GI Cancer Treatment Continues to Evolve, But Unmet Needs Remain

Cathy Eng, MD

A number of unmet needs have been addressed in the gastrointestinal (GI) cancer space, but there are still large patient populations who rely on traditional treatment regimens, said Cathy Eng, MD.

For example, in colorectal cancer (CRC), immunotherapy has had a significant impact in patients who have microsatellite instability-high (MSI-H) tumors. However, the vast majority of patients who are microsatellite stable (MSS) are still treated with chemotherapy, noted Eng, a professor of Gastrointestinal Medical Oncology at The University of Texas MD Anderson Cancer Center.

Targeted agents, such as regorafenib (Stivarga), have made headway in the CRC paradigm. In the ReDOS study, investigators evaluated a dose-escalation strategy of regorafenib beginning at 80 mg and ending at 160 mg for previously treated patients with metastatic CRC.

Positive overall survival and progression-free survival data from ReDOS led to the recommendation of a starting dose of 80 mg/daily on days 1 to 7, escalating to 120 mg/daily on days 8 to 14, and concluding with 160 mg/daily on days 15 to 21. From there, subsequent cycles should comprise 160 mg of regorafenib on days 1 to 21 every 28 days, according to the National Comprehensive Cancer Network guidelines.

“This dosing strategy is something that academic physicians have been doing for a while, it just had not been in the FDA insert,” said Eng. “The ReDOS trial was conducted basically to confirm what we all had already been doing.”

OncLive: How has immunotherapy impacted CRC treatment?

In an interview with OncLive, Eng shared insight on the current paradigm of GI cancers, specifically sharing insight on CRC and hepatocellular carcinoma (HCC).Eng: Immunotherapy has only affected a very small patient population. These are patients who have MSI-H tumors and who either have an inherited form of colon cancer or have hypermethylation due to somatic mutations. MSI-H is not the only biomarker for immune response, but these patients have a high mutational burden, and that is why they respond to this type of treatment.

What is the optimal treatment sequence for patients with CRC who have MSS tumors?

What are some other promising agents that are emerging in the CRC pipeline?

The take-home message here is that MSI status is really agnostic, meaning it should be tested in all patients—not just patients with CRC or those who clinicians think may have Lynch syndrome.Nothing much has changed for them, unfortunately. The reality is that if they have MSS tumors, immunotherapy is not an option and the standard regimens remain. There is a greater recognition now that more patients can utilize FOLFOXIRI as part of their regimen because that has been found to result in high response rates and longer PFS. Could you speak to the ReDOS study and how it led to a new dosing standard for regorafenib in this patient population? The ReDOS study was conducted basically to confirm what we all had already been doing. The dosing strategy allows the patient to tolerate the treatment better. If you give regorafenib at the full dose, patients tend to develop what is called hand-foot-skin reaction within the first 2 months. This is more of a quality of life issue than anything else.Larotrectinib (Vitrakvi) is one that has some promise. [Data on the agent] was previously published, and some data were recently reported at the 2018 ESMO Congress. It is kind of a unique drug because it targets a very rare fusion called TRK. Larotrectinib is a very selective oral agent because these fusions appear in less than 1% of patients, but we are seeing that when there is benefit with this drug, there is significant benefit. The drug also has very little toxicity. Therefore, like MSI-H, TRK is something that should be tested for in all patients.

What are your thoughts on TAS-102?

What is the biggest unmet need in CRC or other GI cancers?

Overall, what has been the biggest breakthrough in the GI cancer space in the past year?

Was there anything specific that led to the explosion of positive trials in HCC?

The study that was presented at the 2018 ESMO Congress and reported in the New England Journal of Medicine has been very intriguing and they are adding more patients to it. The study is widespread across different tumor types.It is like regorafenib where it is currently being used in the refractory setting. Researchers are exploring it with different combinations in different GI cancers. We will see if this drug can be moved to an earlier setting as well.The biggest unmet need is still the average patients who have MSS tumors, specifically the ones with RAS mutations. This a run-of-the-mill patient population that needs to be addressed now. We seem to have more treatment options for the rarer patient populations.It would probably be the fact that there are now several up-and-coming treatment options for patients with HCC, a malignancy for which there were not many options available in the past. Now, it has gotten to a point where there are so many different agents that researchers are going to have to look at sequencing strategies. There is going to be a big decision-making process for physicians who treat those patients.I don't know if there is a true answer to that. The reality is that there are now several pharmaceutical companies that have put an interest in HCC. Many people felt like it was a lost cause for quite a bit. Now, they are realizing that it is an issue that needs to be addressed because HCC has a high incidence rate; it is also a global issue. This is a theme that we are seeing in many other cancer types.

Bekaii-Saab TS, Ou FS, Anderson DM, et al. Regorafenib dose optimization study (ReDOS): Randomized phase II trial to evaluate dosing strategies for regorafenib in refractory metastatic colorectal cancer (mCRC)—an ACCRU Network study. J Clin Oncol. 2018;36 (suppl 4S; abstr 611).