Optimal Treatment of Chemoresistant mCRC - Episode 6
Tanios Bekaii-Saab, MD, FACP:Overall, the patient population in the refractory setting does not do well. There are few patients who do extremely well. There are a number of patients who do somewhat well, and the overwhelming majority actually does not do well because of the setting where patients are treated. In my experience, at least half of the patients will be treated for at least 2 to 3 months with regorafenib. And then beyond that, about 20% of the patients will go beyond 6 months of treatment. In fact, interestingly enough, when we looked at ReDOS, when we looked at the median overall survival [MS], for those patients who actually were able to get through 3 cycles of treatment, so started cycle 3, their median overall survival was a year or more. And that’s the median which means for some patients it was a little bit less, but for some patients we’ve seen the survival benefit extend beyond 1 year, actually some to 2 years.
So, even though this is not every patient, and, in fact, most patients will not achieve a meaningful outcome, but there are few patients who essentially end up achieving a significant outcome. We’ve had patients on our study, for example, going a year plus, and there is, in my clinic, a number of patients who have been on regorafenib for more than 6 months, few more than 1 year. And I’ve had very few patients who actually made it 2 plus years. So they are there. They’re not, unfortunately, the majority or even a large minority, but there are there. And, for those patients, it’s an incredibly meaningful response.
When looking at the totality of the data, what transpires is that perhaps bringing regorafenib to less pre-exposed patients or less heavily pretreated patients, but specifically less pre-exposed patients, may confer, historically at least, may confer a larger benefit. That’s where we learned from CONCUR study versus CORRECT study. CONCUR was a smaller study, it was an Asian study. Less patients received prior. In fact, in CORRECT, everyone had to fail all the biologics. In CONCUR, about 20% to 30% of the patients did not receive prior biologics, either an EGFR or a VEGF inhibitor.
And the deltas around the median survival, the median PFS [progression-free survival] were historically much, much higher with CONCUR versus CORRECT. I think another study that added to this was the REVERCE study which essentially tried to place regorafenib ahead of cetuximab versus the reverse. And that study was powered for survival. It was 100-patient Japanese study, which suggested that there is a significant survival advantage if you start regorafenib ahead of cetuximab versus the reverse. And that survival was a few months higher with that strategy.
Interestingly, in that study, what they’ve shown is that regorafenib seems to perform better if you move it ahead of cetuximab. Cetuximab itself continued to do well, whether you put it ahead or after regorafenib. So, meaning, cetuximab continues to preserve its benefit. All through lines of therapy, regorafenib seems to do better if you move it upwards. And so I think when you look at all these combined and it certainly gives us a moment to pause as the findings are quite intriguing in terms of perhaps trying to think about regorafenib for our patients, for those who may be candidates for it, of course, a little bit earlier before thinking of it as a last ditch effort.
One of the biggest challenges in oncology, as we move more and more to these oral agents, is how do we ensure that our patients adhere to the prescribed medications. There are a lot of elements that confuse the patients. One, many of them are depressed. They may have cognitive impairment. They may not have support at home. We give them all these complicated regimens with TAS-102 [trifluridine/tipiracil], with regorafenib, with others, as well with capecitabine. And more of them coming makes it relatively complex to patients.
So what’s been happening more and more is that we have to rely a lot on close follow-up. Whether you have a nurse or a pharmacist, in our practice it’s a pharmacist that follows up with the patient on a weekly basis to make sure they’re taking the appropriate dosage. Oftentimes, one of the reasons why patients are not compliant with their regimen is that they start having toxicities earlier on and they decide to stop on their own, or they cut down the dose on their own without talking to the physician, or just because of cognitive impairment they just are not taking the right medicine. So the discussion is always very important with the patient, with the family about the importance of adherence.
But I think one of the other important elements is close follow-up, especially in the first month of treatment. If possible, you want to see your patients every week to make sure they’re adhering to the regimen and then you’re watching out for the early toxicities, every week for the first month. If you cannot because patient lives far or they have no means to travel, then make sure that they’re called by a nurse, by a nurse practitioner, by you, or by a pharmacist. And have them seen at least twice in the first month if at all possible. This would optimize adherence. This also would help us pay closer attention to the toxicities if they emerge early. Because it makes a much bigger difference to patients if we can intervene sooner rather than later, especially as we get to the later lines of therapy where time is of the essence, and exposure in the first month or 2 makes a big difference for patients who are able to continue versus not on treatment.
Transcript edited for clarity.
Case: A 60-Year-Old Male With mCRC