Meeting News

Dabrafenib-trametinib combination doubles RFS in resected stage III melanoma

MADRID — Adjuvant treatment with dabrafenib and trametinib doubled RFS compared with placebo among patients with resected stage III BRAF-mutant melanoma, according to results of the randomized phase 3 COMBI-AD trial presented at the European Society for Medical Oncology Congress.

Researcher Axel Hauschild, MD, PhD, professor of dermatology at University of Kiel in Germany, described the results as practice changing.

“This study shows a very remarkable hazard ratio with a very narrow confidence interval for this new treatment modality for the adjuvant setting,” Hauschild said during a press conference. “Given the manageable safety profile of this combination, I believe it is a good novel treatment option for BRAF-mutated patients, who represent 40% of the melanoma population.”

Most patients with localized melanoma can be cured with surgery. However, those with stage III disease — characterized by regional nodal involvement — are at higher risk for relapse and death after resection.

No standard exists for adjuvant treatment of stage III melanoma. Although interferon is approved for use in this setting, it increases RFS by only 20% compared with placebo, Hauschild said.

Prior phase 3 trials have showed the combination of the BRAF inhibitor dabrafenib (Tafinlar, Novartis) and the MEK inhibitor trametinib (Mekinist, Novartis) improved clinical outcomes for and appeared well tolerated by patients with advanced or metastatic BRAF V600-mutant melanoma.

The double-blind, placebo-controlled COMBI-AD trial included 870 patients with high-risk, stage IIIA (18%), IIIB (41%) or IIIC (40%) BRAF V600E/V600K-mutant melanoma. Patients had undergone complete surgical resection within 12 weeks prior to randomization, but they had not undergone anticancer therapy.

Researchers randomly assigned 438 patients to dabrafenib 150 mg twice daily plus trametinib 2 mg once daily. The other 432 patients received matching placebos. Treatment continued for 12 months.

RFS served as the primary endpoint. Secondary endpoints included OS, distant metastasis-free survival, freedom from relapse and safety.

After median follow-up of 2.8 years, dabrafenib plus trametinib significantly reduced risk for disease recurrence or death by 53% compared with placebo (HR = 0.47; 95% CI, 0.39-0.58). Median RFS was not reached in the combination therapy group vs. 16.6 months in the placebo group (P < .001).

“This is the best Kaplan-Meier survival curve for relapse-free survival we have ever seen for malignant melanoma,” Hauschild said. “You see differences after 1 year, 2 years and 3 years, so the benefit is maintained over the years.”

The RFS benefit appeared consistent across all patient subgroups, including those stratified by BRAF mutation status and disease stage.

The combination also conferred significant benefits in OS (HR = 0.57; 95% CI, 0.42-0.79), distant metastasis-free survival (HR = 0.51; 95% CI, 0.4-0.65) and freedom from relapse (HR = 0.47; 95% CI, 0.39-0.57).

More patients assigned the combination experienced any-grade adverse events (97% vs. 88%;) and grade 3/grade 4 adverse events (41% vs. 14%). Most toxicities appeared manageable, Hauschild said. However, nearly nine times as many patients assigned the combination as placebo discontinued treatment due to adverse events (26% vs. 3%).

“This could be because 90% of patients had no progressive disease and were treated for the scheduled full year,” Hauschild said. “The longer patients receive treatment, the more likely they are to have adverse events. But there were no new toxicities compared to those already seen in stage IV disease and, overall, we can say the treatment was well tolerated.” – by Mark Leiser

Reference:

Hauschild A, et al. LBA6_PR. Presented at: European Society for Medical Oncology Congress; Sept. 8-12, 2017; Madrid.

Disclosures: GlaxoSmithKline funded this study. Hauschild reports clinical trial support, speaker’s honoraria or consultant fees from Amgen, Bristol-Myers Squibb, Merck Serono, Merck Sharp & Dohme, Novartis, OncoSec, Philogen, Pierre Fabre, Provectus, Regeneron and Roche. Please see the abstract for a list of all researchers’ relevant financial disclosures.

MADRID — Adjuvant treatment with dabrafenib and trametinib doubled RFS compared with placebo among patients with resected stage III BRAF-mutant melanoma, according to results of the randomized phase 3 COMBI-AD trial presented at the European Society for Medical Oncology Congress.

Researcher Axel Hauschild, MD, PhD, professor of dermatology at University of Kiel in Germany, described the results as practice changing.

“This study shows a very remarkable hazard ratio with a very narrow confidence interval for this new treatment modality for the adjuvant setting,” Hauschild said during a press conference. “Given the manageable safety profile of this combination, I believe it is a good novel treatment option for BRAF-mutated patients, who represent 40% of the melanoma population.”

Most patients with localized melanoma can be cured with surgery. However, those with stage III disease — characterized by regional nodal involvement — are at higher risk for relapse and death after resection.

No standard exists for adjuvant treatment of stage III melanoma. Although interferon is approved for use in this setting, it increases RFS by only 20% compared with placebo, Hauschild said.

Prior phase 3 trials have showed the combination of the BRAF inhibitor dabrafenib (Tafinlar, Novartis) and the MEK inhibitor trametinib (Mekinist, Novartis) improved clinical outcomes for and appeared well tolerated by patients with advanced or metastatic BRAF V600-mutant melanoma.

The double-blind, placebo-controlled COMBI-AD trial included 870 patients with high-risk, stage IIIA (18%), IIIB (41%) or IIIC (40%) BRAF V600E/V600K-mutant melanoma. Patients had undergone complete surgical resection within 12 weeks prior to randomization, but they had not undergone anticancer therapy.

Researchers randomly assigned 438 patients to dabrafenib 150 mg twice daily plus trametinib 2 mg once daily. The other 432 patients received matching placebos. Treatment continued for 12 months.

RFS served as the primary endpoint. Secondary endpoints included OS, distant metastasis-free survival, freedom from relapse and safety.

After median follow-up of 2.8 years, dabrafenib plus trametinib significantly reduced risk for disease recurrence or death by 53% compared with placebo (HR = 0.47; 95% CI, 0.39-0.58). Median RFS was not reached in the combination therapy group vs. 16.6 months in the placebo group (P < .001).

“This is the best Kaplan-Meier survival curve for relapse-free survival we have ever seen for malignant melanoma,” Hauschild said. “You see differences after 1 year, 2 years and 3 years, so the benefit is maintained over the years.”

The RFS benefit appeared consistent across all patient subgroups, including those stratified by BRAF mutation status and disease stage.

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The combination also conferred significant benefits in OS (HR = 0.57; 95% CI, 0.42-0.79), distant metastasis-free survival (HR = 0.51; 95% CI, 0.4-0.65) and freedom from relapse (HR = 0.47; 95% CI, 0.39-0.57).

More patients assigned the combination experienced any-grade adverse events (97% vs. 88%;) and grade 3/grade 4 adverse events (41% vs. 14%). Most toxicities appeared manageable, Hauschild said. However, nearly nine times as many patients assigned the combination as placebo discontinued treatment due to adverse events (26% vs. 3%).

“This could be because 90% of patients had no progressive disease and were treated for the scheduled full year,” Hauschild said. “The longer patients receive treatment, the more likely they are to have adverse events. But there were no new toxicities compared to those already seen in stage IV disease and, overall, we can say the treatment was well tolerated.” – by Mark Leiser

Reference:

Hauschild A, et al. LBA6_PR. Presented at: European Society for Medical Oncology Congress; Sept. 8-12, 2017; Madrid.

Disclosures: GlaxoSmithKline funded this study. Hauschild reports clinical trial support, speaker’s honoraria or consultant fees from Amgen, Bristol-Myers Squibb, Merck Serono, Merck Sharp & Dohme, Novartis, OncoSec, Philogen, Pierre Fabre, Provectus, Regeneron and Roche. Please see the abstract for a list of all researchers’ relevant financial disclosures.

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