had a history of ipilimumab treatment. Response rates were also not significantly different among PD-L1–negative patients who had or had not received prior ipilimumab.

Several later-stage trials are now evaluating MK-3475 in metastatic melanoma. A phase III clinical trial is comparing two different doses of MK-3475 with ipilimumab. A PD-L1–positive tumor was not a selection criterion for this ongoing trial. Daud noted that larger studies will better clarify the role of PD-L1 tumor expression on MK-3475 efficacy in melanoma.

Reference

1. Daud AI, Hamid O, Ribas A, et al. Antitumor activity of the anti-PD-1 monoclonal antibody MK-3475 in melanoma (MEL): Correlation of tumor PD-L1 expression with outcome. American Association for Cancer Research Annual Meeting 2014; April 5–9, 2014; San Diego. Abstr CT104.