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Immunotherapy, Sidedness Strategies Enhancing mCRC Treatment

Caroline Seymour
Published: Friday, Mar 23, 2018

Chloe E. Atreya, MD, PhD
Chloe E. Atreya, MD, PhD
Combination immunotherapy has shown great promise in patients with metastatic colorectal cancer (mCRC), specifically in the CheckMate-142 study in which nivolumab (Opdivo) plus ipilimumab (Yervoy) yielded a 55% overall response rate and 80% disease control rate in patients with DNA mismatch repair-deficient (dMMR)/microsatellite instability-high (MSI-H) metastatic colorectal cancer (mCRC).

Although pembrolizumab (Keytruda) is FDA approved for all MSI-H/dMMR solid tumors, and nivolumab for MSI-H/dMMR mCRC, there is still a question as to how ipilimumab is going to fit into clinical practice, according to Chloe E. Atreya, MD, PhD.

“Whether the combination of ipilimumab and nivolumab will take the place of single-agent therapy is still to be determined,” she said in an interview with OncLive.

Aside from immunotherapy, what is clear, says Atreya, is that tumor sidedness is not just a surrogate for other prognostic factors, and therapies should be selected with this in mind. The NCCN guidelines state that EGFR-targeted antibodies are an option for patients who have left-sided RAS wild-type tumors but exclude their use in those with RAS-mutated or right-sided tumors in the first-line setting.

In an interview during the 2018 OncLive® State of the Science Summit™ on Gastrointestinal Cancers, Atreya, an assistant clinical professor, Department of Medicine, University of California, San Francisco Helen Diller Family Comprehensive Cancer Center, discussed the latest treatment advances in mCRC, including tumor sidedness and emerging immunotherapy strategies.

OncLive: What are some recent developments in the mCRC landscape?

Atreya: I focused on sidedness and maintenance strategies for specific subgroups, including patients with MSI-H and BRAF-mutated CRC. With sidedness, I gave an overview of recent research, including Study 80405. I highlighted the NCCN guidelines, which state that EGFR-targeted antibodies are an option for patients with left-sided RAS wild-type tumors. These antibodies should not be considered for patients who have RAS-mutated tumors or right-sided tumors in the first-line setting.

In terms of maintenance strategies, the NCCN guidelines highlight certain studies that show some benefit in progression-free survival (PFS). These include either 5-fluorouracil (5-FU) or capecitabine with or without bevacizumab (Avastin). There is also a new study showing that bevacizumab alone is no better than observation on all endpoints. Other strategies that include 5-FU with or without bevacizumab showed no significant difference in overall survival (OS). The jury is still out about maintenance therapies, so it should be a personalized decision.

With regard to the different subgroups, specifically MSI-high and BRAF-mutated tumors, I highlighted the CheckMate-142 study that combined nivolumab with or without ipilimumab. For BRAF-mutated tumors, the recent NCCN guidelines now include the strategy of irinotecan and cetuximab (Erbitux) with or without vemurafenib (Zelboraf) as a potential option for patients in the second-line setting. Although it is not FDA approved, its inclusion in the NCCN guidelines will make it more available for these patients to receive vemurafenib.

Where is the field in terms of research on tumor sidedness?

Initially, there were a lot of questions about whether or not sidedness was just something related to tumor burden or prognostic and potentially predictive mutations. Now we know that sidedness is an independent prognostic factor.

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