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).
Although they are highly uncommon, patients with underlying mutations, such as RAS
, 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.
OncLive: How would you define the treatment paradigm of newly diagnosed mCRC?
: 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.
What advances have been made in the frontline treatment of these patients?
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
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.
Could you speak to the importance of tumor sidedness in CRC?
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.