Botensilimab and balstilimab are novel therapeutic agents for cancer treatment. These two investigational drugs are often considered together due to their combined action in stimulating the body’s immune system to fight cancer.
Understanding Botensilimab and Balstilimab
Botensilimab is a monoclonal antibody that targets CTLA-4, a protein on immune T-cells. By blocking CTLA-4, botensilimab “releases the brakes” on the immune system, promoting T-cell activation and multiplication. This action increases inflammation within the tumor’s environment. Unlike older CTLA-4 inhibitors, botensilimab is an Fc-enhanced antibody, designed to engage activating Fc receptors on other immune cells more robustly, leading to a broader anti-tumor effect.
Balstilimab is a monoclonal antibody and a programmed cell death protein 1 (PD-1) inhibitor. PD-1 is another immune checkpoint protein on T-cells. Cancer cells often produce PD-ligand 1 (PD-L1), which binds to PD-1 and masks cancer cells from immune detection. Balstilimab blocks this interaction, allowing T-cells to recognize and attack tumor cells.
Synergistic Mechanism of Action
The combined use of botensilimab and balstilimab leverages their distinct yet complementary mechanisms to activate and sustain an immune response against cancer. Botensilimab acts as an “on switch” for immune activation, initiating the inflammatory process against the tumor. This involves priming and activating T cells, reducing immune-suppressing regulatory T cells within the tumor, and activating myeloid cells.
To maintain this anti-cancer activity, balstilimab blocks the PD-1 pathway, preventing the immune response from being prematurely shut down. By “taking off the mask” from cancer cells, balstilimab allows activated T cells to continue fighting the tumor. This dual blockade of CTLA-4 and PD-1 pathways aims to create a more powerful and enduring anti-tumor immune response than either drug could achieve alone. The enhanced Fc portion of botensilimab also depletes immunosuppressive regulatory T cells within the tumor, further amplifying the immune attack.
Investigated Cancer Types
Botensilimab and balstilimab are being investigated for treating cancers, especially those that have responded poorly to single-agent immunotherapies. A significant area of focus is microsatellite stable (MSS) metastatic colorectal cancer (mCRC), which often does not respond to conventional immune checkpoint inhibitors. The combination has shown promising activity in heavily pretreated patients with this type of colorectal cancer, with studies reporting objective response rates and disease control rates.
Beyond colorectal cancer, this combination is also being explored in other challenging malignancies, including advanced/metastatic sarcomas, ovarian cancer, and other solid tumors that are considered “immune-cold.” “Immune-cold” tumors have fewer immune cells, making them less responsive to immunotherapy. Clinical trials are evaluating the combination’s activity in various metastatic, late-line cancers, aiming to extend immunotherapy benefits to a wider range of patients.
Clinical Development and Patient Access
Botensilimab and balstilimab are currently undergoing clinical development, primarily in Phase 1 and Phase 2 trials. Phase 1 trials focus on safety and dosage, while Phase 2 trials evaluate efficacy and assess safety in a larger patient group. Over 1,200 patients have been treated across the botensilimab/balstilimab program in these clinical trials.
Patient access to these drugs outside of clinical trials is primarily through Expanded Access Programs (EAPs) or Named Patient Programs (NPPs). These programs allow patients with serious or life-threatening diseases who have exhausted standard treatments to potentially access investigational therapies before regulatory approval. A patient’s treating physician must request access, and the benefits must outweigh the risks based on the patient’s medical history. These programs ensure ethical and compliance standards are met while providing access to investigational medicines based on clinical evidence and medical need.
Potential Adverse Effects
As with any cancer treatment, botensilimab and balstilimab can cause adverse effects. These drugs are immune checkpoint inhibitors, leading to immune-related adverse events. Common treatment-related adverse events reported in clinical trials for botensilimab plus balstilimab in metastatic colorectal cancer include fatigue, diarrhea, and fever.
More severe side effects, although less common, can include grade 3 or 4 immune-mediated diarrhea or colitis. Other reported adverse events have included nausea, vomiting, rash, pruritus (itching), and arthralgia (joint pain). While side effects can vary, healthcare professionals can manage many of these events, often with medications like steroids.