Safety and Effect of Radiation Therapy Combined with Anti-PD-1 Antibody SHR-1210 as First-Line Treatment on Patients with Intolerable Concurrent Chemoradiotherapy Esophageal Cancer: A Phase 1B Clinical Trial

Immune checkpoint blockade therapy against programmed death 1 (PD-1) protein/ PD-1 ligand (PD-L1) signaling has shown remarkable clinical benefit for recurrent patients with advanced esophageal squamous cell carcinoma (ESCC). For the patients with intolerable concurrent chemoradiotherapy locally advanced ESCC, radiotherapy combined with immunotherapy may be a promising therapeutic strategy, although it has not been reported so far. Our study arms to evaluate the safety and effect of radiotherapy combined with SHR-1210, an anti-PD-1 antibody-drug conjugate, as a first-line treatment on the patients with intolerable concurrent chemoradiotherapy locally advanced ESCC. Twenty newly diagnosed locally advanced ESCC (clinical stage: T3-4N0M0, T1-4N+M0, according to the 8th AJCC stage system) were enrolled. All patients were intolerable to concurrent chemoradiotherapy or refused chemotherapy. Patients were given radiotherapy (60Gy/2Gy/30F) combined with SHR-1210. SHR-1210 was infused intravenously as fixed dose of 200 mg from the start of radiotherapy for every 2 weeks, total 16 consecutive infusions. We evaluated the effect by using Response Evaluation Criteria in Solid Tumors (RECIST1.1), and toxicity by Common Terminology Criteria for Adverse Events (CTCAE4.0). This trial was registered in ClinicalTrials.gov (NCT03222440). Twenty consecutive patients were enrolled between July 24, 2017 and January 25, 2018. Two for stage IIa, one for stage IIb, 14 for stage III, and three for stage IVa. Eighteen patients who at least completed full dose radiotherapy and 4 infusions of SHR-1210 were evaluated by RECIST1.1. There was one (5.6%) grade 3 adverse event of radiation laryngitis. The most common toxicity was cutaneous capillary hemangioma, including 77.8% of the patients (14/18) for grade I and 5.6% (1/18) for grade II. A total of 27.8% of the patients (5/18) suffered grade II radiation esophagitis. A total of 5.6% of the patients (1/18) suffered grade II radiation pneumonitis. Abnormal hepatic function for Grade I was observed in 3 patients (16.7%). We evaluated the therapeutic effect when patients received 40 Gy radiotherapy. Two patients (11.1%) reached complete response, 13 patients (72.2%) reached partial response, 3 patients (16.7%) maintained stable disease. Follow-up update to February 10, 2018, there was one patient who received chemotherapy because of local recurrence. One patient was diagnosed as hepatic metastasis, treated with radiofrequency ablation and without SHR-1210 interruption. The rest patients were in good control. The results from our phase IB clinical trial revealed that radiotherapy combined with SHR-1210 exhibited a promising therapeutic effect with tolerable toxicity although follow-up time was short. This study would provide a new therapeutic strategy for patients with intolerable concurrent chemoradiotherapy locally advanced ESCC. Phase II clinical trial is needed to confirm the present results of this study.