Combination therapy likely to improve metastatic melanoma response

Banff, Alberta - Evidence from ongoing trials will reveal the optimal approach to combining immune therapy and molecularly targeted therapy in the treatment of malignant melanoma, according to a presenter here at the 8th Canadian melanoma conference.

“One of the issues that comes up when you have multiple types of therapies available is trying to determine the right way to use these treatments in patients,” says Ryan Joseph Sullivan, M.D., an assistant in medicine at Massachusetts General Hospital Cancer Center, Boston, and an instructor at Harvard Medical School. “There is a justification to combine immune therapy and BRAF targeted therapy or MEK targeted therapy. There is also work done to show BRAF inhibitors are not immune suppressive, but MEK inhibitors may be. What is not known is if the combination (BRAF and MEK inhibitor) is immune suppressive or not.”

There are a number of trials with BRAF inhibitors or MEK inhibitors (in combination with immune therapies) or BRAF and MEK inhibitors in combination with a number of immune therapies, Dr. Sullivan says.

It has been observed that there is an ability in cancer cells to express proteins on the cell surface, called antigens, which can be recognized by the immune system, he says.

“BRAF mutations are blocking BRAF, and antigens are increased as a result,” Dr. Sullivan says. “There also is an influx of cytotoxic lymphocytes that can recognize these antigens and help destroy the tumor.”

Trial results

The Food and Drug Administration has approved the combination of BRAF and MEK inhibitors such that initiation of BRAF inhibitors alone has been supplanted by the combination of BRAF and MEK inhibitors in the treatment of metastatic melanoma.

Last year, trial investigators halted a melanoma study in which the BRAF inhibitor vemurafenib and ipilimumb - an immune therapy that targets CTLA-4 - were used in combination, citing cases of hepatoxicity.

But despite the cessation of the phase 1 trial last year, it has not dissuaded researchers from using combination therapies, Dr. Sullivan says.

“The preclinical data is compelling and people have opted not to do away with the combination (molecularly targeted therapy and immune therapy),” he says.

Currently, dabrafenib and ipilimumab are being administered in a trial, and there have been no reports of serious adverse events.

“There have not been reports of the same issues (liver toxicity),” Dr. Sullivan says. “One could imagine that the silence means the toxicity is not happening.”

Next: Molecularly targeted therapy

Molecularly targeted therapy

Some of the molecularly targeted approaches include the BRAF inhibitor vemurafenib combined with the MEK inhibitor cobimetinib and the BRAF inhibitor LGX 818 and the MEK inhibitor MEK 162. Still other treatment approaches consist of a single agent BRAF inhibitor or single agent MEK inhibitor combined with immune therapy.

“The whole goal of combination therapy is to increase the response rate of the single agent BRAF inhibitor or BRAF and MEK inhibitors, by adding the durability of immune therapy, and raising the tail of the (survival) curve,” Dr. Sullivan says. “What remains to be seen is what is the best immune therapy and what is the best molecularly targeted therapy and should the molecularly targeted therapy be given in combination (e.g., BRAF inhibitor plus MEK inhibitor) or as a single agent.”

Interferon, a therapy approved by the Food and Drug Administration for the treatment of high-risk, resected melanoma (stages 2 and 3), has been revisited by clinicians in this era of combining treatments, and is being administered in conjunction with therapies like vemurafenib, Dr. Sullivan notes.

“High-dose interferon is being used in stage 4 disease no less,” he says. “Interferon is immunotherapy that is selective because of the effect that the BRAF inhibitor has on interferon signalling.”

Emerging evidence suggests that certain mutations like NRAS render the tumor more susceptible to immune therapy.

“If it is true, there may be ways to modify signalling to make immunotherapy more effective,” Dr. Sullivan says.

While the combination therapies are being currently being given to patients with stage 4 melanoma, it is possible that these therapies would be administered in patients with earlier stage disease in the future, he says.

“That is the model that has been used (in oncology),” Dr. Sullivan says.

Disclosures: Dr. Sullivan reports no relevant financial interests.