Optimizing Treatment Strategies in Relapsed/Refractory Metastatic CRC - Episode 5


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Axel Grothey, MD: When we compare the drugs available that we consider for the third-line setting, number one, of course, is EGFR antibody. I think they have the most solid data either as a single agent or in combination with chemotherapy, based on prior studies. We have also refined the patient population that can benefit, such as RAS, BRAF wild-type tumors, left-sided tumors. This is a standard of care, using pemtumomab, cetuximab, either as single agent or in combination with irinotecan, for instance. They have pretty good efficacy, and we can expect to see some tumor shrinkage when we select the right patient—again, left-sided, RAS, BRAF wild-type tumors.

Regorafenib and TAS-102 [trifluridine, tipiracil hydrochloride] are newer drugs. They are not restricted by any sidedness or molecular profile, so we have no data about whether patients benefit only when they have RAS wild type or BRAF wild type in the later-line setting. The CORRECT study, which was a pivotal study for regorafenib, randomized patients in a third- and fourth-line setting after failure of standard therapy. Patients on regorafenib versus placebo showed an improvement in overall survival 2:1. The hazard ratio was 0.77, which means a 23% reduction of death events in the study was mainly related to disease-control rate, some patients had prolonged disease control. The main issue with regorafenib was the adverse-effect profile, at least with the dosing schedule that was used, 160 mg initially, which we later addressed in a randomized comparison. However, it definitely showed efficacy as a single agent in the later-line setting.

TAS-102 was developed very similarly, about 2 years later after regorafenib. A 2:1 randomization versus placebo, international study. One hundred of 500 patients were pretreated with regorafenib, and there was no difference in outcome for TAS-102 whether the patients had received regorafenib or not, which is an interesting piece of information. Overall survival end point was reached with a hazard ratio of 0.68, so a 32% reduction of death events on the study. The progression-free survival curves of TAS-102 and regorafenib are completely overlapping, you can do a PowerPoint experiment really projecting them on top of each other and you wouldn’t know which line is which. We have very similar data. Disease control was achieved in about 45% to 50% of patients, really no objective responses, and patients normally tolerate TAS-102 better than regorafenib because there are fewer subjective adverse effects. The TAS-102 adverse effect is mainly neutropenia, which now with the coronavirus epidemic is something we don’t like. There are recommendations in terms of sequencing from regorafenib to TAS-102, which is 1 of the questions, to use regorafenib first and reserve TAS-102 for a later time point.

Regorafenib is active as a treatment option in the later-line setting in colorectal cancer and as a cytostatic agent. We want to keep patients on therapy as long as possible, because that is really how this drug will be most active: by prolonged exposure. The problem with regorafenib—especially in a high dose when it was used with 160 mg per day, like in the pivotal registration study—is that a lot of patients will encounter subjective adverse effects like fatigue and hand-foot skin reaction, which is an inflammatory response to the drug from their palms and feet. These adverse effects come early on in the treatment of these patients. We actually see these adverse effects come within the first 2 weeks of therapy, which is different, for instance, than the hand-foot syndrome with capecitabine, which comes over time with more of a delayed effect. When we learned how to use regorafenib, 1 of the important points to recognize was that adverse effects come early and that the first 2 weeks are really the critical time point to monitor adverse effects, make those adjustments, and really get patients used to this drug, because we know the longer they get treated, the better they tolerate it. So that’s an interesting phenomenon. That’s why we ran a randomized comparison trying to optimize the regorafenib dosing administration by comparing the standard 160-mg dose, which is 4 pills a day, 3 weeks on, 1 week off, with starting with half the dose, 80 mg, 2 pills a day, for the first week and then getting a toxicity assessment from patients. If they tolerate 80 mg, we will go on 120 mg per day for week 2 and then really try to go 160 mg, the so-called standard dose, in week 3. Then patients have a week break and come back to cycle 2. Then you can ask them, “Which dose level do you think you really tolerate?” This is the dose level patients will be continued on. This randomized comparison with over 100 patients compared the escalating dosing strategy with the standard starting dose, 160 mg. When you run a study like that, you need to have the right end point because safety and toxicity is only 1 aspect of that. You also want to make sure you are not harming patients, in terms of reducing efficacy, by lowering the starting dose. The end point we chose was how many patients will go to cycle 3, because at 2 cycles, 8 weeks, you got a scan, and patients would continue to cycle 3 only if they tolerated the treatment and had stable disease on the scan. That was the primary end point, and yes, this study met its primary end point. Actually, quite surprisingly, there was about a 20% difference between patients who continued to have started on 160 mg compared with patients who escalated the dose who were able, eventually, to continue treatment into the third cycle. There was a trend—not statistically, not powered for that—toward more improved survival with the lower starting dose, presumably because patients could stay on therapy longer, and their quality of life remained stable. But for patients who started with a higher dose, there was a different quality of life in all our parameters in week 2. I believe the standard of care right now in colorectal cancer dosing regorafenib is starting with half the oral standard dose, 80 mg, and ramping it up slowly. This is embraced by NCCN [National Comprehensive Cancer Network] Guidelines and has really changed the way how we perceive regorafenib. It’s turned from a perceived toxic, not very effective agent, into an agent that can be used in a community practice, even by physicians who don’t have a lot of experience with managing the adverse effects. I believe it really gave regorafenib a second chance.

Transcript Edited for Clarity