Neoadjuvant epacadostat (INCB024360) combined with short course radiotherapy in patients with locally advanced rectal cancer: Efficacy and safety from a phase 2 trial.

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162 Background: In preclinical studies, the tryptophan-metabolizing enzyme, Indoleamine 2, 3-dioxygenase 1 (IDO1), promotes resistance to radiation in colorectal cancer, and IDO1 inhibition with epacadostat improves tumor radiosensitivity. In a phase 1 trial, patients (pts) with locally advanced rectal cancer (LARC, n=17) were treated with epacadostat in combination with short course radiotherapy (SCRT) and CAPOX which was well-tolerated, and the recommended phase 2 dose (RP2D) of epacadostat was 400mg BID. Here we report efficacy and safety from the NCI-supported phase 2 (NCT03516708) multicenter, open-label trial (treatment cohort). Methods: Pts were treated with standard of care (SOC) SCRT, then SOC neoadjuvant chemotherapy (NAC) followed by SOC surgical resection or non-operative management (NOM). Epacadostat (400 mg BID) started with SCRT and continued until starting NAC (a minimum of 21 days). Eight pts were enrolled prior to discontinuation of epacadostat by Incyte in February/March 2025. The primary endpoint is Neoadjuvant Rectal (NAR) score. In patients who underwent NOM, we calculated MRI-based tumor regression grade (MR-TRG). Secondary endpoints are pathologic complete response (pCR) rate, complete clinical response (cCR) rate, and progression free survival (PFS). Results: Table 1 summarizes baseline characteristics and endpoints (primary and secondary). NOM was pursued in 7/8 (87.5%) pts, surgical resection was performed on 1/8 (12.5%). At median follow-up of 12 months, local tumor regrowth occurred in 1 pt initially treated with NOM (after tumor regrowth, he underwent salvage surgery and is currently on surveillance). Treatment with epacadostat was interrupted in 2/8 (25%) patients due to grade 3 maculopapular skin rash. Most frequent treatment-emergent adverse events (TEAEs) regardless of causality (all grades (G)/G3-4) were bloating (75%/0%), increased ALT (62.5%/0%), increased AST (50%/0%), nausea (50%/0%), and constipation (50%/0%). Grade 3 diarrhea and grade 3 non-cardiac chest pain occurred in 1 patient each (both unrelated to epacadostat). Conclusions: Epacadostat demonstrates promising efficacy and manageable safety in patients with LARC. The biomarker cohort and correlative studies are ongoing. Clinical trial information: NCT03516708 . Baseline characteristics and endpoints. Patient Age Sex Ethnicity Stage Surgery/NOM NAR MR-TRG cCR/pCR Recurrence 1 52 M Caucasian T3N1 NOM NA 2 Y/NA No 2 45 M Caucasian T3N1 NOM NA 3 Y/NA Local tumor regrowth 3 48 M Caucasian T3N2 NOM NA 3 Y/NA No 4 61 M Caucasian T4N2 NOM NA 3 Y/NA No 5 57 M Caucasian T3N0 NOM NA 1 Y/NA No 6 60 F Caucasian T3N1 Surgery 15 3 N/ypT3N0 No

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