Botensilimab/Balstilimab Combo Shows Potential for MSS CRC


In an interview with Targeted Oncology, Benjamin Schlechter, MD, FACS, discussed the background of a phase 1a/1b trial in microsatellite stable colorectal cancer and how these findings will influence future research.

Botensilimab (AGEN1181) in combination with balstilimab (AGEN2034) elicited promising clinical activity and durable responses in metastatic heavily pretreated patients with microsatellite stable (MSS) colorectal cancer (CRC), according to findings from a phase 1a/1b study (NCT03860272).

In the trial, 59 patients with metastatic MSS CRC were administered botensilimab at either 1 or 2 mg/kg every 6 weeks along with balstilimab at 3 mg/kg every 2 weeks. Patients were eligible to crossover from monotherapy to receive combination therapy or fixed-dosing of botensilimab 150 mg every 6 weeks and 450 mg balstilimab every 3 weeks.

The goals of the study were to assess botensilimab, an Fc-enhanced next-generation anti-CTLA-4 antibody, in combination with balstilimab, an anti-PD-1 antibody. Primary end points of the study included assessing the incidence of treatment-emergent adverse events (TRAEs), identifying the dose limiting toxicities associated with botensilimab, and determining the recommended phase 2 dose. Secondary end points evaluated the objective response rate (ORR), duration of response (DOR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS).

Among patients enrolled, the median age was 57 years (range, 25-83), 58% of patients were female, and 76% received at least 3 prior lines of therapy, including prior immunotherapy (34%). Patients were required to have a histologically or cytologically confirmed diagnosis of metastatic or locally advanced solid tumors, measurable disease on imaging based on RECIST 1.1, a life expectancy of 3 months or greater, an ECOG performance status of 0 or 1, and adequate organ and bone marrow function.

Findings recently presented at the 2023 American Society of Clinical Oncology Gastrointestinal Cancers Symposium showed that at a median follow-up of 6.4 months (range, 1.6-29.5), the ORR was 22% (95% CI, 12-35), DCR was 73% (95% CI, 60-84), and median DOR was not reached in all evaluable patients. At 12 months, the OS rate was 61% (95% CI, 42-75), and the median OS was not reached. Nine out of 13 patients also have ongoing responses, and among the 13 responders, 9 also had RAS mutations.

Regarding safety, TRAEs of any grade were observed in 88% of patients. TRAES that were grade 3 were seen in 32% of patients, and grade 4 TRAEs were reported in 2%. The only grade 3 or 4 TRAEs to occur in over 3 patients were diarrhea and colitis, and 15% of patients had grade 3 and 2% had grade 4. Further, there were no grade 5 TRAEs reported, 15% of patients discontinued treatment with botensilimab due to their TRAEs, and 12% discontinued both study drugs as a result of TRAEs.

In an interview with Targeted OncologyTM, Benjamin Schlechter, MD, FACS, senior physician at Dana-Farber Cancer Institute, discussed the background of a phase 1a/1b trial in MSS CRC and how these findings will influence future research.

Targeted Oncology: Can you discuss the phase 1a/1b study of botensilimab and balstilimab in MSS CRC?

Schlechter: This is a modified or second-generation combination of a CTLA-4 inhibitor and a PD-1 inhibitor, so checkpoint inhibitors, for refractory colorectal cancer. In the past, conventional checkpoint inhibitors have been universally ineffective in microsatellite stable colorectal cancer. So this is an agent, the CTLA-4 antibody, which is modified to decrease complement fixation and increase NK cell activation, which hopefully can improve the safety profile and improve the activity of the drug. We observed responses in patients with non-hepatic colorectal cancer, that’s a significant minority. It’s not a universal access to the drug.

The disease control was very high at over 70% with an objective response rate over 20%. [There was] significant disease control for patients with non-hepatic disease in refractory colorectal cancer, a population who would otherwise be receiving agents that have had very limited efficacy. The safety profile was manageable. There was a lot of colitis, but that’s something we [can manage]. This is the first, in a phase 1, significant response rate in colorectal cancer for microsatellite stable diseases using checkpoint inhibitor therapy, which is important.

What led up to commencement of this study?

This was a phase 1 trial, a basket trial of all comers, looking at checkpoint inhibitors with this modified agent that was felt to be effective. It was noted early on that patients with non-hepatic disease were deriving benefits and those with hepatic disease were not, and this is a known problem. We’ve known for a while that bulky hepatic metastasis, even in so-called hot tumors, have less of a response, and that metastatic disease and liver have a worse response to checkpoint inhibitors, so it’s not shocking that this is happening.

This was a very dramatic example of the differences between liver metastasis and non-liver metastasis. We pursued that in the trial to dig deep on the non-hepatic population. We quickly discovered there was no problem enrolling patients in the study. Once the decision was made to focus on the non-hepatic population, it became quickly apparent that there was a significant response here with a good disease control rate and adaptive responses.

What were some of the eligibility criteria required for enrollment?

This is a phase 1 trial in refractory metastatic colon cancer. This is a population with no active metastatic disease in the liver, and these are patients who had to have received prior oxaliplatin or irinotecan. They could have received trifluridine/tipiracil [TAS-102; Lonsurf] with or without bevacizumab [Avastin] and regorafenib [Stivarga], which are considered refractory regimens and those are minimally effective combinations. Conventionally, we think of a 3%-5% objective response rate, and pretty limited progression-free survival. These are minimally effective drugs, they have a role for fit individuals, so this was in that population, and obviously, patients with no active immune problems. [We did not want patients] to go into the checkpoint inhibitor trial with active colitis or some other history of immune-related adverse events .

Can you explain the results of the trial?

What we saw was that patients with no active metastatic disease in the liver had excellent disease control in this population of 70 patients. Around 70% of patients had stable disease or better, and that means minimal growth or some degree of shrinkage. Well over 20% had objective responses, so a greater than 30% reduction in their cancer burden. There were patients with near complete responses, so essentially all measurable disease, as far as we can tell, had been suppressed and the survival was prolonged. At the time of the presentation, we had not met median progression-free survival in the non-hepatic population, which is important. Again, this is a population of refractory colorectal cancer [patients], where we measure responses, usually in weeks, and survival for weeks or a few months. To have a population of patients where the median survival is not met is impressive in a large phase 1 study.

What are the implications of these data? What are the main takeaways?

This is the first successful checkpoint inhibitor trial in this special population of non-hepatic disease and I think there’s several things that come up as a consequence. First of all, a randomized phase 2 trial is launching, and phase 3 is planned. That’s as you would expect. There are going to be some dosing schedule assessments in phase 2, and there will be a standard of care control arm against [trifluridine/tipiracil] or regorafenib. That’s an important step to lead to approval of the drug.

We also need to figure out ways to manage patients with active liver metastatic disease. I think the race is on to figure out why patients with active metastatic disease in the liver don’t respond to checkpoint inhibitors generally, and this combination in particular, and what can we do to convert people from active metastatic disease in the liver to no active metastatic. [We have to] expand the population that’s eligible for this trial from 25%-30% of all patients with refractory disease to 100% or nearly 100%. Those are important areas of research and we see a lot about that over the next 2 years.

El-Khoueiry A, Fakih M, Gordon MS, et al. Results from a phase 1a/1b study of botensilimab (BOT), a novel innate/adaptive immune activator, plus balstilimab (BAL; anti-PD-1 antibody) in metastatic heavily pretreated microsatellite stable colorectal cancer (MSS CRC). J Clin Oncol. 2023;41(suppl 4):LBA8. doi:10.1200/JCO.2023.41.4_suppl.LBA8
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