A Phase II Trial of Y90-Resin Microspheres Radioembolization Followed by Nivolumab in Advanced Hepatocellular Carcinoma– CA 209-678

Proposed short titleY90-Resin Microspheres Radioembolization Followed by Nivolumab in Advanced Hepatocellular CarcinomaBackground : Nivolumab (N) and Y90-resin microspheres radioembolization (Y90-RE) aretherapeutic options in advanced hepatocellular carcinoma (aHCC). Emerging evidence suggests synergy between radiotherapy and immune checkpoint inhibitors.  Methods : Eligible Child-Pugh A aHCC patients were treated with Y90-RE followed by N 240mg, 21 days after Y90-RE and every 2 weeks thereafter. Pre- and on-treatment tumor biopsies were obtained. Primary end-point was overall response rate (ORR) (RECIST v1·1), defined as the composite overall response observed for lesions both within and outside Y90-RE field. Secondary end points included progression free survival (PFS), overall survival (OS), and safety. This study is registered with ClinicalTrials.gov, NCT03033446 .Findings : Forty patients were enrolled, 36 received Y90-RE followed by N. At baseline: 61·1% had hepatitis B; 66·7% BCLC stage C; 50·0% had AFP > 400ng/mL; median number of liver lesions was 5 (range 1- >20); median size of largest liver lesion was 78·5 mm (range 14-177mm); 38·9% had prior TACE/RFA/MWA; and 12·5% had prior systemic therapy.  ORR was 30·6% (16·4% to 48·1%). ORR was 43·5% in patients with no extra-hepatic spread (EHS) (n=23). 81% of target lesions within Y90-RE field regressed. Median PFS and OS were 5·6 months (95% CI 2·1 to 8·8 months) and 16.9 months (95% CI 8·1 to 27·6 months). Treatment was well tolerated with only 13·8% experiencing grade (G) 3/4 treatment related adverse events (TRAEs). Immune activation predicted response to Y90-RE followed by N. Interpretation : Y90-RE followed by N resulted in an encouraging ORR of 30·6% in aHCC and of 43·5% in subjects with no EHS.  81% of target lesions within Y90-RE field regressed suggesting synergy. Importantly, this combination is safe and tolerable with low G 3/4 TRAEs of 13·8%. Trial Registration: NCT number: NCT03033446 Funding: Funding for this study was acquired from National Medical Research Council Singapore (NMRC/CIRG/1454/2016), Bristol-Myers Squibb (BMS), and SIRTEX Declaration of Interest: David Tai All support for the present manuscript (e.g., funding, provision of study materials, medical writing, article processing charges, etc.): BMS, SIRTEX, NMRC Singapore (CIRG/1470/2017) Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: IPSEN, Eisai, BMS Consulting fees: Novartis, BMS, MSD Choo Su Pin Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: Roche, BMS, Ipsen, Lilly, AZ, Roche. Consulting fees: BMS, Roche, Ipsen, Servier, Eisai, AstraZeneca. Leadership or fiduciary role in other board, society, committee or advocacy group, paid or unpaid: MOH Medishield Life Cancer Drug committee Stock or stock options: BMS David Ng All support for the present manuscript (e.g., funding, provision of study materials, medical writing, article processing charges, etc.): SIRTEX Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: SIRTEX Joycelyn Lee Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: BMS, IPSEN, Bayer Research Funding: Bayer Pierce K.H. Chow Grants or contracts from any entity: Sirtex Medical, Ipsen, IQVIA, New B Innovation, Perspectum, AMiLi, MiRXES, Genentech, Engine Biosciences. Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: Sirtex Medical, Ipsen, Oncosil, Bayer, Roche, New B Innovation, MSD, BTG PLC, Eisai, Abbott, AZ, IQVIA, Genentech, Worrell Guerbet, LEK Consulting, COR2ED. Leadership or fiduciary role in other board, society, committee or advocacy group, paid or unpaid: AVATAMED Stock or stock options: AVATAMED Too Chow Wei Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: SIRTEX Consulting fees: SIRTEX Ethical Approval: All patients provided written informed consent and the institutional review board committee approved the protocol (Singhealth IRB Ref No. 2016/2613). The study was done in accordance with the Declaration of Helsinki and Good Clinical Practice.