Fc-Enhanced Agents May Expand Anti–CTLA-4 Approaches in GI Cancers

Although conventional CTLA-4 inhibitors such as ipilimumab (Yervoy) and tremelimumab-actl (Imjudo) helped to spark the immunotherapy revolution in cancer care, these agents have generally been most effective in patients with immune-inflamed disease.¹ To extend the benefits of this class of therapies to patients with poorly immunogenic solid tumors, such as hepatocellular carcinoma (HCC), colorectal cancer (CRC), and pancreatic cancer, investigators are developing fragment crystallizable (Fc)–enhanced CTLA-4 inhibitors, including botensilimab (AGEN1181) and vilastobart (XTX101).²

Fc-enhanced CTLA-4 inhibitors are designed to have affinity for the Fcγ receptor; co-engagement with this receptor is believed to play a key role in the activity of CTLA-4 inhibitors.¹ These agents leverage Fcγ receptor–dependent mechanisms to increase T-cell responsiveness, decrease intratumoral regulatory T cells (Tregs), and enhance antigen-presenting cell activation.

“Botensilimab is a second-generation CTLA-4 inhibitor,” Bruno B. Bockorny, MD, explained in an interview with OncologyLive. “Aside from binding to CTLA-4, it has point mutations in the Fc region of the antibody that [enable] increased binding to the activating Fcγ receptor on both antigen-presenting cells and natural killer cells. This mutation [confers] several unique mechanisms relative to first-generation CTLA-4 inhibitors, [such as] increased priming and memory formation of T cells, [which] increases activation of antigen-presenting cells. [This mechanism] also leads to a further decrease in immunosuppressive Tregs and a decrease in complement and mediated toxicities.”

Bockorny is an assistant professor of medicine at Harvard Medical School and a medical oncologist at Beth Israel Deaconess Medical Center in Boston, Massachusetts.

Fc-Enhanced CTLA-4 Inhibitors Display Efficacy in HCC and CRC

Botensilimab is being evaluated as monotherapy and in combination with the anti–PD-1 antibody balstilimab (AGEN2034) in patients with pretreated solid tumors, including HCC, in the phase 1 C-800-01 study (NCT03860272).² The HCC cohort of C-800-01 included patients who experienced disease progression on or after treatment with a previous immunotherapy. Patients had received a median of 2 prior lines of therapy (range, 1-7), and 26% had received at least 3 previous lines of treatment.

Findings from C-800-01 presented during the 2025 American Association for Cancer Research Annual Meeting revealed that efficacy-evaluable patients in the HCC cohort who received the combination (n = 18) achieved an overall response rate (ORR) of 17% (95% CI, 4%-41%), which comprised partial responses exclusively. The disease control and clinical benefit rates were 72% (95% CI, 47%-90%) and 50% (95% CI, 26%-74%), respectively. The median duration of response, progression-free survival, and overall survival were not reached (NR; 95% CI, 9.8-NR), 4.4 months (95% CI, 1.4-6.9), and 12.3 months (95% CI, 8.4-21.4), respectively.

No treatment-related deaths were reported in the safety population (n = 19). Any-grade immune-mediated treatment-related adverse effects (TRAEs) occurred at a rate of 68% and included diarrhea/colitis (37%), hepatitis (21%), and adverse skin reactions (21%). Grade 3 immune-mediated TRAEs occurred in 37% of patients, with the most common being diarrhea/ colitis (16%) and hepatitis (16%).

Botensilimab plus balstilimab is also being tested as neoadjuvant therapy in patients with resectable mismatch repair–proficient and –deficient CRC in the phase 2 NEST-1 trial (NCT05571293).³ The trial’s protocol included patients who received one 75-mg dose of botensilimab plus two 240-mg doses of balstilimab 2 weeks apart (NEST-1) or botensilimab at the same dose as NEST-1 plus up to 4 doses of balstilimab 2 weeks apart (NEST-2).

Data from NEST presented during the 2025 American Society of Clinical Oncology Gastrointestinal Cancers Symposium (ASCO GI) showed that patients with microsatellite stable (MSS) CRC treated with the NEST-1 regimen (n = 7) achieved a pathologic complete response (pCR) rate of 14% (95% CI, 0.4%-58%). The major pathologic response (MPR) rate was 29% (95% CI, 4%-71%). The pCR and MPR rates were 40% (95% CI, 16%-68%) and 47% (95% CI, 21%-73%), respectively, among patients with MSS disease treated with the NEST-2 regimen (n = 15). These respective rates were 75% (95% CI, 19%-99%) and 100% (95% CI, 40%-100%) in patients with microsatellite instability–high tumors who received either regimen (n = 4).

Another Fc-enhanced CTLA-4 inhibitor, vilastobart, is being examined in patients with advanced solid tumors, including metastatic MSS CRC, in a phase 1/2 trial (NCT04896697).⁴ Vilastobart is a tumor-activated agent with high-affinity binding and significantly higher potency than ipilimumab in a preclinical study. The drug is designed to focus its activity on tumor cells and minimize systemic exposure to reduce potential AEs.

Data from the phase 2 portion of the first-in-human study presented during the 2025 ASCO Annual Meeting showed that patients with MSS CRC without liver metastases (n = 27) who received vilastobart in combination with atezolizumab (Tecentriq) achieved an ORR of 26% per RECIST 1.1 criteria. Six of the patients who achieved a response remained on therapy at the data cutoff. Notably, the overall cohort (n = 44), which included patients with and without liver metastases, was heavily pretreated, having received a median of 4 prior lines of therapy (range, 1-8).

No grade 5 TRAEs were reported in terms of safety. The most common any-grade TRAEs included fatigue (30%), infusion-related reactions (23%), and diarrhea/colitis (20%). Two patients discontinued treatment due to TRAEs.

The study authors concluded that these findings support the further development of vilastobart-based combinations in patients with MSS CRC and other cold tumors.

Botensilimab Set for Evaluation as Combination Component in Pancreatic Cancer

Beyond the HCC and CRC spaces, botensilimab plus balstilimab is now being added to combination chemotherapy for the treatment of patients with previously untreated metastatic pancreatic cancer in an ongoing phase 1 trial (NCT06076837).⁵ In addition to the doublet, patients will also receive triplet chemotherapy with nab-paclitaxel (Abraxane), gemcitabine, and cisplatin. Then, in part 2, patients will receive the same regimen plus chloroquine phosphate (Aralen) and celecoxib (Celebrex), if 1 or fewer dose-limiting toxicities are reported in the 6 patients treated in part 1.

“In trying to understand how to improve ther- apies for patients with pancreatic cancer, we’ve looked at immunotherapy and the autophagy pathway,” Erkut H. Borazanci, MD, medical director of the Oncology Research Division at HonorHealth Research Institute in Scottsdale, Arizona, said in an interview with OncologyLive. “The idea is to do what we can to stress the cancer cells. This concept [involves] the unfolded protein response, where you’re stressing these cancer cells and pushing them into apoptosis. The base of [the regimen] is chemotherapy, [then] we’re adding the autophagy agent chloroquine, combining that with botensilimab and balstilimab, and adding the COX-2 inhibitor celecoxib in a 7-drug combination.”

To be eligible for enrollment, patients with previously untreated, histologically confirmed metastatic pancreatic ductal adenocarcinoma must be at least 18 years old and have an ECOG performance status of 0 or 1, a life expectancy of at least 3 months, measurable disease per RECIST 1.1 criteria, and no history of central nervous system metastasis. The study’s primary objectives are to determine the maximum tolerated dose of botensilimab and evaluate the full combination’s safety and tolerability.

Additionally, in an ongoing phase 2 study (NCT05632328), botensilimab is being evaluated in combination with the TGFβ and CD73-adenosine inhibitor dalutrafusp alfa (AGEN1423) in patients with advanced pancreatic cancer.⁶ Investigators have hypothesized that the combination can rescue T-cell functional activity, leading to responses in these patients.

The study is enrolling adult patients with metastatic pancreatic cancer who experienced radiographic disease progression after previous systemic therapy, have measurable disease per RECIST 1.1 criteria, and have received no prior anti–CTLA-4 therapy. The primary end point is ORR per RECIST 1.1 criteria.

“We’re very excited that the first cohort [of patients is being treated] with botensilimab and dalutrafusp alfa,” Bockorny said. “[Study] enrollment has been completed, and so far we have not seen any new safety signals. We are waiting for the data to mature so we can [better] understand the efficacy. I believe later [in 2025], we are going to have a good readout for the study and decide whether or not to move forward with cohort 2, where we will combine botensilimab and [dalutrafusp alfa] with standard gemcitabine and nab-paclitaxel.”

References

1. Chand D, Savitsky DA, Krishnan S, et al. Botensilimab, an Fc-enhanced anti-CTLA-4 antibody, is effective against tumors poorly responsive to conventional immunotherapy. Cancer Discov. 2024;14(12):2407-2429. doi:10.1158/2159-8290.CD-24-0190
2. El-Khoueiry AB, Abou-Alfa GK, Wilky BA, et al. Results from a phase 1 study of botensilimab and balstilimab in treatment refractory hepatocellular carcinoma. Cancer Res. 2025;85(8 suppl 2):LB365. doi:10.1158/1538-7445.AM2025-LB365
3. Hissong E, Jafari MD, Khan S, et al. Neoadjuvant botensilimab (BOT) plus balstilimab (BAL) in resectable mismatch repair proficient (pMMR) and deficient (dMMR) colorectal cancer (CRC): NEST clinical trial update. J Clin Oncol. 2025;43(suppl 4):207. doi:10.1200/JCO.2025.43.4_suppl.207
4. Fakih M, DeVito NC, Parikh AR, et al. Vilastobart (XTX101), a tumor-activated, Fc-enhanced anti–CTLA-4 monoclonal antibody, in combination with atezolizumab in patients with MSS CRC. J Clin Oncol. 2025;43(suppl 16):3553. doi:10.1200/JCO.2025.43.16_suppl.3553
5. Borazanci EH, Jameson GS, Carter B, et al. An open-label, phase 1 trial with expansion cohort of botensilimab (AGEN1181) + balstilimab (AGEN2034) + nab-paclitaxel + gemcitabine + cisplatin + chloroquine + celecoxib in adult patients with previously untreated metastatic pancreatic cancer. J Clin Oncol. 2025;43(suppl 16):TPS4234. doi:10.1200/JCO.2025.43.16_suppl.TPS4234
6. Bockorny B, Berg J, Bullock AJ, et al. A phase 2 study of botensilimab and AGEN1423, an anti-CD73-TGFβ-trap bifunctional antibody, with or without chemotherapy in subjects with advanced pancreatic cancer. J Clin Oncol. 2025;43(suppl 16):TPS4231. doi:10.1200/JCO.2025.43.16_suppl.TPS4231