Safety and tolerability of all-trans-retinoic acid, bevacizumab, and atezolizumab in refractory microsatellite stable colorectal cancer.

Abstract

114 Background: Microsatellite stable (MSS) metastatic colorectal cancer (mCRC) demonstrates limited response to immunotherapy. Preclinical data suggest that all-trans retinoic acid (ATRA) can reduce myeloid-derived suppressor cells and enhance the effects of immune checkpoint blockade. This phase II trial was designed to assess both the safety and efficacy of ATRA combined with bevacizumab and atezolizumab in refractory MSS mCRC. Here we report preliminary safety and tolerability data. Methods: This is a single-arm, open-label, phase II trial (NCT05999812). Eligible patients are ≥18 years with MSS mCRC refractory to at least two lines of standard therapies. Treatment consisted of ATRA 45 mg/m² orally days 1–7, atezolizumab 840 mg IV, and bevacizumab 10 mg/kg IV on day 1 of each 14-day cycle. A safety lead-in (first 6 patients, cycles 1–2) was incorporated. Treatment-emergent AEs (TEAEs) were defined as any AE that started on or after the first dose until ≤30 days after the last dose. AEs were graded by CTCAE v5.0, and safety analyses included all patients receiving ≥1 dose. Results: Among the 16 enrolled patients between April 2024 and June 2025, a total of 136 AEs were reported: 99 (72.8%) grade 1, 34 (25.0%) grade 2, and 3 (2.2%) grade 3, with no events grade ≥3 and no treatment-related deaths. No grade ≥3 AE occurred during the safety lead-in, allowing full enrollment of the study participants. The most common any-grade AEs were headache (n=11, 52.3%), fatigue (n=9, 42.8%), and proteinuria (n=6, 28.5%); all others occurred ≤ 5 times. Grade 3 events included small intestinal obstruction, proteinuria, and dyspnea. Two patients required hospitalization due to AEs: one with grade 2 and 3 events (dyspnea, fever) and one with the grade 3 event (small intestinal obstruction). Five patients (31.3%) required dose interruptions, and 1 patient (6.3%) required dose reduction of ATRA. Bevacizumab-related adverse events occurred in 7 patients (43.8%) with proteinuria (50.0%) and epistaxis (30.0%) amongst the most frequent. Immune-related adverse events were observed in 1 patient. Conclusions: ATRA combined with bevacizumab and atezolizumab demonstrates a manageable safety profile in patients with refractory MSS mCRC, with adverse events consistent with the known profiles of the individual agents. The majority of AEs were low-grade and reversible with standard management. These preliminary safety findings support continued investigation, with efficacy and biomarker data forthcoming. Clinical trial information: NCT05999812 . Safety profile and adverse events summary for all patients (N = 16). Safety, n (%) All pts (N = 16) Grade ≥ 3 3 (18.8%) AE leading to dose delay 5 (31.3%) Leading to dose reduction 1 (6.3%) Leading to dose discontinuation 0 (0.0) Hospitalization due to AEs 2 (12.5%)