Botensilimab is a multifunctional Fc-enhanced anti–CTLA–4 agent that has been shown to enhance T-cell priming, expansion, and memory, as well as increase the frequency of antigen-presenting cells and deplete regulatory T cells. It was also designed to reduce complement-mediated toxicity. The PD-1 inhibitor balstilimab completely blocks PD-1 and PD-L1/PD-L2 interactions, aiming to achieve strong T-cell activation and effector function.

Agenus conducted a Phase Ib trial to determine whether BOT and balstilimab (BAL; anti-PD-1) could confer responses in NLM sites outside the lungs and lymph nodes. Researchers evaluated the data of 77 patients with NLM MSS CRC who received botensilimab 1 or 2 mg/kg every 6 weeks and balstilimab 3 mg/kg every 2 weeks. The study’s primary endpoints included objective response rate (ORR), disease control rate (DCR), duration of response (DOR), and overall survival (OS). The results presented at ASCO 2024 were as follows:

Efficacy outcomes by sites of metastatic disease in patients with NLM MSS mCRC across different NLM sites:

• Response rates ranged from 18-33%

• Disease control rate ranged from 67-82%

• Median OS remained consistent and ranged from 20.7 months to not reached (NR)

Safety overview:

• No new safety signals

• Safety in CRC consistent across tumor types in the study

• No treatment-related deaths

KOL insights

“For MSS CRC, botensilimab and balstilimab are differentiated from previous I-O combinations by producing deep and durable responses even in difficult-to-treat metastatic sites” – Expert Opinion.

“The data underscore the potential of the botensilimab/balstilimab combination as an important treatment option for patients with non-MSI-H CRC”– Expert Opinion.

Conclusion

To conclude, responses to novel immunotherapy (I0) combinations in MSS mCRC have typically been restricted to non-liver metastatic (NLM) populations. Within this subgroup, responses outside of metastatic sites such as the lungs and lymph nodes are rare. However, the trial demonstrated that in patients with NLM MSS mCRC, response rates were comparable across different sites of metastatic disease, including historically poor prognostic sites such as the peritoneum, soft tissue, pleura, and brain. A global randomized Phase II trial of BOT + BAL (versus standard of care) in MSS mCRC is fully enrolled (NCT05608044) and a global Phase III trial is planned.