Flaherty Highlights Best-In-Class Findings With BRAF/MEK Inhibitor Combo in Melanoma

Keith T. Flaherty, MD

Keith T. Flaherty, MD

According to data presented at the 2018 ASCO Annual Meeting, the combination of encorafenib (Braftovi) plus binimetinib (Mektovi) demonstrated best-in-class overall survival (OS) and progression-free survival (PFS) in patients withBRAF-mutant metastatic melanoma.

These findings from the phase III COLUMBUS trial led to the FDA approval of the BRAF/MEK inhibitor combination as treatment for this patient population in June 2018.

At a median follow-up of 36.8 months, combining encorafenib at 450 mg daily and binimetinib at 45 mg twice daily (COMBO450) reduced the risk of death by 39% compared to vemurafenib (Zelboraf) as a monotherapy. Median OS for COMBO450 was 33.6 months (95% CI, 24.4-39.2) versus 16.9 months (95% CI, 14.0-24.5), respectively. Median PFS was 14.9 months for COMBO450 versus 7.3 months with single-agent vemurafenib (HR, 0.51; 95% CI, 0.39-0.67; P&nbsp;<.0001).

The survival benefit was maintained across all subgroups, according to Keith T. Flaherty, MD, coauthor of the study. He added that the combination appeared to be well tolerated.

Moreover, an interim analysis suggested an OS benefit for COMBO450 compared with single-agent encorafenib at 300 mg daily. The 33.6-month median OS for COMBO450 significantly surpassed that of 23.5 months for encorafenib monotherapy. Another analysis looked at the two BRAF inhibitors as single agents, and encorafenib showed superiority over vemurafenib.

In an interview withTargeted Oncology, Flaherty, director of the Termeer Center for Targeted Therapy at Massachusetts General Hospital, professor of Medicine, Harvard Medical School, discussed the results for the combination of encorafenib and binimetinib in patients withBRAF-mutated melanoma investigated in the COLUMBUS trial. He also highlights the potential implications and next steps for this combination.

TARGETED ONCOLOGY:Please provide some background to the COLUMBUS trial.

Flaherty:For several years now, we have known thatBRAFmutations are a bonafide therapeutic target in melanoma, with about 45% of patients with advanced disease harboring these mutations. We had a first wave of advances around 2010 with vemurafenib and dabrafenib (Tafinlar) coming along and essentially proving thatBRAFmutations are a good target. Those drugs ultimately became FDA approved just a couple years later. We began to understand that reactivation of the same pathway in which&nbsp;BRAF&nbsp;resides, the MEK pathway, was a very common theme. There were available MEK inhibitors, which target the downstream pathway from&nbsp;BRAF. It was immediately conceived that if we stitch these 2 drugs together, it would be useful.

That has been validated twice over, with dabrafenib/trametinib (Mekinist) and vemurafenib/cobimetinib (Cotellic) being FDA approved for the same population. Encorafenib was essentially the immediate next generation BRAF inhibitor to come along. It was developed in a laboratory to be a more potent and selective BRAF inhibitor than what we've seen before. It was [preclinically] tested head-to-head and shown to be superior. By the time encorafenib had entered clinical development, we knew that BRAF/MEK combination therapy was the emerging, new standard of care.

A rather quick single-agent phase I trial was done, and then immediately it went into a combination phase I trial. Those results looked promising, both from a safety and efficacy perspective. After the completion of those studies, we quickly launched the phase III study looking at the novel combination of encorafenib and binimetinib and comparing it with vemurafenib and also encorafenib alone. Buried in this study is a direct comparison of encorafenib alone versus vemurafenib alone. We never did that in our field, comparing a next-generation BRAF inhibitor to a previous-generation inhibitor. While it's true that the primary outcome was the combination versus historically standard BRAF monotherapy, that internal comparison is critical.

TARGETED ONCOLOGY:Did the interim analysis show superiority with encorafenib?

Flaherty:PFS was the primary endpoint of the study, and we had previously reported that. OS was the focus of our presentation [at the 2018 ASCO Annual Meeting]. It will suffice to say that encorafenib monotherapy was superior to vemurafenib monotherapy in terms of PFS and OS. It clearly validated that this is, in fact, a better BRAF inhibitor. This is important, but the reality is that we moved on from BRAF monotherapy several years ago in this population. While these were intriguing data, it was to a degree more of a scientific point than a clinically relevant point. The focus then shifts to the combination data.

TARGETED ONCOLOGY:What else is important to report from these findings?

Flaherty:We had seen in the earlier presentation that the median PFS observed for the combination was just a hair under 15 months, which was quite striking. It was a few months longer than had ever been achieved with the other BRAF/MEK combinations. We hadn't seen that with any checkpoint inhibitors either. The response rate, though, was quite similar. With this OS result, one of the surprising features was that it was markedly longer than what we had seen before. The median OS of over 33 months is striking.

Now, a major point of caution is that we didn't directly compare the new BRAF/MEK combinations to the old BRAF/MEK combinations. We are still very excited about this result because melanoma is a very lethal disease. Another important thing to note is that patients will be on this treatment for a long time, so tolerability is important. We saw from this trial that the tolerability was also best in class. It shares some of the same toxicity features as other combinations like this, but it essentially drops a level.

TARGETED ONCOLOGY:Will there be a point where the old and new combinations are being tested head to head?

Flaherty:It's a great question, and the answer lies in who most wants to find it. As a medical oncologist treating patients with melanoma, I would like that answer. My patients would like it, too. It would be perfectly reasonable to randomize patients on such a study. We have exciting data here, but we can't prove anything until we do a trial like this.

Having said that, gone are the years where the National Cancer Institute or cooperative groups would routinely jump to do a study like this. Twenty years ago, and before, a study like this would already be underway. With funding down for clinical research, it's hard to foresee this trial ever kicking off. This will leave us with a challenge. How do we choose between these combinations? It will be an interesting discussion within the field.

Reference:

Dummer R, Ascierto P, Gogas H, et al. Overall survival in COLUMBUS: a phase 3 trial of encorafenib (enco) plus binimetinib (bini) vs vemurafenib (vem) or enco in BRAF-mutant melanoma.&nbsp;J Clin Oncol. 2018;36(suppl; abstr 9504). doi:10.1038/nm.4118.