Nivolumab plus Ipilimumab in Microsatellite-Instability–High (MSI-H) Metastatic Colorectal Cancer

Intro Hello and welcome back to another episode of the Oncology Brothers Podcast. I'm Rahul Ghosain here with my brother and Co host Rohit Ghosain. Today we're discussing yet another recent FDA approval in the world of cancer. Arguably, role of immunotherapy, an MSI high or MMR deficient has been one of the most promising advances we've seen in cancer. From bucket approval of pembrolizumab in this space with their quest to do even better, which takes us to our study today, Checkmate 8HW, where we have seen dual checkpoint inhibitors focusing in metastatic colorectal cancer. To help us unpack the study and touch on key findings, we're joined by Doctor Nicholas Hornstein, AGI Medical Oncologist from Northwell Health. Nick, thanks for joining us. Speaker 2 Thanks so much for having me excited to discuss what is a very impactful approval and study. Speaker 3 And the Nick, let's dive right in. Before we touch on the study design and its findings, a bit of the background here. What is MSI high and how is it tested? What does it mean to be MSI high and what does the testing entail? Are we relying on IHC or NGS? And how prevalent Ms. high is in metastatic colorectal cancer? Speaker 2 So microsatellite high colon cancer is somewhere between 3 and 5% of metastatic colorectal cancer. You see it more in stage 2 and 3 colon cancers as high as 15 to 20%. In terms of our ability to detect it, there's a few different ways. The first line of defense is using immunohistochemistry where we can look for the proteins that are associated with the MSI high phenotype. So things like MSH 2, PMS 2, MLH 1, so on and so forth. But IHC doesn't capture everything. Even though it might pick up something along 95% of MSI high colorectal cancer, there's still that 5% of patients that might slip through the cracks and need more nuanced methodology to detect their MSI high status. For those patients, we rely usually on PCR which can pick it up. These patients are usually detected amongst those that have Lynch syndrome. Those tend to be the ones where you miss it on IHC. You also mentioned next generation sequencing. I'm a big fan of NGS and it comes into play here as well where you have an even more sensitive tool to pick up on MSI High. Speaker 3 Appreciate you laying that foundation, Nick. We know these particular tumors are highly immunogenic. Checkmate ADHW As a result, we have seen pembrolizumab as a bucket approval, Rahul, as you mentioned earlier. But now for colorectal cancer, we have approval of nivolumab, epilumab, dual checkpoint inhibitors based off of Checkmate 8HW. Nick, could you please walk us through the study design and endpoints? Speaker 2 Yeah. So Checkmate ADHW is a fantastic study. And if you remember back to Checkmate 142, I think that's the right one. Around July 2018, this was the first evidence that dual checkpoint inhibitors might be beneficial in MEMSI high metastatic colorectal cancer. There was a phase two study about 80 patients that received the combination of nivolumab and epilumab. But being a single arm study, even though it led to an approval, it didn't really give the evidence many wanted to see to encourage use in this setting, especially when we know there might be some more toxicity with adding on a second checkpoint inhibitor. So in comes Checkmate ADHW. And this is, in my mind, a really beautiful study. So this is 2 main arms that was set up as ipinivo versus nivolumab and then ipinivo versus chemotherapy. So you get a nice separation of components from nivolumab and ampilumab and you're able to kind of tell, hey, is this really working better than one alone? The ability to look at this in the randomization and is nice. And the primary endpoint was progression free survival. So looking at these treatment arms, you have the nivolumab plus ipilumab arm, which was 240 milligrams nivolumab and one MIG per gig ipilumumab. Important to point out because in GI medical oncology, we also see three MIG per gig of ipilumab and HCC, which is not the case here versus chemotherapy in the first line setting. The second arm of this study with nivolumab plus ipilumab 240 milligram and the one Meg per gig during the first four treatments versus the volume map alone was in all lines. There are some differences. You can't directly compare apples to apples, so to speak across them just because of that slight difference in the patient population. All patients were MSI high, with the vast majority of them identified by a central board. And that's kind of the background of the study. Speaker 1 We know one thing I love about this approach, we've seen this with STRIDE regimen and hepatocellular carcinoma. We also saw this with NADINA trial and Melanoma as use of limited CTLA 4 and then continuing on with the PD1 inhibitor. This way we're getting the benefit of dual checkpoint inhibition, but also limiting the side effects. And one thing that you pointed out, neck, the dose of EPI here is 1 milligram per kilogram. This is different than recent approval of EPI NEVO in HCC where the dose of EPI is 3 milligrams per kilogram. OK, coming back to colorectal cancer, so EPI NEVO combination was approved because this was indeed a positive study. EPI-NEVO combination in colorectal cancer Nick, what did the study show? Speaker 2 Yeah. So this study and I think what you're showing is the progression free survival of Nevo, IPPY versus Nevo, which is a great curve. But when we look at Nevo IPPY versus chemo, that's a jaw-dropping PFS curve. What this study showed is giving patients time lipid iplumab which is only four treatments over the first four treatment cycles had a significant benefit to progression free survival. The median progression free survival something like 50-4 months versus 18 months, NEVA IPPY versus Nevo alone generating it has a ratio of .64 is a pretty significant benefit. Based on some of the earlier studies, the jury was kind of out. Is it worth it to add this additional agent? And I think with this evidence, a lot of people are probably weighing towards a yes. This does seem like for most patients coming in with MSI high metastatic or locally advanced unresectable colon cancer, there is a benefit there. And I do think it's worth mentioning that second part. So it's not just patients who have gross metastatic disease that might benefit from the study, It's also those where they just have clearly unresectable disease. But either way, it seems like there is a significant progression free survival benefit here. Speaker 3 Right what you mentioned Nick, with regards to comparison to chemotherapy, that was certainly jaw-dropping. We had a chance to discuss this back from GI ASCO 2024 with Doctor Pamela Coons and that was impressive. Everyone was waiting for this Nevo IP being compared to Nevo and Dr. Korana, and you pointed out how different this is, where the combination is certainly playing a bigger role though. We have used this combination with CTLA 4 and other disease sites as a community of culture as we've seen that in kidney cancer, melanomas and others, This does not come without toxicity. There is significant toxicity associated with it. Nick, could you please point out important side effects that we have seen with the combination? Important side effects of the combination Yeah. With the combination of volumab, ipilimab, as you mentioned, this is seen in multiple tumor types, similar dosing, similar side effects. The main side effects in terms of greater than 20% across patients, things like fatigue, diarrhea, itching, abdominal pain and nausea. We have to keep in mind the things we really worry about for our patients, the things that keep me up at night where if a patient calls me, I say, OK, we need to go to the Ed or we need to start some steroids or other interventions. We're talking about things like pneumonitis, colitis, and, and honestly, sometimes it's a little hard to cancel on immunotherapy. I'd say if you can think of an autoimmune disease, it could happen with this. The other thing I would mention is thyroiditis. Worth keeping in mind just given the high probability, but we have pretty good treatment for it nowadays so not as critical. Speaker 1 We're up again. We're getting more and more comfortable with these immunotherapy options in our clinic, but keeping these side effects on our radar is very important. The common ones and the rare ones as well, be it neurological side effects. I've seen some encephalitis. I actually have a patient in the hospital right now with that. So these are the things that we have to keep in mind. They're not benign. Speaker 3 To the point of grade three, grade 4, and it's pointed out that about 22% or rather 14% were experienced again in community. We have to manage these effectively. Speaker 1 Absolutely, Absolutely. Given the data in hand, most of your patients are going to get EPI Nevo if they qualify for immunotherapy. Who would you choose for single agent immunotherapy? Who would you pick single agent pembro or nivolumab for? Speaker 2 You know, that's a really good question. In the last month, I've had a 91 year old coming to my clinic with that metastatic colorectal cancer and I've had a 26 year old coming to my clinic with MSI colorectal cancer and both of them got EPI Nevo. So the number of patients that and this was after a very long conversation about benefits. I think you're probably expecting me to say the 91 year old got single agent, but I. Speaker 1 Would have picked that. Speaker 2 Yep. I think a lot of this is based on discussion with the patient going through the risks, benefits and making an informed decision with the patient looking at these PFS curves, I think there's a significant benefit to adding on CTLA 4. Here. You could make the case that at least in the Melanoma, we've demonstrated that there can be a rescue effect adding on CTLA 4 later if you're not seeing the response you want to see upfront. I think that's very fair. So I am being a little bit ingest here. This was a very special 91 year old who is still out lifting weights daily in the yard. For our older patient population more frail, you might want to think about doing single agent immunotherapy. For patients that physically fit, robust and you think they could tolerate having an immune related adverse event and survive through it while you're treating it. I don't think it's unreasonable to to reach for CTLA 4 as well, even at an advanced age. Speaker 1 Nick, you touched on Melanoma. BRAFV600E and MSI-HIV Let's take that as an example because we see some of that here in colorectal cancer as well. What if there is that Co mutation of B RAF V 600 E and MSI high disease? It's not very common, but you can run into this subset in this patient population. Are you going to rely on immunotherapy? We've also seen data on the B RAF, the bitter is here. How would you treat that Co mutation? Speaker 2 I think we have multiple trials out, you know, beacon break water. At the end of the day you're talking about very different toxicity profiles and mechanisms of action. If I have a patient in a critical period, maybe an impending organ failure or something that you need to get a response immediately. Maybe you do think about using chemotherapy based strategy at least for the start before you sequence into immunotherapy. I think those patients are hopefully few and far between. My hope is that given the significant benefit with this combination therapy and the stark difference in the side effect profile, I hope to use immunotherapy. Increasingly, I hope we can discover the way to crack the code on microsatellites of colon cancer and find more benefit there. Speaker 1 Can I just reiterate one thing when it comes to BRA FV600 E and MSI Hide Disease, immunotherapy is still very active here because we've seen that if you have an actionable mutation, we shy away from using immunotherapy. But at this time, with MSI Hide Disease and BRA FV600 E bringing immunotherapy and BRAF inhibitors, both options are very viable. Speaker 2 Yeah. And at the end of the day, in terms of the patients that benefit, it's the mutation associated Neoagen load that's gonna tell you your benefits. People who have weird mutations and proteins will benefit from immunotherapy, and those tend to be the ones that have mismatch mismatch repair deficiency. Speaker 3 Again, as always, when multiple options are available, patient shared decision making is certainly the key technology. You're a brave man to be utilizing the dual checkpoint inhibitor in a 91 year old. We continue to say that age is a number. Well, we are eagerly awaiting data on the COMET trial which will be atizo plus chemo. We still have some drop off for survival for some of our patients with immunotherapy, be it because of toxicity or some of them being non responders. Nick, before we close, any final thoughts here? Speaker 2 This is a very exciting study, and the hope is that as the years go by and additional studies come out, we learn how to leverage immunotherapy to a greater extent for a patient population, not just for MSI High colorectal cancer patients, but also for MSSI think we've seen some very promising data in the neoadjuvant setting as well in both MSI HIGH and MSS. And my hope is that we'll continue to see that there's a lot to think about with MSI High in the adjuvant setting and hopefully we'll have some guidance on that over the next few months. Speaker 3 I totally agree with you here, Sir. Since the inception of immunotherapy, it's used and responsiveness has been the most incredible story in oncology where our patients are living much longer and similar is the case we see with Checkmate AHW for colorectal cancer. Nick, thanks for walking us through the study and its findings. For our listeners, let us go over a quick recap today with Doctor Nicholas Hornstein from North Royal Health. We had a chance to discuss the recent approval of nivolumab and epilumab in metastatic colorectal cancer with MSI high disease or MMR deficient disease based off of Checkmate ATHW study. This combination showed improved overall response rate and progression free survival when compared to single agent nivolumab. Speaker 1 I want to bring up the study designed up again as the dose of EPI which was 1 milligram per kilogram is important and patients received 4 doses of EPI, nivo and then they got nivolumab alone. There is a limited exposure of CTLA 4 here. That's sad. We still have to keep immunotherapy related side effects in mind. Speaker 3 Yes, totally agree. Based on this data, this is now yet another treatment option upfront that is available for this subset of disease. Thanks for joining us. Make sure to check out our recent FDA approval questions, conference highlights and treatment algorithms. We look forward to seeing you in person at ASCO 2025. We are the oncology brothers.