Long-term benefits of encorafenib plus binimetinib in the first-line treatment of BRAFV600 mutant melanoma
A five-year landmark analysis of the phase III COLUMBUS trial demonstrates a continued long-term overall (OS) and progression-free survival (PFS) benefit of encorafenib plus binimetinib over vemurafenib in patients with BRAFV600mutant advanced melanoma. This benefit was most pronounced in patients with a low tumour burden, normal LDH levels and less than three involved organs.
Dual BRAF/MEK inhibitor therapy is the current standard of care for the treatment of BRAFV600-mutant locally advanced or metastatic melanoma. Encorafenib is a highly selective ATP-competitive BRAF inhibitor and binimetinib is a potent, selective allosteric, ATP-uncompetitive MEK1/2 inhibitor. The two-part, phase III COLUMBUS trial compared the efficacy and safety of a combination of these two agents against the BRAF inhibitor vemurafenib in patients with BRAFV600-mutant melanoma. In previous reports of this trial, the combination of encorafenib and binimetinib was shown to significantly prolong the median PFS compared to vemurafenib (14.9 versus 7.3 months). Similarly, the median OS was significantly extended with the combination therapy (33.6 versus 16.9 months). At ASCO 2021, a five-year update from part 1 of the COLUMBUS trial was presented.
COLUMBUS study design
The multicentre, randomised, open-label phase III COLUMBUS study enrolled 577 patients from 162 clinical sites in 28 countries. All patients had locally advanced unresectable or metastatic melanoma that was untreated or progressed following first-line immunotherapy. Further inclusion criteria included an ECOG performance status of 0 or 1 and the presence of a BRAFV600E or V600K mutation. Patients were randomly allocated (1:1:1) to encorafenib 450 mg once daily (QD) + binimetinib 45 mg twice daily (BID) (COMBO450), encorafenib 300 mg QD (ENCO300), or vemurafenib 960 mg BID (VEM). The data presented at ASCO 2021 consisted of an updated analysis including PFS, OS, objective response rate (ORR) and safety after a minimum follow-up period of 65.2 months.
Continued long-term benefit of encorafenib plus binimetinib
As reported earlier, patient baseline characteristics, including lactate dehydrogenase (LDH) levels, tumour stage and number of organs involved, were well balanced between the three treatment arms. At the five-year PFS landmark analysis, a PFS rate of 22.9% was reported for the COMBO450 arm, as compared to 19.3% for ENCO300 and 10.2% for VEM. This translates into a median PFS of 14.9, 9.6 and 7.3 months, respectively (COMBO450 vs. VEM HR [95%CI]: 0.51 [0.40-0.67]). Interestingly, the benefit of the combination regimen was much more pronounced in patients with normal LDH levels compared to patients with elevated LDH (22.0 vs. 5.6 months, HR [95%CI]: 4.22 [2.83-6.27]). In an attempt to further identify patients who obtained the largest benefit from COMBO450, the investigators zoomed in on a subgroup of patients with a low tumour burden, a normal LDH level and less than three involved organs. For these patients, a five-year PFS rate of 38.6% was reported with an impressive median PFS of 25.9 months.
At five-years, the OS rate was fairly similar for the combination and encorafenib monotherapy at 34.7 % and 34.9%, respectively. In contrast, for patients treated with vemurafenib this 5-year OS rate was markedly lower at only 21.4%. Overall, a median OS of 33.6, 23.5 and 16.9 months, was observed for the COMBO450, ENCO300 and VEM regimen, respectively. Also in terms of OS, patients with normal LDH levels had a more favourable outcome than patients with an increased LDH level (five-year OS rate 45.1% vs. 9.1%). For patients with low tumour burden, normal LDH levels and less than three organs involved, the five-year OS rate was 47.7%.
For COMBO450, ENCO300 and VEM, the objective response rate (ORR) was 64.1% 51.5% and 40.8% with a median duration of response (DoR) of 18.6, 15.5, and 12.3 months, respectively. Following study drug discontinuation, 43.8% of the patients in the combination arm, 57.7% of patients in the encorafenib arm and 67.0% of patients in the vemurafenib arm required second-line treatment. The most common subsequent treatment in all arms was checkpoint inhibitor monotherapy (34.4%, 37.1% and 42.4% for COMBO450, ENCO300 and VEM, respectively).
The safety profile observed with a longer follow-up was consistent with previous observations with encorafenib and binimetinib. Adverse events (AEs) of all grades occurring in at least 30% of patients in the encorafenib + binimetinib arm were nausea (44.3%), diarrhoea (39.1%), vomiting (33.3%), fatigue (30.2%) and arthralgia (30.2%).
Updated efficacy results demonstrate continued long-term benefits of encorafenib plus binimetinib in the first-line for patients with BRAFV600-mutant melanoma. Moreover, the head-to-head comparison of the two BRAF inhibitors encorafenib and vemurafenib in this trial also suggests that the pharmacological specificities of encorafenib also translate into an improved efficacy. The safety profile observed with a longer follow-up was consistent with previous observations with encorafenib and binimetinib.
Dummer R, et al. Five-year overall survival (OS) in COLUMBUS: A randomized phase 3 trial of encorafenib plus binimetinib versus vemurafenib or encorafenib in patients (pts) with BRAF V600-mutant melanoma. Presented at ASCO 2021; Abstract 9507.