Strickler Stresses Continued Focus on Molecular Subtypes in mCRC

John Strickler, MD

Effective therapies are being tailored to small subsets of patients with certain molecular abnormalities in their tumors, but the next steps for research in metastatic colorectal cancer (mCRC) are to turn these incremental benefits into long-term survival, said John Strickler, MD.

As treatment options become more widespread in this space, there is also a greater focus on quality of life. In the phase II ReDOS trial, investigators evaluated a dose-escalation strategy of regorafenib (Stivarga) beginning at 80 mg and ending at 160 mg daily for patients with mCRC. Regorafenib is an active TKI, but it can come with significant toxicities, such as hand-foot syndrome and fatigue.

Results from the trial suggested that the dose-escalation strategy was not only noninferior to the previous standard dose, but was also more tolerable. Positive overall survival (OS) and progression-free survival (PFS) data 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. If patients can tolerate the next level of dosing, subsequent cycles should use 160 mg of regorafenib on days 1 to 21 every 28 days, according to updated NCCN guidelines.

OncLive: What agents and targets are being explored in relapsed/refractory CRC?

In an interview at the 2019 OncLive^® State of the Science Summit™ on Gastrointestinal Cancers, Strickler, an assistant professor of medicine at Duke University School of Medicine and a gastrointestinal oncologist at Duke Cancer Institute, highlighted important data in the mCRC space and challenges that remain for oncologists working in the field.Strickler: A number of the agents and targets are for patients with variants of the disease, discovered oftentimes through comprehensive molecular profiling. Most recently, of course, microsatellite instability—high (MSI-H) and mismatch repair deficiency (dMMR) have been shown to respond to checkpoint inhibitor therapy.

How did the ReDOS trial impact the CRC treatment paradigm?

For example, single-agent pembrolizumab (Keytruda) and the combination of nivolumab (Opdivo) and ipilimumab (Yervoy) have shown activity in these patients. Additionally, genomic targets that have been evaluated in recent research include BRAF mutations, which we have known about for many years. We now have more active agents for [patients with] those tumors who come into the clinic. More recently, for patients with NTRK fusions, there is a newly FDA-approved therapy called larotrectinib (Vitrakvi), which has been shown to be quite active in those tumors. Those alterations are quite rare, but when they are found, they are quite [responsive] with that new therapy.The ReDOS trial was an outstanding way for us to begin to pressure test real-world application of how to give a therapy that, for many patients, is not well tolerated. [The rationale for the trial] came out of a debate amongst colleagues on whether starting low and escalating a dose or starting at the highest dose is the right approach. This study randomized patients to a dose-escalation design versus just giving the standard treatment. What investigators found is that the study was positive for its primary endpoint—patients were able to continue on the third month of treatment without progression if they used this dose-escalation strategy as opposed to the standard dosing. They also found that the quality of life—particularly 2 weeks into treatment—was better if patients started at a lower dose.

Then, there were some intriguing signals—this was not a primary endpoint, it was a secondary endpoint—to look at survival or PFS. There was a hint that use of the dose-escalation strategy rather than the standard approach improved PFS and OS. However, the study was not powered to detect that difference.

Could you discuss the use of immunotherapy in patients with CRC who have microsatellite stable (MSS) disease? What were the findings from the IMblaze370 trial?

This study is very influential for us in the clinic because we have struggled for some time on determining the optimal approach for dosing of regorafenib. This study, with its positive results, suggests that we should be starting at a lower dose and then escalating up to our patient's maximum-tolerated dose. In most cases, that is about three-quarters of the full dose. Already, the results of this study have been incorporated into the NCCN guidelines.We have known for a couple of years that immune checkpoint inhibitors are highly active in patients whose tumors have dMMR. The challenge is that [dMMR is only present in] about 4% of patients with CRC. We have been trying to figure out what to do for the rest of our patients; 96% of our patients don't have that in their tumors, they have MSS tumors.

Are there any other studies in this space that you are excited about?

What is a big area of unmet need that you would like to see addressed in the next few years?

This study was meant to test a strategy that would potentially sensitize a tumor to an immune checkpoint blockade that wouldn't otherwise be sensitive. [To do this, investigators] combined a PD-L1 antibody, atezolizumab (Tecentriq), with cobimetinib (Cotellic), a MEK inhibitor. Unfortunately, it was a negative trial. With respect to immunotherapy strategies, we are back to the drawing board for most patients.We are excited about novel anti—BRAF strategies for our patients. We will be hearing a lot more about ways to attack BRAF within the next year. Additionally, we are finding that HER2 amplification is a strong biomarker of benefit for HER2 inhibitors. We will be hearing much more about this in the next year as well, as there are several ongoing trials looking at various therapeutic strategies for that patient population. Although we had a negative result with IMblaze370, we will soon be seeing success in biomarker-selected patient populations over the next year.We are chipping away at the problem for patients with mCRC, in that we are increasingly finding small patient subsets that experience tremendous benefit from certain targeted therapies. That is exciting for us. The challenge for the bulk of our patients is that we still do not have a silver bullet; we are still looking at incremental advances. This is great because through these incremental advances, we have been able to substantially prolong survival, but what we need in the future is a paradigm shift so that we can continue to make CRC a chronic disease that people can live with for a long time. There is still much work left to be done.

Bekaii-Saab TS, Ou F-S, Anderson DM, et al; ACCRU Network Investigators. 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). doi: 10.1200/JCO.2018.36.4_suppl.611.