Survival benefit of adjuvant dabrafenib/trametinib in patients with stage III melanoma maintained at 10 years of follow-up

According to more than 8 years of follow-up results from the phase 3 COMBI-AD trial (NCT01682083) published in 2024, although the benefits in overall survival (OS) and melanoma-specific survival (MSS) were not statistically significant, they were comparable to placebo. The combination of dabrafenib/trametinib continues to show superior survival rates when used as adjuvant therapy for patients with stage III melanoma.

The final analysis showed that at 8 years, the OS rate of the combination group (n=438) was 71%, while the OS rate of the placebo group (n=432) was 65%. Median OS was not available (NA) in the combination group (95% confidence interval, 120.7-NA) or placebo group (95% confidence interval, NA-NA) (HR, 0.80; 95% confidence interval: 0.62-1.01; P=0.063). Median MSS in the ITT population was NA in both groups (HR, 0.78; 95% CI, 0.59-1.02); the 8-year MSS rate was 76% in the dabrafenib/trametinib group and 70% in the placebo group.

Additionally, the combination reduced the risk of relapse by 48% compared with placebo (HR, 0.52; 95% CI, 0.43-0.63). Median relapse-free survival (RFS) was 93.1 months (47.9-NA) compared with 16.6 months (12.7-22.1) in the placebo group, with RFS rates of 50% and 35% at 96 months. The median distant metastasis-free survival (DFMS) in the combination group and placebo group was NA (95% CI, NA-NA) and 114.6 months, equivalent to a 44% reduction in the risk of distant metastasis (HR, 0.56; 95% CI, 0.44-0.71). The 8-year DFMS incidence rate was 64% for dabrafenib/trametinib and 53% for placebo.

reported the longest follow-up of resected stage III melanoma with any standard available adjuvant therapy of up to 10 years. Dabrafenib plus trametinib produced durable improvements in DFS and DMFS compared with placebo, with numerical improvements in OS and MSS that were not statistically significant, despite effective systemic therapy after relapse. These results are consistent with the 3-year (86% and 77%, respectively) and 5-year (79% and 70%, respectively) OS rates seen in early data from the trial. At 5 years of follow-up, the median RFS was not reached (NR) for the combination (95% CI, 47.9-NR) and placebo (HR, 0.51; 95% CI, 0.42-0.61), nor was the median RFS at 16.6 months (95% CI, 12.7-22.1). The five-year RFS rates were 52% (95% CI, 48%-58%) and 36% (95% CI, 32%-41%) respectively.

Based on the COMBI-AD study results, dabrafenib plus trametinib was approved in April 2018 The U.S. Food and Drug Administration (FDA)approved it for the adjuvant treatment of patients with BRAF V600E/K mutations and lymph node involvement after complete resection. The double-blind, placebo-controlled, phase 3 COMBI-AD trial enrolled patients with completely resected cutaneous melanoma harboring the BRAF V600E/K mutant. Patients requiring disease stage IIIA, IIIB, or IIIC underwent resection within 12 weeks before randomization and they were previously ineligible for systemic therapy. They also need to have an ECOG performance status of 0 to 1.

Participants were randomized to receive dabrafenib 150 mg twice daily and trametinib 2 mg once daily (n=438) or matching placebo (n=432). Treatment continued for 1 year or until relapse, unacceptable toxicity, withdrawal of consent, or death. Stratification factors included BRAF mutation (V600E or V600K) and disease stage (IIIA, IIIB, or IIIC). The primary endpoint is RFS, and secondary endpoints are OS, DMFS, relapse-free and safety.

Primary analysis includedRFS (HR, 0.47; 95% CI, 0.39-0.58; P<0.001) , DMFS (HR, 0.51; 95%CI, 0.40-0.65) and OS (HR, 0.53; 95%CI, 0.42-0.79; P=0.0006) data, the median follow-up time was 34 months. An updated analysis included RFS and DMFS data, with a mean follow-up of 44 months. The most recent previous analysis reported RFS and DMFS data with a median follow-up of 60 months.

The results presented at the 2024 ASCO Annual Meeting are post hoc analyses, reporting on RFS, DMFS, and MSS. OS is reported over the longest follow-up period, up to 125 months. The median follow-up time was 100.0 months (range 0-125) in the combination group and 82.5 months (range 1-122) in the placebo group. 71% and 69% of patients, respectively, underwent OS analysis. The relapse rates were 46% in the combination group and 63% in the placebo group. Twenty-nine percent and 31% of patients in each group died; 23% and 26%, respectively, of these patients died from melanoma. At the end of the study, 51% of patients in the combination group and 44% of patients in the placebo group continued to be followed.

Baseline characteristics were well balanced between the two groups. The OS benefit of dabrafenib/trametinib was observed in most prespecified subgroups, except for the BRAF V600K-mutated subgroup (n = 37; HR, 1.95; 95% CI, 0.84-4.50).

On further inspection, inAmong patients with BRAF V600E mutations, the 8-year OS rate was 71% in the dabrafenib/trametinib group versus 63% in the placebo group (HR, 0.75; 95% CI, 0.58-0.96), compared with 77% versus 64% in the BRAF V600K mutation group (HR, 1.95; 95% CI, 0.84-4.50). However, note that the confidence interval is very wide and it is a small subgroup.

atBRAF In the V600E mutant subgroup, median RFS was 109.3 months (95% CI, 47.9-NA) with dabrafenib/trametinib versus 16.6 months (95% CI, 12.7-22.1) with placebo (HR, 0.52; 95% CI, 0.42-0.63); in BRAF In the V600K subgroups, the respective median RFS were 55.5 months (95% CI, 22.5-NA) and 16.6 months (95% CI, 5.6-NA) (HR, 0.59; 95% CI, 0.32-1.09). In the BRAF V600E mutation group, the 8-year RFS rates were 51% and 35% with dabrafenib/trametinib and placebo, respectively, compared with 43% and 36% in the BRAF V600K mutation group.

The median time to first systemic therapy after disease relapse was 8.6 weeks (range, 3.9-26.7) in the dabrafenib/trametinib group compared with 8.4 weeks (range, 4.6-25.1) in the placebo group. Post-treatment systemic therapy was received by 37% and 49% of patients, respectively. In the dabrafenib/trametinib group, these included anti-PD-1 (26%), anti-CTLA-4 (18%), BRAF-targeted therapy (21%; BRAF inhibitor, 21%; MEK inhibitor, 18%), chemotherapy (6%), biological therapy (2%), investigational therapy (2%, or other (<1%)).

In the placebo group, subsequent systemic therapy included antiPD-1 (22%), anti-PD-L1 (<1%), anti-CTLA-4 (19%), talimogene laherparepvec(<1%), BRAF-targeted therapy (37%; BRAF inhibitor, 37%; MEK inhibitor, 22%), chemotherapy (7%), biological therapy (3%), or experimental therapy (5%).

Safety results were consistent with previous COMBI-AD reports, with the majority of patients with malignancies having events resolved or resolved with dabrafenib/trametinib (73%) and placebo (86%). There were no new safety concerns or irreversible long-term toxicities, and malignancies occurred mainly during the first 3 years of follow-up. The rate of adverse cancer events was 12% in the combination group and 9% in the placebo group.