Thermal Ablation Plus Toripalimab In Patients With Advanced Hepatocellular Carcinoma

Background and purpose: Thermal ablation has been showed to induce immunogenic cell death and enhance the effect of anti-programmed death-1(PD-1)in preclinical study.The open label phase I/II trial evaluated the safety and efficacy of ablation plus toripalimab(a humanized PD-1 antibody)in patients with unresectable hepatocellular carcinoma(HCC).Phase I results on time scheduling,safety and preliminary antitumor activity are reported.Patients and methods: Eligible patients were aged at least 18 years old;had histologically confirmed unresectable HCC;was not amenable to curative-intent therapy with surgical resection or ablation;had at least one lesion that could be completely ablated by radiofrequency or microwave ablation according to the evaluation of the investigators;had disease progression or were intolerance on one or more systemic drugs.In phase I,patients randomized into 3 arms.In arm A,patients received toripalimab(240mg,Q3W)as monotherapy.In arm B,patients received subtotal ablation,defined as complete treatment of 1-5 lesions by thermal ablation and leave others lesions intact.Toripalimab(240mg,Q3W)was started on day 3 after ablation.In arm C,patients received toripalimab(240mg,Q3W)on day 14 after ablation.Results: Forty-eight patients(16 per arm)were included.Seventy five percent of patients experienced treatment-related adverse events(TRAE).No dose limiting toxicity occurred in the three arms.The most common TREAs were mild(grade 1/2)and included influenza-like symptoms(25%),transaminase elevation(22.9%),hypothyroidism(22.9%),hypertension(16.6%),diarrhea(14.6%)and proteinuria(12.5%).Grade 3/4 TRAEs was reported in 18.7% of patients in arm A,25.0% in arm B and C,respectively.One patient in arm A(6.3%)and one in arm B discontinued toripalimab treatment because of TRAE.No TRAE led to death.The objective response rate(ORR)was 18.8% in arm A,37.5% in arm B and 31.2% in arm C.In arm B,2 patients(12.5%)achieved complete response(CR).The progression-free survival(PFS)was 3.8months(95% CI,3.4-4.2 months)in arm A,6.8 months(95% CI,5.5-7.5months)in arm B,and 5.5 months(95% CI,2.5-8.5 months)in arm C.The overall survival(OS)was 14.0 months(95% CI,11.1-14.9 months)in arm A,21.0 months(95% CI,10.0-31.8 months)in arm B,and 17.7months(95% CI,10.3-25.1 months)in arm C.Initiating toripalimab treatment on day 3 after ablation was recommended for phase II evaluation.Conclusion: Toripalimab was tolerable and showed promising antitumor activity,as monotherapy or in combination with subtotal thermal ablation,in unresectable HCC.