Instructor, Medicine, Harvard Medical School and an attending Physician, Medical Oncology, Dana-Farber Cancer Institute.

Dr Schlechter on the Safety of Botensilimab Plus Balstilimab in Pretreated MSS CRC

“The principal toxicity of botensilimab plus balstilimab is immune-related diarrhea/colitis. In this trial, we learned that early initiation of TNF inhibition is critical to the safety of patients and to keeping them on treatment.”

Benjamin L. Schlechter, MD, senior physician in the Gastrointestinal Cancer Center at Dana-Farber Cancer Institute and an instructor in medicine at Harvard Medical School, discussed the safety profile of botensilimab in combination with balstilimab for the treatment of patients with refractory microsatellite-stable (MSS) metastatic colorectal cancer (CRC) without active liver metastases.

2025 ESMO Gastrointestinal Cancers Congress

, data from an updated analysis of the phase 2 C-800-01 trial (NCT03860272) showed that the most common any-grade immune-mediated adverse effect (imAE) with the combination in the overall population (n= 123) was diarrhea/colitis (41%), Schlechter began. Grade 3 diarrhea/colitis was reported in 15% of patients in the overall cohort. During the study, investigators learned that early initiation of treatment with tumor necrosis factor (TNF) inhibitors was key to enhancing patient safety and keeping patients on treatment, he added. TNF inhibitors such as infliximab (Remicade) are a steroid-sparing approach that maintains the beneficial immune response of the regimen, he concluded.

Additional safety data from C-800-01 revealed that any-grade imAEs occurred in 58% of patients in the overall population; 29% of these were grade 3 events. Beyond diarrhea/colitis, other common any-grade imAEs included immune thyroiditis (7%), pneumonitis (5%) hepatitis (5%), adrenal insufficiency (3%), and dermatologic events (3%). Other grade 3 AEs consisted of pneumonitis (2%), hepatitis (2%), adrenal insufficiency (2%), and dermatologic events (1%). Moreover, there was a low incidence of visceral toxicities outside of the gastrointestinal tract, only 1 imAE across the treatment cohorts, and no treatment-related deaths. The study authors concluded that the safety profile of botensilimab in combination with balstilimab was manageable in this patient population with no new safety signals.

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Benjamin L. Schlechter, MD, discusses safety with botensilimab plus balstilimab in MSS CRC.

Benjamin L. Schlecter, MD, discusses the potential next steps in research for botensilimab for the treatment of patients with metastatic colorectal cancer.

Dr Schlechter on the Potential Future Implications of Botensilimab and Balstilimab in MSS mCRC

“There are several [future directions with] botensilimab. Number 1 is in refractory disease, and we need to push forward with the approval of this agent through randomized trials in the refractory setting. That’s important, and it’s very compelling that there are some early trials.”

Benjamin L. Schlechter, MD, a senior physician in the Gastrointestinal Cancer Center at Dana-Farber Cancer Institute, discussed the next steps in research in terms of botensilimab (AGEN1181) for the treatment of patients with previously treated, microsatellite-stable (MSS) metastatic colorectal cancer (mCRC) with no active liver metastases in combination with balstilimab (AGEN2034).

There are several ways botensilimab can fit into the mCRC treatment paradigm in the future, Schlechter began. Of note, working towards getting botensilimab approved by the FDA is an important next step, particularly in the refractory setting, he explained. Currently, there are early trials investigating botensilimab in colorectal cancer, including the phase 2 NEST-1 (NCT05571293) and UNICORN (EU-CT 2022-501308-90-0) trials, he added. Both trials have demonstrated that in earlier stages of disease, botensilimab showed benefit, he asserted. However, he noted that this needs to be taken forward in all lines of therapy, especially because patients with the most refractory and advanced disease have achieved similar efficacy.

NEST-1 evaluated the efficacy and safety of neoadjuvant botensilimab plus balstilimab for the treatment of patients with resectable mismatch repair proficient (pMMR) and mismatch repair deficient (dMMR) colorectal cancer. At a median follow-up of 13.1 months in NEST-1 and 4.8 months in NEST-2, no patients experienced disease recurrence, and circulating tumor DNA findings were negative. Furthermore, the UNICORN study assessed perioperative botensilimab with or without balstilimab for the treatment of patients with resectable locally advanced pMMR or dMMR colon cancer.

Moving botensilimab into earlier lines of therapy could be feasible, as studies have demonstrated that the in situ primary tumor, along with in situ lymph nodes, can provide a training ground for the immune system, which is essential in promoting immune responses in earlier-stage disease, Schlechter emphasized. With this hypothesis, the idea that botensilimab and balstilimab can be given in earlier lines of therapy as a nonoperative management in patients with cold tumors is important to continue investigating, he concluded.

Dr Schlechter on Updated Data for Botensilimab Plus Balstilimab in MSS mCRC

“The benefit of the [combination] is maintained and the toxicity is similar across all lines of therapy, which is a novel finding, and a very important finding [with] this combination of botensilimab and balstilimab.”

Benjamin L. Schlechter, MD, of Dana-Farber Cancer Institute, discussed updated data from an expanded cohort of patients with previously treated, microsatellite-stable (MSS) metastatic colorectal cancer (mCRC) and no active liver metastases treated with the Fc-engineered, CTLA-4 inhibitor botensilimab in combination with the anti–PD-1 antibody balstilimab during the phase 2 C-800-01 trial (NCT03860272).

, findings from the updated analysis included 123 patients with pretreated MSS mCRC, expanding on previously published data from 77 patients. At a median follow-up of 18.0 months (range, 0.7-53.3), the overall response rate (ORR) was 20% (95% CI, 13%-28%), with a disease control rate (DCR) of 69% (95% CI, 60%-77%) at 6 weeks. Median progression-free survival (PFS) was 4.0 months (95% CI, 2.8-4.1), and the median overall survival (OS) reached 20.9 months (95% CI, 16.2-26.6). Durable benefit was further supported by a median duration of response (DOR) of 16.6 months (95% CI, 5.7-not reached). Additionally, the clinical benefit rate was 28% (95% CI, 20%-36%) at week 24.

Schlechter emphasized the consistency of clinical activity across treatment-refractory subsets, including a 37-patient fourth- or later-line subgroup lacking available standard therapies; the ORR in this group was 19% (95% CI, 8%-35%) with a median OS of 22.5 months (95% CI, 12.6-NR). Notably, efficacy outcomes were similar regardless of prior lines of therapy, underscoring the immune-driven mechanism of action of the regimen.

Benjamin L. Schlechter, MD, discusses efficayc and safety of botensilimab in combination with the anti–PD-1 antibody balstilimab in mCRC.

Benjamin L. Schlechter, MD, senior physician, Dana-Farber Cancer Institute, instructor, medicine, Harvard Medical School, discusses the future implications of TAC01-HER2 therapy in patients with HER2-positive solid tumors.

The ongoing, phase 1/2 TACTIC-2 trial (NCT04727151) is evaluating the efficacy and safety of autologous TAC01-HER2 T-cell therapy in patients with HER2-positive breast, colorectal, gall bladder, gastroesophageal junction (GEJ), gastric, esophageal, lung, and ovarian cancers.

Interim findings from this trial, which were presented at the 2023 ASCO Annual Meeting, showed 2 partial responses with the therapy, 1 in a patient with refractory GEJ cancer, and 1 in a patient with refractory gastric cancer. In the patients with gastric, GEJ, or esophageal cancer, the disease control rate (DCR) was 83% and the overall response rate was 33%. In heavily pretreated patients, the DCR was 67%. One dose-limiting toxicity (DLT), grade 3 pneumonitis, was observed, and 1 patient had grade 3 cytokine release syndrome. No incidence of immune effector cell–associated neurotoxicity syndrome has been reported.

These findings indicate that HER2 can be targeted safely and effectively in several solid tumor populations, Schlechter says. The differences in responses between the heavily pretreated breast cancer population and the gastrointestinal (GI) cancers population may have arisen because of the biology of each disease, Schlechter explains. The patients with breast cancer were pretreated with chemotherapy and HER2-directed therapies, which bind differently to TAC01-HER2 and create a tumor microenvironment that may suppress immune responses to this therapy, Schlechter notes. However, the patients with GI cancer were less heavily pretreated and therefore may have had a more favorable tumor microenvironment for TAC01-HER2, according to Schlechter. In addition, heavily pretreated patients have inferior T cells, which may produce inferior outcomes when generated as effector T-cell therapies, Schlechter says. Delivering TAC01-HER2 as an earlier line of therapy may produce optimal patient outcomes, Schlechter notes.

Moreover, these findings demonstrate that TAC01-HER2, a non-CAR T-cell therapy, can safely target HER2, which is expressed on both tumor and normal tissue, Schlechter emphasizes. Although other HER2-directed therapies can produce excessive toxicities, TAC01-HER2 does not cause as many off-target effects and lowers the risk for DLTs, Schlechter says. A T-cell therapy that is slightly less effective than conventional treatment options but produces fewer DLTs is a favorable alternative compared with a drug that may become unusable in many patients because of its toxicity profile, Schlechter concludes.

Benjamin L. Schlechter, MD, discusses the future implications of TAC01-HER2 therapy in patients with HER2-positive solid tumors.

Benjamin L. Schlechter, MD

Articles

Dr Schlechter on the Safety of Botensilimab Plus Balstilimab in Pretreated MSS CRC

Dr Schlechter on the Potential Future Implications of Botensilimab and Balstilimab in MSS mCRC

Dr Schlechter on Updated Data for Botensilimab Plus Balstilimab in MSS mCRC

Dr Schlechter on TAC01-HER2 Therapy in HER2+ Solid Tumors