Dabrafenib/Trametinib Yields Sustained Survival During Long-Term Follow-up in Advanced Melanoma

Continued survival was observed in dabrafenib/trametinib combination after 8 years follow-up in patients with advanced melanoma.

Eight years of follow-up found adjuvant dabrafenib (Tafinlar) and trametinib (Mekinist) continued to increase survival for patients with stage III melanoma, though overall survival (OS) and melanoma-specific survival (MSS) vs placebo, according to the phase 3 COMBI-AD trial (NCT01682083).

These results were presented at the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting and simultaneously published in The New England Journal of Medicine.^1,2

Results of the final analysis showed that, at 8 years, the OS rate with the combination (n = 438) was 71% compared with 65% of those who received placebo (n = 432). The median OS was not available (NA) in either the combination (95% CI, 120.7-NA) or placebo arm (95% CI, NA-NA; HR, 0.80; 95% CI, 0.62-1.01; P = .063).

Additionally, there was a 62% 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. Median relapse-free survival (RFS) was 93.1 months (47.9-NA) compared with 16.6 months (12.7-22.1) for 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) and 114.6 months, leading to a 44% reduction in the risk of distant metastasis with the combination vs placebo (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 relapse-free survival and distant metastatic-free survival 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 overall survival and melanoma-specific survival […] 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 COMBI-AD.2 At 5 years of follow-up, the median RFS was not reached with the combination (95% CI, 47.9-NA) 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% and 36%, 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

In the double-blind, placebo-controlled, phase 3 COMBI-AD trial, patients with BRAF 600E/K-mutant stage III melanoma were randomized to receive 150 mg of twice-daily dabrafenib and 2 mg of once-daily trametinib (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.

To be eligible for enrollment, patients had to have completely resected cutaneous melanoma that was BRAF V600E/K mutant; be of stage IIIA, IIIB, or IIIC disease; had undergone resection within 12 weeks prior to randomization; did not have prior systemic therapy; and had an ECOG performance status of 0 to 1. Stratification factors included BRAF mutation (V600E or V600K) and disease stage (IIIA, IIIB, or IIIC).

The primary end points were OS; secondary end points were RFS, DMFS, FFR, 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 data (HR, 0.57; 95% CI, 0.42-0.79; P = .0006) at a median follow-up of 34 months; an updated analysis included RFS and DMFS data a median follow-up of 44 months. The most 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, reporting on RFS, DMFS, and melanoma-specific survival (MSS). Long noted that the last patient had their last visit on July 31, 2023, officially closing the COMBI-AD trial.

The OS reported is over the longest period of follow-up of up to 125 months. The median follow-up in the combination arm was 100.0 months (range, 0-125) months 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 the study closure.

Baseline characteristics were similar and well-balanced between the 2 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 (35.5%), more than 4 (17%), or unknown positive lymph nodes (6.5%). Lymph node involvement was microscopic (35.5%), macroscopic (36.5%), or unknown (27.5%). More than half of patients had 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.

Median RFS in the BRAF V600E-mutant subgroup was 109.3 months (HR, 0.52; 95% CI, 0.42-0.63) vs 55.5 months in the BRAF V600K subgroup (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 comprised, these 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%).

Twenty-nine percent of patients in both arms received salvage immunotherapies. Twenty-one percent of patients in the combination arm had salvage targeted therapy vs 37% of those in the placebo arm.

Further findings showed that 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.

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.”

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