A randomised phase 2 study of intermittent versus continuous dosing of dabrafenib plus trametinib in patients with BRAF(V600) mutant advanced melanoma (INTERIM) (1).
This study was a phase 2 clinical trial. The population under investigation comprises patients with BRAF(V600) mutant advanced melanoma. The intervention being investigated was the administration of dabrafenib and trametinib in two different dosing regimens. Patients were randomized to either a continuous dosing group (CONT) or an intermittent dosing group (INT). The CONT group received continuous dosing, while the INT group received dabrafenib on days 1-21 and trametinib on days 1-14 of each 28-day cycle.
The study enrolled a total of 79 patients, with 39 in the INT group and 40 in the CONT group. These patients had a median age of 67 years, with 65% being in stage IV M1c according to the AJCC (7th edition) and 29% having brain metastases.
The results of the study showed that the intermittent dosing regimen was inferior in all efficacy measures compared to the continuous dosing regimen. Specifically, the median progression-free survival (PFS) for the INT group was 8.5 months compared to 10.7 months for the CONT group (HR 1.39, 95% CI 0.79-2.45, p=0.255). The median overall survival (OS) for the INT group was 18.1 months versus not reached in the CONT group (HR 1.69, 95% CI 0.87-3.28, p=0.121). The objective response rate (ORR) was 57% in the INT group compared to 77% in the CONT group. Furthermore, patients in the INT group experienced fewer treatment-related adverse events (76% vs. 88%) but had more grade >3 adverse events (53% vs. 42%). Quality of life measures favored the continuous dosing group.
Additionally, the study found that the detection of mutant BRAF(V600E) ctDNA before treatment was associated with worse overall survival (HR 2.55, 95% CI 1.25-5.21, p=0.01) in both treatment groups. However, a change to undetected ctDNA during treatment did not significantly predict better overall survival.
Clinical Significance
The standard treatment for patients with advanced melanoma harboring the BRAF(V600) mutation typically includes targeted therapy with BRAF inhibitors (such as dabrafenib or vemurafenib) and MEK inhibitors (such as trametinib or cobimetinib). This combination has been shown to improve survival outcomes compared to monotherapy with either class of drugs alone. Additionally, immunotherapy, using agents like PD-1 inhibitors (nivolumab or pembrolizumab) or CTLA-4 inhibitors (ipilimumab), has also become a crucial part of the treatment landscape for advanced melanoma, either as first-line therapy or following targeted therapy.
The results of the "INTERIM" study are particularly impactful in the context of optimizing treatment regimens for patients with BRAF(V600) mutant advanced melanoma. The study's findings suggest that an intermittent dosing regimen of dabrafenib plus trametinib is inferior to continuous dosing in terms of efficacy measures such as progression-free survival, overall survival, and objective response rate. This is significant because it provides important insights into the dosing strategy for these drugs, an area of active research in oncology.
The impact of these results can be considered in several aspects:
Clinical Practice: The findings provide evidence against intermittent dosing as a strategy to improve outcomes or manage side effects in this patient population. Thus, they reinforce the current practice of continuous dosing of BRAF and MEK inhibitors for the treatment of BRAF(V600) mutant advanced melanoma.
Future Research: The results could influence future clinical trials in melanoma, shifting the focus away from intermittent dosing strategies towards other methods of overcoming resistance or improving patient outcomes.
Patient Management: The study highlights the importance of managing side effects in patients receiving continuous dosing, as this group showed a higher rate of treatment-related adverse events.
Personalized Medicine: The correlation of mutant BRAF(V600E) ctDNA with worse overall survival underscores the potential role of biomarkers in guiding treatment and monitoring disease progression.
In summary, while the INTERIM study results do not change the current standard treatment, they are important for confirming the superiority of continuous dosing of BRAF and MEK inhibitors over intermittent dosing in this patient group. This information is valuable for oncologists in making treatment decisions and could guide future research and clinical practice in melanoma.
Dayimu A, Gupta A, Matin RN, Nobes J, Board R, Payne M, et al. A randomised phase 2 study of intermittent versus continuous dosing of dabrafenib plus trametinib in patients with BRAF(V600) mutant advanced melanoma (INTERIM). Eur J Cancer. 2024;196:113455.