Using I/O in MSI-H Tumors in mCRC

Fortunato Ciardiello, MD, PhD: In terms of immunology, it’s very important to discuss what we consider a microsatellite unstable tumor. As you know, we can define these in 2 different kinds of assays. One is related to immunohistochemistry, which looks at lack of proteins that are produced when genes are mutant or altered, and so a tumor that is MSI high lacks some specific proteins that are specific DNA-repair proteins. The other is by genetic analysis, and this can be done most likely using next-generation sequencing [NGS] panels. We can measure gene mutations in these genes that account for the genetic alterations. Both assays have some pros and some cons; both assays would hence work.

My feeling is that the more we are using extended gene mutation, rearrangement, deletion panels by next-generation sequencing, the more this will be used, especially because the extended knowledge about next-generation sequencing approaches through liquid biopsy. Even in plasma we can get this information. We don’t need to go back to the primary tumor to extract DNA from the tissue and worry about all the caveats that can some way hamper the real readout and the real results. In my opinion, immunohistochemistry could play an important role, especially in the expert hands of hepatologists. More and more, we will see data coming out by NGS analysis and more and more by liquid biopsy use of NGS analysis.

Axel Grothey, MD: At this point in time, in 2020, every single patient with colorectal cancer, independent of stage and age, needs to be tested for the MSI status. This could be done by immunohistochemistry for the mismatch repair proteins, because mismatch repair deficiency—meaning the absence of 1 protein expression and 4 proteins for testing—is really kind of synonymous with MSI high and microsatellite instability. Microsatellite instability was routinely tested with pCR [pathologic complete response] reaction of 5 different loci. Nowadays, we get most of our MSI status through next-generation sequencing, the comprehensive panels that also includes the MSI status, even in liquid biopsies. We have various ways to test for these, for MSI status as mismatch repair deficiency. Unfortunately, when you look at FDA approval of pembrolizumab and nivolumab, for instance, they don’t care how we test for this phenomenon of MSI-high mismatch repair deficiency. They even allow local testing, to confirm sometimes in clinical trials. No one can tell me to test the patient for MSI. I actually think, based on the fact that pembrolizumab, for instance, is approved for all mismatch repair deficient MSI-high cancers anywhere, every single cancer—at least solid tumor—should be tested for mismatch repair deficiency, or MSI high.

Heinz-Josef Lenz, MD, FACP: The new presentation of KEYNOTE-177 shows that pembrolizumab is significantly better than chemotherapy, but this trial also gave us some interesting insights. We already knew that MSI-high tumors are more refractory to chemotherapy. This is a treatment option that I have no doubt moving to first-line. I was a little surprised when the data represented that 30% had progression of disease as the best response. That is a little scary because you don’t want to have progression in a big tumor burden patient with MSI-high tumors, missing the option of going to other chemotherapy options. This data also raised the question: What is the role of CTLA4 in the combination with immune checkpoint inhibitors? As you know, we presented the update on nivolumab-ipilimumab at ASCO this year, and we showed incredible efficacy with a response rate of 69%, and 13% had a complete remission. We didn’t see this 30% progression of disease. Now, it’s a much smaller study, so it’s limited. However, this data should raise the question, what is the role of a CTLA4 in combination with the immune checkpoint, versus an immune checkpoint alone?

Now, nivolumab-ipilimumab is already approved in refractory patients and is actually included in the NCCN Guidelines in first-line if a patient is not a candidate for chemotherapy. I have used this many times in first line because of our ongoing results and efficacy, so I’m very comfortable doing that. I think the pembrolizumab data in KEYNOTE-177 are very provocative and should be further investigated. When you look at the other data on KEYNOTE-164, they are actually very consistent. There are 20% to 30% progression of disease. The first 6 months, the chemotherapy is better than the immunotherapy in these patients, and we need to really understand the best combination for these patients in first-line.

Axel Grothey, MD: So far, immunotherapy has only clear evidence in microsatellite instable tumors, meaning mismatch repair deficient tumors. We just saw data at ASCO for pembrolizumab in first-line, the KEYNOTE-177 study, using immune checkpoint inhibitors in first-line as a first step and will augment the activity later by adding chemotherapy and other checkpoint inhibitors. MSS tumors, which constitute 95% of the metastatic disease, have been frustratingly refractory to approaches with immune checkpoint inhibitors. There are some MSS tumors that have high tumor mutation burden. For instance, for a patient with POLE mutations or tumors with POLE mutations, we generate an ultramutated phenotype. Those patients have a chance to respond to immune checkpoint inhibitors, but they are less than 1%. I’ve seen a handful of patients in 2 years in our breast cancer center, where we routinely test for POLE mutations, so we can’t really rely on that. The future of immunotherapy in MSS tumors is likely a combination of immune checkpoint inhibitors plus a VEGF inhibitor plus something else. I mean, the data we’ve seen so far, the most interesting preclinical and clinical data, come from PD-1 antibodies plus a VEGF inhibitor plus a kinase inhibitor, to a certain degree. We have seen data of pembrolizumab and lenvatinib, for instance, in MSS endometrial cancer that are very intriguing. We have seen some preliminary data of regorafenib plus nivolumab; in the Japanese study, mainly lung metastases responded. We’ve seen at ASCO data of regorafenib plus avelumab, which showed higher-than-expected disease-control rate. I believe there is a future, but I don’t know exactly where this future is going. We need to clearly validate all preclinical findings, translational findings, in clinical trials because modulating the immune system is tricky. It’s not clear that you can really translate data that you generate in an animal model into a human organism.

Transcript Edited for Clarity