Immunotherapy First for BRAF V600-Mutated Advanced Melanoma

Activating BRAF V600 mutations are present in around 50% of patients with advanced melanoma. Targeted therapy with combinations of BRAF/MEK inhibitors, such as dabrafenib/trametinib, and immune checkpoint inhibitors, such as the combination of nivolumab/ipilimumab, have shown significant survival benefit in these patients. However, the best upfront therapeutic approach for these patients is not defined. Currently in the US, approximately half of all BRAF-mutant patients receive a BRAF/MEK inhibitor combination and about a quarter receive nivolumab/ipilimumab as initial therapy. Results of the trial that will define the optimal sequence of immunotherapy and targeted therapy were eagerly awaited.

In the live inaugural session of the ASCO Plenary Series, which aims to present practice-changing and clinically relevant research in between ASCO meetings, results from the randomized, phase III DREAMseq trial in advanced melanoma were presented by Michael Atkins, MD (Georgetown Lombardi Comprehensive Cancer Center, Washington, US). The aim of the trial was to identify the best treatment sequence for patients with previously untreated BRAF V600-mutant advanced melanoma. The sequence of nivolumab/ipilimumab (4 cycles of immunotherapy combination and then nivolumab maintenance) followed by targeted therapy with dabrafenib/trametinib at the time of disease progression was compared with the alternative sequence (targeted therapy first followed by immunotherapy). Patients (n=265) were stratified according to ECOG performance status 0/1 and lactose dehydrogenase (LDH) normal/high, and randomized in ‘Step 1’ to receive either nivolumab/ipilimumab (Arm A; n=133) or dabrafenib/trametinib (Arm B; n=132). If patients experienced disease progression they crossed over to ‘Step 2’, in which they received the alternate therapy. In total, 73 patients were eligible for crossover, with 46 patients receiving immunotherapy (Arm D) and 27 patients receiving dabrafenib/trametinib (Arm C). The median follow-up was 27.7 months. The results showed that 72% of patients who received immunotherapy first were alive at 2 years vs. 52% of patients who started with the targeted therapy (log-rank P=0.0095). The superior overall survival (OS) with immunotherapy upfront became evident after 10 months of treatment. In addition, first-line nivolumab/ipilimumab resulted in a longer duration of response (not reached vs. 12.7 months; P < 0.001). Of note, the 2-year OS benefit of immunotherapy as upfront treatment was seen across all subgroups including in those with PS0, normal LDH, and stage ≤M1c. Grade ≥3 treatment-related adverse events were similar between the arms in both Step 1 (60% vs. 52%) and Step 2 (54% vs. 50%). There were two treatment-related deaths in the immunotherapy arm in Step 1, due to myocarditis and GI toxicity, and one death in the targeted therapy arm of Step 2, resulting from stroke.

Dr. Atkins concluded that the results are practice-changing and “nivolumab/ipilimumab followed by BRAF/MEK inhibitors (if necessary) should be the preferred treatment sequence for patients with BRAF mutant melanoma”. The abstract discussant, Keith Flaherty, MD (Dana-Farber Cancer Institute/Harvard Medical School and Massachusetts General Hospital, Boston, US) highlighted that for patients with high disease burden and for whom the toxicity profile of combined PD-1/CTLA-4 immunotherapy is not concerning, nivolumab/ipilimumab may be the best initial treatment choice. However, he pointed out that PD-1 monotherapy is a commonly used strategy for lower risk patients because of its high therapeutic index and that nivolumab/ipilimumab combination has never demonstrated superior outcomes to PD-1 monotherapy. He stressed that this remains an important unanswered question.

Atkins, MB et al. J Clin Oncol. 2021;39 (suppl 36): Abstract 356154.