PD-L1 Expression Potential Biomarker for Response to Immunotherapy with MK-3475

May 2014, Vol 5, No 4

San Diego, CA—Two studies, one in melanoma and one in non–small-cell lung cancer (NSCLC), presented at the 2014 American Association for Can­-cer Research meeting attempted to correlate response to the anti–programmed cell death (PD)-1 inhibitor MK-3475 with the biomarker PD-L1. The hope is that the level of PD-L1 expression will be a biomarker for the selection of patients for treatment with this new agent.

The first study suggests that PD-L1 expression may become a marker for determining which patients with melanoma will best benefit from MK-3475, and the second study indicates that PD-L1 is a robust predictor of response and outcomes in patients with NSCLC treated with this drug. Ongoing studies are looking for additional evidence.

MK-3475 is an investigational potent antibody that inhibits PD-1. This immunotherapy is designed to restore the ability of the immune system to recognize and target cancer cells by selectively achieving dual blockade of 2 ligands of the PD-1 protein: PD-L1 and PD-L2.

Melanoma Results
The first study involved patients with melanoma, and the results were presented by lead investigator Adil I. Daud, MD, Codirector of the Melanoma Center at the University of California, San Francisco (UCSF) and Director of melanoma clinical research at the UCSF Helen Diller Family Comprehensive Cancer Center.

“We found a major difference in the response rates between patients with PD-L1–positive and PD-L1–negative tumors treated with MK-3475,” said Dr Daud. “This is the largest data set yet, to my knowledge, looking at PD-L1 expression in tumors from melanoma patients treated with PD-1 inhibitors.”

In this study, 195 patients with advanced melanoma had a mandatory biopsy and were then treated with 1 of 3 doses of MK-3475 for 12 weeks when response was assessed; responders continued receiving treatment until disease progression, and nonresponders discontinued the study. Patients treated previously with ipilimumab had no restriction on previous therapies; those who were ipilimumab-naïve could have had up to 2 previous therapies. Among 125 patients who were evaluable for PD-L1 expression, PD-L1 expression was positive in 89 tumors (71%), and 36 patients were PD-L1–negative.

In unselected patients, the response rate was 40%. Among PD-L1–positive patients, the response rate was 49% versus 13% among PD-L1–negative patients (P = .007). The responses were durable in PD-L1–positive and PD-L1–negative patients, Dr Daud said.

Progression-free survival (PFS) curves also showed major differences between PD-L1–positive and PD-L1–negative patients. The median PFS was 10.6 months in PD-L1–positive patients versus 2.9 months in PD-L1–negative patients (P = .051). The overall survival data are not mature.

Among patients with melanoma who received MK-3475, those whose tumors expressed PD-L1 had an overall response rate (ORR) of 46% compared with 17% ORR in patients without PD-L1 expression. After 6 months of therapy with MK-3475, 64% of the patients whose tumors were PD-L1–positive had no disease progression, compared with 34% of those whose tumors were PD-L1–negative.

Similarly, 86% of the patients whose tumors were PD-L1–positive were alive after 12 months compared with 72% of patients whose tumors were PD-L1–negative.

When discussing the study at a press briefing, Dr Daud emphasized that these were preliminary results and more data are needed to verify the utility of MK-3475 as a biomarker for patients with advanced melanoma, saying, “Because we saw durable responses in PD-L1–negative patients, the clinical utility of selecting patients for treatment with MK-3475 based on PD-L1 expression is not clear in advanced melanoma.”

Data from ongoing studies may indeed provide additional information on the relationship between PD-L1 expression and response to MK-3475. The US Food and Drug Administration (FDA) has assigned a priority review for the manufacturer’s application for the licensing of MK-3475 (now known as pembrolizumab) for the treatment of patients with advanced melanoma, with a final FDA decision expected in October 2014.

NSCLC Results
A second presentation from an early-phase study showed that PD-L1 expression of >50% was predictive of response to MK-3475 in patients with NSCLC. These findings were also based on an analysis of a training set of 146 patients from the ongoing phase 1 study, and were reported by Leena Gandhi, MD, PhD, Thoracic Oncologist, Dana-Farber Cancer Institute, Boston.

The ORR for PD-L1–positive and PD-L1–negative groups was 19%. However, strong positivity (>50% expression) clearly differentiated responders from nonresponders. Approximately 25% of the cohort was PD-L1–positive using this cutoff.

The median PFS was 14.1 weeks in the PD-L1–positive patients versus 9.3 weeks in the PD-L1 weakly positive or negative patients. Overall survival times were 9.3 months versus 7.3 months, respectively, which were not statistically significant.

“PFS was markedly improved in those with strong PD-L1 staining, and responses were durable. We expect that these median and final PFS may change over time. As with melanoma, there is no statistically significant difference in survival at this point, but we do see a trend favoring PD-L1 positivity,” Dr Gandhi said.

Ongoing studies will analyze more patients in the phase 1 study, and there is an ongoing randomized study of 2-mg/kg MK-3475 versus 10-mg docetaxel in patients with NSCLC.

MK-3475 is also being evaluated as a single agent and in combination with other drugs in patients with multiple solid tumors and hematologic malignancies.

A major problem with this effort is that the tests for PD-L1 expression are not standardized. Several tests for PD-L1 expression are being developed by pharmaceutical companies, and they differ in many aspects, including set points for positivity and reagents.

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