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China’s NMPA approved ipilimumab N01 plus sintilimab as neoadjuvant therapy for stage IIB to III resectable MSI-H/dMMR colon cancer.
China’s National Medical Products Administration (NMPA) has approved ipilimumab N01 injection (IBI310; Tabosun) a domestically developed CTLA-4 monoclonal antibody, for use in combination with sintilimab (Tyvyt) as neoadjuvant therapy for patients with stage IIB to III resectable microsatellite instability–high/mismatch repair–deficient (MSI-H/dMMR) colon cancer.1 Notably, this marks the world’s first approval of a CTLA-4 monoclonal antibody for neoadjuvant treatment of colon cancer, according to Innovent Biologics, the developer of ipilimumab N01.
The approval was supported by data from a phase 3 portion of the NeoShot study (NCT05890742) comparing neoadjuvant ipilimumab N01 plus sintilimab vs surgery alone. As of the November 28, 2024, data cutoff, 41 of the first 50 patients in the experimental arm experienced a pathological complete response (pCR), translating to a pCR rate of 82%. Safety risks were not increased in the experimental arm vs surgery alone. Full findings from this portion of the trial will be presented at an upcoming medical meeting.
In the phase 1b portion of the trial, patients treated with ipilimumab N01 combined with sintilimab (n = 51) achieved a pCR rate of 78.4% (95% CI, 64.7%-88.7%) compared with 46.7% (95% CI, 31.7%-62.1%) for those given sintilimab alone (n = 45; P = .0015).2 The major pathologic response rates were 94.1% vs 73.3%, respectively.
"There remains a substantial unmet clinical need for neoadjuvant therapies for stage IIB to III resectable MSI-H/dMMR colon cancer in China,” explained Hui Zhou, MD, PhD, chief R&D officer, Oncology, at Innovent Biologics, stated in a news release.1 “Interim analysis has shown that the NeoShot trial met its primary end point. Through Innovent's efficient and high-quality clinical development, ipilimumab N01 has become China's first domestically developed innovative CTLA-4 inhibitor approved by the NMPA, offering a new treatment option for patients in China with stage IIB to III resectable MSI-H/dMMR colon cancer.”
NeoShot enrolled patients at least 18 years of ag with histologically confirmed primary colon adenocarcinoma that was stage IIB to III per AJCC Stage VIII criteria.3 Patients needed to have MSI-H or dMMR disease, at least 1 evaluable lesion per RECIST 1.1 criteria, and an ECOG performance status of 0 or 1. Patients needed to be eligible for radical excision prior to neoadjuvant therapy.
In phase 1b, patients were randomly assigned to receive ipilimumab N01 plus sintilimab or sintilimab alone. In the experimental arm, patients received 2 cycles of neoadjuvant therapy comprising ipilimumab N01 at 1 mg/kg and sintilimab at 200 mg in cycle 1, then sintilimab alone in cycle 2. Patients in the control arm received sintilimab along at 200 mg in both cycles.
During phase 3, patients were randomly assigned to ipilimumab N01 plus sintilimab or radical surgery alone. In the experimental arm, patients received the combination on the same 2-cycle schedule as phase 1b.
The study’s primary end points were pCR rate and event-free survival.
Additional efficacy analyses from the phase 1b portion of the study showed that the pCR benefit with neoadjuvant ipilimumab N01 plus sintilimab was generally consistent across prespecified subgroup evaluations, including age, weight, ECOG performance status, and baseline risk. Among patients with non–clinically significant Lynch syndrome mutations (n = 66), pCR rates favored the combination arm (80.0% vs 35.5%), yielding a between-groups difference of 36.7% (95% CI, 16.7%-56.7%). In contrast, among patients with pathogenic or suspected pathogenic Lynch syndrome mutations (n = 30), pCR rates were comparable between arms (75.0% vs 71.4%; P > .05). Similarly, pCR outcomes were comparable in the N0 subgroup (n = 20; 72.2% vs 66.7%) and in patients with stage IIB disease (n = 17; 66.7% vs 62.5%).
At the June 17, 2025, data cutoff, EFS and overall survival (OS) data were immature at a median follow-up of 21.4 months (range, 1.5-24.6).
Treatment-emergent adverse effects (TEAEs) were reported in 94.2% of patients who received neoadjuvant ipilimumab N01 plus sintilimab (grade ≥3, 30.8%) vs 87.8% of those given sintilimab alone (grade ≥3, 18.4%). Serious treatment-related AEs (TRAEs) occurred in 5.8% and 6.1% of patients, respectively, and TRAEs led to treatment interruption in 1.9% of patients in the combination arm vs 4.1% in the monotherapy arm. TRAEs resulted in surgery delays in 3.8% of patients in the combination arm and surgery cancellation in 2.0% of patients in the monotherapy arm; a TRAE leading to death was reported in 2.0% of patients treated with sintilimab alone.
The most common TEAEs reported in at least 15% of patients with ipilimumab N01 plus sintilimab were anemia (all grade, 30.8%; grade ≥3, 3.8%), increased alanine aminotransferase levels (23.1%; 0%), hypoalbuminemia (23.1%; 0%), abdominal pain (19.2%; 0%), cough (19.2%; 0%), rash (17.3%; 0%), hypothyroidism (15.4%; 0%), increased aspartate aminotransferase levels (15.4%; 0%), and pyrexia (15.4%; 0%). In the sintilimab monotherapy arm, the most common TEAEs occurring in at least 15% of patients were anemia (32.7%; 2.0%), abdominal pain (20.4%; 0%), cough (18.4%; 0%), and hypoalbuminemia (16.3%; 0%).
Immune-related AEs were observed in 48.1% of patients in the combination arm (grade ≥3, 3.8%) and 38.8% of patients in the monotherapy arm (grade ≥3, 8.2%).
