Biomarker identifies melanoma patients who may respond to immunotherapy
Research uncovers mechanism of melanoma resistance to newly approved drug combination therapy
Among melanoma patients treated with PD-1 inhibitor MK-3475, those whose tumors had the protein PD-L1 had better immune responses and higher survival rates. These research results were presented at the American Association for Cancer Research 2014 Annual Meeting, in San Diego, California.
When the protein PD-L1, which is present on some melanoma tumors, binds to PD-1, a protein present on T cells, brakes are applied to these T cells, preventing them from attacking the cancer cells. The immunotherapy MK-3475 blocks PD-1, releasing the brakes on T cells and enabling them to attack the cancer cells.
This study found that among patients with melanoma who received MK-3475, those whose tumors had PD-L1 had an overall response rate of 46%, whereas 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.
“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, codirector of the University of California San Francisco (UCSF) Melanoma Center, and director of melanoma clinical research at the UCSF Helen Diller Family Comprehensive Cancer Center.
“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 versus ipilimumab or chemotherapy to establish the validity of this marker,” added Daud.
To evaluate the relationship between tumor PD-L1 expression and clinical outcome, Daud and colleagues 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 another immunotherapy drug called ipilimumab.
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 had the protein. They found that, of the 125 evaluable tumor samples, 89 were PD-L1-positive and 36 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.