The BOT/BAL Breakthrough: A New Era for Colorectal Cancer Treatment

Colorectal cancer remains a significant global health challenge, with a particularly dire prognosis for patients with advanced disease. Despite advances in chemotherapy, a critical unmet need persists: the lack of effective immunotherapy options. This interview with Benjamin Schlechter, MD, senior physician in the Gastrointestinal Cancer Center at the Dana-Farber Cancer Institute, delves into a groundbreaking clinical trial that may finally change the tide. Schlechter discusses the innovative combination of botensilimab and balstilimab (BOT/BAL), a treatment designed to activate and sustain the body's immune response against cancer. He explains the unique mechanism of action, the surprising findings from a recent trial, and the profound implications this research holds for a patient population that has long been without a viable immunotherapy solution.

Targeted Oncology: What are some of the unmet needs in the patient population that this research focused on?

Benjamin Schlechter, MD: There are a few important unmet needs in advanced colorectal cancer. I would say the most prominent one is the fact that there is no immunotherapy that works. The only therapies that we have are chemotherapies, which are moderately effective. So, the principal problem is that there are whole classes of drugs that just don't work in colon cancer, and that's part of what this trial is seeking to address.

How does BOT/BAL work?

The goal is to promote inflammation, and that's part of the immune response. The other part of the immune response is to prevent that inflammation from going away. Everything in your body has an on switch and an off switch. When you activate inflammation, that's what the botensilimab would do. [But] you need something else to keep that inflammation going. And in this case, that is what balstilimab does. BOT to start the process, BAL to maintain the process.

That speaks to the design of the treatment. We have discovered that you don't need much BOT—between 1 and 4 doses to get started—depending on what disease you're treating. Then you do a maintenance regimen of BAL to maintain that efficacy. The BOT/BAL combination is really the successor of the prior generation of CTLA-4 inhibitors that promote inflammation with maintenance PD-L1 inhibitors.

Could you describe the study’s design?

What we presented was the expansion cohort for the phase 1 trial looking at [patients with] colorectal cancer. Early on in that phase 1 trial was the dose-finding of BOT. It was observed that [patients with] colorectal cancer were deriving benefit. This was unexpected. Colorectal cancers have not benefited from any checkpoint inhibitor in the past, at least when we're talking about the most common type of colorectal cancer, microsatellite stable colorectal cancer.

The other observation was that these were a particular subgroup of patients with no liver metastases. We've known for a while that the liver is an organ that interacts differently with the immune system. I think we could call it an organ of tolerance, which is that it allows things to happen. It creates blind spots in the immune system. So, the clinical trial was working on finding the dose, and it did find the effective dose for BOT. Then, we did a dose expansion. We added patients with nonhepatic colorectal cancer, and we observed patients with liver metastases. There were some [cases of] stable disease, but by and large, objective responses and prolonged responses were not present in patients with liver metastases with advanced disease.

In the advanced disease population, we previously showed data from 77 patients where we saw impressive efficacy and manageable toxicity. Now, we have published a larger cohort, so everyone in the trial had no liver metastases with long-term follow-up of 123 patients. There are several important points about those patients. It wasn't just patients who had a couple of prior lines of therapy. We have a subset who had multiple, multiple, multiple previous lines of therapy, the most refractory colorectal cancer. Here, the patients who received the most treatment did the same as the patients who received less treatment.

That speaks to the fact that the drug is fundamentally different than chemotherapy. Botensilimab works on the immune system to allow it to do its job correctly. As a result, if you have an immune system, these drugs have the capacity, potentially, to work. They don't work universally. They work very well in a subset of individuals, around 20%, and they work okay in a significant number of individuals. That's a very important point, because chemotherapy becomes more dangerous and less effective the more lines of therapy you have. That's not what we saw here. This is a very different thing. This is immunotherapy, and it is as good late as it is early. And I suspect if you move it earlier, it's even better, because there's a threshold effect and fitness of the immune system, where the fitter patients probably do better. That was the principle finding: we showed everyone who had had the drug—123 patients—the safety and efficacy is identical across populations.

Could you describe the patient population?

It is a relatively reflective population. The youngest patient was in their late 20s, and the oldest was in their late 70s. This reflects a real-world population, and that's what we see in colorectal cancer. Traditionally, colorectal cancer diseases the elderly, but that's not true anymore. In fact, every year since 1970, adults under the age of 50 have had an increase in colorectal cancer. Just within the past few years, colorectal cancer became the leading cause of cancer death in men under the age of 50 and by 2030 will pass breast cancer as the leading cause of cancer death in women under the age of 50. There is a changing demographic: patients are getting younger.

What are the next steps in this line of research?

The critical thing is getting the [regimen] FDA approved, EMA approved in Europe, and so forth. There is a planned phase 3 trial for refractory disease that was a [Canadian Cancer Trials Group (CCTG)] trial that would take place in Canada, Australia, and France, and hopefully that will get the drug into patients and get approval.

In terms of the next big American trials, I think it remains to be seen. A lot depends on funding and research. Obviously, I think it is well established that academic research is struggling right now with funding alterations and regulations. Even for biotech, it's a problem, because when the FDA behaves in ways that are unpredictable and unusual, then it's hard for investors, whose job is to invest money and make money, to take risks on new drugs. So, there's a chilling effect that even if drug companies are not directed by the change in federal policy around research and around regulation, it still harms them because it creates uncertainty. The reality is that thousands of patients are being deprived access to good drugs because of uncertainty in federal regulation and federal policy.

Chemo is good. Let’s not undercut the benefit of chemo. But chemo works by delivering a very carefully managed injury. And immunotherapy is also good and has its own risks and benefits. Fundamentally, the more things you can do for a patient, the better you can make things. When you have someone in their 30s or 40s who’s managing a family and making the major earnings of their life and is pulled out of that because of lack of effective therapy, that's bad for patients and families. Society benefits when we have more treatments. BOT/BAL is bringing a whole new class of drugs to colon cancer that literally was not available before, so this really adds a lot to a broad population of patients in need.