Long-Term Follow-Up Still Shows Tafinlar/Mekinist Benefit in Melanoma

Tafinlar (dabrafenib) plus Mekinist (trametinib) continued to be efficacious in the postsurgical treatment of patients with stage 3 melanoma, according to eight-plus years of follow-up from the COMBI-AD clinical trial.

Results of the final analysis, which were presented at the 2024 ASCO Annual Meeting and published in The New England Journal of Medicine, showed that, at eight years, the overall survival (OS; time from treatment until death of any cause) rate with the combination (438 patients) was 71% compared with 65% in those who received placebo, which is an inactive drug (432 patients).

The median OS was not available (NA) in either the combination or placebo groups. This means that not enough patients had died to calculate an average. Of note, the OS difference was not statistically significant, meaning that the researchers could not say with certainty that one regimen was better than the other.

Additionally, there was a 48% reduction in the risk of relapse with the combination versus placebo in the intent-to-treat population. The median relapse-free survival (RFS; time patients live without their disease coming back) was 93.1 months compared with 16.6 months with placebo, and the RFS rates were 50% and 35%, respectively, at 96 months.

Furthermore, the median distant metastasis-free survival (DMFS; time patients live without disease spreading to other body parts) was NA versus 114.6 months with the combination versus placebo, respectively, translating to a 44% reduction in the risk of distant metastasis. The eight-year DMFS rates were 64% with Tafinlar/Mekinist 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 3 melanoma. There were durable improvements in DFS and DMFS with [Tafinlar] combined with [Mekinist] versus placebo,” senior author Dr. Georgina V. Long, 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 [melanoma-specific survival (MSS)] […] were numerically improved — however, not statistically significant — and this was despite effective post-relapse systemic therapy.”

The results were consistent with the three-year (86% versus 77%, respectively) and five-year (79% versus 70%) OS rates seen in earlier data from the trial.At five years of follow-up, the median RFS was not reached (NR) with the combination and 16.6 months with placebo. Five-year RFS rates were 52% and 36%, respectively.

Tafinlar plus Mekinist was approved by the Food and Drug Administration in April 2018 for use as an post-surgical treatment for patients with BRAF V600E/K mutations and lymph node involvement following complete resection, based on the COMBI-AD findings.

About the COMBI-AD Trial

The phase 3 COMBI-AD trial, enrolled patients with surgically removed cutaneous melanoma that was BRAF V600E/K mutant. Patients needed to have stage 3A, 3B or 3C 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, which indicates that they can perform all daily tasks independently.

The primary end point was RFS, and secondary end points were OS, DMFS, freedom from relapse and safety.

The primary analysis comprised RFS, DMFS and OS 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, meaning that it was analysis after all the data was collected, 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 group was 100 months and 82.5 months in the placebo group. 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 groups, respectively. Twenty-nine percent and 31% of patients in each group 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.

Patient characteristics at the start of the trial were well-balanced between the two groups. Across the groups, 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, indicating that they had no restrictions on their daily activity.

The disease stage breakdown was stage 3A (17.5%), 3B (41%), 3C (39.5%) and 3 unspecified (1.5%). Patients either had one (41%), two or three (36.5%), more than four (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 Tafinlar/Mekinist were observed across most prespecified subgroups, except for those with a BRAF V600K mutation (37 patients).

When examined further, the eight-year OS rates were 71% with Tafinlar/Mekinist versus 63% with placebo in those with BRAF V600E mutations compared with 77% versus 64% in those with BRAF V600K mutations.

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

A confidence interval is a range of numbers that researchers calculate that determines, with 95% certainty, where the true median lies.

The median RFS in the BRAF V600E-mutant subgroup was 109.3 months with Tafinlar/Mekinist versus 16.6 months with placebo; in the BRAF V600K subgroup, the respective median RFS was 55.5 months and 16.6 months, respectively. The eight-year RFS rates were 51% versus 35% with Tafinlar/Mekinist and placebo in the BRAF V600E-mutant group compared with 43% versus 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 to 26.7) on Tafinlar/Mekinist compared with 8.4 weeks (range, 4.6 to 25.1) on placebo. A total 37% and 49% of patients, respectively, received posttreatment systemic therapy. In the Tafinlar/Mekinist group, 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 (less than 1%).

In the placebo group, subsequent systemic treatment included anti-PD-1 (22%), anti-PD-L1 (less than 1%), anti-CTLA-4 (19%), Imlygic (talimogene laherparepvec; less than 1%), BRAF-targeted therapy (37%; BRAF inhibitor, 37%; MEK inhibitor, 22%), chemotherapy (7%), biologic therapy (3%) or investigational therapy (5%).

Further findings showed that the median MSS in the ITT population was NA in both groups; the eight-year MSS rates were 76% with Tafinlar/Mekinist and 70% with placebo.

Safety results were consistent with prior COMBI-AD reports, and most patients with malignancies had resolved or recovered events with Tafinlar/Mekinist (73%) and placebo (86%).

Long noted that there were no new safety concerns nor irreversible long-term side effects, and malignancies were mainly seen in the first three years of follow-up. Adverse cancer event rates were 12% in the combination group and 9% in the placebo group.

“This can be accounted for because more patients in the [Tafinlar/Mekinist] [groups] were on protocol in that first three years and underwent mandatory skin surveillance. This may account for the higher number of skin cancers detected,” Long concluded.

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