New approval from the field of molecular precision medicine

The targeted combination therapy with encorafenib and binimetinib has recently become available in Switzerland for adults with non-resectable or metastatic melanoma with a ^BRAFV600 mutation. The approval is based on the Columbus study, in which the primary endpoint of progression-free survival as well as several secondary endpoints were met.

This expands the range of therapies for this indication by an effective and at the same time tolerable option, as Prof. Dr. med. Reinhard Dummer, Deputy Clinic Director at the Clinic for Dermatology and Head of the Skin Tumor Center at the University Hospital Zurich and first author of the pivotal COLUMBUS study demonstrated at a press briefing organized by Pierre Fabre on the basis of current data. BRAF-MEK inhibition (^BRAFTOVI® and ^MEKTOVI®) was approved in the U.S. in July 2018 and in the EU two months later. Since December 2019, the combination therapy is now also available in Switzerland [1–3]. After a prolonged period of lack of significant progress in the field of BRAF-mutated melanoma treatment research, several BRAF and MEK inhibitors as well as immunotherapies have received marketing approval in Europe since 2011. The combination therapy encorafenib/binimetinib, now also available in Switzerland, has been shown to be effective and tolerable in advanced ^BRAFV600 mutated melanoma. This is another milestone in the advancement of treatment options in oncology molecular precision medicine, which has significantly improved the likelihood of survival for those affected.

Combination leads to better effects than monotherapy

Efficacy and safety were assessed in the randomized, open-label, active-controlled phase III COLUMBUS trial [4]. Included were 577 patients with locally advanced, unresectable, or metastatic malignant melanoma with BRAFV600 ^mutation(subtype V600 E or K). Encorafenib 450 mg (once daily) and binimetinib 45 mg (twice daily) were compared with encorafenib 300 mg (once daily) monotherapy and vemurafenib 960 mg (twice daily) monotherapy. Prof. Dummer, principal investigator and first author of the COLUMBUS study, emphasizes that the much higher dosing of encorafenib is possible when combined with the MEK inhibitor because, in contrast to the monotherapy condition, there is no dose-dependent increase in side effects, which can be explained by the biological mechanism of paradoxical activation of the signal transduction pathway [1]. Randomization to the three treatment arms was in a 1:1:1 ratio. Although pretreatment with immunotherapy was allowed in the advanced/metastatic setting, more than 90% of patients received first-line study therapy, Prof. Dummer explained [1,4].

Results of the COLUMBUS study

The primary endpoint was progression-free survival (PFS) after central evaluation with combination therapy compared with vemurafenib monotherapy. The main secondary endpoint was PFS with combination therapy compared with encorafenib monotherapy and vemurafenib. With a median PFS on combination targeted therapy of 14.9 months, encorafenib plus binimetinib was significantly superior to vemurafenib monotherapy (7.3 months) (HR: 0.54; 95% CI: 0.41-0.71; p<0.0001) and also fared better than encorafenib treatment alone (9.6 months; HR: 0.68; 95% CI: 0.52-0.90; p<0,007) [4].

Overall survival (OS) showed that this was 33.6 months median under the combination, whereas it was 16.9 months median under vemurafenib (HR: 0.61; 95% CI: 0.47-0.79; nominal p<0.0001) [5]. The data also make clear that subsequent immunotherapies did not appear to impact OS outcomes in the study, as vemurafenib monotherapy in the comparator arm provided very consistent results with previous studies, Prof. Dummer noted. Median overall survival, median progression-free interval, and response rate are very consistent across the three large trials with vemurafenib as control (COLUMBUS I, COMBI-v, coBRIM) [1].

Good long-term data over period of four years

In a recent follow-up presented at the ASCO Congress, data were re-evaluated after 48.8 months of follow-up [6]. The difference in median PFS remained constant compared with previous evaluations at 14.9 vs. 7.3 months (HR: 0.51; 95% CI: 0.39-0.67) [4,5]. OS on combination therapy was a median of 33.6 months (95% CI: 24.4-39.2). In contrast, patients on vemurafenib monotherapy survived a median of 16.9 months (95% CI: 14.0-24.5). “Over the longer observation period of four years, it appears that the survival curves of ^BRAFTOVI® plus ^MEKTOVI® and vemurafenib remain clearly separated,” Dummer explained. Overall, the probability of survival at four years was 39% vs. 25% (HR: 0.61; 95% CI: 0.48-0.79).

The most common adverse events (all grades) on combination therapy remained virtually unchanged after four years. They were nausea (44%), diarrhea (39%), vomiting (32%), fatigue (30%), arthralgia (29%), creatine phosphokinase elevation (26%), headache (26%), and constipation (25%). Substance-typical manifestations requiring regular monitoring, such as increased photosensitivity or pyrexia, were observed with rather low frequency under encorafenib plus binimetinib [6]. Other side effects, mainly BRAF inhibitor-induced skin reactions, are also less pronounced in combination therapy than in monotherapy [1]. Prof. Dummer added, “The side effects under combination therapy are well managed in practice.”

Life expectancy higher than with previous treatment options

Until 10 years ago, median overall survival was expected to be only 8.5 months despite therapy, which has since changed [7,8]. “Long-term survival is increasingly becoming a realistic therapeutic goal,” Prof. Dummer emphasized. In addition to immune checkpoint inhibitors, the introduction of BRAF and MEK inhibitors a few years ago was a milestone for the prognosis of affected patients – this therapy option is now firmly established. The combination of BRAF and MEK inhibitors improves response rates as well as overall survival, while reducing many toxicities compared to monotherapy, allowing for long treatment duration at high dose intensity [9,10].

Source: Pierre Fabre

Literature:

Dummer R: Presentation, Prof. Reinhard Dummer, MD, University Hospital Zurich, Dermatology Clinic,
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