Safety and efficacy of ONO-4578 plus nivolumab in metastatic colorectal cancer

Background: The prostaglandin E₂-EP4 signaling is involved in immunosuppression in cancers. In the dose escalation part of the ONO-4578-01, open-label, uncontrolled phase 1 study, ONO-4578, an EP4 antagonist, plus nivolumab (4578+NIV) demonstrated manageable safety profile and antitumor activities in metastatic or advanced solid tumors. CRC cohort assessed safety, preliminary efficacy, and biomarkers of 4578+NIV in patients with metastatic colorectal cancer (mCRC). Methods: The CRC cohort was conducted at 12 sites in Japan and it included patients aged $20 years with mCRC; those with microsatellite-instability-high, deficient mismatch repair, or BRAF mutations were excluded. The optimal dose was determined based on the results of dose escalation part of ONO-4578-01. Patients received oral ONO-4578 (40 mg, daily) and intravenous nivolumab (480 mg, every 4 weeks) in 28-day cycles. The primary endpoint was safety. Exploratory endpoints included efficacy and biomarkers. Results: A total of 51 patients were enrolled: 24 (47.1%) were male and the median age was 59.0 (range, 33–79) years. Adverse events (AEs) occurred in 48 patients (94.1%), wherein grade 3–4 AEs occurred in 23 (45.1%). No patients died due to AEs. Serious AEs occurred in 11 (21.6%) patients. The most common AEs of any grade were rash (33.3%) and anemia (31.4%). Any-grade and grade $3 treatment-related AEs (TRAEs) occurred in 36 (70.6%) and 13 (25.5%) patients, respectively. Two patients achieved partial response and 18 had stable disease; the objective response rate was 3.9% (90% confidence interval [CI], 0.7–11.8) and the disease control rate was 39.2% (90% CI, 27.7–51.7). The median progression-free survival and overall survival (OS) were 1.54 (90% CI, 1.41–2.79) and 10.68 months (90% CI, 6.67–not reached [NR]), respectively. The proportion of patients continuing treatment and OS in subgroups of different PD-L1 combined positive scores (CPS) showed a tendency toward favorable efficacy in CPS-positive subgroups: the proportion of patients continuing treatment for 6 months was 4.5% (1/22) in those with CPS of 0 vs 20% (5/25) in those with CPS $1, and the median OS was 9.4 months (90% CI, 5.65–12.06) in those with CPS of 0 vs NR (90% CI, 10.41–NR) in those with CPS $1. Conclusions: 4578+NIV showed an acceptable safety profile in patients with mCRC, and no new safety signals were detected. 4578+NIV also showed antitumor activity in patients with mCRC. Favorable efficacy was observed in the PD-L1 CPS-positive subpopulation. Clinical trial information: jRCT2080223441. Research Sponsor: Ono pharmaceutical Co., LTD.