Expert Highlights Promising Research in mCRC and Other GI Cancers

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 = .029).

OncLive: What is the current state of treatment in mCRC?

Please expand on sequencing agents in this setting.

In an interview during the 2018 OncLive^® State of the Science Summit^TM 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.Morse: 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, and BRAF.Patients with colon cancer, particularly if they have RAS or BRAF 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.

How are patients treated if they’ve progressed on third-line therapies?

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.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.

In terms of hepatocellular carcinoma (HCC), what are some of the developments with immunotherapy?

I'm very intrigued by the data of sequencing regorafenib followed by cetuximab. Although that’s a preliminary study, it raises a question about where earlier regorafenib may have the most benefit for patients. HCC is clearly where immunotherapy has shown a benefit. We have an FDA-approved drug, nivolumab (Opdivo), which in a single-arm study showed response rates, depending on the underlying cause of the cirrhosis or HCC, of 13% to 17%.

The ongoing CheckMate-459 study is looking at nivolumab compared with sorafenib (Nexavar) in the first-line setting, although nivolumab is the current FDA-approved drug for patients who have had sorafenib in the first-line setting. Pembrolizumab (Keytruda) has been studied in a similar scenario and has shown fairly comparable response rates and durability of response. Pembrolizumab is also being studied in a randomized clinical trial against best supportive care.

How has the treatment of GI cancers evolved in recent years?

In terms of other therapies for people who have had sorafenib and progressed, regorafenib has been available in the last couple of years. Now, there's another tyrosine kinase inhibitor that has also shown benefit in the second-line setting, and that’s cabozantinib (Cabometyx). Compared with placebo, it has shown an OS and progression-free survival benefit. In treating patients with HCC, the key thing to avoid is nihilism. In the past, it was felt that a local regional therapy might be fine instead of systemic therapies. Patients are often declining in performance status. They have underlying liver disease that might also be impairing their outcome. Some people die of underlying cirrhotic complications before they necessarily die of their liver cancer.

Now, we have 2 lines of therapy for HCC with a survival benefit. It’s important that people are at least offered the opportunity to take these drugs.

Regarding biliary tract cancers, it’s been much slower in developing new drugs. In the advanced setting, we've had gemcitabine and cisplatin, or gemcitabine and oxaliplatin as an option, but we have not moved beyond that. Recently, it’s been observed that a substantial fraction of biliary tract malignancies have targetable molecular alterations. For example, there's HER2 amplification in some patients with gallbladder cancer. In other patients with intrahepatic cholangiocarcinoma, there are FGFR2 alterations, such as fusions and sometimes mutations and amplifications.

There are clinical trials now that are addressing FGFR2 alterations that show very high rates of either response or control of disease. We also have IDH1 mutations that are observed in anywhere from 10% to 15% of people with predominantly intrahepatic cholangiocarcinomas, and there are drugs in development that target IDH1 or IDH2. We eagerly await the frontline study comparing an IDH1 inhibitor with placebo.

Shitara K, Yamazaki K, Uetake H, et al. Randomized phase II study of regorafenib followed by cetuximab versus reverse sequence for wild-type KRAS metastatic colorectal cancer previously treated with fluoropyrimidine, oxaliplatin, and irinotecan (REVERCE). J Clin Oncol. 2018;36 (suppl 4S; abstr 557).