PD-L1 Provides Predictive Value for MK-3475 Responses in Melanoma, NSCLC

Article

PD-L1 levels adequately predict response and clinical outcomes for PD-1 inhibitor MK-3475 in patients with non-small cell lung cancer (NSCLC) and melanoma.

Leena Gandhi, MD, PhD

Image courtesy Dana-Farber Cancer Institute

Leena Gandhi, MD, PhD

PD-L1 levels adequately predict response and clinical outcomes for PD-1 inhibitor MK-3475 in patients with non-small cell lung cancer (NSCLC) and melanoma, according to two analyses presented at the 2014 AACR Annual Meeting.

In NSCLC, patients whose tumors expressed high-levels of PD-L1 saw improvements in disease progression and survival rates, compared with those who had low levels of PD-L1. In melanoma, patients whose tumors expressed PD-L1 saw greater immune responses, slower disease progression, and higher survival rates, compared with patients whose tumors had no PD-L1. In both studies, patients with low-levels of PD-L1 still experienced some level of response to treatment.

“In both types of advanced cancers studied, we are seeing durable responses in a wide range of patients, including those with PD-L1 negative tumors,” Eric Rubin, MD, vice president, Oncology, Merck Research Laboratories, said in a statement. “We will continue to explore PD-L1 expression and other selection markers across tumors in our MK-3475 development program.”

NSCLC

The phase I NSCLC analysis included data from 146 patients. After 6 months of treatment with MK-3475, 72% of patients with high-levels of PD-L1 were alive compared with 53% for those with low-levels. The rate of progression-free survival (PFS) was 41% compared with 17%, for high and low PD-L1 expression, respectively.

“Patients with previously treated NSCLC have a very poor outlook and there is a real need for new treatment options,” Leena Gandhi, MD, PhD, lead author on the study, assistant professor of medicine at Harvard Medical School, and thoracic oncologist at the Dana-Farber Cancer Institute, said in a statement. “The responses we have seen among patients whose tumors express high levels of PD-L1 appear to be quite durable, which is extremely exciting.”

Researchers determined that a pretreatment tumor PD-L1 level of greater than 50%, as measured by immunohistochemistry, was the best cutoff for differentiating between positive and negative.

Melanoma

MK-3475 was administered to 195 patients with late-stage melanoma in the phase I clinical trial, some of which received prior ipilimumab. Following 6 months of treatment with MK-3475, the overall response rate (ORR) for patients who expressed PD-L1 was 46% compared with 17% for those who did not. The PFS rate 64% versus 34%, respectively, for patients who expressed PD-L1 and those who did not. Further, 86% of patients treated with MK-3475 whose tumors had PD-L1 were alive after 1 year, compared with 72% of patients whose tumors did not have PD-L1.

Adil I. Daud, MD

Image courtesy UCSF

Adil I. Daud, MD

“Data from this study identifies PD-L1 as a robust marker in determining which melanoma patients may be well served when treated with MK-3475,” Adil I. Daud, MD, lead author on the study, co-director of the UCSF Melanoma Center, and director of melanoma clinical research at the UCSF Helen Diller Family Comprehensive Cancer Center, said in a statement. “However, we are studying more samples from randomized trials of PD-1 inhibitor versus ipilimumab or chemotherapy to establish the validity of this marker.”

In the trial, PD-L1 positivity was determined if at least one cell per 100 tumor cells expressed the protein. Of 125 evaluable samples, 89 had PD-L1 while 36 did not.

ORR was not significantly different among patients with PD-L1-positive tumors who received prior ipilimumab compared with those who did not (44% versus 47%) and among those with PD-L1-negative tumors (14% versus 17%). This indicates, Daud said in a statement, that prior treatment with ipilimumab impacted neither response nor PD-L1 as a marker of response to MK-3475.

The development of MK-3475 (formerly lambrolizumab) has been eventful over the past year.

In April 2013, MK-347 received a Breakthrough Therapy designation for the treatment of patients with advanced melanoma.

In February 2014, Merck announced the signing of clinical collaboration agreements to evaluate the agent in combination with axitinib in renal cell carcinoma, talimogene laherparepvec (T-VEC) in previously untreated advanced melanoma, the immunotherapy INCB24360 in previously treated metastatic recurrent NSCLC, and PF-2566 in multiple cancer types.

MK-3475 is now under evaluation in 13 trials across more than 30 types of cancer including bladder, colorectal, gastric, head and neck, melanoma, non-small and small cell lung, renal, pancreatic, prostate, triple negative and estrogen-receptor positive HER2-negative breast, gynecologic, and hematologic malignancies.

Recent Videos
1 KOL is featured in this series.
1 KOL is featured in this series.
1 KOL is featured in this series.
1 KOL is featured in this series.
1 KOL is featured in this series.
Related Content