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

Abstract

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.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.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.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.