Botensilimab + Balstilimab for Rectal Cancer

Recruiting at 6 trial locations

Overseen By Paul Romesser, MD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Memorial Sloan Kettering Cancer Center

Must not be taking: Anticancer, Experimental, Immunosuppressive, others

Disqualifiers: Recurrent cancer, Active infection, HIV, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

40 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial examines the effectiveness of combining two drugs, botensilimab and balstilimab, for individuals with a specific type of rectal cancer. The focus is on ensuring the safety of these drugs and assessing their compatibility with standard chemotherapy. The trial targets individuals with locally advanced rectal cancer that has not metastasized. Those with a confirmed diagnosis and no prior treatments, such as chemotherapy or surgery, may qualify. As a Phase 2 trial, the research measures the treatment's effectiveness in an initial, smaller group of participants.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, you cannot take other experimental therapies or systemic corticosteroids (a type of medication that reduces inflammation) one week before starting the study drug. It's best to discuss your specific medications with the trial team.

Is there any evidence suggesting that the combination of botensilimab and balstilimab is likely to be safe for humans?

Research has shown that the combination of botensilimab and balstilimab is generally safe. Most side effects are mild and manageable. Importantly, no new immune-related safety issues have emerged, indicating the treatment does not cause unexpected immune problems.

In another study, about 70% of patients experienced stable disease or better, meaning their condition did not worsen. While the main focus is on the treatment's effectiveness, this safety information demonstrates that it is generally well-tolerated by patients.

Overall, existing studies indicate that botensilimab and balstilimab together are generally safe for humans, with side effects that are usually mild and manageable. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about Botensilimab and Balstilimab for treating rectal cancer because they use a unique approach compared to standard therapies like chemotherapy and radiation. Balstilimab is an anti-PD-1 antibody, which works by unleashing the immune system to attack cancer cells more effectively. Botensilimab enhances this effect by targeting the immune system further, potentially improving the body's ability to fight cancer. This combination could offer a new, more effective option for patients with locally advanced rectal cancer who have limited treatment choices.

What evidence suggests that the combination of botensilimab and balstilimab might be an effective treatment for rectal cancer?

This trial will evaluate the combination of botensilimab and balstilimab for treating locally advanced rectal cancer. Studies have shown that this combination holds promise for treating colorectal cancer, including rectal adenocarcinoma. Research indicates that this treatment combination has helped about 17% of patients with hard-to-treat colorectal cancer by shrinking some tumors. It has proven effective in both types of colorectal cancer, including microsatellite stable (MSS) types, like the one studied in this trial. Additionally, patients treated with these drugs lived an average of about 21 months, which exceeds the usual survival time. Initial findings suggest that the combination is safe and does not delay surgery, indicating its potential as a treatment option. ^{1 6 7 8 9}

Who Is on the Research Team?

Andrea Cercek, MD

Principal Investigator

Memorial Sloan Kettering Cancer Center

Are You a Good Fit for This Trial?

This trial is for individuals with locally advanced rectal adenocarcinoma that's mismatch repair proficient (MMRp)/microsatellite stable (MSS). Participants must meet certain health criteria to join, but specific inclusion and exclusion details are not provided.

Inclusion Criteria

Radiologically measurable or clinically evaluable disease per Protocol Section 13.0.

My cancer has not spread to distant parts of my body.

I can give or my representative can give consent for me to join the trial.

Exclusion Criteria

Known active hepatitis B (e.g., HbsAg reactive) or hepatitis C (e.g., HCV RNA [qualitative] is detected).

My rectal cancer has come back.

My tumor is blocking my intestines but I have a temporary bypass.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Neoadjuvant Treatment

Participants receive neoadjuvant combination of botensilimab and balstilimab

12 weeks

Chemotherapy

Participants receive standard chemotherapy in combination with BOT/BAL

12 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

1 year

What Are the Treatments Tested in This Trial?

Interventions

• Balstilimab
• Botensilimab

Trial Overview

The study tests the safety and effectiveness of combining two drugs, Botensilimab and Balstilimab (BOT/BAL), with standard chemotherapy in treating rectal adenocarcinoma. It aims to determine if this combination leads to few or mild side effects.

How Is the Trial Designed?

Group I: Participants with locally advanced rectal cancer Experimental Treatment 2 Interventions

Up to 40 patients with mismatch repair proficient (MMRp)/microsatellite stable (MSS) locally advanced (stage II or III) rectal cancer

Who Is Running the Clinical Trial?

Memorial Sloan Kettering Cancer Center

Lead Sponsor

Trials

1,998

Recruited

602,000+

Agenus Inc.

Industry Sponsor

Trials

58

Recruited

4,900+

Published Research Related to This Trial

In a neoadjuvant setting for patients with locally advanced pMMR/MSS colon and rectal cancer, the combination of botensilimab (an anti-CTLA-4 antibody) and balstilimab (an anti-PD-1 antibody) showed exceptional responses, indicating potential efficacy of this immunotherapy approach.

The unique 'inside-out' tumor regression pattern observed suggests a novel mechanism of action for botensilimab, which may influence future clinical trial designs and offer alternatives to chemotherapy for these patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neoadjuvant botensilimab plus balstilimab response pattern in locally advanced mismatch repair proficient colorectal cancer. Kasi, PM., Hidalgo, M., Jafari, MD., et al.[2023]

In a study involving 18 patient-derived xenograft models of colorectal cancer, 60% of tumors showed regression when treated with a combination of MEK and CDK4/6 inhibitors, indicating significant therapeutic efficacy for RAS mutant colorectal cancer.

The clinical trial of binimetinib and palbociclib confirmed the safety of this treatment approach and provided preliminary evidence of its effectiveness, while also revealing mechanisms of resistance that could be targeted for improved outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Targeting RAS Mutant Colorectal Cancer with Dual Inhibition of MEK and CDK4/6. Sorokin, AV., Kanikarla Marie, P., Bitner, L., et al.[2023]

In a study of 43 patients with BRAF V600-mutant metastatic colorectal cancer, the combination of dabrafenib and trametinib showed activity, with 12% of patients achieving a partial response and one patient achieving a complete response lasting over 36 months.

All patients evaluated during treatment showed a significant reduction in phosphorylated ERK levels, indicating effective inhibition of the mitogen-activated protein kinase signaling pathway, although the response was less pronounced than in BRAF-mutant melanoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combined BRAF and MEK Inhibition With Dabrafenib and Trametinib in BRAF V600-Mutant Colorectal Cancer. Corcoran, RB., Atreya, CE., Falchook, GS., et al.[2022]

A disproportionality analysis of 33,327 reports identified 687 cases of adverse reactions associated with alpelisib, with hyperglycaemia being the most significant adverse event, indicating a strong association with this medication.

The most frequently reported adverse events included hyperglycaemia, rash, and diarrhoea, highlighting the need for monitoring these effects in patients receiving alpelisib.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adverse events of alpelisib: A postmarketing study of the World Health Organization pharmacovigilance database. Chen, X., Wei, L., Chi, L., et al.[2022]

BGB-283, a dual RAF kinase/EGFR inhibitor, shows strong potential in treating BRAF(V600E) colorectal cancer by effectively inhibiting tumor growth and preventing the reactivation of EGFR signaling, which is often a problem with first-generation BRAF inhibitors.

In preclinical studies, BGB-283 demonstrated selective cytotoxicity against cancer cells with BRAF(V600E) mutations and EGFR alterations, leading to significant tumor regressions in animal models, indicating its promising efficacy as a new treatment option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

BGB-283, a Novel RAF Kinase and EGFR Inhibitor, Displays Potent Antitumor Activity in BRAF-Mutated Colorectal Cancers. Tang, Z., Yuan, X., Du, R., et al.[2020]

In the BEACON CRC study involving 216 patients with BRAFV600E-mutated metastatic colorectal cancer, the combination of encorafenib and cetuximab was generally well tolerated, with most adverse events being mild to moderate in severity and resolving quickly, typically within 1-2 weeks.

The most common adverse events included dermatological toxicity (75.5%), arthralgia/myalgia (56.0%), and fatigue/asthenia (56.0%), with notable survival benefits observed in patients experiencing these side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adverse Events Associated with Encorafenib Plus Cetuximab in Patients with BRAFV600E-mutant Metastatic Colorectal Cancer: An in-depth Analysis of the BEACON CRC Study. Taieb, J., Lonardi, S., Desai, J., et al.[2023]

Activated T-cells armed with a bispecific antibody targeting CD3 and EGFR significantly increased tumor infiltrating lymphocytes (TIL) and reduced tumor cell viability, indicating enhanced anti-tumor activity.

Combining this bispecific antibody approach with targeted expression of LIGHT further improved T-cell proliferation and infiltration, leading to observable tumor regressions in a model of microsatellite stable colon cancer, suggesting a promising strategy for combination immunotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

LIGHT enhanced bispecific antibody armed T-cells to treat immunotherapy resistant colon cancer. Qiao, G., Kone, LB., Phillips, EH., et al.[2022]

A total of 3120 adverse event cases related to avapritinib were reported to the FDA, with 44% occurring within the first 30 days of treatment, highlighting the importance of monitoring patients closely during this period.

The study found that elderly male patients are at a higher risk for serious adverse events, indicating that clinicians should exercise caution when prescribing avapritinib to this demographic.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A post-marketing pharmacovigilance study of avapritinib: Adverse event data mining and analysis based on the United States Food and Drug Administration Adverse Event Reporting System database. Rong, L., Xie, M., Jiang, M., et al.[2023]

Immunotherapy, particularly with checkpoint inhibitors like anti-PD1 and anti-CTLA-4 agents, has shown high response rates in cancer treatment, but it can lead to a variety of immune-related adverse events that are not selective.

Real-world data suggests that the characteristics and management of these adverse events may differ from clinical trial recommendations, highlighting the need for tailored approaches in using corticosteroids and other treatments for severe cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Toxicities from immunotherapy: From clinical trials to real-world clinical practice. Riveiro-Barciela, M., Trallero-Araguás, E., Martínez-Valle, F.[2021]

In the final analysis of the KEYNOTE-164 study, pembrolizumab demonstrated a 32.8% objective response rate in patients with advanced MSI-H/dMMR colorectal cancer who had received multiple prior treatments, indicating its efficacy in this difficult-to-treat population.

The treatment was associated with a median overall survival of 31.4 months for patients with more prior therapies and 47.0 months for those with fewer, while maintaining a manageable safety profile with no new safety concerns reported.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab for previously treated, microsatellite instability-high/mismatch repair-deficient advanced colorectal cancer: final analysis of KEYNOTE-164. Le, DT., Diaz, LA., Kim, TW., et al.[2023]

Citations

1.

investor.agenusbio.com

investor.agenusbio.com/news/news-details/2025/Agenus-Presents-Data-at-ASCO-GI-Demonstrating-Impact-of-BOTBAL-in-Colorectal-Cancer-Across-Neoadjuvant-and-Advanced-Disease/default.aspx

Agenus Presents Data at ASCO GI Demonstrating Impact ...

Data from five presentations underscore the transformative potential of BOT/BAL across multiple lines of therapy in colorectal cancer.

2.

nature.com

nature.com/articles/s41591-024-03083-7

Botensilimab plus balstilimab in relapsed/refractory ...

Most notably, the combination of BOT and BAL resulted in promising efficacy, with an ORR of 17% (17/101 patients; ORR 18% with an additional ...

3.

ascopubs.org

ascopubs.org/doi/10.1200/JCO.2025.43.4_suppl.207

Neoadjuvant botensilimab (BOT) plus balstilimab (BAL) in ...

Neoadjuvant BOT/BAL is safe, with no delays to surgery, and effective. We observed high MPR rates in both MSS and MSI-H CRC with no recurrences to date.

4.

onclive.com

onclive.com/view/botensilimab-plus-balstilimab-shows-durable-activity-in-refractory-crc-across-lines-of-therapy

Botensilimab Plus Balstilimab Shows Durable Activity in ...

The median progression-free survival (PFS) was 4.0 months (95% CI, 2.8-4.1), and median overall survival (OS) was 20.9 months (95% CI, 16.2-26.6) ...

5.

oncodaily.com

oncodaily.com/oncolibrary/botensilimab-balstilimab-esmo-gi-2025

Botensilimab and Balstilimab Show Durable Survival in ...

Botensilimab plus balstilimab delivers 21-month overall survival in MSS colorectal cancer, per updated Phase 1b data at ESMO GI 2025.

6.

ascopubs.org

ascopubs.org/doi/10.1200/JCO.2025.43.16_suppl.e15602

A phase 2 study of SR-8541A in combination with ...

Around 70% of patients had stable disease or better, with a 17-19% objective response rate, a 30% reduction in cancer burden, and near-complete ...

7.

investor.agenusbio.com

investor.agenusbio.com/news/news-details/2025/Agenus-BOTBAL-Achieves-42-Two-Year-Survival-in-Refractory-MSS-CRC-Advances-Toward-Registration-with-FDA-Alignment-on-Phase-3/default.aspx

Agenus' BOT/BAL Achieves 42% Two-Year Survival in ...

Agenus' BOT/BAL Achieves 42% Two-Year Survival in Refractory MSS CRC, Advances Toward Registration with FDA Alignment on Phase 3 · ESMO‑GI ...

8.

asco.org

asco.org/abstracts-presentations/ABSTRACT391646

Results from a phase 1a/1b study of botensilimab (BOT) ...

In all pts, objective response rate (ORR) was 22% (95% CI, 12-35), disease control rate (DCR) was 73% (95% CI, 60-84), and median duration of response (DOR) was ...

9.

clinicaltrials.gov

clinicaltrials.gov/study/NCT05608044

NCT05608044 | A Study of Botensilimab and Balstilimab ...

This is an open-label, Phase 2, multicenter study to evaluate the efficacy, safety, tolerability, and pharmacokinetic profiles of botensilimab as monotherapy ...