Botensilimab Plus Balstilimab Shows Promising Activity in Heavily Pretreated Metastatic Colorectal Cancer

Anthony El-Khoueiry, MD, University of Southern California, Norris Cancer Center, Los Angeles, discusses results from an analysis of patients with microsatellite stable colorectal cancer treated with botensilimab plus balstilimab in an expanded phase 1a/b study. The analysis showed that botensilimab plus balstilimab demonstrates unprecendented activity in these patients with a manageable safety profile.

These results were presented at the 2022 ESMO World Congress on Gastrointestinal Cancer in Barcelona, Spain.

Transcript:

Hello, I'm Anthony El-Khoueiry from the University of Southern California Norris Comprehensive Cancer Center in Los Angeles. We are here at ESMO World GI Congress 2022 in Barcelona. Today, I'd like to share with you a summary of my presentation on an ongoing study of botensilimab, which is a novel innate and adaptive immune activator, and next generation CTLA-4 antibody, in combination with basiliximab, in a cohort of patients with microsatellite stable colorectal cancer.

As a brief background, there is an unmet need for patients with advanced metastatic colorectal cancer who have failed standard therapy, especially in third line and beyond. Current options have low response rate, modest survival benefit, and single agent anti–PD-1, PDL-1 agents are inactive. Responses are very rare with first generation CTLA–4-based combinations. For example, in a recently reported CCTG study, there was one response out of 119 patients treated with tremelimumab and durvalumab.

With that background, it would make sense to explore novel immunotherapy agents in this space. Botensilimab is an Fc-enhanced CTLA-4 antibody. In addition to blocking the interaction of CTLA-4 with its ligands, the enhanced Fc portion grants it several unique properties, such as increased frequency of dendritic cell concentration, a boost in T-cell formation, T-cell memory formation, T-cell priming, and enhanced T-reg depletion. Basiliximab is an IgG4, anti–PD-1 antibody that's been evaluated in over 650 patients. It has a similar profile to other anti–PD-1 agents. This cohort is part of an ongoing phase 1 study, the first-in-human dose escalation part is complete. And today we were sharing the results from an ongoing cohort of microsatellite stable colorectal cancer patients. So these patients come from both the dose escalation and dose expansion.

And that course is continuing to enroll patients who were treated with botensilimab at 1 or 2 milligrams per kilograms, every 6 weeks and basiliximab 3 milligrams per kilograms, every 2 weeks. Microsatellite stability was an eligibility requirement and was determined by local assessment. We had 41 evaluable patients, defined as patients that had at least 1 staging scan from baseline. The baseline demographics were reflective of an advanced colorectal population, but this was a heavily pretreated population with a median of 4 prior lines. More than 50% of patients had 4 lines or more. By design, all patients were microsatellite stable, and the RAS and RAF mutation status was as expected in the 41 evaluable patients. The objective response rate by 1.1 was 24% with 10 patients having a partial response and 20 having stable disease. So the disease control rate was 73% at immediate follow up of 5.8 months.

Eight of the 10 responses are still ongoing and 3 responses have gone beyond 1 year. When we look at the waterfall plot, we see that responses occurred independent of RAS mutation status. Only 1 responder was reported to have high PDL-1 expression, and all responders had a TMB of 10 or less. Because of the emerging data showing a higher response rate in patients without liver metastasis, we did a retrospective exploratory analysis of responses by liver disease status. With patients who have no liver metastases or whose liver metastases were resected or ablated without recurrence, there was an enriched response rate there. The ORR was actually 42% and the disease control was 96%.

In the patients with active liver metastasis, we did not see objective responses, but we did see some target lesion reduction and prolonged stability up to 24 weeks. In regards to safety, 76% of patients had a treatment related adverse events, but the majority of these were grade 1 and 2. Grade 3 adverse events were limited to 24%. The most common adverse events were GI related with 16 patients having diarrhea colitis, but only 4 of these actually had grade 3 diarrhea colitis that was manageable with steroids and infliximab. There were no grade 4 or 5 treatment related adverse events and IRAEs reported by investigators where in 46% of patients, but only 17% had grade 3 IRAEs.

In summary, this is a novel combination with an Fc-enhanced CTLA-4 antibody with anti–PD-1. We did see deep durable responses in this cohort of microsatellite stable colorectal cancer patients on exploratory analysis. That is an enrichment of the response rate in the patients without active liver metastases. Actually the ORR of 42% is quite promising and intriguing. A randomized phase 2 study in MSS colorectal cancer patients will launch later this year. Thank you for your attention.

Source:

Bullock A, Grossman J, Fakih M, et al. Botensilimab, a novel innate/adaptive immune activator, plus balstilimab (anti-PD-1) for metastatic heavily pretreated microsatellite stable colorectal cancer. Presented at: ESMO World Congress on Gastrointestinal Cancer; June 29-July 2, 2022. Barcelona, Spain. Abstract LBA O-9.