A phase 1 trial of folinic acid, fluorouracil, oxaliplatin, bevacizumab, botensilimab, balstilimab (FOLFOX-3B) in microsatellite stable metastatic colorectal cancer.
Authors: Marwan Fakih, Xiaochen Li, Jian Ye, Nikeeta Prajapati, Chongkai Wang
Journal: Journal of Clinical Oncology (2025)

180 Background: Botensilimab (BOT) is a novel Fc fragment engineered CTLA4 inhibitor designed to boost innate and adaptive immune response. The combination of BOT and the PD-1 antibody balstilimab (BAL) has been associated with durable and deep responses in microsatellite stable (MSS) metastatic colorectal cancer (mCRC). Given the potential synergistic activity between checkpoint inhibitors and oxaliplatin and VEGF(R) inhibitors, we performed a phase 1 clinical trial of folinic acid, fluorouracil, oxaliplatin, bevacizumab, botensilimab, and balstilimab (FOLFOX-3B). Methods: We enrolled ECOG performance status 0-1 patients (pts) with measurable MSS mCRC, up to 2 prior lines of therapy, and without progression following prior oxaliplatin. FOLFOX was given at a fixed dose, every 2 weeks, across the study: folinic acid at 400 mg/m 2 x 2 hours (hr), oxaliplatin at 85 mg/m 2 x 2 hr, and fluorouracil at 2400 mg/m2 x 46 hrs. BOT was administered at 2 dose levels (DL) of 25 mg and 75 mg IV Q6 weeks x 2. BAL was administered at a fixed dose of 240 mg IV Q2 weeks. The study followed a 3 x 3 escalation design with up to 9 patients per DL. A dose level was deemed safe if &lt; 1 out of 6 pts or &lt; 2 out of 9 pts had a DLT (expansion to 9pts only if 2 DLTs encountered in the 1 st 6 pts). The DLT period consisted of 6 weeks. Pts should have received all intended BOT/BAL and FOLFOX doses in the 1 st 6 weeks to be deemed DLT-evaluable. Results: 14 pts were enrolled on study: 9/14 with liver metastatic disease, 5/14 RAS -mutated, all TMB low. 7 were treated on DL1 and 7 on DL2. 6/7 pts at DL1 had received 1-2 prior lines of therapy, 4 of whom included oxaliplatin. 6/7 of pts at DL2 had 1-2 prior systemic therapy, all of whom received prior oxaliplatin. No DLT were noted at DL1 or DL2. 1 pt at each DL was not DLT-evaluable as they were not able to receive all intended therapy due to treatment interruptions. Grade (G)2 and above immune related toxicities included: one pt at DL1 with transient G3 AST/ALT elevation and transient G2 colitis (resolved with steroids and infliximab), one pt at DL1 with G2 hypothyroidism and one patient at DL2 with G2 hyperthyroidism. At DL1, 4/7 had a partial response (PR) - including 2/4 with prior oxaliplatin exposure. At DL2, 6/7 pts had a PR – including 5/6 with prior oxaliplatin exposure. 3 patients proceeded to surgical resection or ablation and are currently followed with observation only. In the combined cohort of DL1 and DL2, the median progression free survival (PFS) is 8 months and remains unreached for DL2. Overall survival outcome has not matured at the time of this analysis. Conclusions: FOLFOX-3B with BOT at 75 mg IV Q6 weeks x 2 in combination with BAL 240 mg Q2 weeks is well-tolerated and is associated with promising clinical activity with 5/6 PR and prolonged PFS. The study was amended to explore additional DL that explore higher doses of BOT (150 mg) or longer duration of BOT 75mg (4 doses). Clinical trial information: NCT05627635 .