Biomarker Identifies Melanoma Patients Who May Respond to Immunotherapy MK-3475
Among melanoma patients treated with the PD-1 inhibitor MK-3475, those whose tumors had the protein PD-L1 had better immune responses and higher survival rates, according to results presented at the American Association for Cancer Research (AACR) Annual Meeting 2014 in San Diego.
When the protein PD-L1 binds to PD-1, a protein present on T cells, it prevents the T cells from attacking cancer cells. The immunotherapy MK-3475 blocks PD-1, releasing the “brakes” on T cells and enabling them to attack the cancer cells.
Study Details
To evaluate the relationship between tumor PD-L1 expression and clinical outcome, the investigators studied tumor samples collected from 195 patients recruited to a phase I clinical trial testing MK-3475 at three different doses. All patients had late-stage melanoma, and some of them had received prior treatment with ipilimumab (Yervoy), another immunotherapy drug.
The investigators measured the amounts of PD-L1 in the tumor samples and considered them PD-L1–positive if at least one cell per 100 tumor cells contained the protein. They found that, of the 125 evaluable tumor samples, 89 were PD-L1–positive and 36 were PD-L1–negative.
Improved Response Rate in PD-L1–Positive Tumors
Among melanoma patients who received MK-3475, those whose tumors had PD-L1 had an overall response rate of 46%, while those whose tumors did not have PD-L1 had an overall response rate of 17%. At 6 months, 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 1 year, compared with 72% of those whose tumors were PD-L1–negative.
Patients with PD-L1–positive tumors had disease that did not progress for about 50 weeks, while disease progressed at about 12 weeks for those with PD-L1–negative tumors.
The investigators also found that among patients whose tumors were PD-L1–positive, overall response rates between those who had and had not received prior therapy with ipilimumab (44% vs 47%) were not significantly different. Similarly, among patients whose tumors were PD-L1–negative, overall response rates between those who had and had not received prior therapy with ipilimumab (14% vs 17%) were not significantly different.
“This suggests that prior treatment with the anti–CTLA-4 antibody ipilimumab does not impact the ability of these tumors to respond to MK-3475, nor does it affect the viability of PD-L1 as a marker of response to MK-3475,” said Dr. Daud.
The investigators found a 24% and 17.5% increase in CD8-positive and CD4-positive T cells in the blood of patients treated at three different doses of MK-3475 for 6 weeks, leading them to suggest that the treatment improved the immune response in these patients at all doses tested.
‘Robust’ Biomarker
“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 Adil I. Daud, MD, Co-Director of the UCSF Melanoma Center, and Director of Melanoma Clinical Research at the UCSF Helen Diller Family Comprehensive Cancer Center. “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.
“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. However, we are studying more samples from randomized trials of PD-1 inhibitor vs ipilimumab or chemotherapy to establish the validity of this marker,” added Dr. Daud.
This study was funded by Merck. Dr. Daud has served on the advisory boards of Merck and GlaxoSmithKline PLC.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
