Optimal Sequencing in Later Lines of Therapy for mCRC - Episode 6

mCRC Treatment: Potential Game Changers

Axel Grothey, MD:When we look into the future, I’m really excited about what’s happening in colorectal cancer. We see comprehensive molecular profiling becoming commonplace in the management of patients. At my institution, we profile patients with whole exome sequencing, whole transcriptome sequencing up front, not to miss patients withNTRKfusions, for instance, or other targetable mutations, alterations, which is really exciting for these individual low-frequency patients.

Then there are new combinations that I find quite interesting. The combination of TAS-102 plus bevacizumab was just published inThe Lancet Oncology. This was a randomized comparison from Denmark showing that the addition of bevacizumab to TAS-102 improved survival and progression-free survival in what I believe was a clinically relevant way, and without a lot of toxicity. This makes sense because we know that bevacizumab adds activity when added to fluoropyrimidines, which TAS-102 is.

I think the most interesting combination emerged at ASCO [the American Society of Clinical Oncology annual meeting] 2019. This was a combination of regorafenib plus nivolumab. Regorafenib is a multikinase inhibitor. It’s known, or it has been known to modulate immune responses. It modulates the activation of macrophages, for instance. It modulates the activity of checkpoint inhibitors like nivolumab.

This ties into something we have seen in other cancers, like endometrial cancer. The combination of lenvatinib, which is a multikinase inhibitor with an anti-VEGF component similar to regorafenib, plus pembrolizumab has shown to be effective. It’s actually FDA approved now.

So the combination of regorafenib/nivolumab showed very interesting activity, particularly in MSS [microsatellite stable] tumors, which we normally do not consider immunogenic at all. In this 25-patient study from Japan, which is small of course, and we need to have more validated, larger information about these patients, the 25 patients had a 36% response rate in MSS tumors. This is very interesting, because regorafenib’s response rate in the later-line setting is perhaps 1%. Nivolumab’s response rate in a later-line setting in MSS tumors is 0%. So there seems to be some synergism going on.

It’s also interesting that the dose of regorafenib that was needed to mediate this immune activation was only 80 mg. That’s half. So there seems to be something going on in terms of biologic synergism, augmentation of immune response. If the data hold up, that’s going to be a game changer, not just for colorectal cancer but for a lot of tumors.

Otherwise, I do believe that augmented immune therapy, enhanced immune response is really the holy grail of where we’d like to go in the management of colorectal cancer. We have our subset of patients—4% to 5% of patients with metastatic colorectal cancer—carved out, who respond beautifully to immune checkpoint inhibitors: The MSI [microsatellite instability]-high, mismatch repair deficient tumors. But right now, the vast majority of patients are not candidates for immunotherapy. We need to change that. Hopefully we are headed in the right direction with the combination of immune checkpoint inhibitors plus/minus multikinase inhibitors.

Transcript edited for clarity.