Optimal Therapy for BRAF-Mutated mCRC

Transcript: Scott Kopetz, MD, PhD: For patients with newly diagnosed metastatic BRAF V600E colorectal cancer, the initial goal is to really try to get the patients started on some systemic chemotherapy. These are patients whose tumors can be very aggressive, and treatment initiation soon is critical.

I think what we see is that these are patients who can derive some modest benefit from initial chemotherapy, whether that’s FOLFOX [folinic acid, fluorouracil, oxaliplatin] or there were some older data suggesting that FOLFOXIRI [folinic acid, fluorouracil, oxaliplatin, irinotecan] and bevacizumab may be beneficial. Although it should be noted that the more recent data from the TRIBE-2 trial do not support that observation. But nevertheless, the sense is that there may be some benefit with that cytotoxic chemotherapy.

But it’s really then moving on to alternate second-line therapies with the targeted treatments. And here we’re thinking about regimens such as encorafenib and cetuximab, which has really been borne out of the BEACON study; or vemurafenib, irinotecan, and cetuximab from the randomized SWOG 1406 study.

We utilize less of the triplet of dabrafenib, trametinib, and panitumumab just because of the lack of randomized data in that setting. But that’s something that at least at the moment is on NCCN [National Comprehensive Cancer Network] guidelines, although that may be updated in the near future.

Richard Kim, MD: We know that patients with BRAF-mutated tumors have very poor prognosis. Therefore, in most of the cases we start more aggressive chemotherapy with a FOLFIRINOX [folinic acid, fluorouracil, irinotecan, oxaliplatin]-based regimen. But in 2020, now we have drugs targeting the BRAF pathway. In the past, they’ve used the BRAF inhibitors as single agents in small studies in colon cancer. However, the data were very modest because the response rate was very low, low PFS [progression free survival], and very short OS [overall survival] as well. And the reason for that makes sense. At least in colon cancer, unlike melanoma, by blocking the BRAF pathway alone, there’s actually a feedback loop that goes and stimulates the EGFR pathway, thus activating the MAP kinase pathway.

Therefore, we learned from that experience that you not only need to block the BRAF pathway, but you also have to block the EGFR pathway. Based on that concept, Dr Kopetz did a SWOG study. It was a randomized phase II study where they combined the BRAF inhibitor, vemurafenib, plus irinotecan plus cetuximab, or the VIC regimen, versus the control arm with irinotecan and cetuximab. The primary endpoint of the study was a PFS, and by adding a BRAF inhibitor in combination with chemotherapy, the vemurafenib, irinotecan, cetuximab regimen, the PFS doubled from about 2 months in the control arm to 4 months. And there was a trend toward overall survival, and there was an improvement in response rate as well. In that study, the patients who got standard control arm therapy were able to cross over and get the vemurafenib, irinotecan, cetuximab regimen. And once they crossed over, there was also a response rate seen as well. So based on those data, the vemurafenib, irinotecan, cetuximab regimen is part of the NCCN guidelines now and something we could use for patients with BRAF-mutated tumors.

Recently at ESMO [the European Society for Medical Oncology annual meeting], there was a presentation from the trial called the BEACON study. This was a larger phase III study. It was as 3-arm study that actually compared the triplet arm. They combined a BRAF inhibitor called encorafenib plus a MEK inhibitor, binimetinib, plus cetuximab versus a control arm of chemotherapy, FOLFIRI [folinic acid, fluorouracil, irinotecan] plus cetuximab or irinotecan plus cetuximab. The last arm was just a combination of the BRAF inhibitor plus an EGFR inhibitor, just like the SWOG study.

And the primary end point is overall survival comparing the triplet regimen to the standard arm. And the trial met its end point. With the triplet regimen, there was improvement in overall survival, there was improvement in response rate, and there was improvement in PFS as well. It was a clear winner, and therefore that triplet regimen will most likely become standard practice in the near future and hopefully will get FDA approval. But if you look at the doublet arm, which is interesting as well, when you compare the doublet arm to the control arm, there was once again improvement in overall survival, PFS, and response rate. Now, the trial is not written to compare the triplet arm to the doublet arm. But if you compare them, it seems like by adding a MEK inhibitor, there’s a slight increase in response rate and slightly longer OS and PFS.

If we look at the toxicity profile, actually the toxicity profiles for the triplet and doublet were very close, very similar. However, by adding a MEK inhibitor, you are adding more toxicity to it in terms of eye toxicity and in terms of cardiac toxicity. Therefore, I think that based on those findings, for anybody with BRAF-mutated tumors, at least in second-line setting, I would definitely bring in the triplet regimen at the beginning. And if there’s any toxicity issue with that, then I would just drop the MEK inhibitor, knowing that the doublet regimen still has OS benefit, PFS benefit, and response rate benefit over the control arm. The biggest question is, can you use this regimen in the first line? And I think that is still yet to be determined. There’s a trial called the ANCHOR study that’s using the triplet regimen in the first-line setting. Having said that, with the FOLFIRINOX plus bevacizumab approach in the first-line TRIBE study, response was I believe close to around 60%. So that’s a high bar to clear. As of today, I will still use folinic acid, fluorouracil, irinotecan, oxaliplatin plus bevacizumab first line but then try to bring the triplet regimen into the second-line setting in patients who have BRAF-mutated colorectal cancer.

Transcript Edited for Clarity