Data from the five-year analysis featuring extended follow-up from the phase III COMBI-AD study have confirmed that 12 months of adjuvant therapy with Dabrafenib ( Tafinlar ) plus Trametinib ( Mekinist ) led to durable long-term benefit regarding relapse-free survival ( RFS ) in patients with resected stage III melanoma with BRAF V600 mutations.
The efficacy of adjuvant treatment with Dabrafenib plus Trametinib on long-term overall survival ( OS ) remains to be determined.
The latest study findings are published in The New England Journal of Medicine ( NEJM ).
Anti-PD-1 therapy with Nivolumab and Pembrolizumab and a combination of targeted drugs Dabrafenib and Trametinib have shown significant RFS benefits and are considered to be the current standard-of-care adjuvant therapies in resected melanoma.
However, the durability of these benefits with continued follow-up remains an important open issue.
In the phase III COMBI-AD study that involved the patients with resected stage III melanoma with BRAF mutations, 12 months of adjuvant Dabrafenib plus Trametinib resulted in significantly longer three-year relapse-free survival than placebo ( 58% vs 39%; hazard ratio [ HR ] 0.47; 95% CI 0.39 to 0.58; p less than 0.001 ).
Three-year comparison of overall survival between Dabrafenib plus Trametinib and placebo ( 86% vs 77%; HR 0.57; 95% CI 0.42 to 0.79; p = 0.0006 ) in a pre-planned interim analysis that was based on a 26% information fraction did not reach the prespecified significance threshold.
To confirm the long-term stability of the relapse-free survival benefit associated with 12 months of adjuvant treatment with Dabrafenib plus Trametinib, researchers reported the five-year analyses, including relapse-free survival and survival without distant metastasis as the site of first relapse, based on extended follow-up.
The study researchers randomly assigned 870 patients who had resected stage III melanoma with BRAF mutations to receive 12 months of oral Dabrafenib plus Trametinib or two matched placebos.
The study primary endpoint was relapse-free survival.
The overall survival was not analyzed, since the required number of events to trigger the final overall survival analysis had not been reached.
The minimum duration of follow-up was 59 months with median patient follow-up of 60 months for Dabrafenib plus Trametinib and 58 months for placebo.
At 5 years, the percentage of patients who were alive without relapse was 52% ( 95% CI 48 to 58 ) with Dabrafenib plus Trametinib and 36% ( 95% CI 32 to 41 ) with placebo ( HR for relapse or death, 0.51; 95% CI 0.42 to 0.61 ).
The percentage of patients who were alive without distant metastasis was 65% ( 95% CI: 61 to 71 ) with Dabrafenib plus Trametinib and 54% ( 95% CI: 49 to 60 ) with placebo ( HR for distant metastasis or death, 0.55; 95% CI: 0.44 to 0.70 ).
Updated safety analyses were not performed at this data cut-off because no patients were continuing to receive therapy during the extended follow-up period, and reporting of side effects after that point was at the investigator’s discretion.
The vast majority of patients had side effects only during the initial 12 months treatment window. Overall, no clinically meaningful difference in the incidence or severity of serious side effects was reported during the follow-up period between the groups.
In conclusion, in the five-year follow-up of a COMBI-AD study, 12 months of adjuvant therapy with Dabrafenib plus Trametinib resulted in a longer duration of survival without relapse or distant metastasis than placebo with no apparent long-term side effects. ( Xagena )
Source: European Society for Medical Oncology ( ESMO ), 2020