Up to 10 Years of Follow-Up Uphold Survival Benefit With Adjuvant Dabrafenib/Trametinib in Stage III Melanoma

The combination of dabrafenib (Tafinlar) and trametinib (Mekinist) continued to showcase improved survival vs placebo when used as an adjuvant treatment in patients with stage III melanoma, although overall survival (OS) and melanoma-specific survival (MSS) benefits were not statistically significant, according to more than 8 years of follow-up from the phase 3 COMBI-AD trial (NCT01682083) that were presented during the 2024 ASCO Annual Meeting and simultaneously published in The New England Journal of Medicine.¹

Results of the final analysis showed that, at 8 years, the OS rate with the combination (n = 438) was 71% compared with 65% in those who received placebo (n = 432). The median OS was not available (NA) in either the combination (95% CI, 120.7-NA) or placebo (95% CI, NA-NA) arm (HR, 0.80; 95% CI, 0.62-1.01; P = .063). The median MSS in the ITT population was NA in both arms (HR, 0.78; 95% CI, 0.59-1.02); the 8-year MSS rates were 76% with dabrafenib/trametinib and 70% with placebo.

Additionally, there was a 48% reduction in the risk of relapse with the combination vs placebo (HR, 0.52; 95% CI, 0.43-0.63) in the intent-to-treat population. The median relapse-free survival (RFS) was 93.1 months (47.9-NA) compared with 16.6 months (12.7-22.1) with placebo, and the RFS rates were 50% and 35%, respectively, at 96 months.

Furthermore, the median distant metastasis-free survival (DFMS) was NA (95% CI, NA-NA) vs 114.6 months with the combination vs placebo, respectively, translating to a 44% reduction in the risk of distant metastasis (HR, 0.56; 95% CI, 0.44-0.71). The 8-year DFMS rates were 64% with dabrafenib/trametinib and 53% with placebo.

“I have just reported the longest follow-up—up to 10 years—for any of the standardly available adjuvant treatments for resected stage III melanoma. There were durable improvements in DFS and DMFS with dabrafenib combined with trametinib vs placebo,” senior author Georgina V. Long, MD, MSc, chair of melanoma medical oncology and translational research, at The University of Sydney in Australia, said in a presentation of the meeting. “The OS and MSS […] were numerically improved—however, not statistically significant—and this was despite effective post-relapse systemic therapy.”

The results were consistent with the 3-year (86% vs 77%, respectively) and 5-year (79% vs 70%) OS rates seen in earlier data from the trial.² At 5 years of follow-up, the median RFS was not reached (NR) with the combination (95% CI, 47.9-NR) and 16.6 months (95% CI, 12.7-22.1) with placebo (HR, 0.51; 95% CI, 0.42-0.61). Five-year RFS rates were 52% (95% CI, 48%-58%) and 36% (95% CI, 32%-41%), respectively.

Dabrafenib plus trametinib gained FDA approval in April 2018 for use as an adjuvant treatment for patients with BRAF V600E/K mutations and lymph node involvement following complete resection, based on the COMBI-AD findings.³

The double-blind, placebo-controlled, phase 3 COMBI-AD trial, enrolled patients with completely resected cutaneous melanoma that was BRAF V600E/K mutant. Patients needed to have stage IIIA, IIIB, or IIIC disease, have undergone resection within 12 weeks prior to randomization, and they could not have received prior systemic therapy. They also needed to have an ECOG performance status of 0 to 1.

Participants were randomized to receive 150 mg of dabrafenib twice daily and 2 mg of trametinib once daily (n = 438) or matching placebos (n = 432). Treatment was administered for up to 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 end point was RFS, and secondary end points were OS, DMFS, freedom from relapse, and safety.

The primary analysis comprised RFS (HR, 0.47; 95% CI, 0.39-0.58; P <.001), DMFS (HR, 0.51; 95% CI, 0.40-0.65), and OS (HR, 0.57; 95% CI, 0.42-0.79; P = .0006) data, which had a median follow-up of 34 months. An updated analysis included RFS and DMFS data at a median follow-up of 44 months. The most recent prior analysis reported RFS and DMFS data at a median follow-up of 60 months.

The results presented at the 2024 ASCO Annual Meeting was of the post-hoc analysis, which reported on RFS, DMFS, and MSS. Long noted that the last patient had their last visit on July 31, 2023, officially closing the trial.

The OS is reported over the longest period of follow-up, which is up to 125 months. The median follow-up in the combination arm was 100.0 months (range, 0-125) and 82.5 months (range, 1-122) in the placebo arm. A total 71% and 69% of patients, respectively, were censored for the OS analysis.

Relapse rates were 46% and 63% in the combination and placebo arms, respectively. Twenty-nine percent and 31% of patients in each arm died; 23% and 26% of these patients, respectively, died due to melanoma. A total 51% of those on the combination and 44% of those on placebo remained on follow-up at study closure.

Baseline characteristics were well-balanced between the 2 arms. Across the arms, the median age was 50.5 years (range, 18-89), 45% of patients were male, and 91% of patients had BRAF V600E status. Ninety-one percent of patients had an ECOG performance status of 0. The disease stage (AJCC 7) breakdown was stage IIIA (17.5%), IIIB (41%), IIIC (39.5%), and III unspecified (1.5%). Patients either had 1 (41%), 2 or 3 (36.5%), more than 4 (17%), or unknown (6.5%) positive lymph nodes. Lymph node involvement was microscopic (35.5%), macroscopic (36.5%), or unknown (27.5%). More than half of patients did not have primary tumor ulceration (58%), and most did not have in-transit disease (89.5%).

The OS benefit with dabrafenib/trametinib were observed across most prespecified subgroups, except for those with a BRAF V600K mutation (n = 37; HR, 1.95; 95% CI, 0.84-4.50).

When examined further, the 8-year OS rates were 71% with dabrafenib/trametinib vs 63% with placebo in those with BRAF V600E mutations (HR, 0.75; 95% CI, 0.58-0.96) compared with 77% vs 64% in those with BRAF V600K mutations (HR,1.95; 95% CI, 0.84-4.50).

“However, please note, the confidence interval is very wide, and it was a small subgroup,” Long added.

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

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

In the placebo arm, subsequent systemic treatment included anti–PD-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%), biologic therapy (3%), or investigational therapy (5%).

Safety results were consistent with prior COMBI-AD reports, and most patients with malignancies had resolved or recovered events with dabrafenib/trametinib (73%) and placebo (86%). Long noted that there were no new safety concerns nor irreversible long-term toxicities, and malignancies were mainly seen in the first 3 years of follow-up. Adverse cancer event rates were 12% in the combination arm and 9% in the placebo arm.

“This can be accounted for because more patients in the dabrafenib/trametinib arm were on protocol in that first 3 years and underwent mandatory skin surveillance. This may account for the higher number of skin cancers detected,” Long concluded.

Disclosures: Long cited honoraria from Bristol Myers Squibb and Pierre Fabre, and consulting or advisory roles with Agenus, Amgen, Array BioPharma, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Evaxion Biotech, Hexal, Highlight Therapeutics, Immunocore Ireland, Innovent Biologics, IO Biotech, Merch Sharp & Dohme, Novartis, OncoSec, PHMR, Pierre Fabre, and Regeneron.

References

1. Hauschild A, Dummer R, Santinami M, et al. Long-term follow up for adjuvant dabrafenib plus trametinib in stage III BRAF-mutated melanoma: final results of the COMBI-AD study. J Clin Oncol. 2024;42(suppl 16; abstr 9500). doi:10.1200/JCO.2024.42.16_suppl.9500
2. Dummer R, Hauschild A, Santinami M, et al. Five-year analysis of adjuvant dabrafenib plus trametinib in stage iii melanoma. N Engl J Med. 2020;383(12):1139-1148. doi:10.1056/NEJMoa2005493
3. FDA approves dabrafenib plus trametinib for adjuvant treatment of melanoma with BRAF V600E or V600K mutations. FDA. News release. April 30, 2018. Accessed May 31, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-dabrafenib-plus-trametinib-adjuvant-treatment-melanoma-braf-v600e-or-v600k-mutations