Michael A. Morse, MD
At the 2018 Gastrointestinal (GI) Cancers Symposium, results from the phase II REVERCE study revealed the superiority of sequencing regorafenib (Stivarga) before cetuximab (Erbitux) to the reverse sequence in patients with metastatic colorectal cancer (mCRC) who progressed on standard chemotherapy.
The administration of regorafenib prior to cetuximab was linked to longer median overall survival (OS) of 17.4 months compared with 11.6 months in the reverse sequence. At a median follow-up at 29.0 months reflected 81 deaths, data showed that there was a 39% reduction in the risk of death with the regorafenib-cetuximab sequence versus the cetuximab-regorafenib sequence (HR, 0.61; 95% CI, 0.39-0.96; P
In an interview during the 2018 OncLive®
State of the Science SummitTM
on Gastrointestinal Cancers, Michael A. Morse, MD, professor of medicine, Department of Surgery, Duke University School of Medicine, Duke Cancer Institute, discussed a number of key trials that have broadened the treatment landscape of mCRC, the importance of toxicity management in this setting, and other ongoing developments in GI cancers.
OncLive: What is the current state of treatment in mCRC?
The developments at the 2018 GI Symposium in advanced colon cancer, specifically patients who have progressed on standard third-line therapies and beyond, focused on several areas. There was an interesting study that questioned the preferred order of regorafenib and then cetuximab in patients. Patients were randomized to receive regorafenib first, followed by cetuximab at progression, or cetuximab followed by regorafenib at progression. Surprisingly, there was an OS benefit for the sequence where patients received regorafenib first followed by cetuximab. This was mainly in the group of patients who had primary left-sided tumors and were wild-type for KRAS, NRAS,
Please expand on sequencing agents in this setting.
Patients with colon cancer, particularly if they have RAS
wild-type tumors, essentially have 5 lines of therapy. It’s important that people receive all of the lines of therapy to have the best chance of survival. In frontline treatments, people have a choice of different chemotherapy drugs, depending on what toxicities they’re concerned about. They have a choice of biologic agents, assuming they’re RAS
wild-type and have a left-sided tumor. We have effective second-line therapies, predominantly using what wasn't used in the first-line setting. We also have oral agents for later lines of therapy.
The exact choice and order of those is based on discussion with patients. In particular, when we're talking about oral agents such as TAS-102 (Lonsurf)—a combination of trifluridine and tipiracil—or regorafenib, it’s clear they have very different side effect profiles. TAS-102 predominantly results in neutropenia and some GI effects. Regorafenib results in diarrhea, fatigue, and sometimes oral lesions as in hand-foot syndrome. With regorafenib, one of the challenges is keeping patients on the therapy. Ultimately, it’s a decision that’s contingent on which drug a patient is likely to tolerate better and which drug a person is able to comply with on a regular basis, so if a patient progresses, they can go on to receive the other therapy.
How are patients treated if they’ve progressed on third-line therapies?
I'm going to assume this a person who has gotten 5-fluorouracil, oxaliplatin, irinotecan, and anti-VEGF therapy. If they're RAS
wild-type, they've had an anti-EGFR agent. Going forward, we have 2 oral agents; one of them predominantly causes neutropenia, and the other has side effects that can include hand-foot syndrome and diarrhea. Our goal is for them to be able to stay in good shape by managing the toxicities, so that if they do progress on whichever one they start, they'll be able to get the other one.
My personal preference has been to use TAS-102 because it’s better tolerated in patients. However, patients who are already experiencing neutropenia are not ideal candidates for this therapy. On the other hand, there are patients who have done very well with anti-VEGF therapies who have previously had a long duration [of response] on bevacizumab (Avastin) and might still be sensitive to an antiangiogenic agent, such as regorafenib.