Management of R/R mCRC: Sequencing for Later-Line Therapies



Marwan Fakih, MD: When do I think about using TAS-102 [trifluridine, tipiracil] for my patients? The RECOURSE trial is the registrational study that has led to the approval of TAS-102, Lonsurf [trifluridine, tipiracil], in the United States. In that particular trial, the inclusion criteria were that these patients should have failed or progressed following standard chemotherapy, including a fluoropyrimidine such as 5-FU [5-fluorouracil] or capecitabine, oxaliplatin, and irinotecan, as well as an antiangiogenic agent—namely bevacizumab—as well as an anti-EGFR therapy, in the event that they were eligible for anti-EGFR therapy. Those patients were refractory to all standards of care or progressed following all standards of care.

I think that is the indication for the use of TAS-102. When do I consider TAS-102? I consider it in my patients who have progressed on those agents. I consider it in patients who have normal liver function, because we also know that patients who have high bilirubin have higher toxicity with TAS-102. I also like to incorporate it in patients with an ECOG performance status of 0 or 1, because the benefit in patients who have poor performance status is less than patients with good performance status.

Scott Kopetz, MD: In my clinical practice, where I’ll utilize anti-EGFR therapy earlier in the disease course, I’m commonly evaluating the options of TAS-102, regorafenib, or an EGFR rechallenge as my 3 go-to options in this setting. But this is also a setting where I recognize that there’s not a whole lot of durability for many patients in any of those options. Always thinking about experimental studies in this setting is warranted. We don’t have to wait until we’ve exhausted a regorafenib or TAS-102 to explore those treatments as well. But in my practice, depending on the patients’ adverse effects, tolerance, and performance status, I’ll commonly utilize regorafenib followed by TAS-102 and then an EGFR rechallenge as well.

Axel Grothey, MD: When we talk about the treatment sequence and rechallenging approaches with EGF receptor antibody, nowadays we actually have tools to see whether patients can respond to these EGF receptor antibodies. When I’ve treated patients with first-line panitumumab- or cetuximab-based therapy, I do realize that some of the resistance to these agents is driven by the emergence of RAS or BRAF-mutant clones. We can test for those in circulating tumor DNA [ctDNA] assays, which are commercially available. When we do that, we actually see there is a smattering of different clones that emerge, which all can confer resistance to cetuximab and panitumumab.

We’ve seen emerging data from an Italian study, the CRICKET study, published in early 2019, for instance, that when we test for ctDNA and we see there’s no RAS-mutant clone visible on the molecular basis, the likelihood for patients to respond again to EGF receptor antibodies is higher. We’ve seen data from The University of Texas MD Anderson Cancer Center, Dr Kopetz’s group, that if we detect mutant clones, they actually have a half-life of about 4 to 6 months. Then they wash out and might disappear. The idea right now is this is an area of investigation, but I think it’s almost ready for clinical practice. Before we rechallenge patients with the EGF receptor antibody, No. 1, test for the presence of these RAS-mutant clones in patients’ blood.

Secondly, design treatments that can delay the use of EGF receptor antibody by bridging it, for instance, with regorafenib or non-EGF receptor antibody-based treatment doesn’t put a selection pressure on the cancer anymore, and then these antibodies can work again. It’s a very interesting way to personalize treatment approaches, be better doctors, and molecularly define resistance mechanisms for this specific class of agents.

The sequencing of agents in the later-line setting is an area of interest. We have data on regorafenib and TAS-102, which is an oral cytotoxic agent, which are emerging, at least from observation studies. But there was a very provocative Japanese study, the so-called REVERCE study, which looked at the sequence of EGF receptor antibody-based therapy plus irinotecan in 60% of these patients or regorafenib. What should we use first? The data that they presented, the REVERCE data from Japan and published recently, in 2019, showed that regorafenib used first followed by cetuximab plus irinotecan was associated with a 6-month overall survival benefit.

It’s a randomized study which actually didn’t accrue exactly to the accrual goal, but it’s more than 100 patients that we’re looking at. We had this very unexpected finding of 6 months’ difference in overall survival just by a different sequence. Why would that happen? What we saw is that when we break it down, what happens in the regorafenib phase and the later-line, the crossover, phase is that apparently—at least in the study—the EGF receptor antibody plus irinotecan worked better after regorafenib than regorafenib after EGF receptor antibody. That was really what was driving the overall survival difference.

The investigators did a lot of analysis, including the use of ctDNA to detect mutant clones, and 1 of the hypotheses is that when we use EGF receptor antibody later and regorafenib first, we delay the onset, delay the emergence of mutated RAS and BRAF-mutated clones, which could then also drive biology because they’re poor prognostic factors. But that’s just a hypothesis. We need to look at more markers or rerun the study, get more data. There are actually efforts in the United States to run another REVERCE study to tease out if this is really what’s happening, because it would have implications for clinical practice.

Transcript Edited for Clarity

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