Botensilimab/Balstilimab Yields Durable Responses in Non-MSI-H mCRC

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Encouraging responses with substantial survival benefits were observed with the combination of botensilimab (AGEN1181) and balstilimab (AGEN2034) among patients with microsatellite stable or non-microsatellite instability-high (non-MSI-H) metastatic colorectal cancer previously resistant to chemotherapy and/or immunotherapy, according to findings from a phase 1b trial (NCT03860272).¹

Findings were presented during a late-breaking session at the 2023 European Society of Medical Oncology (ESMO) World Congress on Gastrointestinal Cancer. The combination produced a median overall survival (OS) of 20.9 months for patients without active liver metastases, surpassing the 12.9-month benchmark with standard of care in this patient population.

"The new survival data underscore the potential of the botensilimab/balstilimab combination as an important treatment option for patients with non-MSI-H colorectal cancer. The patients in our study face one of the most challenging cancers to treat and represent the largest patient population with colorectal cancer where only a 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," said Andrea Bullock, MD, assistant professor of medicine, Harvard Medical School, and study investigator, in a press release.

In the open-label, multicenter, phase 1, study, investigators are examining the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of botensilimab monotherapy and in combination with balstilimab.² The study plans to assess the maximum tolerated dose (MTD) in patients with advanced solid tumors and aims to determine the recommended phase 2 dose (RP2D) of botensilimab alone and with balstilimab.

The study is utilizing a 3+3 dose-escalation where patients will be given different dose levels of botensilimab as a monotherapy and in combination with balstilimab. Once enrolled, patients will remain in the cohort of the dose level and schedule assigned at study entry, however, they can be replaced for any reason other than a dose-limiting toxicity. Treatment will be given to patients ≤ 2 years or until progressive disease, unacceptable toxicity, or if there is criterion for stopping the study drug or if withdrawal of trial occurs.

The primary end points of the study are incidence of treatment-emergent adverse events (TEAES), DLTs of botensilimab, and RP2D of botensilimab. Secondary end points of the trial will consist of objective response rate (ORR), duration of response (DOR), disease control rate (DCR), progression-free survival, overall survival, PK, and PD.

A total of 101 patients with refractory non-MSI-H metastatic colorectal cancer were enrolled in the trial and given botensilimab at a dose of either 1 or 2 mg/kg every 6 weeks with balstilimab 3 mg/kg every 2 weeks.¹ Among those enrolled, patients had a median of 4 prior lines of therapy, and 25% had previously failed immunotherapy.

The investigators evaluated efficacy in 87 patients who had undergone at least 1 six-week post-baseline imaging scan, and 69 of these patients had no active liver metastases. Further, half of the patients had poor-prognostic metastatic sites beyond the liver, including bone and soft tissue.

Additional findings from the trial showed that patients with active liver metastases had a 12-month OS estimate of 30% and a median OS of 8.7 months. These data surpassed the recently reported 5.9-month benchmark observed with the standard of care. For patients in the efficacy evaluable and intent-to-treat populations, the median OS estimates were comparable.

Among evaluable patients without active liver metastases, the confirmed ORR was 23% and the DCR was 80%. These findings were also significantly higher than what has previously been reported as a response rate of 3% with standard of care. Overall, responses were durable with 69% of objective responses ongoing at the time of the data cutoff. The duration of responses ranged from 1.4-24.3 months or more in recently treated patients.

Regarding safety, the botensilimab/balstilimab combination demonstrated a manageable safety profile and no new safety concerns were observed.

In addition to the ongoing phase 1b study, Agenus plans to submit a biologics license application to the FDA for the treatment of patients with non-MSI-H metastatic colorectal cancer. Previously, the FDA granted a fast track designation for the ongoing, global, randomized, phase 2 trial for patients with non-active liver metastases, and currently, global, randomized, phase 2 trials evaluating the combination of botensilimab and balstilimab for patients with melanoma, as well as botensilimab and chemotherapy for patients with pancreatic cancer are underway. There are also plans to initiate phase 3 studies evaluating the combination for patients with colorectal and non–small cell lung cancer.

"The data from our expanded cohort demonstrate remarkable median overall survival and sustained responses in heavily pre-treated patients that historically haven’t responded to immunotherapy. These findings provide evidence of the benefit of botensilimab/balstilimab in metastatic colorectal cancer, the second leading cause of cancer death in the U.S.," said Steven O’Day, MD, chief medical officer at Agenus, in the press release. "Our clinical research has shown confirmed responses in 8 other refractory tumor types, indicating the potential to transform clinical practice and patient outcomes for multiple challenging cancers."

REFERENCES:

1. ESMO GI data: Agenus' botensilimab/balstilimab combination achieves unprecedented survival in advanced colorectal cancer. News release. Agenus. June 30, 2023. Accessed July 6, 2023. https://tinyurl.com/bddrc7t3

2. Fc-engineered anti-CTLA-4 monoclonal antibody in advanced cancer. ClinicalTrials.gov. Updated April 28, 2023. Accessed July 6, 2023. https://classic.clinicaltrials.gov/ct2/show/NCT03860272