PD-1, PD-L1 pathway inhibition represent melanoma treatment strategy

Banff, Alberta - New research suggests that there are some potential predictive biomarkers relating to the efficacy and toxicity of emerging treatments for metastatic melanoma.

Speaking here at the annual Canadian Melanoma conference, Jeffrey Weber, M.D., Ph.D., a medical oncologist and director of the Donald A. Adam Comprehensive Melanoma Research Center, Moffitt Cancer Center, Tampa, Fla., discussed the potential for sequential treatment of metastatic melanoma that will have a significant impact on the number of responders to treatment.

“They (ipilimumab and anti-PD-1 antibody) appear to have two separate modes of action, and you can fail one and respond to another, which would set up a sequential strategy which would make sense and which everyone is interested in now,” Dr. Weber says.

Studies are pointing to the importance of the programmed death-1 (PD-1) pathway and antibodies that target the PD-1 pathway. There is recognition that PD-1, a checkpoint protein expressed on T lymphocytes, plays a key role in immune tolerance.

Data are suggesting that PD-1 and PD-L1 pathway inhibition are clinically effective strategies to manage disease, and some have even put forth the idea that immunotherapy that targets the PD-1 pathway may serve as the backbone of cancer treatment in the future.

Study results

Research presented at last year’s scientific meeting of the American Society of Clinical Oncology (ASCO) revealed about a third of metastatic melanoma patients, who had failed at least one other therapy, but had not received ipilimumab (Bristol-Myers Squibb), had an objective response, either partial or complete, with the administration of a PD-1 antibody.

The treatment regimen was applied not only to patients with metastatic melanoma, but those with renal cell carcinoma and non-small-cell lung cancer.

“We have now shown that it is safe to give (anti) PD-1 antibody after ipilimumab, which provoked a newly initiated international phase 3 study of PD-1 versus chemotherapy in patients that have failed ipilimumab,” Dr. Weber says. “We have defined further a number of biomarkers for outcomes with (anti) PD-1 antibodies as part of our trial.”

Data presented at last year’s ASCO meeting and other investigations indicate an association between PD-L1 expression and clinical outcome. More specifically, metastatic lesions in melanoma patients that were positive for PD-L1 were linked to improved survival in patients with stage 3 and stage 4 melanoma. Lesions were biopsied and immunohistochemical staining was performed to detect whether lesions were positive or negative for PD-L1 (Taube JM, Anders RA, Young GD, et al. Sci Transl Med. 2012;4(127):127ra37).

“You can treat patients with the vaccine and the PD-1 antibody and can define endpoints relating to changes in antigen-specific T cells and T-regulatory cells,” adds Dr. Weber, noting that patients with resected disease, as well as metastatic disease, have been treated to date.

Unknown adverse effects

The possibility for sequential or simultaneous treatment may mean that patient response rates rise from the current 15 percent to as high as 50 percent, but the side effect profile of the sequential or simultaneous regimens remain to be determined, Dr. Weber says. “The question is what will the toxicity look like,” he says.

Ipilimumab and an anti-PD-1 antibody have not been compared in a head-to-head fashion, but the toxicities associated with ipilimumab and an anti-PD-1 antibody are different, which stands to reason given they target different biological pathways.

Infusion reactions that are mild have been more frequently reported with the use of an anti-PD-1 antibody, while severe colitis has been reported related to use of ipilimumab in patients but is an infrequent adverse event in patients who have been administered an anti-PD-1 antibody.

Apart from BMS-936558, other anti-PD-1 antibodies are being explored, one of which is Merck’s MK-3475, which, like BMS-936558, is being tested in patients who have failed ipilimumab, Dr. Weber notes. It has not been tested in a large number of patients yet, but it has produced partial remissions and complete remissions in patients.

The side effect profile of the drug appears to be favorable, with adverse events like rash, influenza, and pruritus being reported. In less than 10 percent of cases, adverse events rated grade three through five give were reported.

The limitation of the sequential treatment approach is that patients who have a history of autoimmune disease or who have conditions which require immunosuppressive therapies are not suitable candidates for a sequential therapeutic regimen.

The next step forward in treating metastatic melanoma will be the application of checkpoint protein inhibition to adoptive cell therapies, Dr. Weber says.

Disclosures: Dr. Weber has received honoraria from Bristol-Myers Squibb for his attendance at advisory board meetings.