Relapsed or Refractory Metastatic CRC - Episode 6
Axel Grothey, MD: The data that we have for efficacy of treatment in third-line therapy are based on large randomized trials that showed survival benefit for drugs like regorafenib and TAS-102 [trifluridine, tipiracil]. The inclusion criteria for the pivotal trial, the CORRECT study, that gave the approval for regorafenib was that a patient had to have progression of disease on oxaliplatin—5-FU [fluorouracil], and irinotecan-based therapy with potential inclusion of bevacizumab for a KRAS and then later RAS wild-type tumor, for an EGF-receptor antibody. These patients did not have any other treatment options, and that’s why in the CORRECT study, randomization between regorafenib and best supportive care or placebo in a 2:1 fashion was actually justified.
The subsequent study clearly showed that the use of regorafenib was associated with a survival benefit with a hazard ratio of 0.77, meaning a 23% reduction of death events on the study, which is moderate but real, even though we know that it’s a fifty-fifty split whether patients have benefit or not when we look at the progression-free survival curve. When I talk to my patients about the CORRECT data and the benefit they might have after 2 cycles, meaning after 8 weeks of therapy, there’s a fifty-fifty chance patients have disease progression—stable disease or some minor responses. If they don’t have a progression, they have a 50% chance to live more than a year, which for a patient is important. This is because a year means they get another birthday, another Christmas, etc. All these types of things. A year sounds OK in the later-line setting when we commonly are backed against the wall.
The question is how active regorafenib is after we had the CORRECT data. It is now 8 years ago that we published the data in a more modern setting. There actually were 2 trials that inform No. 1, how active regorafenib is right now in a more modern, better patient-selection situation. Second, it informs how we best dose and administer regorafenib. Let me talk about the second question first.
One of the issues we had in the CORRECT study, in the real-world use of regorafenib, is that the initial dosage that we selected—160 mg, 4 tablets per day, 3 weeks on, 1 week off—was considered quite, let’s say, toxicity prone for a lot of patients. The toxicities actually came early. Adverse effects on regorafenib come commonly within the first 2 weeks, mainly in the form of fatigue and hand-foot-skin reaction, which can even lead to blisters on hands and feet. It’s really affecting patients’ quality of life. I’ve personally seen in several patients, when started on this higher dose, within 2 weeks they could not tolerate the treatment anymore and had to stop.
For a cytostatic agent like regorafenib, we need to make sure patients continue on therapy as long as possible. Duration of therapy matters to have the best anti-tumor efficacy, and that is a critical point. How do we do that? How can we keep patients on treatment longer? One of the approaches we actually tested in a randomized comparison was to use the standard dosage—160 mg per day, 3 weeks on, 1 week off—or use a dosage-escalation strategy starting with 80 mg per day, 2 pills a day in the first week. Then we would escalate to 3 and then 4 pills potentially in the third week over time in the first treatment cycle.
We use the time where patients normally experience the major toxicities early on to ease patients into this treatment, to escalate the dose. The ReDOS study was this randomized trial of 123 patients, which was published in 2019 in Lancet Oncology. The interesting part was we saw that patients who started low and went up stayed on therapy longer. There was a much higher chance for patients to go beyond the first scan into cycle 3. That’s a critical point because patients would only go beyond the first scan after 8 weeks, No. 1, if they have no progression of disease and efficacy and, No. 2, if they have tolerated the treatment.
It’s a composite end point. We saw highly statistically significant, more patients continuing therapy into the third month when they started low and went up. This was associated actually with the best overall survival we’ve actually seen ever on regorafenib with 9.8 months. The CORRECT study that led to the approval of regorafenib had an overall survival of about 6.5 months. We’ve seen a shift in efficacy, more survival nowadays in more mature and more modern trials than before.
The IMblaze370 study was an interesting study in the sense that there was a lot of excitement about augmented immune therapy with a combination of a MEK inhibitor, cobimetinib, and in addition to the PD-L1 [programmed death-ligand 1] inhibitor, atezolizumab. This was based on a very small patient population with a potential response rate of 20% in an early phase Ib study with an expansion cohort. This led to the generation of a phase III study in the later-line setting in which regorafenib was used as a control arm. I do believe that the designers of the study thought regorafenib is a low bar to beat. It was not beaten by the combination of cobimetinib and atezolizumab.
In fact, adverse effects and treatment discontinuation were more common in the cobimetinib-atezolizumab immune combination arm. Regorafenib came out as the de facto winner of this study, not in terms of statistically significant prolonged overall survival. But survival was, again, better than expected in the range of about 8.5 months, 8.6 months in overall survival. It clearly established itself again as a standard of care in this setting.
Transcript Edited for Clarity