Synergistic effect of triple with immunotherapy and targeted therapy?
melanoma
MELANOMA, ADVERSE EVENTS, BRAIN METASTASES, MUTANT, SECONDARY, METASTASES
Consequently, three major prospective randomized clinical trials have been initiated and conducted which are in the follow up phase now.IMspire150 was the first phase III study to investigate combination of IT and TT (triple therapy) in stage IIIC-IV BRAFV600-mutant melanoma [Ascierto et al. have just now published data from a longer follow-up including overall survival data for IMspire150 [We need to stress that these advantages in important outcome parameters are accompanied by additional adverse events and discomfort for the patients due to the repeated infusion procedures. In this study, the subgroup analysis is also interesting, as we see that the benefit from the triplet is preferentially found in the patient population with good prognostic features including normal lactate dehydrogenase (LDH) and limited number of metastases. Patients of advanced age seem to profit more than younger patients. The research community would have preferred to see the benefit of the triplet therapy mainly in high-risk patients characterized by elevated LDH and multiple organ involvement, because these patients have a very high medical need. The triple combination of atezolizumab, vemurafenib and cobimetinib was also used in patients with brain metastases [Keynote-022 is a phase II study that investigated another triple combination with anti-PD-1 antibody pembrolizumab combined with BRAF inhibitor dabrafenib and MEK inhibitor trametinib. Hundred-twenty patients that were randomized at 1:1 ratio to receive pembrolizumab, dabrafenib and trametinib, or dabrafenib and trametinib. The primary endpoint of Keynote-022 was PFS; secondary endpoints were ORR, DoR and overall survival (OS). A numerical improvement in PFS and OS was reported in the triplet arm, compared to control arm, however, not statistically significant and the trial did not meet the primary endpoint [Another study that investigated the combination of IT and TT in patients with unresectable stage IIIC-IV cutaneous In summary, we can conclude that the triple approach did not result in a convincing benefit in the first line setting in mostly previously untreated advanced melanoma patients. Therefore, it was essential to understand how the two major treatment strategies should be sequenced to optimize the outcome in the BRAF mutant patient population.