麻豆传媒

MADRID -- Adjuvant nivolumab (Opdivo) significantly improved progression-free survival in resected high-risk melanoma as compared with ipilimumab (Yervoy), according to data reported here.

After a minimum follow-up of 18 months, patients who received nivolumab after surgery had a 12-month recurrence-free survival (RFS) of 66% as compared with 53% for patients treated with ipilimumab. Treatment-related grade 3/4 adverse events occurred three times more often with ipilimumab, Jeffrey Weber, MD, of NYU Langone Medical Center in New York City, reported at the congress.

"Over time, the [RFS] difference opens up," said Weber. "At 1-year, the absolute difference was about 10% and then as we got to 18 months it was 13%. The benefit for nivolumab was observed for virtually all of the prespecified subgroups. Nivolumab had a superior profile in comparison to ipilimumab."

Another study reported at ESMO showed that combination adjuvant therapy significantly reduced the rate of recurrence compared with placebo. After almost 3 years of follow-up, patients treated with dabrafenib (Tafinlar)/trametinib (Mekinest) combination therapy had relapse-free survival of 58% versus 39% for patients treated with surgery alone, as reported by Axel Hauschild, MD, of University Hospital Schleswig-Holstein in Kiel, Germany.

Both studies were reported simultaneously in the .

For patients with early-stage melanoma, surgery offers effective treatment associated with high-rates of 5-year survival. Patients with resectable stage III-IV, however, remain at high risk for recurrence after locoregional resection, and many eventually die of metastatic disease. Effective adjuvant therapy might reduce the risk of recurrence after surgical resection of high-risk disease.

Both nivolumab and ipilimumab have FDA-approved indications for advanced/metastatic melanoma. Additionally, ipilimumab received approval as adjuvant therapy for resected stage III melanoma, based on superior recurrence-free survival versus placebo in a . However, 42% of patients in the ipilimumab arm had grade 3/4 adverse events, and half of ipilimumab-treated patients had relapsed after 5 years of follow-up.

A of adjuvant nivolumab for resected stage IIIC and IV melanoma produced encouraging relapse-free and overall survival. The findings of that preliminary study contributed to the rationale for the randomized phase III , comparing nivolumab and ipilimumab as adjuvant therapy in 906 patients with completely resected stage IIIB-IV melanoma.

The trial had a primary endpoint of RFS. Secondary endpoints included overall survival, safety and tolerability, and health-related quality of life.

Data analysis after a minimum follow-up of 18 months for all patients showed a statistically significant 35% reduction in the hazard for RFS in favor of nivolumab (95% CI 0.51-0.83, P<0.0001). Median RFS had yet to be reached in either treatment group, Weber said. The data remained immature for an analysis of overall survival.

A safety analysis showed a 14% incidence of treatment-related adverse events in the nivolumab arm versus 46% in the ipilimumab group. Eight times as many patients discontinued because of treatment-related adverse events with ipilimumab as compared with nivolumab (32% versus 4%). Two treatment-related deaths occurred in the ipilimumab arm versus none in the nivolumab group.

Hauschild reported findings from the that evaluated combination therapy with the BRAF inhibitor dabrafenib and the MEK inhibitor trametinib versus placebo in patients with completely resected stage IIIA-C melanoma. Previous studies showed the combination improved survival in patients with unresectable or metastatic melanoma, Hauschild said.

Investigators randomized 870 patients to the two treatment arms. The trial had a primary endpoint of RFS, and secondary endpoints included overall survival, distant metastasis-free survival, freedom from recurrence, and safety.

The primary analysis showed that the placebo group had a median RFS of 16.6 months, whereas the median had yet to be reached in dabrafenib/trametinib arm. Patients treated with the adjuvant combination had a 53% reduction in the risk of relapse at 3 years as compared with the placebo group (95% CI 0.39-0.58, P<0.001).

In contrast to the CheckMate 238 trial, the largest absolute difference in RFS occurred during the first year (88% versus 56%), decreasing to 23% at 2 years (67% versus 44%) and to 19% at 3 years (58% versus 39%).

A preliminary survival analysis showed a 3-year overall survival of 86% with the combination and 77% with placebo, representing a 43% reduction in the hazard ratio (95% CI 0.42-0.79, P=0.0006). Survival follow-up will continue, as the result did not meet the prespecified definition of a statistically significant difference (P=0.000019).

"The rate of salvage therapy is similar in the two treatment groups, so this is unlikely to affect overall survival," said Hauschild.

The combination adjuvant therapy was associated with higher rates of adverse events, including grade 3/4 events (41% versus 14%), treatment-related serious adverse events (27% versus 4%), adverse events requiring dose interruption (66% versus 15%) or dose reduction (38% versus 3%), and events leading to treatment discontinuation (26% versus 3%).

Differences in the two trials' designs make comparisons difficult, said Reinhard Dummer, MD, of the University of Zurich in Switzerland.

"The good news is that we have two positive trials, and the results of both of the trials are extremely encouraging. Both of the results will change our current practice."