Phase II study of modulation of sorafenib (SOR)-induced autophagy using hydroxychloroquine (HCQ) in advanced hepatocellular cancer (HCC).

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586 Background: SOR is the first systemic therapy approved for advanced HCC, but has shown only modest improvements in survival. Resistance to SOR in pre-clinical models has been attributed to autophagy induction. Autophagy inhibition with HCQ enhanced SOR-induced cell death and apoptosis in early pre-clinic and clinical studies. Data from the phase I study of SOR plus HCQ in advanced solid tumors at showed clinical safety and efficacy. Therefore, we conducted a prospective study to evaluate efficacy of SOR and HCQ in advanced HCC patients (pts) (NCT03037437) and report the final efficacy analysis. Methods: Prospective phase II study of SOR 400 mg po BID + HCQ 400 mg daily in pts with advanced HCC (CP A-B8 cirrhosis). Cohort 1: first-line SOR/HCQ. Cohort 2: add HCQ upon progressing on SOR. CP B pts started at 200 mg BID, with dose escalation as tolerated. Cycle = 4 weeks. Primary endpoint: mTTP. Secondary endpoints: mOS, objective response rate (ORR) by RECIST; AEs (NCI-CTCAEv3.0); PD analysis for markers of autophagy and immunity. Pts evaluable for efficacy if completed C1. Historically, the mTTP for patients treated with sorafenib is 5.5 mo (SHARP trial). We predicted the addition of HCQ will improve mTTP by 50% to 8.2 months. Results: N=33 completed C1. Median age 64.1 years SD 8.6 (46- 80). 88% Male; 58% Hispanics. ECOG 0-1: 100%. CP B cirrhosis: 35%. Etiology of cirrhosis: HCV 68%, ETOH 32%, NASH 11%. BCLC B 19%, C 81%. AFP>400: 43%, PVT: 27%, extrahepatic/metastases: 68%, post-transplant: 27%. N=5 (14%) were in cohort 2 (prior SOR). Reason off study: PD (n=21), toxicity (n=5), lost to f/u (n=1), withdrew (n=3). mTTP is 8.0 months (95% CI: 4.0-19.0). mOS 10.0 months (95% CI: 6.0-22.0). ORR (CR+PR): 27%. Best response: CR n=1 (3%), PR n=8 (24%), SD n=14 (42%). 4+ cycles: n=19 (58%). AE on treatment: grade 1 (68%), 2 (24%), 3 (7%), 4 (0.6%), 5 (0.3%). No Gr 4/5 related to SOR or HCQ. Dose interruption (20%), dose reduction (10%). Conclusions: SOR/HCQ had a better mTTP (8.0 months) than historical control (mTTP=5.5 months, p=0.03), and the trial met its primary endpoint. SOR/HCQ ORR (27%) was higher than historically SOR alone (ORR 2%, SHARP) in pts with advanced HCC, predominantly BCLC C, with CP A and B cirrhosis (35%), and was tolerable. While immune checkpoint inhibitors (ICIs) are taking the forefront in advanced HCC, SOR/HCQ may still have a role in patients with CP B cirrhosis, post-transplant, or contraindications to ICIs. Further, analysis of predictive markers of response is ongoing. Clinical trial information: NCT03037437 .