Neoadjuvant Botensilimab Plus Balstilimab Is Active, Safe Regardless of Mismatch Repair Status in Solid Tumors

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Neoadjuvant therapy with the combination of botensilimab and balstilimab led to high response rates and a low rate of high-grade immune-related adverse effects (irAEs) in patients with solid tumors, according to data from the phase 2/3 pan-cancer NEOASIS trial (NCT06279130) presented at the 2025 AACR Annual Meeting.1

During the safety run-in which evaluated 25 mg of botensilimab plus 450 mg of bastilimab, all 10 patients received both cycles of therapy. No grade 3 or greater irAEs occurred, and there were no dose-limiting toxicities (DLTs). irAEs (70%), which were only grade 1 or 2, included cutaneous toxicity (30%), fatigue (20%), and hypothyroidism (20%) and were mild and manageable.

When botensilimab was escalated to 50 mg, 80% of patients (n = 10) experienced irAEs, including fatigue (30%), immune-related hepatitis (20%), and infusion-related reaction (20%). Only 1 patient experienced a grade 3 event (immune-related hepatitis), which resolved entirely with steroids. Two patients did not receive the second cycle of therapy, both due to liver toxicity. In addition to no cases of immune-related colitis, there were no DLTs or surgical delays.

“Combination treatment with botensilimab plus balstilimab is safe with primarily low-grade & manageable irAEs and no surgical delays,” senior study author Myriam Chalabi, MD, PhD, medical oncologist and group leader at the Netherlands Cancer Institute in Amsterdam, said in a presentation of the data.

NEOASIS Basis and Study Protocol

Several trials have shown the benefit of neoadjuvant immunotherapy in several tumor types including melanoma, urothelial, rectal, and colon cancer. High response rates have been reported in mismatch repair–deficient (dMMR) colon cancers. In the phase 2 NICHE-2 trial (NCT03026140) investigators reported a pathological response rate of 98% (n = 109; 95% CI, 94%-100%) in patients with locally advanced dMMR colon cancer who received neoadjuvant therapy with the combination of nivolumab (Opdivo) and ipilimumab (Yervoy).2

dMMR is also found in other solid tumors although the majority are mismatch repair–proficient (pMMR).1 Botensilimab and balstilimab are next-generation CTLA-4 and PD-1 inhibitors, respectively, that have shown activity in a host of previously immune nonresponsive tumors such as pMMR metastatic colorectal cancer (CRC), metastatic sarcoma, and metastatic ovarian cancer.

“[We wanted to know whether] the efficacy seen in dMMR CRC translates to dMMR tumors of other origins and whether neoadjuvant botensilimab and balstilimab induces responses in immune cold tumors,” Chalabi said.

With this rationale investigators launched the investigator-initiated, nonrandomized, NEOASIS basket trial which enrolled two cohorts of patients with dMMR and pMMR tumors. Both cohorts had a safety run-in in which the first 5 patients received 25 mg of botensilimab on day 1 plus 450 mg of bastilimab on days 1 and 22. If there was no more than 1 DLT another 5 patients received 50 mg of botensilimab on day 1 plus 450 mg of bastilimab on days 1 and 22. If no more than 2 DLTs occurred with 50 mg of botensilimab, accrual continued in the efficacy cohorts.

A DLT was defined as any grade 5 event, a grade 4 event lasting longer than 3 weeks, a grade 3 event lasting longer than 6 weeks, and any treatment-related toxicity delaying surgery by more than 2 weeks.

The study enrolled patients with nonmetastatic solid tumors with no prior chemotherapy or immunotherapy and plans to undergo surgery. No standard of care neoadjuvant therapy was required for patients with pMMR tumors unless there was an adjuvant equivalent available.

After completing treatment patients underwent surgery at week 8 and follow-up every 6 months for 3 years according to local guidelines.

Patient Demographics and Efficacy Data

Baseline characteristics in the pMMR population (n = 10) indicated that the median patient age was 54 years (range, 34-78). Most patients were female (90%) and had an ECOG performance status of 0 (80%) and triple-negative breast cancer (TNBC; 60%). Other tumor types included estrogen receptor (ER)–positive breast cancer (20%), Merkel cell carcinoma (MCC; 10%), and undifferentiated pleiomorphic sarcoma (UPS; 10%). In the dMMR population (n = 10) the median patient age was 67 years (range, 50-71). Half of patients were female and 60% had an ECOG performance status of 0. All but 1 patient, who had duodenal cancer, had CRC (90%).

With respect to efficacy in the pMMR cohort, the major pathologic response (MPR) rate was 70% in the combined safety run-in cohorts, with all 5 patients in the 25-mg dose level (n = 2, TNBC; n = 1, ER-positive breast cancer; n = 1, UPS; n = 1, MCC) achieving MPR and 2 of 5 patients in the 50-mg dose level (n = 2, TNBC) achieving MPR. Looking at only patients with breast cancer (n = 8) the MPR rate was 63%.

In the dMMR cohort, the combined MPR rate was 80%, with a pathologic complete response (pCR) rate of 70%. In the 25-mg dose level 3 of 5 patients (n = 2, rectal cancer; n = 1, colon cancer) achieved MPR; 2 also achieved pCR. All 5 patients (n = 5, colon cancer) in the 50-mg dose level achieved pCR.

“One patient with duodenal cancer showed limited response of the primary tumor. In contrast, during surgery multiple lesions of the peritoneum, diaphragm and liver [were seen]. These lesions were biopsied and showed a pCR,” Chalabi said.

Regarding next steps, Chalabi explained, “recruitment in MMR-specific baskets is ongoing, [and we will be] expanding to organ preservation cohorts. Translational analyses including whole-exome sequencing, single-cell RNA sequencing, and circulating tumor DNA analyses are also ongoing,” she concluded.

Disclosures: Chalabi disclosed serving in an advisory role for Bristol Myers Squibb (BMS), Merck Sharp & Dohme (MSD), Roche, and Agenus; and grant/research support from BMS, Roche, MSD, and Agenus.

References

1. De Gooyer PGM, van den Dungen LDW, Geukes Foppen MH, et al. Neoadjuvant botensilimab plus balstilimab in MMR proficient and deficient early-stage cancers: first results of the pan-cancer NEOASIS study. Presented at: 2025 AACR Annual Meeting; April 25-30, 2025; Chicago, IL. Abstract CT130.
2. Chalabi M, Verschoor YL, Batista Tan P, et al. Neoadjuvant immunotherapy in locally advanced mismatch repair–deficient colon cancer. N Engl J Med. 2024;390(21):1949-1958. doi:10.1056/NEJMoa2400634