Melanoma Drugs Effective as Adjuvants

Several melanoma drugs already approved to treat metastatic disease can also help prevent recurrence when used as postsurgical adjuvant therapies for high-risk melanoma.

Researchers at the European Society for Medical Oncology (ESMO) Congress in Madrid, Spain, reported on a trio of large phase III trials testing adjuvant strategies in melanoma—a BRAF inhibitor, a combination of a BRAF inhibitor with a MEK inhibitor, and a PD-1 inhibitor. All decreased the risk of disease recurrence compared with placebo or an approved adjuvant therapy following surgery in newly diagnosed patients.

“The newer agents appear to be very active in the adjuvant setting and have very acceptable toxicity,” says Vernon Sondak, MD, of the Moffitt Cancer Center in Tampa, FL, who was not involved in any of the trials. “I think people will look back at 2017 and say, ‘This was the year of adjuvant therapy for melanoma. This was the year that everything changed.’”

The CheckMate 238 study compared the anti–PD-1 checkpoint inhibitor nivolumab (Opdivo; Bristol-Myers Squibb) with the anti-CTLA4 drug ipilimumab (Yervoy; Bristol-Myers Squibb), which has previously been shown to improve relapse-free survival by 25% compared with placebo. The new trial showed that nivolumab reduced the 1-year rate of recurrence or death by 35% relative to ipilimumab, with fewer serious side effects. That's “a very solid improvement,” says Keith Flaherty, MD, of Massachusetts General Hospital in Boston, who participated in the trial. With the usual caveats about cross-trial comparisons, he says, “you do the math serially and end up with a 50% improvement.”

Two other studies presented at ESMO focused on BRAF inhibitors. The COMBI-AD trial of 870 patients with completely resected stage III BRAF-mutated disease evaluated a combination of the BRAF inhibitor dabrafenib (Tafinlar; Novartis) and the MEK inhibitor trametinib (Mekinist; Novartis). Adjuvant treatment with this regimen cut the risk of relapse or death over 3 years by 53% compared with placebo.

The 498-person BRIM8 trial assessed the BRAF inhibitor vemurafenib (Zelboraf; Roche), in a similar patient population and demonstrated a 46% reduction in recurrence compared with placebo, but only among patients with resected stage IIC, IIIA, or IIIB BRAF-mutated melanoma. Among those with more advanced stage IIIC disease, in which the cancer had spread to many lymph nodes, vemurafenib yielded no statistically significant benefit, unlike the BRAF and MEK combination tested in COMBI-AD. These findings, however, “are just not really relevant anymore,” says Jason Luke, MD, of the University of Chicago Medicine in Illinois, who was not involved in this trial. Although BRAF inhibitors were being used as monotherapy when BRIM8 started 5 years ago, he says, now vemurafenib is almost always combined with the MEK inhibitor cobimetinib (Cotellic; Exelixis/Roche) to reduce toxicities and delay resistance.

The fact that the COMBI-AD and BRIM8 trials involved a placebo arm, rather than an active comparator, reflects the paltry selection of FDA-approved adjuvant therapies. When these trials began, the only drug shown to eliminate residual microscopic melanoma after surgery was IFNα. Although it delayed recurrences, it caused serious side effects, with little improvement in overall survival. Thus, adjuvant use of IFNα has remained controversial—Luke says he almost never uses it; Sondak says he regularly does—and investigators leading those trials felt that observation, with a placebo for the sake of blinding, was the more clinically relevant comparison.

Assuming that COMBI-AD and CheckMate 238 lead to FDA approvals for adjuvant use, Luke doubts anyone will prescribe IFNα or ipilimumab following surgery. Yet it's unclear whether a targeted agent or a PD-1 inhibitor would be more effective for the 40% to 50% of patients with melanoma who have BRAF mutations. Additional research into predictive biomarkers should help physicians decide what's best for each patient, but for now, Luke says, “I think a lot of it will come down to doctor preference.”

That's not ideal, but at least physicians have options for two therapeutic strategies they can deploy “with equal confidence,” says Flaherty. Then, “whichever approach is not pursued remains available for use in those patients who do develop a recurrence.” –Elie Dolgin