Neoadjuvant ONO-4578, an EP4 antagonist, in combination with nivolumab after chemoradiation therapy in locally advanced resectable rectal cancer.

3588 Background: Neoadjuvant nivolumab (NIV) after preoperative chemoradiation therapy (CRT) demonstrated promising pathologic complete response (pCR) in patients (pts) with locally advanced resectable rectal cancer (LARC) (Bando, Clin Cancer Res 2022). On the other hand, the prostaglandin E 2 -EP4 signaling is known to induce immunosuppression in tumors. ONO-4578 (4578), an antagonist of EP4, in combination with NIV has shown a manageable safety profile and signs of anti-tumor activity in pts with solid tumors. In this ONO-4578-03 study, we evaluated safety, preliminary efficacy, and biomarkers of 4578 plus NIV after preoperative CRT in pts with LARC. Methods: Pts with LARC who received preoperative CRT (50.4 Gy with capecitabine 1,650 mg/m 2 ) were eligible. Pts were divided into two groups for neoadjuvant therapy: 4578 monotherapy lead-in (lead-in) and the combination group. Pts in the lead-in group received 4578 (40 mg, oral, daily) alone for 6 weeks, and then 4578 plus NIV (240 mg, intravenous, every 2 weeks) for 4 weeks, while pts in the combination group received 4578 plus NIV for 10 weeks. Subsequently, pts in both groups received radical resection. The primary endpoint was safety. Secondary endpoint was efficacy, including pCR rate using the AJCC tumor regression grading. Ongoing exploratory endpoints include tissue and blood biomarkers. Results: We enrolled 31 pts: 10 and 21 to the lead-in and combination groups, respectively. The median age was 62.0 (range, 39–76) years, 20 pts (64.5%) had a disease stage of III, and all pts were classified as microsatellite stable. The pCR (AJCC grade 0) rates in the lead-in group, the combination group, and overall population were 50.0% (5/10 pts), 23.8% (5/21 pts), and 32.3% (10/31 pts), respectively; the major pathological response (MPR; AJCC grade 0+1) rates were 70.0% (7/10 pts), 71.4% (15/21 pts), and 71.0% (22/31 pts), respectively. Among all pts, any-grade treatment-emergent adverse events (TEAEs) occurred in 23 pts (74.2%). including 3 pts (9.7%) with grade 3 TEAEs (appendicitis, ileus, drug-induced liver injury, hypertension) and 1 pt with serious TEAEs (ileus, drug-induced liver injury). None of the TEAEs led to treatment discontinuation or death. Any-grade treatment-related adverse events (TRAEs) occurred in 11 pts (35.5%), including 1 pt with a serious TRAE (grade 3 drug-induced liver injury). Radical resection was not performed within the protocol-defined window in 1 pt in the lead-in group and in 2 pts in the combination group due to progressive disease, a TRAE (grade 1 hyperthyroidism), or clinical CR, respectively. As of the final analysis, 5 pts experienced recurrence and 1 pts died in the overall population, after the median follow-up of 23.29 (range, 15.9–32.9) months. Conclusions: Neoadjuvant 4578 plus NIV after CRT showed a manageable safety profile and promising pCR rates and MPR rates in pts with LARC. Clinical trial information: jRCT2051200096 .