Botensilimab Plus Balstilimab Elicits Encouraging Responses in MSS mCRC Without Liver Mets

The addition of balstilimab to botensilimab led to a higher objective response rate (ORR) than that achieved with botensilimab alone in patients with microsatellite stable (MSS) metastatic colorectal cancer (mCRC) with no liver metastases, according to preliminary data from a phase 2 study (NCT05608044) presented during the 2025 Gastrointestinal Cancers Symposium.1

At a median follow-up of 12.7 months (range, 1.6-19.7), botensilimab at a dose of 75 mg every 6 weeks (Q6W) plus balstilimab (n = 62) led to a confirmed objective response rate (cORR) of 19% (95% CI, 10%-31%), and a disease control rate (DCR) of 55% (95% CI, 42%-68%).

When botensilimab was given at a dose of 150 mg Q6W plus balstilimab (n = 61), the cORR was 8% (95% CI, 3%-18%) at a median follow-up of 12.9 months (range, 0.1-20.6); in this arm, the DCR was 54% (95% CI, 41%-67%). When botensilimab was given as a monotherapy at a dose of 75 mg Q6W (n = 38) or of 150 mg Q6W (n = 40), the respective cORRs were 0% (95% CI, 0%-9%) and 8% (95% CI, 2%-20%); the respective DCRs were 37% (95% CI, 22%-54%) and 38% (95% CI, 23%-54%). The median follow-up in those arms was 9.8 months (range, 0.6-17.7) and 13.4 months (range, 0.7-21.1), respectively.

The median duration of response (DOR) has not been reached, and 70% of responses are ongoing.

“This is proof that botensilimab monotherapy is not as effective at 75 mg and that we do need the combination of balstilimab/botensilimab, so we did meet the primary end point of identifying contribution of component,” Marwan G. Fakih, MD, of the Department of Medical Oncology and Therapeutics Research at City of Hope Comprehensive Cancer Center, in Duarte, California, said in a presentation of the data. “…Unprecedented confirmed response rates with an IO-only combination in chemo-refractory mCRC has been seen in a powerful sample size and I would like to note that the durability of responses is quite impressive...Based on safety and efficacy data seen on the study, 75-mg botensilimab in combination with balstilimab 240-mg is the recommended dose for a phase 3 trial.”

Setting the Stage

Fakih underscored that CRC is a leading cause of death on a global scale and the incidence of this disease continues to climb in younger individuals. There is an unmet need for safe and effective options for patients with MSS CRC, particularly those who had progressed on 2 lines of treatment. Due to poor immunogenicity, immunotherapy approaches have historically missed the mark in this population.

Previously, a phase 1 trial (NCT03860272) was launched to examine what benefits could be derived when the Fc-enhanced CTLA-4 inhibitor botensilimab was paired with the PD-1 inhibitor balstilimab in patients with MSS mCRC.2 They found that in the overall population without liver metastasis (n = 77), the doublet elicited a cORR of 23% (95% CI, 15%-34%). When botensilimab was given at 1 mg/kg (n = 36) or 2 mg/kg (n = 41) plus balstilimab, the respective cORRs were 25% (95% CI, 12%-42%) and 22% (11%-38%).

Diving Into the Phase 2 Trial: Population, Treatment, Objectives

With the global phase 2 study, investigators set out to determine the optimal dose of botensilimab and the contribution of balstilimab to the agent.1 The study enrolled patients with MSS CRC who did not have active liver metastasis and had prior fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, as well as an anti-VEGF and/or anti-EGFR agent if medically appropriate.

Patients were randomized to 1 of 5 arms: botensilimab monotherapy at 75 mg Q6W (ITT, n = 38; safety, n = 37), botensilimab at 75 mg Q6W plus balstilimab at 240 mg every 2 weeks (Q2W; ITT, n = 62; safety, n = 62), botensilimab monotherapy at 150 mg Q6W (ITT, n = 40; safety, n = 39), botensilimab at 150 mg Q6W plus balstilimab at 240 mg Q2W (ITT, n = 61; safety, n = 60), or standard-of-care (SOC) trifluridine/tipiracil (Lonsurf) or regorafenib (Stivarga; ITT, n = 33; safety, n = 21).

The primary end point of the study was investigator-assessed ORR by RECIST v1.1 criteria, and secondary end points included DOR, progression-free survival (PFS), and overall survival (OS). Safety was also evaluated, along with pharmacokinetics and immunogenicity.

A total of 234 patients were enrolled on the study and 219 of them were dosed. “The patient characteristics were relatively similar on all 5 arms,” Fakih said, “with the exception of some characteristics associated with poor prognosis, such as peritoneal disease, larger tumor burden, and a shorter onset of metastatic disease until randomization—and those unfavorable characteristics were more common on the 75-mg/240-mg arm.”

Additional Efficacy Insights

Fakih took a deeper dive into the efficacy observed in the treatment arms. He noted that responses were achieved on the monotherapy 150-mg arm and similar objective responses were seen with the combination when botensilimab was given at that dose, although the DCR was higher with the combination. Responses proved “deep and durable” on both arms.

“I would like to highlight this particular patient on the lower arm at 84 weeks of follow-up; this patient has now completed 2 years of therapy. It is a patient of mine that I’ve treated with botensilimab/balstilimab, who had refractory CRC with KRAS G12C [mutation] and retroperitoneal metastases, history of cytoreduction of peritoneal disease, extensive lung metastases, and who was on high-dose methadone,” he said. “The patient became pain free after 2 months, and now is circulating tumor DNA negative, with no measurable disease in the retroperitoneum, and only small fibrotic changes in the lung that are residual.”

When looking at the SOC, he underscored that no patients achieved objective responses, which was expected. “Note that only 21 patients were dosed, so the ability to compare is quite limited,” he added.

Safety Spotlight

Regarding safety, botensilimab at 75 mg plus balstilimab (n = 62) showcased the best risk-benefit profile of the different approaches evaluated. In this arm, any treatment-related adverse effects (AEs) occurred in 87% of patients and they were grade 3 or higher for 35% of patients. The most common immune-mediated AEs included diarrhea/colitis (35%), hypothyroidism (13%), and skin toxicities (6%). The most common grade 3 or higher AEs were diarrhea/colitis (18%), pneumonitis (3%), and hepatitis (2%).

No treatment-related deaths occurred, and no new safety signals were observed.

“Time-to-event secondary end points of DOR, PFS, and OS will be presented at a future meeting, [and] DOR and OS data continue to mature,” he concluded.

Disclosures: Dr Fakih received honoraria from Amgen. He serves in a consulting or advisory role for AbbVie, Adagene, Bayer, Bristol-Myers Squibb, Delcath Systems, Eisai, Entos, Janssen Research & Development, Merck, Microbial Machines, Mirati Therapeutics, Nouscom, Pfizer, Roche/Genentech, Taiho Pharmaceuticals, Tempus, and Totus Medicines. Research funding was provided by Agenus (Inst), Roche/Genentech (Inst), and Verastem (Inst).

References

1. Fakih M, Segal NH, Schlechter BL, 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). J Clin Oncol. 2025;43(suppl 4):23. doi:10.1200/JCO.2025.43.4_suppl.23
2. Bullock AJ, Schlechter BL, Fakih MG, et al. Botensilimab plus balstilimab in relapsed/refractory microsatellite stable metastatic colorectal cancer: a phase 1 trial. Nat Med. 2024;30(9):2558-2567. doi:10.1038/s41591-024-03083-7