Botensilimab Plus Balstilimab Provides OS Benefit in Heavily Pretreated MSS mCRC

The combination of botensilimab (AGEN1181) and balstilimab (AGEN2034) elicited durable responses and provided overall survival (OS) benefits in patients with microsatellite stable (MSS) metastatic colorectal cancer (mCRC) that is resistant to chemotherapy and/or immunotherapy, according to data from the phase 1 C-800-01 trial (NCT03860272).¹

Data from the non–microsatellite instability-high (MSI-H) cohort presented at the 2023 World Congress on Gastrointestinal Cancer in a late-breaking session showed that at a median follow-up of 9.8 months (range, 1.4-36.5), the doublet resulted in a median OS of 20.9 months (95% CI, 20.9-not reached [NR]) in patients without active liver metastases (n = 69). In those with active liver metastases (n = 18), the median OS was 8.7 months (95% CI, 6.1-NR) at a median follow-up of 7.8 months (range, 2.3-21.7).

Moreover, in all patients evaluable for efficacy (n = 87), at median follow-up of 9.3 months (range, 1.4-36.5), the median OS was 20.9 months (95% CI, 10.6-NR); the median OS was also 20.9 months (95% CI, 10.3-NR) in the intention-to-treat (ITT) population (n = 101) with a median follow-up of 8.2 months (range, 0.5-36.5).

The combination elicited an objective response rate (ORR) of 18% (95% CI, 11%-28%) in all efficacy-evaluable patients; this was comprised of a complete response rate of 1%, a partial response rate of 17%, and a stable disease rate of 52%. Thirty percent of patients experienced progressive disease. In those with and without liver metastases, the ORRs observed with the doublet were 0% (95% CI, 0%-19%) and 23% (95% CI, 14%-35%), respectively. The disease control rate (DCR) in all evaluable patients was 70% (95% CI, 59%-80%); these rates were 80% (95% CI, 68%-88%) in those without liver metastases and 33% (95% CI, 13%-59%) in those with metastases.

Notably, those without active liver metastases achieved durable responses with botensilimab plus balstilimab, with 69% of the 16 responders still experiencing a response to treatment at the time of data cutoff (range, 1.4+ to 24.3+).

“The new survival data underscore the potential of the botensilimab/balstilimab combination as an important treatment option for patients with non-MSI-H CRC,” Andrea J. Bullock, MD, MPH, lead study author and assistant professor of medicine at Harvard Medical School in Boston, Massachusetts, stated in a press release.² “The patients in our study face one of the most challenging cancers to treat and represent the largest patient population with CRC where only one-quarter of patients survive beyond 1 year with standard-of-care therapy. Botensilimab plus balstilimab continues to show deep and durable responses with 69% of objective responses still ongoing at the data cutoff.”

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

The first-in-human study enrolled patients with advanced cancer. Those with CRC needed to have refractory metastatic disease that was MSS.^1,3 Patients were required to have a total bilirubin level of no more than 1.5 times the institutional upper limit of normal (ULN), and aspartate aminotransferase/alanine transaminase levels no higher than 2.5 times the ULN. Patients were allowed to have previously received immunotherapy.

Study participants were administered botensilimab at 1 mg/kg or 2 mg/kg every 6 weeks plus balstilimab at 3 mg/kg every 2 weeks. Treatment was continued for up to 2 years.¹

The key efficacy end points of the study were ORR, DCR, duration of response, progression-free survival, and OS. Investigators also evaluated the safety of the doublet by examining adverse effects (AEs).

In the ITT population, the median age was 54 years (range, 25-82). More than half of patients were female (55%) and had an ECOG performance status of 1 (56%). Regarding primary disease site per internal medical review, this was in the colon (64%) and the rectum (36%). Moreover, 4% of patients had tumor mutational burden of greater than 10 mut/Mb. Fifty-eight percent of patients had tumors harboring a RAS mutation, and 4% had BRAF-mutated disease.

The median number of prior lines of therapy was 4 (range, 1-10), with 72% of patients having received at least 3 lines of previous treatment. Twenty-five percent of patients previously received an immunotherapy.

A total of 101 patients with non-MSI-H disease received at least 1 dose of treatment with the combination; 77 patients did not have active liver metastases and 24 did. A total of 87 patients received at least 1 post-baseline imaging scan at 6 weeks, and thus, comprised the efficacy evaluable population; 69 patients did not have active liver metastases and 18 did.

Additional efficacy findings indicated that the 12-month OS rate in all evaluable patients was 62% (95% CI, 49%-73%). In those without active liver metastases, the OS rate at 1 year was 74% (95% CI, 59%-84%); this rate was 30% (95% CI, 11%-52%) in those with active liver metastases.

No new safety signals were observed. All 101 patients experienced any-grade treatment-emergent AEs (TEAEs) with the doublet; these effects were grade 3 for 57% of patients and grade 4 for 4% of patients.

The most common TEAEs experienced by at least 15% of patients in the ITT population included diarrhea (all grade, 50%; grade 3, 8%; grade 4, 0%), nausea (41%; 5%; 0%), vomiting (30%; 4%; 0%), colitis (28%; 13%; 1%), abdominal pain (27%; 3%; 0%), constipation (15%; 0%; 0%), fatigue (46%; 3%; 0%), reduced appetite (44%; 3%; 0%), pyrexia (30%; 4%; 0%), chills (28%; 0%; 0%), headache (22%; 2%; 0%), decreased weight (16%; 0%; 0%), peripheral edema (15%; 0%; 0%), increased alanine aminotransferase (ALT; 20%; 2%; 0%), increased aspartate aminotransferase (19%; 2%; 1%), increased blood alkaline phosphatase (16%; 3%; 0%), arthralgia (24%; 1%; 0%), pruritus (24%; 0%; 0%), maculopapular rash (20%; 0%; 0%), anemia (29%; 12%; 0%), cough (26%; 0%; 0%), dyspnea (24%; 4%; 0%), hypokalemia (23%; 2%; 1%), hyponatremia (20%; 3%; 0%), dehydration (17%; 2%; 0%), hypoalbuminemia (17%; 0%; 0%), and hypophosphatemia (16%; 0%; 0%).

Any-grade treatment-related AEs (TRAEs) occurred in 88% of patients; these effects were grade 3 in 37% of patients and grade 4 in 2% of patients. The most frequent TRAEs occurring in 15% or more of the ITT population were immune-mediated diarrhea or colitis (all grade, 40%; grade 3, 16%; grade 4, 1%), nausea (20%; 2%; 0%), fatigue (32%; 3%; 0%), reduced appetite (27%; 0%; 0%), pyrexia (25%; 4%; 0%), chills (24%; 0%; 0%), increased ALT (16%; 2%; 0%), arthralgia (18%; 1%; 0%), pruritus (18%; 0%; 0%), and maculopapular rash (15%; 0%; 0%).

Safety data observed in those with CRC proved to be consistent across tumor types.

Thirty-three percent of patients discontinued treatment with the combination because of TRAEs; 33% of patients discontinued botensilimab and 17% discontinued balstilimab.

No treatment-related deaths occurred.

Previously, in April 2023, the FDA granted fast track designation to botensilimab plus balstilimabfor use as a potential therapeutic option in patients with non-MSI-H/mismatch repair–deficient mCRC without active liver involvement.⁴ The designation is intended for heavily pretreated patients who are resistant or intolerant to fluoropyrimidine, oxaliplatin, and irinotecan, and who have also received a VEGF inhibitor, an EGFR inhibitor, and/or a BRAF inhibitor, if indicated.

Botensilimab with or without balstilimab is being compared with standard-of-care treatments in patients with non-MSI-H CRC in an ongoing global phase 2 trial (NCT05608044).⁵

Editor’s Note: Dr Bullock disclosed that she received consulting fees from Exelixis, Panovance, and Oncolytics.

References

1. Bullock AJ, Fakih MG, Gordon MS, et al. Results from an expanded phase 1 trial of botensilimab, a multifunctional anti-CTLA-4, plus balstilimab (anti-PD-1) for metastatic heavily pretreated microsatellite stable colorectal cancer. Ann Oncol. 2023;34(suppl 1):S178-S179. doi:10.1016/j.annonc.2023.04.014
2. ESMO GI data: Agenus’ botensilimab/balstilimab combination achieves unprecedented survival in advanced colorectal cancer. News release. Agenus. June 30, 2023. Accessed July 5, 2023. https://investor.agenusbio.com/news-releases/news-release-details/esmo-gi-data-agenus-botensilimabbalstilimab-combination-achieves
3. Fc-engineered anti-CTLA-4 monoclonal antibody in advanced cancer. ClinicalTrials.gov.Updated April 28, 2023. Accessed July 5, 2023. https://clinicaltrials.gov/study/NCT03860272
4. Agenus receives fast track designation for botensilimab and balstilimab in colorectal cancer. News release. Agenus. April 17, 2023. Accessed July 5, 2023. https://investor.agenusbio.com/news-releases/news-release-details/agenus-receives-fast-track-designation-botensilimab-and
5. A study of botensilimab and balstilimab for the treatment of colorectal cancer. ClinicalTrials.gov. Updated April 18, 2023. Accessed July 5, 2023. https://clinicaltrials.gov/study/NCT05608044