Initiating Therapy for mCRC

Axel Grothey, MD: Your choice of first-line treatment sets in motion a sequence of events. When we start with, let's say, an oxaliplatin-based regimen, we want to use an irinotecan-based regimen in the second line. The choice of the biologic agent is determined by molecular factors, RAS and BRAF mutation analysis, MSI [microsatellite instability] now with immune checkpoint inhibitors, but also adverse effects. We know that left-sided tumors have a chance to respond to EGFR-antibody therapy, and I consider them, for most patients, standard of care. So, cetuximab, panitumumab, added to backbone chemotherapy, either a chemotherapy doublet or even a chemotherapy triplet, and then we would use bevacizumab in a second and potentially even in the third-line setting, with bevacizumab beyond progression.

These sidedness questions really determine, in a way, the sequence of events and how many lines of therapy we have available. In the right-sided tumor, even if it is RAS and BRAF wild type, I would not use an EGFR antibody in the first line. I might, however, consider the EGFR antibody after failure of all standard therapy, which would then include regorafenib and TAS-102 [trifluridine/tipiracil], because there are very likely patients with right-sided tumors who do benefit from EGFR antibody therapies. We have not been able to characterize those patients yet, but I would not withhold treatment when a right-sided tumor patient’s back is against the wall when I believe EGFR antibodies have not been used before.

Fortunato Ciardiello, MD, PhD: What we have learned over the past 20 years is that metastatic colorectal cancer is a very heterogeneous disease, depending on which are the most important or relevant genetic alterations that drive tumor development and progression. Depending also on where the tumor arises, if it’s a localized primary tumor in the right side or in the left side, because these are usually accompanied by different genetic alterations and so different potential genetic drivers, and different potential molecular targets for specific therapies. Therefore, before first line for metastatic disease, what we do is try to characterize, as much as possible, the genetic makeup of the tumor in a patient.

In large comprehensive cancer or academic cancer centers, this is achieved usually by a next-generation sequencing approach. In most cases in the big countries in Europe, most patients, before starting first-line [therapy], are characterized in their tumor, at least for the presence of mutations in the KRAS and NRAS genes, presence or absence of mutations for the BRAF gene, and more recently, for DNA repair deficiency or proficiency. Therefore, microsatellite stability or microsatellite instability is measured in these patients.

To summarize my answer, I will say that at least for the large cancer centers in Europe, RAS, RAF mutations, MSI status, primary tumor location, and FDG [fluorodeoxyglucose] amplification status are routinely measured before starting first-line treatment. These define what is our choice because usually what we decide to use first line is a chemotherapy doublet like FOLFIRI [folinic acid, fluorouracil and irinotecan] or FOLFOX [folinic acid, fluorouracil and oxaliplatin] that is combined with an appropriate biologic agent, such as an antiangiogenic drug, most likely bevacizumab, or an anti-EGFR monoclonal antibody for RAS/RAF wild-type patients, mostly if they have a tumor localized on the left side of the colon, with cetuximab and panitumumab. For MSI-high patients in Europe, this is different from what happens in the United States, unfortunately PD-1 or PD-L1 inhibitors have not yet been registered by our authority, EMA [European Medicines Agency]. So we cannot use them outside of clinical trials, either in first line or subsequent lines. I’m sure this will change soon in Europe after the presentation at the ASCO [American Society of Clinical Oncology] 2020 annual meeting of the results of the KEYNOTE-177 study, in which pembrolizumab showed a very important progression-free survival advantage over standard chemotherapy in first line of MSI-high patients.

Regarding patients with a BRAF mutation, after the BEACON data reported at the end of last year, clearly what is known now is that for second- and third-line patients, a combination of BRAF selective inhibitor encorafenib, and cetuximab, the anti-EGFR monoclonal antibody, is the primary option for second line. Whereas, what is the primary option for first-line patients with a BRAF mutation is still under debate, unless these patients have an MSI-high status in which I think immunotherapy plays a major role. After first line, all patients are candidates for second line. However, unfortunately, a proportion of them after progression are not fit for second line. What happens in general in Europe is that between 50% and 80% of patients after first-line failure are suitable and fit for the second-line treatment.

Heinz-Josef Lenz, MD, FACP: I think the decision for first-line treatment is really the most important decision you'll make for your patients. I think it is critical to understand the molecular makeup. You need to know RAS status, BRAF status, microsatellite instability, because that will determine your choice of first-line treatment. For RAS wild-type and left-sided colon cancers, for us, it would be a combination of chemotherapy with an EGFR inhibitor. I like FOLFOX [folinic acid, fluorouracil and oxaliplatin] with cetuximab. If this would be a mutation of KRAS, where you cannot use an EGFR inhibitor, you would use bevacizumab. Here it comes to a decision about how aggressive you want to be with your chemotherapy backbone. If dealing with a big tumor burden, borderline resectable, young, fit patients, I would consider a modified FOLFOXIRI [folinic acid, fluorouracil, oxaliplatin and irinotecan] regimen. I do the same for right-sided colon cancer with wild-type RAS, because right-sided colon cancers are significantly associated with poor outcomes, and here I step up the aggressiveness with a chemotherapy backbone.

Fortunato Ciardiello, MD, PhD: An important issue for treatment of patients with first-line metastatic colorectal cancer is, which is the best chemotherapy backbone. In my opinion and according to the guidelines, like the ESMO [European Society for Medical Oncology] guidelines, a chemotherapy doublet should be offered to all patients regardless of age, unless these patients are unfit for therapy. A major question is do we need to intensify doublet chemotherapy, either FOLFIRI [folinic acid, fluorouracil and irinotecan] or FOLFOX [folinic acid, fluorouracil and oxaliplatin] to FOLFOXIRI [folinic acid, fluorouracil, oxaliplatin and irinotecan]? The answer is, in some patients who are fit, especially with bad prognostic characteristics, maybe the choice of FOLFOXIRI [folinic acid, fluorouracil, oxaliplatin and irinotecan] as a backbone for first-line treatment is a good choice. In our practice, we usually use FOLFOXIRI [folinic acid, fluorouracil, oxaliplatin and irinotecan] instead of FOLFIRI [folinic acid, fluorouracil and irinotecan] or FOLFOX [folinic acid, fluorouracil and oxaliplatin] for fit patients with RAS mutations in which we would like to have a rapid tumor shrinkage. In this case, we combine it with bevacizumab. Also for fit patients with BRAF mutations, for which we require important tumor shrinkage, we use.

In these cases, we don’t know if FOLFOXIRI [folinic acid, fluorouracil, oxaliplatin and irinotecan]/bevacizumab is better than FOLFOXIRI [folinic acid, fluorouracil, oxaliplatin and irinotecan] alone. But in our experience, FOLFOXIRI [folinic acid, fluorouracil, oxaliplatin and irinotecan] as a chemotherapy backbone, as compared to FOLFIRI [folinic acid, fluorouracil and irinotecan] or FOLFOX [folinic acid, fluorouracil and oxaliplatin], is reserved for fit patients with RAS or RAF mutations where we need a rapid and sustained tumor shrinkage.

Transcript Edited for Clarity