Expert Highlights Significance of BRAF/MEK Findings, Ongoing Research in Melanoma

Paolo A. Ascierto, MD

Paolo A. Ascierto, MD

In June 2018, the FDA approved the BRAF/MEK inhibitor combination encorafenib (Braftovi) plus binimetinib (Mektovi) for the treatment of patients withBRAF-mutant metastatic melanoma. This approval came based on data from the COLUMBUS trial, which were presented at the 2018 ASCO Annual Meeting.

In this phase III trial, the combination was compared to vemurafenib (Zelboraf) or encorafenib. At a median follow-up of 36.8 months, combining encorafenib and binimetinib was found to reduce the risk of death by 39% versus vemurafenib alone. The median OS for the combination 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 the combination versus 7.3 months with vemurafenib alone (HR, 0.51; 95% CI, 0.39-0.67;P<.0001).

In an interview prior to the FDA approval of encorafenib/binimetinib, Paolo A. Ascierto, MD, director of the Unit of Melanoma, Cancer Immunotherapy and Innovative Therapy at the National Tumor Institute Fondazione G. Pascale in Naples, discussed results from the COLUMBUS trial and shed light on how physicians can use these findings when choosing treatments for their patients. He also shared his insights on the CheckMate 238 trial investigating nivolumab in the adjuvant setting.

TARGETED ONCOLOGY: What is important to know about the COLUMBUS trial?

Ascierto:During this ASCO, we [got] the data in terms of overall survival for the COLUMBUS trial. The COLUMBUS trial is important because it compared a new combination, BRAF plus MEK, with vemurafenib monotherapy. It was also important because it compared 2 different BRAF inhibitors altogether, encorafenib versus vemurafenib. This is important because encorafenib showed to be superior to vemurafenib, so it&rsquo;s really a new class of BRAF inhibitor. More importantly, it probably adds something to the combination. If you look to the side of the COLUMBUS trial, we had 2 different combinations with different doses, but this was just a request of the FDA in order to really compare if binimetinib added something to encorafenib. We know now, yes.

The combination was interesting because, in terms of efficacy, it gave more or less the same data from the other combination. Probably, the most interesting thing looking to the safety profile, it seems to be the best safety profile with less fever and less photosensitivity. This is important for our patients because patients could stay on this treatment [longer]. This is important.

TARGETED ONCOLOGY: Now that we know this combination is superior, what kind of challenges do you come across in determining what patient should get this treatment?

Ascierto:Being that these 3 different combinations are similar in terms of efficacy, the choice of treatment for our patients would be based on the safety profile. This would be important and would guide our treatment decisions. With BRAF/MEK, binimetinib/encorafenib, having the better safety profile, I think that in the future this would be good news for our patients because they have an available combination with less side effects.

At the moment we are studying in a trial for the right sequence for the targeted therapies from the SECOMBIT trial, using encorafenib and binimetinib with ipilimumab/nivolumab in order to try and explore which would be the best sequence.

There is another approach, [which is] the possibility to treat patients with targeted therapy at first for 2 months in order to get first impact of disease, and then with another progression, the best response is to monotherapy. We will see in the future with data from the SECOMBIT trial.

TARGETED ONCOLOGY: Do you foresee the possibility of a triplet regimen in the future? Perhaps, a BRAF/MEK combination with an additional immunotherapy?

Ascierto:Yes, it is an area of interest. We will get data from 4 different phase I trials, the old one was the trial of combination of dabrafenib and trametinib and durvalumab (Imfinzi), but nothing happened because it was just the phase I. The other triplet combination we have now is going into phase II/III is dabrafenib (Tafinlar) and trametinib (Mekinist) and pembrolizumab, the KEYNOTE-022. We will probably see the data for this probably at ESMO. The TRILOGY trial [looks at] the combination of vemurafenib, cobimetinib, and atezolizumab and COMBI-I [investigates] the triplet dabrafenib and trametinib plus spartalizumab, an anti-PD-L1. From this phase III trial compared with targeted therapy, we will see if the addition of anti-PD-1 can really add something real in terms of long-term benefit.

TARGETED ONCOLOGY: What would you say is the key takeaway from the COLUMBUS trial?

Ascierto:We have an opportunity now with the combination encorafenib plus binimetinib in terms of efficacy. We can say that encorafenib is the best BRAF inhibitor. Mainly looking at the safety profile, this is really interesting because patients can get this treatment without high incidence of fever and photosensitivity.

TARGETED ONCOLOGY: What is important to note on the CheckMate 238 trial?

Ascierto:CheckMate 238 was an interesting and important trial because the most treated and high-risk population was stage IIIB/C and IV with no evidence of disease. In the adjuvant setting, to be better than ipilimumab, it was the only trial which had active comparative data. The first report showed that nivolumab was able to reduce the risk of disease progression by over 35%. Now we have a 2-year update that seems to confirm the data that we&rsquo;ve seen. Nivolumab in the treatment of adjuvant is relatively high for high-risk patients. This is important because if you look at long-term benefit, we have about 50% of patients can get a long-term benefit but 50% of patients could still die. We have the possibility to increase this 50% with a new active combination. This is what is happening. Probably in the future, we will have more patients with this long-term benefit.

TARGETED ONCOLOGY: Were there any surprising data?

Ascierto:The data in terms of safety with nivolumab seem to confirm what we have seen. The safety profile is good with really low incidence of grade 3 and 4, so it&rsquo;s an important treatment with less side effects. What is also important is that the efficacy is independent by the BRAF status, PD-L1 if it is positive or negative, and also in both stage 3 and 4 can get the benefit of this treatment. That is important for our patients, and it&rsquo;s important news.