Dabrafenib plus trametinib as adjuvant treatment of stage III BRAF V600-mutated melanoma: final results from the COMBI-AD trial

At the 2024 ASCO Annual Meeting, researchers reported the final follow-up analysis of the Phase III COMBI-AD trial and published the results of this important study. The trial had a maximum follow-up time of more than 10 years, with a median follow-up time of 8 years, and the results showed continued improvement in recurrence-free and distant metastasis-free survival. This study focuses on patients with resected stage III melanoma, especially those carrying BRAF V600E or V600K mutations, using an adjuvant combination of dabrafenib/dabrafenib plus trametinib. The results show that this combination can reduce the risk of death by 20%.

Previous preliminary analysis has shown that the combination of dabrafenib and trametinib treatment significantly prolonged relapse-free survival after 12 months. This result laid the foundation for the US Food and Drug Administration (FDA) to approve the combination of dabrafenib and trametinib in April 2018. The researchers noted that the 5-year results of this trial showed that adjuvant treatment with dabrafenib plus trametinib significantly improved recurrence-free survival and distant metastasis-free survival compared with the placebo group, but they also emphasized that longer-term data, especially data on overall survival, are needed.

The study was a double-blind randomized controlled trial that enrolled 870 patients, who were randomly assigned in a 1:1 ratio to the dabrafenib plus trametinib group (n=438) and the placebo group (n=432). Treatment lasted for 12 months and the dose of dabrafenib was 150 mg twice daily and trametinib 2 mg once daily. The median duration of follow-up data was 8.3 and 6.9 years, respectively, and baseline characteristics showed a good balance between the two groups, however the investigators noted that black patients were underrepresented in the sample.

In this long-term follow-up analysis, the primary endpoint was recurrence-free survival, while overall survival was assessed as a key secondary endpoint. Other secondary endpoints include distant metastasis-free survival and safety analysis. At 8 years, dabrafenib plus trametinib appeared to have a nonsignificant overall survival benefit compared with placebo, with survival rates of 71% and 65%, respectively, and a hazard ratio (HR) of death of 0.80 (95% confidence interval [CI] 0.62-1.01, stratified log-rank P = 0.06). The researchers also reported a hazard ratio for death of .75 (95% confidence interval, .58–.96) among 792 patients with the BRAF V600E mutation, showing consistent results.

In terms of recurrence-free survival, the median value of the dabrafenib combined with trametinib treatment group wasThe hazard ratio for recurrence or death was .52 (95% confidence interval, .43–.63). Among patients who received these interventions, 28% of the dabrafenib plus trametinib group experienced distant metastatic recurrence compared with 37% of the placebo group (hazard ratio for distant metastasis or death, .569, 95% confidence interval, .44–.71). The estimated 10-year relapse-free survival rate was 48% in the dabrafenib plus trametinib group and 32% in the placebo group. The results for distant metastasis-free survival were equally encouraging, at 63% and 48%, respectively.

Regarding the occurrence of adverse events, 97% of patients treated with dabrafenib combined with trametinib and 88% of patients in the placebo group experienced adverse events, of which 41% and 13% experienced serious adverse events. The investigators observed no new safety signals, but the data showed that the incidence of primary or secondary cancer was higher in the dabrafenib plus trametinib group than in the placebo group (events per 100 patient-years: 4. vs. 2.6). The researchers believe this is due to protocol-mandated skin monitoring and greater patient compliance with the drug regimen. Although there were no deaths in the study group, the most common adverse events included the development of skin cancers, such as basal cell carcinoma, new primary malignant melanoma, and squamous cell carcinoma.

After more than 10 years of follow-up, the researchers concluded that one year of adjuvant treatment with dabrafenib plus trametinib resulted in better recurrence-free survival and distant metastasis-free survival compared with placebo, with no long-term safety issues and a 20% lower risk of death than the placebo group. For melanoma patients with the BRAF V600E mutation, the risk of death is even lower, as much as 25%. These results not only further confirm the effectiveness of dabrafenib and trametinib combination therapy in melanoma, but also provide an important reference for clinical practice and demonstrate the potential of targeted therapy in cancer management.

References:https://ascopost.com/issues/september-25-2024/adjuvant-dabrafenib-plus-trametinib-for-stage-iii-braf-v600-mutated-melanoma-final-results-of-the-combi-ad-trial/