Previous/Concurrent Radiation Enhanced the Response of Toripalimab in Advanced and Recurrent Liver Cancer: A Pilot Study

PURPOSE/OBJECTIVE(S): Anti-programmed death-1 (PD-1) is an emerging paradigm for treating metastatic malignancies. However, limited response rate and unsatisfactory results of PD-1 inhibitor as monotherapy in advanced liver cancer prompted the exploration of combination strategies. Preclinical studies demonstrated that combination of radiation and PD-1 inhibitors can synergistically augment the anti-tumor efficacy induced by both agents. This study addressed the hypothesis that the application of radiation combined with Toripalimab, an anti-PD-1 agent, may foster immune efficacy in metastatic and recurrent liver cancer. MATERIALS/METHODS: We did this study in patients with stage IV (defined by the American Joint Committee on Cancer 8th edition staging system) or recurrent liver cancer in 2nd-line or 3rd-line treatment, with an Eastern Cooperative Oncology Group performance score of 0-2, child-Pugh grade of A-B. All enrolled patients received radiation at doses of 40-60Gy. Toripalimab (240mg per day, 21 days per cycle) was delivered during and/or after radiation until progression or severe toxicities. The primary endpoint was progression-free survival and the secondary endpoints were objective response, overall survival and toxicities. Survivals were calculated from the beginning of immunotherapy. RESULTS: From April 2017 to September 2020, 17 patients were enrolled and evaluable. Sixteen patients (94.1%) were male and 1(5.9%) was female. The median age was 56 years old (range 36-74 years old). Ten patients (58.8%) had hepatocellular carcinoma. Sixteen patients (94.1%) were with Child-Pugh grade A. Fifty-two lesions, including 15 venous tumor emboli, 13 metastatic bones, 12 lymph nodes, 11 liver malignancies and 2 other sites, received radiation. The median radiation dose is 53Gy (40-60Gy, 2-4Gy per fraction). Sixteen patients received targeted therapy (9 patients with sorafenib, 3 patients with lenvatinib, 3 patients with regorafenib and 1 patient with apatinib) during the treatment of immunotherapy and radiotherapy. The objective response rate and disease control rate were 64.7% (the complete response was 5.9% and partial response was 58.8%) and 88.2%. Grade≥3 adverse events were observed in 5 patients (29.4%), including 3 with thrombocytopenia (2 with grade 4, 1 with grade 3),1 with gastrointestinal event and 1 with infection. All the adverse events were cured after treatment. The median follow-up time was 15.9 months. At the last follow up, 6 patients died. No in-field relapse was recorded. Progression-free survival was 43.3% at 1 year and 21.6% at 2 years, overall survival was 60% at 1 year and 24% at 2 years. The median survival time and progression free survival time were 12.1 months and 11.1 months, respectively. CONCLUSION: For patients with advanced or recurrent liver cancer, toripalimab in combination with concurrent or previous radiotherapy is an effective treatment with tolerable toxicities. A prospective trial with large number of patients is warranted.