Second-Line Treatment for mCRC

Fortunato Ciardiello, MD, PhD: When we plan a continuum of care for the patient with metastatic disease, we should keep in mind what are the therapeutic options for second, third, and fourth line if we choose A or B as first-line therapy. Basically, the destiny of subsequent lines is in some way dictated by first-line choice. Therefore, for all RAS and RAF wild-type patients, in first line, especially if patients have a left-sided primary tumor, the first-line choice is an anti-EGFR monoclonal antibody, either cetuximab or panitumumab, plus FOLFIRI [folinic acid, fluorouracil, and irinotecan] or FOLFOX [folinic acid, fluorouracil, and oxaliplatin]. In this case, the second line upon progression of disease will be the alternate chemotherapy regimen—so FOLFIRI if FOLFOX was first line, or vice versa. After failure on a combination of FOLFIRI or FOLFOX in the first line with cetuximab or panitumumab, in the second line we incorporate bevacizumab with a chemotherapy doublet, or if using FOLFIRI, we will be incorporating aflibercept.

For patients with RAS-mutated tumors, the choices are again either FOLFIRI, or FOLFOX , or FOLFOXIRI [folinic acid, fluorouracil, oxaliplatin and irinotecan], in the way I explained it before, in combination with bevacizumab. Upon progression, if a patient was treated with FOLFIRI, we will utilize antiangiogenic treatment beyond progression with bevacizumab; or with aflibercept, substituting FOLFOX with FOLFIRI for example. More complex is what we choose if we’re treating a first-line patient with FOLFOXIRI. In this case, the second line will be decided also based on chemotherapy adverse effects in terms of bone marrow toxicity if the patient can be treated again, either with irinotecan or oxaliplatin in combination with 5-FU [fluorouracil] in the second line.

For patients who have a tumor that is BRAF mutated now, the second-line first option for us is a combination of the anti–BRAF-mutated inhibitor encorafenib, and anti-EGFR monoclonal antibody cetuximab. So encorafenib/cetuximab is the preferred second line, regardless of the chosen first line, in a patient with a BRAF mutation. So although this is not yet used in Europe and is used mostly within clinical studies, I hope in a short time this will change, and finally we will also have approval in Italy.

Heinz-Josef Lenz, MD, FACP: I think it all, of course, depends what you use in first line. I think it's very easy when you use the FOLFOX/cetuximab in first line for left-sided colon cancer. The next best effective treatment is FOLFIRI with bevacizumab. If you use FOLFOX with bevacizumab or FOLFIRI with bevacizumab, the question is if this is a wild-type or a mutant RAS. For a mutant RAS, I think the next subsequent treatment would be FOLFIRI with bevacizumab after FOLFOX with bevacizumab. I think it's more complicated for patients who failed on FOLFOXIRI with bevacizumab, and what the next line of treatments are, because you basically failed on the standard of care cytotoxic and the targeted agents approved for this situation. I often go to a regorafenib combination. We have now a clinical trial with regorafenib and pembrolizumab as a second-line treatment, as we learned regorafenib may be more beneficial in earlier lines of treatment, and this combination had very promising results presented by Dr. Shota Fukuoka, at ASCO [the American Society of Clinical Oncology annual meeting] last year.

Axel Grothey, MD: The reason to move from first line to second line therapy is clear progression of disease, that is indisputably likely the most important reason, the other one being tolerability of therapy. The emergence of biomarkers that have become available also plays a role. For instance, if a patient has not been tested for MSI [microsatellite instability] status up front, which should not have happened, and we see this patient is barely hanging in there with chemotherapy, has toxicities, but now has an MSI-high tumor, then I would of course switch to immune checkpoint inhibitor therapy, either single agent or combination with a CDK-4 [cyclin-dependent kinase 4] antibody. There are various determinants that help us: progression of disease, toxicity, adverse effects, tolerability of therapy, and then of course, the emergence of molecular markers.

Heinz-Josef Lenz, MD, FACP: I think depending on the first-line treatment, for second line you choose the most effective treatment, FOLFOX to FOLFIRI, or FOLFIRI to FOLFOX. In wild type you switch from cetuximab to bevacizumab. Most of the time in second line, it depends on the progression of disease, the tumor burden, how aggressive you want to be. The most used and the most effective treatment is switching to the other backbone of chemotherapy. As mentioned before, the dilemma is a little bit more difficult when deciding what to move to after you use FOLFOXIRI with bevacizumab. In the case of wild type, this is often not an issue for our practice because we use the cetuximab first line. For my colleagues who use bevacizumab first line, they could choose a cetuximab combination in second line.

Axel Grothey, MD: Regorafenib has so far mainly been used as a single agent in the later-line therapy. There have been some attempts to combine it with chemotherapy like FOLFIRI in the second-line setting. That was a randomized, phase 2 study, FOLFIRI plus either regorafenib or placebo. The study overall, showed improvement in progression-free survival, no difference in overall survival. Most recently at ASCO, there was an analysis based on BRAF and RAS mutation status, and it appeared that regorafenib did not improve progression-free survival, at least not statistically significantly, in patients with BRAF- and RAS-mutated tumors. This is something that is not unique to regorafenib, there are a lot of subgroup analyses of existing trials, even looking at VEGF inhibitors, that are not perfectly solid in terms of whether bevacizumab or other VEGF inhibitors would add activity to RAS-mutated tumors. This must be taken with a grain of salt because these are unplanned subgroup analyses that are narrowing down the patient population. There might be other confounding factors that we haven't realized. At this point, since we’re not using regorafenib in combination with FOLFIRI in second-line therapy, I would use this as hypothesis generating. I would not translate these data, and I would not restrict the use of bevacizumab in the RAS-mutated tumors.

Transcript Edited for Clarity