Dr. Benjamin Schlechter on Botensilimab: Practice-changing Drug | Most Promising Cancer Drugs 2024

In this episode of OncoDaily Interviews, Dr. Benjamin Schlechter, a distinguished medical oncologist at the Dana-Farber Cancer Institute, joins host Amalya Sargsyan to discuss Botensilimab, a next-generation anti-CTLA-4 therapy for immunotherapy. Dr. Schlechter shares his involvement in trials, highlighting the drug’s innovation in overcoming resistance in immune therapies, particularly in MSS colorectal cancer.

Dr. Benjamin Schlechter is a Senior Physician at Dana-Farber Cancer Institute, specializing in gastrointestinal cancers, including colorectal, anal, pancreatic, and neuroendocrine cancers. Previously, he served as the Director of Inpatient Hematology and Oncology at Beth Israel Deaconess Medical Center and was the Assistant Program Director for the Internal Medicine Residency Program.

Dr. Amalya Sargsyan is a Medical Oncologist at Yeolyan Center,  a Research Physician at the Immune Oncology Research Institute, and Senior Editor at Oncodaily. She holds an MD from Yerevan State Medical University and an MSc in Precision Medicine from the University of Cyprus.

Dr. Sargsyan completed her clinical training at the Bank of Cyprus Oncology Center and has been honored with an ASCO IDEA award.  Her research focuses on the potential of novel immune checkpoint inhibitors (ICI) in low- and middle-income countries (LMICs), aiming to bridge disparities and enhance access to innovative cancer care.

Amalya Sargsyan: Hello, everyone, and welcome to OncoDaily. Today, we’re discussing 10 of the most promising cancer drugs in solid tumors which are not yet approved. We are discussing novel drugs from different perspectives, including development with the company, insights from the investigators, leading the trials, and patient experiences.

Today, our focus will be on Botensilimab, next-generation anti-CTLA for immunotherapy. And today, we have the honor of welcoming Dr. Benjamin Schlechter, a Distinguished Medical Oncologist at Dana-Farber Cancer Institute and an instructor in medicine in Harvard Medical School. Dr. Schlechter has experience of treating GI malignancies and is one of the leading investigators in trials involving Botensilimab. I’m Amalya Sargsyan, a Medical Oncologist and Senior Editor at OncoDaily. Dr. Schlachter, hello, and thank you for accepting our interview invite. It’s an honor to meet you here.

Benjamin Schlechter: Thank you for having me.

Amalya Sargsyan: So, before we wrap up into the trial details, can you a little bit explain us your role in Botensilimab trials and a little bit about your background?

Benjamin Schlechter: Yeah, so I guess I can start with my background. So, I’m a GI oncologist. I didn’t come to GI oncologist intentionally.

I thought I would be a breast cancer doctor, a lymphoma doctor. I think, and through exposure and fellowship, learned that GI is just a great place to be an oncologist. A tremendous area of need and a lot of growth needs to happen, and I think is beginning to happen.

And for many years, I’ve had an interest in immune therapy and to be honest, had begun to lose faith in immune checkpoint blockade. And so, this drug is a really important innovation because it took some of the things that we knew about checkpoint inhibitors and how they worked and how they failed really and tried to engineer out some of the mechanisms of failure and engineer in some of the mechanisms of success. And so, the drug has really been impressive in data-driven, science-driven modifications of existing CTLA-4 monoclonal antibodies to improve outcomes for what was previously called cold tumors.

I don’t know if a cold is the right term or more like immune therapy-resistant tumors like colon cancer.

Amalya Sargsyan: Thank you for sharing this and congratulations on the recent publication in Nature and all the investigators who are involved in the trial. Can you share with us a little bit more on how were the results how were you involved in this trial and what are your general comments on the results? Were they satisfactory to you and were there something you prognosed?

Benjamin Schlechter: Yeah, so we were one of the lead investigating sites at Dana-Farber with our colleagues at Beth Israel, City of Hope, among other institutions, MD Anderson. It’s a very large phase-one clinical trial. The trial was launched as sort of a standard phase one trying to find the safety profile of Botensilimab, the sort of next-generation multifunctional CTLA-4 inhibitor in combination with a conventional PD-1 antibody, balstilimab.

And early on in the experience, there was an observation that there was efficacy in colorectal cancer patients. And this generated a lot of excitement because, to date, there really has not been real efficacy of immune therapy in MSS colorectal cancer. Clearly, for dMMR is a great story of success, but in MSS colon cancer, the response has been rare and very moderate.

And here we saw early on patients were developing benefits, but it wasn’t all patients with colorectal cancer. There was also an observation that it was patients without active liver metastases who appeared to derive benefit. And stuff has been written about this before by many investigators, including our co-investigator, Dr. Fakih. And we saw that this drug really did work with deep and profound responses and prolonged responses for patients with non-hepatic disease with advanced colorectal cancer.

And while the majority of patients with colorectal cancer do have liver metastases, it’s a significant minority that doesn’t, maybe a quarter of patients. And when you account for the fact, this is an extremely common malignancy, helping a quarter of patients with very refracted colorectal cancer with immune checkpoint blockade is really a practice-changing finding if this bears fruit in phase three.

So, it was a very exciting time to be involved in a new drug, in a data-driven drug that’s meant to overcome the limitations of existing CTLA4 inhibitors. And yeah, it’s great to have something new in colon cancer. We’ve had very few new drugs and new classes of drugs in this disease, in MSS colon cancer.

Amalya Sargsyan: Yes, indeed. It’s very interesting. As a traditional, you would think that this is a cold tumor and immunotherapy has no role.

But now we’re changing the landscape into treating those patients with immunotherapy. And you have also mentioned about the safety, as a person who was directly working with patients, how you see them experiencing it, where it was better or worse tolerated and how was the safety profile. Was it manageable?

Benjamin Schlechter: Yeah, so immune therapy always has a different safety profile than chemotherapy. And we have to be careful how we look at these safety profiles and how we talk about them because chemotherapy is reliable and recurrent and relentless impact on patients in terms of the recurrent toxicity, we all know, be it fatigue or alopecia, which would be persistent or worsening neuropathy, it’s cumulative. And the immune checkpoint inhibitors don’t do that.

And this drug doesn’t do this. There are random events that happen on immune checkpoint blockade, and this drug has them. And so, the experience of patients day-to-day on Botensilimab with Balstilimab is actually quite positive.

They have very, very few day-to-day toxicities the way you would have with chemotherapy. It has a lot more in common with say ipilimumab and nivolumab or pembrolizumab or durvalumab and tremelimumab. But there are real differences in the toxicity profile of this compared to conventional immune checkpoint blockade.

First of all, there’s prominent itching like you see in a lot of checkpoint inhibitors. There’s also sort of an early activation syndrome where patients have a febrile illness in the first few weeks, and that seems to go away after a few weeks. They respond very nicely to NSAIDs and occasionally require a load of steroids.

The most prominent and interesting side effect or adverse event in this agent has been colitis. And a significant portion of patients had colitis. At higher doses of therapy, up to maybe 40% of patients would develop colitis.

At more moderate doses, it’s a lower rate of colitis, maybe a quarter to a fifth, 20, 25% of patients will have immune-mediated colitis. The other learning experience in this trial was that early initiation of TNF inhibitors, so with infliximab, made a big difference in treating the colitis and preventing recurrence, and keeping patients on the drug long enough to derive benefit by taking a steroid-sparing approach to address the most common toxic event, which was immune-mediated diarrhea and colitis, significant at least. We could both prevent that toxicity, treat that toxicity, and keep patients on trial long enough to derive substantial benefits.

So, I don’t think that this is really that different than other immune checkpoint inhibitors. Maybe there’s some slightly different character like any new drug, but the experience for patients is really substantially easier than chemotherapy. And keep in mind, this is a very refractory population.

So, these are patients who had had multiple antibodies five or a few oxaliplatin, irinotecan, monoclonal antibodies, either EGFR or VEGF, lonsurf, regorafenib, and even fruquintinib. So it’s a very heavily pre-treated population. And so, for many of the patients, it was a very, very positive experience because the day-to-day quality of life on a drug like this is actually quite positive.

And we were very good over time at managing the immune-related adverse events, in particular with the early initiation of infliximab and related drugs.

Amalya Sargsyan: It sounds very impressive. And indeed, you mentioned that this was heavily pre-treated population. So, giving some personal insights into this.

You said they’re heavily pre-treated, already exhausted prior lines of treatment. How these patients were reacting to being involved in the trial, which eventually led to some promising data. Were they different from those who are treated in the first line, in the clinical trial settings?

What is your experience with it?

Benjamin Schlechter: Yeah, I mean, that’s always the challenge of phase one trials, where it’s a very special population who gets on trials like this because you have to be very, very fit. Now, keep in mind, that the enrollment criteria for the trial were prior oxaliplatin, irinotecan, 5-FU, and a monoclonal antibody is appropriate. And that actually could be a second-line treatment for colorectal cancer because the efficacy of trifluridine, Lonsurf, even with bevacizumab and regorafenib and fruquitinib is so very, very limited.

Those are sort of marginally effective drugs and pretty toxic drugs, either hematologic toxicity or clinical toxicity, and their objective response rates are in the single digits. So, this trial allowed patients to enroll after the big three, 5-FU, oxaliplatin, irinotecan, which means some patients were receiving this even in the second line. And so that’s a fitter population, I think a more day-to-day clinical population.

Nobody was treated in the first lines. We can’t comment on that, but we would speculate, and trials will be coming, of course, that that’s a population that would do well. But there’s a broad spectrum of patients here, both treated everywhere from the second line after FOLFOX/IRI all the way to fourth or fifth line.

And I think for fitter individuals, they tolerated it just fine. Frankly, even for less fit individuals, by and large, it was well-tolerated, but clearly immune-related toxicity, colitis, and other such things, that are not benign in a less fit patient. And so, you have to be very proactive to treat that.

But again, patients did very well on this, even in the most refractory population.

Amalya Sargsyan: Yeah. And as it is a phase 1 trial, and you were among the first who was involved in this and tested it. And when enrolling the first patient, were you expecting these results to come?

Benjamin Schlechter: I’ll be honest. I entered this trial out of hope and out of faith in the co-investigators. I was not especially at first optimistic, and I quickly learned that the drug was as good as it sounded.

I think there’s a lot of skepticism for Botensilimab and balstilamab because of the long history of failure with ipi and nivo and durva and tremi and every other attempt in colorectal cancer, that’s MSS. But the drug kind of proved itself in its efficacy profile and in the safety profile. So, I think there was slow adoption of the trial, but now this has been a gigantic phase one trial across many diseases, not just colorectal cancer, many hundreds of patients have received the combination.

And we’ve seen efficacy, not just in colon cancer, but the publications coming out in a variety of diseases. But as a GI oncologist, obviously, colorectal cancer is important to me. And when you think about the burden of disease, colorectal cancer is now the leading cause of death, cancer-related death in adult men under the age of 50 and will surpass breast cancer by 2030.

So, there are many important diseases, but this is certainly a very common one, and having an immune checkpoint inhibitor available for those patients without active liver metastases, I think is really quite critical.

Amalya Sargsyan: So, you do think that it is going to change the landscape of treatment of colorectal cancer in the near future?

Benjamin Schlechter: Yeah, I think this is a practice-changing drug. I don’t think there’s really any question. There are patients with deep and profound responses.

There are complete responses. There are durable responses. It’s a new drug.

I can’t tell you what the five-year survival is on this drug because it has not been around for five years, but I can say that for the non-liver met population, for the responders, we have not met a survival endpoint because patients are still alive. So, I really do think this is a practice-changing drug in a lot of ways. Importantly, it’s an effective immune therapy in MSS colon cancer, and we can’t ignore that.

It also emphasizes the absence or presence of liver metastases as a biomarker for response. And that will inform not just this trial, but many, many other immune therapy trials. As we think about enrollment in these trials and the design of these trials, there are a couple of things.

Number one, we’re trying to assess the efficacy of immune checkpoint blockade in these so-called cold tumors. We need to look at the organs. And number two, we urgently need to address how is it that liver metastases have a different resistance profile, and then treat that, and overcome it, so that we can provide this drug not to the 20, 25% of patients without liver mets, but to the broad swath of colorectal cancer patients who are in desperate need of other therapies beyond chemotherapy.

Amalya Sargsyan: So, you do think that maybe managing the liver metastasis also can have more people come into this population and be treated with this?

Benjamin Schlechter: Yeah, there are two ways to look at that. Number one is to find a drug that overcomes the resistance in the liver, or number two is to carefully study patients who’ve had treated liver metastases. In this trial, patients who had treated liver metastases were enrolled, although it’s a small population, and they appear to derive benefits, but we need to study it prospectively.

So, I would not cavalierly start ablating things in the liver that would not otherwise be a candidate for ablation to put someone on a phase one trial. But at the same time, I think that we have to look closely at the possibility that that’s the right thing for patients and study it prospectively.

Amalya Sargsyan: Yes, that’s some studies that I believe will be upcoming. And as someone who is involved in it and seeing the results, how do you see the prognosis of the drug? What do you think will be the next steps, maybe to use in combination or come to the frontline?

You have partially addressed it, but just to wrap it up.

Benjamin Schlechter: Yeah, there are lots of great questions to address, right? Is this a frontline drug in combination with a FOLFOX, Bevacizumab? Is this a second-line drug in place of FOLFIRI?

Is this a drug used at maintenance on 5-FU? You know, if you look at the checkpoint inhibitor data in mismatch repair deficient cancers, there’s that early group where checkpoint blockade is inferior to chemotherapy. And then in the long run, that’s where the benefit is derived.

And so, we have to be careful as we design these studies to account for the fact that not everyone’s going to respond and we want to be careful about that. We need to study ablation of liver metastases as opposed to just ablating liver metastases because it could be the issue is the liver, in which case by clearing the liver of disease, we can potentially give patients benefit. It could be the issue is the cancer and the ability of the cancer to invade the liver confers resistance to the drug.

We don’t know that yet, so we need to be thoughtful about how we study this. I don’t think that we should make assumptions just yet.

Amalya Sargsyan: Yeah, thank you for sharing your envision and how you see the future of the drug going on. And just to wrap up, as someone who has already been there and as it is going to expand and more people will be involved in the research with Botensilimab, what would be your general advice to other medical oncologists when they are using Botensilimab?

Benjamin Schlechter: First of all, I’d say put patients on trial of this drug. We need to get through our phase three trial. We need to get this drug approved because I really and truly believe this is a practice-changing drug.

So, number one, for now, find the trials, open the trials, get people on this trial and every trial so we can get new drugs. Like any new drug, it’s a learning curve and you have to read closely the protocols the clinical experience and the information from the company. I think the critical lesson of this drug has been the early initiation of therapy for immune-related adverse events because it’s not just a CTLA4 inhibitor.

And the experience in Phase 1 and the design of Phase 2 and Phase 3 was the early use of infliximab for immune-related colitis. That made a huge difference. So, patients going on this drug need to be tested for things like TB prior to initiation of therapy so that you can comfortably use infliximab and need to be ready to treat immune-related adverse events early, not to stop the drug, but actually to keep people on the drug.

The goal of a steroid-sparing approach is to keep patients on and give them time to benefit because immune therapy is not fast. And even when you see early progression on this drug, you have to remember that pseudoprogression is very common with CTLA4 inhibitors, especially this CTLA4 inhibitor, this next-generation CTLA4 inhibitor. And so when a patient is doing well, but the scan doesn’t look so good, you just keep going.

And it takes a little bit of bravery, a little bit of reassurance, and just keep at it. And patients really do derive benefit. And by 16 weeks, it’s usually pretty clear if they’re benefiting or not, but you got to get those first two doses six weeks apart and then sometimes the third dose at 18 weeks.

Amalya Sargsyan: Thank you for sharing these. Actually, it was very important because we usually see how patients are happy with the results. And we also see the drug developers who are happy that the results are satisfactory.

And we are missing the points where the ones who are at the bedside and who are seeing the results first and who are dealing with the patients first are reacting to these drugs. And it’s very important to see your perspective also. Thank you for your time and for being with us today.

And it was a very impressive and informative talk. And if you want to give the last comments, feel free to do so.

Benjamin Schlechter: No, thank you for having me. Thank you for featuring this effort. This is a huge effort with the company Agenus for the co-investigators with Dr. Bullock, co-first author and Dr. Fakih, and Dr. Tsimberidou, and Dr. El-Khoury, our senior author. This is a really, really huge effort in colon cancer and needed effort. And I’m glad we can report success. It’s great to have something new and exciting in colon cancer.

Amalya Sargsyan: Yes, especially in the population where there is an unmet need, seeing the results is very promising and drives even more excitement to see how the future and what the future will bring to us. Thank you, Dr. Schlechter for being with us today, and see you the next time. Hopefully with the better results and hopefully with the phase three trials.

Benjamin Schlechter: That’s the plan.