Make That a Double

Amid all the excitement over recently approved immunotherapies and targeted drugs for the treatment of later-stage melanoma is an important emerging message: In many cases, two is better than one. Researchers and the FDA have been considering combinations of these newer drugs and, in some cases, finding that these pairs are more effective.

Immunotherapies work by overriding the immune system’s natural checks and balances (known as “checkpoints”) so that the body can recognize and fight cancer cells. Yervoy (ipilimumab) targets CTLA-4, one of the body’s methods of keeping the immune system at bay. Opdivo (nivolumab) targets PD-1, another set of brakes that controls the immune system.

Research suggests that Opdivo and other drugs that inhibit PD-1 are twice as effective as CTLA-4 inhibitors when used alone to fight melanoma. But perhaps even more encouraging has been the finding that the best results come when CTLA-4 and PD-1 inhibitors are combined.

The CheckMate 067 trial, whose results were presented at the annual meeting of the American Society of Clinical Oncology in June, demonstrated that median progression-free survival was 11.5 months for patients who took both Opdivo and Yervoy, 6.9 months for those who took Opdivo alone, and 2.9 months for those who took Yervoy alone. An important aspect about this effect is that some responses are long-lived — for years, suggesting that the immune system continues to work over time.

Combinations of drugs that target the mutated genes that are “drivers” of melanoma are also showing promise. It turns out that the BRAF inhibitor Tafinlar (dabrafenib) and an inhibitor of the MEK gene, Mekinist (trametinib), work better together than either does alone. Another BRAF/MEK inhibitor combination recently approved by the FDA is Cotellic (cobimetinib) with Zelboraf, which was more effective in patients with a specific gene mutation than Zelboraf alone. These kinds of combinations can also help delay melanoma’s ability to develop resistance against treatment.

In some cases, the incidence of side effects increases with combination regimens, but that doesn’t always happen; when it does, these symptoms are often manageable.

Unfortunately, all these drugs have their limits. In all, modern medications can elicit very good responses only in about a quarter of patients with advanced melanoma. The immune system is complicated — we are still learning about its intricate details and finding different levers we can pull using a sophisticated array of biological agents.

More medications like checkpoint inhibitors, along with other drug classes, are being explored in the clinic, and scientists are searching for ways to make existing drugs, both alone and in combination, work for a wider swath of melanoma patients.

As they continue that search, researchers will be guided by the knowledge that combining promising new drugs, most likely in a personalized fashion, may spark greater success.

Debu Tripathy, MDEditor-in-ChiefProfessor of MedicineChair, Department of Breast Medical OncologyThe University of Texas MD Anderson Cancer Center