Marwan Fakih, MD, City of Hope Comprehensive Cancer Center, Duarte, California, discusses study results which identified the optimal phase 2 dosage of botensilimab and balstilimab for patients with refractory microsatellite stable colorectal cancer without liver metastases. 

Transcript: 

Hi, my name is Marwan Fakih, I'm a medical oncologist and the division head of GI oncology at City of Hope Comprehensive Cancer Center. I will be providing some updates on the presentation we presented at GI ASCO on the randomized phase 2 clinical trial of botensilimab and balstilimab in refractory microsatellite stable colorectal cancer without liver metastases. 

As a background, botensilimab is a CTLA-4 inhibitor. It is what we call an Fc fragment enhanced or engineered CTLA-4 inhibitor, which is more potent than the approved agents such as tremelimumab and ipilimumab. It does have more enhanced activation of effector t-cells and it's more potent in depleting regulatory t-cells, what we call Tregs, and hence it may have a bigger potential in cold tumors or tumors that historically don't respond to immunotherapy. The main rationale of this randomized phase 2 clinical trial is number 1, we had seen previously with the combination of botensilimab and balstilimab in a phase 1 clinical trial, a large phase 1 clinical trial with over 70 patients without liver metastases with microsatellite stable colorectal cancer, that a substantial number of those patients either had disease control or significant tumor shrinkage, 23% of the patients on that study had an objective response, meaning a shrinkage of more than 50%, and on that particular trial 2 dose levels of botensilimab were interrogated, 75 [mg] and 150 [mg], and both were effective and hence the question became was there a better dose to move into a phase 3 trial. At the same time, there were questions related to the fact that we did not have a large cohort of patients who received botensilimab alone, and what if botensilimab alone gives the same result as botensilimab and balstilimab, balstilimab is PD-1 inhibitor, and therefore this randomized phase 2 trial was designed. The main rationale for the study was, number 1, identify what is the optimal dose of botensilimab, is it 75 mg or 150 mg, and number 2, really to define, do we need botensilimab plus balstilimab, or in other words is balstilimab needed in this combination. 

To answer these questions, the randomization was to 4 treatment arms. Botensilimab alone at 2 different dose levels, 75 mg and 150 mg given every 6 weeks for up to 4 doses, or the combination of the same dosage, same frequency of botensilimab plus balstilimab, given at a fixed dose at 240 mg every 2 weeks for up to 2 years, those were the experimental arms. There was a 5th arm that is the standard of care arm, which was either trifluridine or regorafenib, and that’s what is FDA-approved for third-line treatment. That was the main rationale of the study and the design. The primary end point was obviously response rate, to see if the response rate appears to be higher with a combination arm versus the monotherapy, and to see if there was 1 particular combination that had a better response than the other. In this design, we enrolled a large number of patients, 234 patients actually were randomized, but 219 only received treatment and that's partly because the standard of care arms patients dropped off when they were randomized to the standard of care and did not pursue the study treatment. This is the largest clinical trial with a CTLA-4/PD-1 inhibitor in microsatellite stable colorectal cancer, a patient population that historically does not respond to immunotherapy. 

Now to the results, what we have seen is that the combination of botensilimab/balstilimab with the 75 mg dose level of botensilimab had the highest response rate. The overall response rate in that population was 19% and the disease control rate, stable disease plus objective response, was 55%. The combination of 150 mg of balstilimab plus botensilimab also had a significant disease control rate of 54%, almost matching what we saw with a lower dose of botensilimab plus balstilimab, but had a lower response rate of 8%. When we look at the monotherapy arms, the monotherapy arms had definitely a lower disease control rate of 37% and 38% than the combinations. No responses were noted with 75 mg of botensilimab alone while 8% of patients (3/40) receiving botensilimab at 150 mg had an objective response. Now the good thing is that these responses tend to be very durable, as a matter of fact, the median time of follow-up at the time of the data cut off point was about almost 13 months, the 70% of the patients who had responded had not progressed yet, so the median duration of response has not been reached as of yet.

To conclude, based on this study, number 1, the highest response rate was seen with the lower dose of botensilimab plus balstilimab, so 75 mg/240 mg for bot[ensilimab]/bal[stilimab] is the recommended phase 2 dose. From a safety perspective, that was also safer than the higher dose level. We saw less immune-mediated side effects of the combination. There was less colitis, less diarrhea associated with the 75 mg compared to the 150 mg so, from both the safety perspective and from the perspective of efficacy, the recommended dose level is 75 [mg] and 240 [mg]. As expected, the standard of care arm was associated with less efficacy, with a lower efficacy, and no responses were noted on the standard of care arm in 21 patients who received the treatment, the intended treatment of trifluridine or regorafenib. 

So, good news for our patients that we have more conclusively still shown that the combination of bot[ensilimab]/bal[stilimab] is effective, and I think this data support moving this combination and this dose further to a phase 3 clinical trial that will hopefully help the registrational efforts of botensilimab and balstilimab in chemotherapy-resistant metastatic microsatellite stable colorectal cancer without liver metastases.  

Source:

Fakih M, Segal N, Schlechter B, et al. Preliminary results from a randomized, open-label, phase 2 study of botensilimab (BOT) with or without balstilimab (BAL) in refractory microsatellite stable metastatic colorectal cancer with no liver metastases (MSS mCRC NLM). Presented at the 2025 ASCO Gastrointestinal Cancers Symposium. January 23-25, 2025; San Francisco, CA. Abstract 23