Among melanoma patients treated with the PD-1 inhibitor MK-3475, those whose tumours had the protein PD-L1 had better immune responses and higher survival rates, according to results presented at the AACR Annual Meeting.
When the protein PD-L1, which is present on some melanoma tumours, binds to PD-1, a protein present on T cells, “brakes” are applied on 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.
The study found that among melanoma patients who received MK-3475, those whose tumours had PD-L1 had an overall response rate of 46 percent, while those whose tumours did not have PD-L1 had an overall response rate of 17 percent.
At six months, 64 percent of the patients whose tumours were PD-L1-positive had no disease progression, compared with 34 percent of those whose tumours were PD-L1-negative.
Similarly, 86 percent of the patients whose tumours were PD-L1-positive were alive after one year, compared with 72 percent of those whose tumours were PD-L1-negative.
“We found a major difference in the response rates between patients with PD-L1-positive and PD-L1-negative tumours treated with MK-3475,” said Adil I. Daud, M.D., 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 tumours 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 versus ipilimumab or chemotherapy to establish the validity of this marker,” added Daud.
To evaluate the relationship between tumour PD-L1 expression and clinical outcome, Daud and colleagues studied tumour samples collected from 195 patients recruited to a phase I clinical trial 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 tumour samples and considered them PD-L1-positive if at least one cell per 100 tumour cells had the protein.
They found that, of the 125 evaluable tumour samples, 89 were PD-L1-positive and 36 were PD-L1-negative.
Patients with PD-L1-positive tumours had disease that did not progress for about 50 weeks, while disease progressed at about 12 weeks for those with PD-L1-negative tumours.
The investigators also found that among patients whose tumours were PD-L1-positive, overall response rates between those who had and had not received prior therapy with ipilimumab (44 percent versus 47 percent) were not significantly different.
Similarly, among patients whose tumours were PD-L1-negative, overall response rates between those who had and had not received prior therapy with ipilimumab (14 percent versus 17 percent) were not significantly different.
“This suggests that prior treatment with the anti-CTLA-4 antibody ipilimumab does not impact the ability of these tumours to respond to MK-3475, nor does it affect the viability of PD-L1 as a marker of response to MK-3475,” said Daud.
The investigators found a 24 percent and 17.5 percent increase in two types of activated T cells, CD8-positive and CD4-positive T cells, in the blood of patients treated at three different doses of MK-3475 for six weeks, leading them to suggest that the treatment improved the immune response in these patients at all doses tested.
(30 Jan 2015)
(30 Jan 2015)