Expert Highlights Evidence-Based Decision-Making in mCRC

Michael S. Lee, MD

Expanding molecular profiling—particularly for RAS status—paired with continued attention to tumor sidedness will help propel the field forward in metastatic colorectal cancer (mCRC), said Michael S. Lee, MD.

While many patients with mCRC are still treated with traditional chemotherapies, investigators have recently analyzed the necessary duration of this treatment. According to Lee, an assistant professor in the Department of Molecular Therapeutics at the University of North Carolina Lineberger Comprehensive Cancer Center, patients can be treated with a shorter period of FOLFOXIRI followed by low-intensity maintenance therapy. Typically, chemotherapy is combined with bevacizumab (Avastin).

OncLive: How would you define the treatment paradigm of newly diagnosed mCRC?

What advances have been made in the frontline treatment of these patients?

Could you speak to the importance of tumor sidedness in CRC?

Although they are highly uncommon, patients with underlying mutations, such as RAS and BRAF, can be matched with targeted therapy. For the patients with microsatellite instability—high tumors, treatment with immunotherapy either as a single agent or in combination has proven to be an effective approach. In an interview during the 2019 OncLive^® State of the Science Summit™ on Gastrointestinal Malignancies, Lee shed light on the treatment options available in the mCRC space and highlighted strategies poised to improve patient outcomes.Lee: The first question that arises is whether the patients have resectable disease or not. That's clearly an important breaking point. Presuming they do not have resectable disease, the current standard of care for most patients who are otherwise fairly fit is a doublet chemotherapy backbone with fluoropyrimidine plus oxaliplatin or irinotecan. This is typically combined with a biologic agent—options for that would include the antiangiogenic bevacizumab or an EGFR inhibitor, such as cetuximab (Erbitux). There are some data [supporting that] very fit patients in particular scenarios should receive triplet therapy. That approach could be used in select patients. For a less fit patient, you could treat them with a less aggressive chemotherapy backbone, such as fluoropyrimidine monotherapy.A lot of the research done in the frontline therapy of mCRC has been focused on evaluating strategies to best personalize therapy. This really revolves around selection of the biologic agent to pair with chemotherapy. We know that the chemotherapy backbone of either FOLFOX versus FOLFIRI are equivalent, and that has been shown reproducibly in recent studies. The question that arose then is, “If there was a particular biologic that makes the most sense to pair [with chemotherapy], is there a better benefit?” That [answer] really depends on the patient's underlying mutation status. For example, patients with KRAS and NRAS mutations are not eligible to receive an EGFR antibody. If you're going to give them a biologic, it's going to be bevacizumab. For patients with RAS mutations, there have been a range of studies examining whether outcomes are better if you pair chemotherapy with bevacizumab versus an EGFR inhibitor.Primary tumor sidedness has emerged as a very important clinical feature that helps us personalize therapies. This emerged over the last 2 to 3 years with findings from 2 large phase III trials. Both [studies] paired chemotherapy and randomized patients with RAS wild-type disease to receive either bevacizumab or cetuximab. At first, the initial analyses of these 2 large studies among all-comers looked discordant. The American study showed no significant difference with adding bevacizumab versus cetuximab. The European study showed a significant improvement in OS in patients who received cetuximab as part of their frontline therapy.

However, it emerged that there were actually differences in the proportion of patients who had right- versus left-sided primary tumors. A subsequent analysis of both studies that broke down outcomes based on primary tumor site actually showed that among patients with a left-sided tumor, outcomes were statistically significantly better for those who received cetuximab as part of their first-line therapy as opposed to bevacizumab. Among patients who had a right-sided primary tumor, outcomes tended to be worse for patients who received cetuximab as opposed to bevacizumab for frontline therapy.

What are some maintenance strategies being used for these patients?

The way that has ultimately been instilled into our national consensus guidelines is that for patients with right-sided tumors—even if they are RAS wild-type—we would not recommend treatment with an EGFR antibody as part of their frontline regimen. Therefore, if you are going to give them a biologic, it would be bevacizumab combined with chemotherapy. For patients with a left-sided tumor, the data do support a survival benefit with an EGFR antibody paired with chemotherapy. However, at least in the United States, we do feel that it is a reasonable discussion to have with a patient—talking about the alternative approach of starting with bevacizumab plus chemotherapy. It is important to have that discussion and to tailor treatment based on toxicity concerns, side effect profiles, etc.Maintenance is an important approach in giving chemotherapy, particularly in regimens such as FOLFOX or CAPOX, where you are pairing a fluoropyrimidine with oxaliplatin. Oxaliplatin [is associated with] progressive, cumulative, peripheral neuropathy, which we know tends to become impactful roughly between months 4 to 6. There was an initial series of trials called the OPTIMOX studies, which looked at a stop-and-go strategy of induction chemotherapy with FOLFOX followed by maintenance with fluoropyrimidine alone. What we found was that outcomes were comparable with continuing the full FOLFOX regimen.

What are your thoughts on the BEACON CRC findings?

Subsequent trials showed that continuing a maintenance approach with fluoropyrimidine plus bevacizumab after induction with CAPOX plus bevacizumab resulted in superior PFS and a trend toward better OS compared with not receiving any maintenance therapy but a total chemotherapy break. Generally, at least among patients who start with CAPOX or FOLFOX plus bevacizumab, it is worth having a discussion about maintenance with a fluoropyrimidine plus bevacizumab, typically after 6 cycles of chemotherapy.This is a very interesting trial in which investigators are looking at the combination of targeted therapies among patients with mCRC who have a BRAF mutation. Now, BRAF mutations are fairly uncommon; they probably present in about 5% of patients with mCRC. But, we know that [these mutations] harbor a particularly poor prognosis, with a median OS of roughly 1 year. This is significantly inferior to the broader population of patients with mCRC. As such, this is a huge area of unmet need. While there are BRAF inhibitors that are commercially available, early trials found that monotherapy with a BRAF inhibitor is not effective. This was quite different than [what has been observed in] other types of malignancies with BRAF mutations, such as melanoma.

Were there any other highlights from the 2019 Gastrointestinal Cancers Symposium that you wanted to highlight?

Subsequently, important work performed in basic science laboratories has shown a fair amount of feedback activation, upstream receptors, and bypass activation of other pathways to result in reactivation of cell growth of proliferation. This is if you're treating with a single-agent BRAF inhibitor. That led to this approach of combinatorial strategies. At this point, one of the more promising approaches has been the combination of a BRAF inhibitor and a MEK inhibitor, plus an EGFR antibody. The early data have been quite promising in terms of responses and PFS. We are waiting to hear the final results of the study, but it gives us hope that there will be novel approaches for this patient population in great need of some advances in therapy.The oral abstract session for CRC was really quite interesting; it highlighted 2 major themes. One of them highlighted some of the challenges with immunotherapy in CRC. One of the oral abstracts presented was, unfortunately, a negative trial of a MUC1-targeted cancer vaccine. Administering this vaccine did not result in improved outcomes; in fact, it led to a trend towards worse outcomes.

The other trial was a Canadian phase III study of dual checkpoint inhibitors with durvalumab (Imfinzi) plus tremelimumab in patients with very refractory disease. The conclusion of the trial was that the combination of these therapies did result in a statistically significant improvement in OS, although there was no improvement in PFS. The improvement in OS was around 2 months, or somewhat less than that. I will say that there was a note of caution despite the fact that this was a positive trial, regarding the need for confirmation or optimization of this strategy. At this point, I would not recommend this as a standard approach in a microsatellite stable patient with CRC.

What is your take-home message to your colleagues who are working in the field?

The other theme of the oral abstracts focused on new evidence for surgical approaches. Therefore, one abstract I will highlight was a trial of adjuvant hyperthermic intraperitoneal chemotherapy (HIPEC) surgery among patients who had high-risk colon cancer that was perforated, or T4. Unfortunately, this was a negative trial as well. There are a lot of caveats to it. It is pretty difficult to get any trials with HIPEC, and we are building our evidence base for this important therapeutic option. I would be pretty cautious about offering HIPEC for this group of patients.First, in the frontline setting for patients with mCRC, I would make sure that you are testing for expanded RAS mutation status very early. That is comprised of NRAS and KRAS. A lot of assays actually do not test for all the codons, they usually test for the most common ones, such as codons 12 or 13. A sizable proportion of patients who are deemed RAS wild-type based on codon 12 or 13 only actually harbor a mutation in one of these other extended RAS mutations. It is really important, especially if you are talking about the prospect of first-line anti-EGFR therapy.

Second, I would really pay attention to the sidedness of the tumor. I would think about how this impacts frontline therapy options, and think about prognosis. Finally, it is important to perform more extensive mutational profiling. We know that CRC is a heterogeneous disease—some of the most active mutations are fairly uncommon, but we still need to be testing for them.