Sequencing of Therapy in Refractory mCRC


Andrea Cercek, MD: In the third-line setting, we often think about the best way to sequence the drugs. This is obviously a huge challenge. We really don’t know what’s right. There are some active studies and areas of research interest, at this time, in terms of determining what will provide the best tolerability, best quality of life, and prolong survival.

What we do know is that for patients who are RAS wild-type, who have not received anti-EGFR therapy up front in the third-line setting, either cetuximab or panitumumab with or without irinotecan is initiated. We often try to include irinotecan because we know that the data are better with the combination. Beyond that, the MSI—high population benefits from immunotherapy. So, that’s certainly an option that is FDA approved. Albeit, it’s a very small population. Only about 2% to 4% of our patients have metastatic disease.

With regard to choosing between regorafenib and trifluridine/tipiracil, very little is known. In the original TAS-102 study, about 114 patients did have prior exposure to regorafenib. They still benefited from TAS-102. This suggests that sequencing could be regorafenib followed by TAS-102, without actually compromising the efficacy of TAS-102. It was retrospectively reviewed, so we don’t know if this can be extrapolated. But it was about 17% of the patients. Clearly, there was still a benefit with TAS-102 over placebo in this population.

Zev A. Wainberg, MD: When we face patients who are in the third-line colon cancer setting, who are microsatellite stable and have been through FOLFOX or FOLFIRI-based regimens, the approved FDA drugs include TAS-102 and regorafenib. Choosing between one or the other is somewhat arbitrary because there isn’t really any data to support one before the other. They’re both approved and used in similar settings. There are certain people who prefer one or the other, based on toxicity profile or based on biology. But at the end of the day, both TAS-102 and regorafenib are approved for those indications.

We talk to patients about the different toxicity profile between the agents and what to expect. In most institutional practices, I would say that the majority of patients do start with TAS-102 before regorafenib, although it really differs. Some data presented at ASCO’s 2018 Gastrointestinal Cancers Symposium would suggest that starting earlier with regorafenib might actually be biologically indicated. But we need some more data to truly answer this question.

When we’re talking to patients about which drug to choose, we also talk to them, at this point, obviously, about participating in clinical trials. This is a very common thing that third-line colon cancer patients do—whether they’re immunotherapy combinations, of which there are many. As you can see from ASCO’s 2018 Gastrointestinal Cancers Symposium, many are being studied in this space. We’re looking at alternative strategies to combine other medications at this point. This is something that everyone is looking at really closely.

Tanios Bekaii-Saab, MD, FACP: Patients who are MSI-high who go on a PD-1 inhibitor, pembrolizumab or nivolumab, typically do extremely well. There’s a small percentage of patients who tend to progress a little early, but the majority of patients progress much later. Most of the patients that have done well on one of the PD-1 inhibitors, in my clinic, with MSI-high tumors, have actually continued to do well and continue to do well. I’ve had very few patients progress.

However, for those patients who do progress, in the absence of a clinical trial that looks at immunomodulation and trying to rekindle the response to PD-1s or using other immunomodulatory agents, I would go back to the standard. Our standard is regorafenib and TAS-102, sequentially. Those patients would still benefit from the treatment options that the non-MSI, the MSS patients, would benefit from.

Transcript Edited for Clarity

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