With Immunotherapy, Longer Survival May Come With a Cost in Melanoma

Immunotherapy showed improved survival benefits for stage 3 and 4 melanoma, but it came at a price of greater toxicity, according to a randomized, double-blind phase 3 study that compared 10 mg/kg Yervoy (ipilimumab) or a lower dose of the anti-CTLA-4 anticlonal antibody.

In the study, performed at 87 medical centers in 21 countries, researchers found that median overall survival (OS) for 364 patients receiving 10 mg/kg of Yervoy was 15.7 months compared with 11.5 months for 362 patients assigned to 3 mg/kg of Yervoy.

However, patients in the 10 mg/kg group had a higher incidence of grade 3/4 treatment-related adverse events (AEs), including diarrhea (10 percent vs 6 percent), colitis (5 percent vs 2 percent), increased alanine aminotransferase (3 percent vs 1 percent) and hypophysitis (3 percent vs 2 percent).

Lead author Paolo A. Ascierto, M.D., told CURE that, at least in some patients, improved outcomes outweigh the risk for increased toxicity.

“In the era of anti—PD-1s and the combination of ipilimumab/nivolumab [Opdivo], there is no role for ipilimumab in first-line treatment of advanced melanoma because such treatments showed a better outcome than ipilimumab monotherapy,” he said. “However, ipilimumab might have a role in patients refractory to a first-line immunotherapy—for instance, BRAF wild-type patients who progressed after an anti–PD-1 treatment.

“With ipilimumab, with only four cycles, we have still the possibility to reach a long-term benefit. If it’s true that with 10 mg/kg we have a higher incidence of severe adverse events than with a lower dosage [37 percent vs 18 percent], it’s true as well that in refractory patients, where we have no other options to get a long-term benefit, this is superior to the risks.”

Researchers enrolled adult patients with histologically or cytologically confirmed unresectable stage 3 or 4 melanoma from February 2012 to July 2012. Eligible patients could have been treated previously, as long as they had not received BRAF inhibitors, CTLA-4 or PD-1 antagonists, or PD-L1 or CD137 agonists. Patients who had been treated previously were required to undergo a washout period of four weeks for all previous anticancer therapy and of at least two years for systemic immunosuppressive drugs, except for episodic low-dose corticosteroids.

At a minimum follow-up of 43 months, patients in the 10 mg/kg group received a median of four doses of Yervoy in the initial treatment phase, with 58 percent of patients completing all four doses. Patients in the 3 mg/kg group also received a median of four doses and 67 percent completed all four doses.

At the data cutoff of March 2016, 6 percent of patients in the 10 mg/kg group and 9 percent of patients in the 3 mg/kg group entered the first retreatment phase.

In the initial treatment phase, disease progression and treatment-related adverse events (AEs) were the most common reasons for discontinuation in both treatment groups. Patients in the 3 mg/kg group were more like to experience progression (43 percent vs 30 percent), but patients in the 10 mg/kg group were more likely to leave the study due to treatment-related AEs (24 percent vs 10 percent).

About one-third (36 percent) of patients in the 10 mg/kg group proceeded to systemic therapy, including 16 percent who underwent subsequent immunotherapy (16 percent) and 10 percent who proceeded to targeted therapy. The numbers were similar for patients in the 3 mg/kg group; 38 percent proceeded to systemic therapy, including 14 percent who received immunotherapy and 13 percent who had targeted therapy.

Researchers found that a similar proportion of patients with BRAF-positive tumors received subsequent therapy in both dose groups, 54 percent (43 of 80 patients) in the 10 mg/kg group versus 59 percent (47 of 79 patients) in the 3 mg/kg group. Patients in the 10 mg/kg group were more likely to receive subsequent anti—PD-1 therapy (19 percent vs 10 percent).

Post-hoc analyses showed that patients in both groups who received subsequent immunotherapy, primarily anti—PD-1, had better OS than those who received BRAF and MEK inhibitors or chemotherapy.

Writing in an accompanying editorial, Alexander Menzies, M.D., Ph.D., and Georgina V. Long, Ph.D., M.B.B.S., both with Melanoma Institute Australia, University of Sydney, argued that AEs are less of a concern compared with survival.2

“The best chance of long-term survival (over five years years) might require higher doses of ipilimumab. In an era of increased awareness and prompt management of (predominantly reversible) immunotherapy toxicity, improvements in efficacy might outweigh additional toxicity,” they wrote. “We have yet to reach a point where we are curing most patients with metastatic melanoma. Anti—CTLA-4 therapy is important in achieving this, and this study by Ascierto and colleagues suggests that dosing is important too. Further research is needed, not only into novel targets and combinations, but also into optimum dosing of anti–CTLA-4 in combination.”