Michael J. Overman, MD
Physicians must perform molecular testing in each patient with metastatic colorectal cancer (mCRC) as early as possible in order to identify subsets within the disease, as this information can have a prognostic impact in terms of treatment, said Michael Overman, MD.
“Microsatellite instability (MSI) status has to be obtained as well as BRAF
, and now, HER2
, is one that I would say is key,” said Overman. “We have to obtain [information regarding] all of those alterations in our patients and, if found, all have treatment-relevant implications.”
If a patient’s tumor is MSI-high (MSI-H), immunotherapy might be an effective treatment approach, whereas the same choice would not be made with a patient who has microsatellite stable (MSS) disease.
“It is frustrating when we look at tumor types like melanoma or lung cancer where you have this great PD-1–based response, whereas in MSS CRC we don't have those agents right now,” said Overman. “There is no standard immunotherapy option. The only differential is if [a patient has] MSI-high [disease]—which should be tested [for] in all patients with CRC—then there is an immunotherapy option.”
Detection of RAS
alterations can also be used to inform treatment decisions, especially if patients end up developing resistance to agents that had shown prior success. For example, an anti-EGFR rechallenge approach may be beneficial for RAS
wild-type patients with CRC who have developed resistance to therapy, according to data from the phase II E-Rechallenge trial presented at the 2019 Gastrointestinal (GI) Cancers Symposium.
The study examined the predictability of efficacy for cetuximab (Erbitux) rechallenge by liquid biopsy and showed that the rechallenge approach resulted in activity in the salvage setting, in patients who previously responded to cetuximab. With the use of liquid biopsy, physicians can identify who may benefit from this approach, which could potentially become a standard of care in the future, said Overman.
In an interview with OncLive®
during the 2019 State of the Science Summit™ on Gastrointestinal Cancers, Overman, a professor in the Department of Gastrointestinal Medical Oncology, Division of Cancer Medicine, at The University of Texas MD Anderson Cancer Center, highlighted data from pivotal trials presented at the 2019 Gastrointestinal Cancers Symposium and discussed where research efforts should be focused to improve the treatment of patients with CRC.
OncLive: What are the clinical implications of the CCTG CO.26 findings?
: This was a randomized clinical trial from Canada that examined the idea of combination immunotherapy in MSS CRC. Specifically, it looked at the combination of durvalumab (Imfinzi) and tremelimumab—a PD-L1–targeted agent and a CTLA-4–targeted agent—and compared that with best supportive care.
Patients with MSI-high CRC account for 4% to 5% of all mCRC cases, and we have tremendous immunotherapy activity there—those patients are a really unique subset. But the rest [of these patients], the 95%, have MSS tumors. We really had a challenge getting immunotherapy to [be effective] in that group.
There have been several trials looking at more single-agent checkpoint inhibitors and they haven't worked, and so, this is one of the first trials where we're looking at a big data set [with] combination therapy. The trial was a positive clinical trial. The endpoint was OS difference between the combination of durvalumab and tremelimumab versus best supportive care and that marker was met.
There are some caveats to the trial because the trial was designed to be a little bit more exploratory in nature, and there were some [small] differences between the groups in how the study was performed. The most unique aspect that really is the key that needs further confirmation is that there was a difference in OS, but we didn't see any difference in regard to PFS or in terms of response rate. Therefore, there's some discrepancy in regard to the efficacy endpoints we classically look at. Immunotherapy does have some different mechanisms of action, and you can see this component of maybe not as much antitumor obvious effect but still a benefit in OS.