mCRC: Best Approaches to Frontline Therapy

Axel Grothey, MD:When we start the process of exposing patients to all active agents on this journey in the palliative setting, first-line treatment choices are important. We direct our first-line treatment based on patient characteristics, tumor characteristics, goals of therapy, goals of care. There are a lot of factors that we take into account. One of the most critical factors is, how much treatment does a patient need? How threatening is the disease, in terms of how intense does the treatment need to be? Is the patient threatened by tumor load? Do we need to really shoot for a rapid and dramatic response to potentially turn things around for the patient?

Then, of course, molecular parameters come around. This is probably a more interesting part of the discussion about first-line therapy. We look forRASmutation status,BRAFmutation status, MSI [microsatellite instability] status, or mismatch repair deficiency status, which can select patients, potentially, for immunotherapy, even early on. And sidedness is a big issue. We know that right-sided tumors, when we consider the definitions of right-sided tumors and left-sided tumors, it’s a bit vague. Where does the transverse colon really belong to? But most commonly, the definition is, anything proximal to the splenic flexure is considered right-sided, and distal from the splenic flexure would be left-sided.

Right-sided tumors do not benefit from EGFR antibodies, at least not in the first-line setting. Even for aRAS/BRAFwild-type tumor, which we normally think has a chance to respond to EGFR antibodies like panitumumab and cetuximab, I would not treat a right-sided tumor, at least not in the first-line setting. In the second-line setting, with an EGFR antibody added to chemotherapy.

So these parameters come into play. For left-sided tumors, however, when we do aBRAFandRASmutational analysis, if they areRASandBRAFwild-type, they do benefit from EGFR antibody therapies in the first-line setting. This is based on European data and an American trial. My standard of care is to use FOLFOX [folinic acid, fluorouracil, oxaliplatin] or FOLFIRI [folinic acid, fluorouracil, irinotecan] plus panitumumab or cetuximab as frontline therapy. For the right-sided tumors, or for theRASandBRAF-mutated tumors, I use bevacizumab.

Now, there are targeted agents that really come about and now targetBRAFV600E-mutated tumors, specifically. We have data in the second-line and third-line settings, not yet in the first-line setting. But this is a field that is rapidly evolving. The patients with MSI-high tumors, with mismatch repair deficient tumors, might actually benefit from frontline immunotherapy, which would take chemotherapy, at least initially, out of the equation.

Frontline choices are more granular than they’ve ever been. I do believe, based on what I see here, especially in the United States, that most patients receive FOLFOX [folinic acid, fluorouracil, oxaliplatin] plus bevacizumab as their frontline treatment. That is not correct anymore. We really need to look for molecular parameters, and note patient needs, how intense the treatment needs to be, tumor sidedness factors, goals of therapy. FOLFOX [folinic acid, fluorouracil, oxaliplatin] plus bevacizumab is 1-size-fits-all. It’s no longer appropriate for the majority of patients.

There are patients for whom I would actually select a chemotherapy triplet as backbone therapy for the addition of EGFR antibodies or bevacizumab: Patients with high tumor volume, for whom we really need a rapid response, and if patient’s bilirubin is still intact, because irinotecan use really depends on normal liver function. Also, patients for whom I know that their prognosis is likely quite poor.BRAFV600E-mutated tumors are quite aggressive. There are conflicting data as to whether those patients with these aggressive tumors really benefit from a triplet like FOLFOXIRI [folinic acid, fluorouracil, oxaliplatin, irinotecan] or FOLFIRINOX [folinic acid, fluorouracil, irinotecan, oxaliplatin]. It depends what type of regimen you’re choosing. But I do believe it makes sense that biologically aggressive tumors should be treated with a more aggressive regimen to counteract the biologic behavior.

In my clinical practice, I use FOLFOXIRI [folinic acid, fluorouracil, oxaliplatin, irinotecan] in patients for whom I would like to see a rapid and reliable response. Then, I do add panitumumab to this treatment, which I was initially hesitant to do because we were worried about toxicities. However, we’ve now learned to manage these toxicities, and the combination of FOLFOXIRI [folinic acid, fluorouracil, oxaliplatin, irinotecan] plus panitumumab in a left-sidedRAS/BRAFwild-type tumor gives us a response rate that is over 90%. That is remarkable. So we should not miss this opportunity, if we find the right patient, where we need a rapid and reliable response.

Within this context of continuum of care, maintenance therapy approaches play a major role. This is particularly true when we start out with an oxaliplatin-based regimen—FOLFOX [folinic acid, fluorouracil, oxaliplatin]/bevacizumab, for instance. We know that patients need to stop oxaliplatin even before they have progression of disease because we manage neurotoxicity. We actually do not treat to neurotoxicity, but stop oxaliplatin at a time point before patients run into issues of hopefully not permanent neurotoxicity.

One of the strategies that I personally employ is when I start with FOLFOX [folinic acid, fluorouracil, oxaliplatin], for instance, plus bevacizumab, or FOLFOXIRI [folinic acid, fluorouracil, oxaliplatin, irinotecan] plus bevacizumab, I take oxaliplatin out after 8 cycles, meaning 2 months of therapy, and then use a fluoropyrimidine plus bevacizumab maintenance therapy. This is based on data that we’ve seen, randomized data that show that this maintenance therapy can actually delay progression of disease. And this ties, again, into this continuum of care, for which we want to expose patients continuously to well tolerable treatment using the least amount of treatment necessary to control the disease in the palliative setting.

Transcript edited for clarity.