There are many hopes that combining immune checkpoint inhibitor drugs, or combining them with drugs of other types (immunotherapy, targeted therapy, or chemotherapy) is the future of treatment for many kinds of cancer. Literally hundreds of clinical trials are actively exploring these combinations, and melanoma is the cancer for which trials of this type abound. Last month, the annual meeting of the American Society of Clinical Oncology (ASCO) in Chicago featured just a few presentations in this area, apparently because it is too early to report results from the many ongoing trials with drug combinations.
Options for patients who had no response to immune checkpoint drugs: Several studies have addressed the unmet needs of melanoma patients who have had no response to U.S. Food and Drug Administration (FDA)-approved immune checkpoint drugs (including nivolumab, pembrolizumab, and ipilimumab) or have relapsed after treatment. In one clinical trial, a drug consisting of an antibody to the immune checkpoint protein LAG-3 was examined in combination with nivolumab (an anti-PD-1 drug) in 55 melanoma patients who previously had no response to or relapsed after receiving anti-PD-1 drugs. 12.5% of these patients had a response to the combination treatment. Notably, patients whose biopsies showed LAG-3 expression in at least 1% of immune cells within the tumor faired better, with a 20% response rate (versus 7% in patients with a LAG-3 presence of less than 1%).
More promising results were reported for the combination of an oncolytic (cancer-killing) cold virus called CVA21 (brand name CAVATAK) with ipilimumab (an anti-CTLA4 immune checkpoint inhibitor drug). CVA21 is injected intralesionally; i.e., directly into accessible tumors. Of 22 evaluable patients, responses were observed in 11 (50%), with 4 complete responses, and all responses of long duration. This included some patients previously treated with checkpoint inhibitors, who had a somewhat lower but significant response rate of 36%.
Newly diagnosed melanoma: For patients with newly diagnosed melanoma, addition of epacadostat to nivolumab proved to be quite effective, bumping the response rate up from the historical 32% with nivolumab alone to 56%, with 6% complete remissions. Epacadostat is a small-molecule drug that inhibits the regulatory T cells that dampen the immune system response to cancer. Interestingly, response to epacadostat was still at least somewhat dependent on the presence of the protein PD-L1 in tumors, with a 71% response rate in PD-L1-positive patients versus 29% in PD-L1-negative patients.
Brain metastases: Some encouraging news was reported for melanoma patients with brain metastases. For patients with BRAF-mutant melanoma that had metastasized to the brain, a study from Texas demonstrated a 58% overall response rate with the drugs dabrafenib and trametinib. The duration of response was not as long as usually seen in patients without brain metastases, but it was still impressive, with a median duration of 6.5 months.
In an Australian study, combination of nivolumab with ipilimumab was able to induce responses in 46% of melanoma patients who received the treatment.
Numerous other trials are exploring combinations of immune checkpoint drugs that target about a dozen different proteins that regulate the function of the immune system. There is hope that at least some of these combinations will prove to be more active than any single immune checkpoint drug on its own.