Molecular Status and Subsequent Therapies in mCRC



Marwan Fakih, MD: How does the molecular profile of the tumor affect subsequent therapies? The management of colorectal cancer has become quite complicated because we have many options of treatment. The treatment options are defined by the molecular profile, but even within 1 molecular profile, we have multiple options. For patients with RAS wild-type and BRAF wild-type colorectal cancer that has originated from the left side of the colon, we know now from several randomized clinical trials that the administration of anti-EGFR therapy in the first-line treatment with metastatic colorectal cancer is associated with a better response rate and associated with improvement in overall survival.

This is based on data comparing chemotherapy plus anti-EGFR therapy with chemotherapy alone. In addition, we have data from randomized clinical trials comparing anti-EGFR therapy with bevacizumab, again showing that RAS wild-type, BRAF wild-type colorectal cancer that is left-sided derives a better benefit from anti-EGFR therapy versus bevacizumab. That’s clear for the first-line setting. If we have taken that approach in those patients in the first-line treatment, then obviously we do not continue anti-EGFR in the second-line setting. In those patients, we’ll proceed to using antiangiogenic agents, bevacizumab, for example, in combination with systemic therapy in the second-line treatment.

As far as the third-line treatment for those patients, our approaches are to use the FDA-approved agents, including regorafenib or TAS-102 [trifluridine, tipiracil]. That’s based on randomized clinical data that show that those patients do benefit in terms of overall survival. One question in these patients is the value of anti-EGFR rechallenge. Do we re-treat these patients in the refractory setting with anti-EGFR therapy? We know from 1 particular trial, the CRICKET trial, that for patients who have received anti-EGFR therapy in earlier lines of treatment, if they have taken a break from that anti-EGFR therapy after a protracted response followed by acquired resistance, could those patients actually also benefit from a rechallenge with anti-EGFR therapy. Especially if the ctDNA [circulating tumor DNA] from those patients does not show any evidence of biomarkers of resistance to anti-EGFR at the time of rechallenge. So that’s 1 pathway for left-sided colon cancer with RAS wild type, BRAF wild type.

The story becomes a little easier for patients with a RAS mutation because patients with a RAS mutation, whether it’s left-sided or right-sided, the management of those patients does not vary. For those patients, we typically treat them with cytotoxic chemotherapy in the first-line setting in combination with antiangiogenics. When they progress, we switch to the alternate combination chemotherapy; for example, FOLFOX [folinic acid, 5-fluorouracil, oxaliplatin]—bevacizumab to FOLFIRI [folinic acid, irinotecan, 5-flourouracil]–bevacizumab in the second-line treatment. Again, our options of therapy in refractory disease for those patients is to proceed with further antiangiogenic therapy with regorafenib or the use of TAS-102 in the management of those patients. Of course, clinical trials should also be on our mind.

Again, it gets more complicated for patients who are BRAF mutated who have BRAF V600E. Those patients typically are treated with combination chemotherapy in the first-line setting. Of course, that is based on the BEACON trial that has been presented at ESMO [European Society for Medical Oncology Congress] and was updated at ASCO GI [Gastrointestinal Cancers Symposium], we know that using encorafenib plus cetuximab in those patients will improve the overall survival and improve the progression-free survival. That’s our second-line treatment for BRAF V600E—mutated colon cancer at this point. Again, could these patients benefit from further treatment with regorafenib or TAS-102? It’s possible, but those have a very aggressive disease.

Last is the RAS wild-type, BRAF wild-type right-sided colon cancer, where we have debated what to do with those patients in the second-line treatment. The management of those patients in the first-line setting, despite the lack of RAS mutation, is not to use anti-EGFR therapy, because we have no evidence that anti-EGFR therapy improves the outcome. When these patients progress on first-line therapy with combination chemotherapy and bevacizumab, we actually continue with the alternate chemotherapy with bevacizumab, aflibercept, or ramucirumab if it is a FOLFIRI second-line treatment. Again, when they progress, they can receive regorafenib or TAS-102 as far as a treatment option.

One thing I didn’t mention is the microsatellite instability, and at this point we have emerging data that show that nivolumab and ipilimumab in the first-line setting is quite effective. But it’s not approved for that indication. Based on NCCN [National Comprehensive Cancer Network] Guidelines and the predominance of the data, those patients do receive chemotherapy in the first-line setting, but we highly encourage the early integration of immunotherapy, whether it’s a PD-1 [programmed cell death protein 1] inhibitor alone, such as pembrolizumab or nivolumab, or the combination of a PD-1 and a CTLA4 inhibitor, nivolumab plus ipilimumab in the second-line treatment or third-line treatment of these patients. But I have to say that immunotherapy appears to be more effective than chemotherapy in these patients, even in the first-line setting when we compare across trials.

Transcript Edited for Clarity

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