Key Takeaways in the Treatment of Advanced Colorectal Cancer - Episode 7

Key Takeaway 7: Role of Immunotherapy in MSI-High MCRC


Tanios S. Bekaii-Saab, MD: There is about 30% to 50%, probably closer to one-third of the patients, with MSI [microsatellite instability]—high who will also have a BRAF mutation and BRAF V600E or BRAF non-V600E mutation. Specifically for the BRAF V600E mutation, do these patients behave differently? We know that BRAF confers a worse prognosis. When we look at those patients in at least the nivolumab study that had BRAF mutations and MSI-high, they do seem to benefit somewhat from the PD-1 [programmed cell death protein 1] or PD-1 plus CTLA4, so nivo [nivolumab] and nivo plus ipi [ipilimumab].

What we haven’t looked at—and I think it’s needed, although it’s going to be a challenging study—is for those patients, can we introduce the concept of bringing BRAF-targeted strategies before I/O [immunotherapy], with I/O, or I/O first? We know from the BEACON trial, which was recently presented at ESMO GI [European Society of Medical Oncology World Congress on Gastrointestinal Cancer], that a combination of binimetinib, encorafenib, and cetuximab, so the triplet RAF, MEK, and EGFR, conferred a significant response and other outcomes—so PFS [progression-free survival] and OS [overall survival] improvements versus FOLFIRI [leucovorin calcium, 5-fluorouracil, irinotecan] plus cetuximab. The response rate was about 26% with the combination of FOLFIRI [leucovorin calcium, 5-fluorouracil, irinotecan] plus cetuximab. It was 2.5%, and this was statistically significant. The hazard ratio for survival was actually close to 0.5. So the outcomes were quite significant for the triplet versus what would have been considered standard, although one would argue that BRAF alterations confer lack of response for EGFR inhibitors.

The question is, for that subgroup of patients, do we expose them first to the encorafenib-binimetinib plus cetuximab before introducing the immuno-oncology agents, so the PD-1 inhibitor or PD-1 plus, or should we start first with the immune agent? As I said, there’s the possibility that perhaps we could study the combination of the 2 in a reduced manner. I don’t think it’s 3 plus 1. It would be 2 plus 1 or some other combination. So that has to be looked at. This is a very small but very interesting subgroup of the MSI-high that perhaps behaves a little differently.

I think a very important question is what is the role of these agents—the immune-driven agents—in the treatment of microsatellite stable tumors, which essentially are 96% of all colorectal cancers in the metastatic setting. It’s 4% MSI-high, 96% not. Those 96% of patients do not seem to have or do not exhibit any response to challenge with these agents, whether PD-1 inhibitors, PD-L1 [programmed death-ligand 1] inhibitors, or PD-L1 inhibitors plus CTLA4. They confer 0% response rate. An attempt essentially to make those tumors more warm or hot, to essentially increase their likelihood of responding to these agents, started with a study combining a MEK inhibitor called cobimetinib plus atezolizumab. And this study, IMblaze370, attempted to reproduce some of the promising results in the lab that suggested exposure to MEK inhibitors inflames the tumor and makes it more susceptible to PD-1 and PD-L1 inhibition.

Then there was some promise from an early phase Ib study that suggested that indeed there were responses in the microsatellite stable cohort. They put this regimen to the test versus regorafenib, and essentially it failed to show improvement in outcome. If anything, 1 element was actually worse. The PFS was worse with the combination versus regorafenib. The survival was no better, and the response rate was about the same as regorafenib. This study unfortunately ended up being negative and certainly put a little kibosh on this area.

Fortunately, there’s still some interest in developing strategies to bring those PD-1 and PD-L1 inhibitors into microsatellite stable tumors. Some of these look at different elements that target the similar pathways as the MEK inhibitor: parallel pathways, agents that manipulate essentially the microenvironment, the macrophages, and others that may essentially make PD-1 inhibitors more active in these tumors. There’s also the possibility that in combining VEGF inhibitors with these PD-1 inhibitors, we’ll have some hints from a small study with bevacizumab and atezolizumab. But we will hear more about results from a study with atezolizumab, bevacizumab, and capecitabine versus capecitabine and bevacizumab at the ESMO 2019 Congress. This was a randomized study that looked at the combination of bevacizumab and atezo [atezolizumab] versus bevacizumab alone with chemotherapy. We’ll find out more about whether that strategy may be viable.

We know there are hints from the ASCO [American Society of Clinical Oncology] 2019 Annual Meeting, from a study with regorafenib and nivolumab in both gastric cancer and metastatic colorectal cancer, that were microsatellite stable that showed that in some of these patients, they’ve had some significant responses. They did have to get down on the dose of regorafenib to 80 mg. Mind you, this was primarily a Japanese-only patient study, but the responses were actually quite impressive, especially in the gastric cancer cohort. But they were also really good in the colorectal cancer cohort. I think at this point of time, we are understanding a little more about these combination strategies that may essentially bring immuno-oncology into the microsatellite stable tumors.

Transcript Edited for Clarity