Ivonescimab (ivo) with oxaliplatin + fluorouracil (5-FU) + leucovorin calcium (mFOLFOX6) for patients (pts) with unresectable metastatic colorectal cancer (mCRC): A phase 2 study.

3576 Background: Ivonescimab is an investigational tetrameric bispecific antibody targeting both programmed death protein 1 and vascular endothelial growth factor that demonstrated efficacy and a tolerable safety profile in multiple phase 3 studies in pts with non-small cell lung cancer, and is being investigated in other solid tumor types. This multi-part phase 2 study (NCT05382442) evaluated ivo + chemotherapy as first-line treatment of mCRC. Here, we report interim results from the multiregional regimen extension phase of the study, which evaluated ivo 20 or 10 mg/kg + mFOLFOX6. Methods: Adult pts (≥18 years) in China and the US with confirmed mCRC who had an Eastern Cooperative Oncology Group score of 0-1, were not candidates for radical surgical resection or local therapy, and had not received systemic anti-tumor therapy in the recurrent or metastatic stage were enrolled; pts who received prior neoadjuvant or adjuvant therapy were permitted if first recurrence/metastasis occurred ≥12 months (mo) after the last dose. Pts were randomly assigned 1:1 to receive intravenous ivo (20 mg/kg or 10 mg/kg) + mFOLFOX6 once every 2 weeks for up to 8 cycles, followed by maintenance with 5-FU + ivo until disease progression, intolerable toxicity, or withdrawal of consent for up to 2 years. The primary endpoints were objective response rate (ORR; assessed by Response Evaluation Criteria in Solid Tumors v1.1) and incidence and severity of treatment-emergent adverse events (TEAEs). Secondary efficacy endpoints included disease control rate (DCR) and progression-free survival (PFS). Results: At the time of data cutoff for this interim analysis (December 31, 2025), 49 pts were enrolled (ivo 20 mg/kg + mFOLFOX6, n = 25; ivo 10 mg/kg + mFOLFOX6, n = 24) with an overall median age of 58 years; 79.6% of pts had left-sided tumors, 53.1% had KRAS or BRAF tumor mutations, and 67.3% had liver metastases. Median follow-up was 7.5 mo (range, 3.5-10.3) and 7.1 mo (range, 1.9-10.3) in the ivo 20 mg/kg + mFOLFOX6 and ivo 10 mg/kg + mFOLFOX6 arms, respectively. ORR was 70.8% in each treatment arm; all were partial responses. DCR was 100% in each treatment arm. Median PFS was not reached. PFS rate at 6 months was 95.2% and 84.8% in the ivo 20 mg/kg + mFOLFOX6 and ivo 10 mg/kg + mFOLFOX6 arms, respectively. Grade ≥3 TEAEs related to ivo occurred in 40.0% and 33.3% of patients in the ivo 20 mg/kg + mFOLFOX6 and ivo 10 mg/kg + mFOLFOX6 arms, respectively, and serious TEAEs related to ivo were reported in 24.0% and 16.7% of pts, respectively. TEAEs led to discontinuation of ivo in 4.0% in the ivo 20 mg/kg + mFOLFOX6 arm and in 0% in the ivo 10 mg/kg + mFOLFOX6 arm. No TEAEs led to death. Conclusions: With 7.3 mo follow-up, ivo + mFOLFOX6 showed encouraging efficacy and a manageable safety profile in pts with untreated mCRC. Clinical trial information: NCT05382442 .