Abstract Background: Dysregulated sphingolipid metabolism is common to many cancer types, including mCRC, and leads to elevated concentrations of specific sphingolipids, including pro-tumoral gangliosides (GM3), lactosylceramides (LacCer), glucosylceramides (GluCer) and sphingosine-1-phosphate (S1P) and lower concentration of anti-tumoral ceramides. In mCRC patients, several studies have shown elevated concentrations of the pro-tumoral sphingolipids are associated with a worse prognosis and poor survival. Therefore, targeting dysregulated sphingolipid metabolism and returning sphingolipid metabolism to homeostasis could be a promising therapeutic approach. BXQ-350 is a nanovesicle of Saposin C, an allosteric activator of sphingolipid metabolism, that affects dysregulated sphingolipid metabolism. BXQ-350 lowers GM3, LacCer, GluCer and S1P levels while it also increases ceramide levels promoting a return to homeostasis and an anti-tumoral environment. In a single agent Phase 1 study, BXQ-350 was safe and well-tolerated (no DLT, no MTD) and showed signs of activity. Among patients with PFS 6 months, there were 4 recurrent CRC patients: 1 patient had a PFS of ∼12 months, 2 of ∼18 months, and 1 is still on study after 7 years. Method: BXQ-350 is being investigated in a Phase 1b/2a study in combination with mFOLFOX7 and Bevacizumab as SoC in newly diagnosed mCRC patients (NCT05322590) to assess the efficacy and safety of BXQ-350.The Phase 1b/2a is a safety dose escalation part to establish the RP2D exploring 1.8 and 2.4 mg/kg BXQ-350 in combination with SoC. Primary objectives are to assess safety and preliminary efficacy of BXQ-350 in this combination. Secondary objectives include longitudinal analysis of several biomarkers, including sphingolipid profiling. Results: A total of 32 evaluable patients were enrolled, and all 32 patients have completed SoC treatment schedule plus BXQ-350. Amongst these 32 patients, 21 (66%) are alive and in active follow-up. The disease control rate was 94% (30 pts had SD, PR or CR). As of September 2025, ORR was 59% and PFS was 10.6 months. Analysis of sphingolipid profiles shows that BXQ-350 significantly ( 50%) and durably lowers plasma levels of GM1-3, LacCer, GluCer and S1P while increasing Cer levels ( 50%); furthermore, statistically significant associations between LacCer, Cer, Cer/S1P and Glu/Cer levels and survival were observed. Conclusions: BXQ-350 was safe and well tolerated in combination with SoC in 1L mCRC. Ongoing monitoring of patients suggests that BXQ-350 may provide a clinical benefit to 1L mCRC patients in combination with FOLFOX 7 + Bevacizumab. Basal and longitudinal analysis of sphingolipid showed that BXQ-350 impacts plasma levels of critically important sphingolipids and associations between key sphingolipids and survival were noted. Citation Format: Gilles H. Tapolsky, TARIQ ARSHAD, Michael Gazda, Jackson Bond, Nikhil Wilkins, James Beach. BXQ-350: A novel biologic that targets dysregulated sphingolipid metabolism and normalizes key anti-tumoral and pro-tumoral sphingolipids in newly diagnosed metastatic colorectal carcinoma patients (mCRC) abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 3737.
Tapolsky et al. (Fri,) studied this question.