Safety and Efficacy of PD-1 Antibody SHR-1210 Combined with Concurrent Chemoradiotherapy to Treat Locally Advanced Esophageal Squamous Cell Carcinoma: A Phase Ib Clinical Trial

Poor survival remains in patients with locally advanced esophageal squamous cell carcinoma (LAESCC) after definitive concurrent chemoradiotherapy (dCCRT). The effect of dCCRT combined with PD1 antibody as a first-line treatment on LAESCC is little known. We report here an early report of the first clinical trial. We aim to explore the safety, tolerability and efficacy of PD1 antibody combined with dCCRT for LAESCC. Twenty patients with newly diagnosed LAESCC (clinical stage: T3-4N0M0, T1-4N+M0, stage II-IV, according to the 8th AJCC stage system) and ECOG performance status 0 or 1 were enrolled. Patients are delivered 8 cycles (4 weeks/cycle) of PD1 antibody SHR-1210 concurrently combined with 6 weeks of RT (2.0 Gy × 30 fractions) and 4 weeks of chemotherapy (cisplatin 25 mg/㎡/w plus docetaxel 25 mg/㎡/w administrated on day 1, 8, 15, 22) and Apatinib (250 mg/d from the 11th week to the end of treatment). The primary endpoints are treatment-related adverse events (AEs) (CTCAE 4.0) and serious adverse events (SAEs). The second endpoints are objective response rate (ORR), progression-free survival (PFS) and overall survival (OS). ORR was evaluated after 40 Gy RT. Twenty patients were enrolled between Sep 11, 2018 and May 17, 2019. 18 patients were male. Median age was 63 (56-74) years old. One in stage I, 6 in stage III and 13 in stage IV. Six (30%) patients did not complete RT as planned, but at least received 52 Gy in PGTV. Two (10%) patients discontinued SHR-1210 treatment, one for progressive disease and the other for esophageal fistula. Ten (50%) patients received 4-cycle chemotherapy and another 10 (50%) received 3-cycle chemotherapy. Treatment-related AEs occurred in all patients; no grade 4-5 events were reported. The most common AE was radiation esophagitis, occurring in 16 (80%) patients, 40% (8/20) in grade 2 and 20% (4/20) in grade 3. Grade 1 cutaneous capillary hemangioma occurred in 10 (50%) patients. Apatinib decreased the severity of cutaneous capillary hemangioma. Grade 2 interstitial pneumonitis occurred in 2 (10%) patients. No grade III pneumonitis occurred. Grade 2 pulmonary infection occurred in 2 (10%) patients. Esophageal fistula occurred in 2 (10%) patients. Grade II and III fatigue occurred in 1 (5%) patient, respectively. Grade 2 and 3 neutropenia occurred in 6 (30%) and 1 (5%) patients. Two (10%) patients reached complete response, 11 patients (55%) reached partial response and 7 (35%) patients maintained stable disease. With a follow-up time of Jan 31, 2020, the OS and PFS rate was 86.4% and 80.0% at 12 months. One patient developed local-regional recurrence and 4 patients suffered metastasis. The results from our original phase Ib clinical trial revealed that dCCRT combined with SHR-1210 exhibited a remarkable therapeutic effect with tolerable toxicity, which would provide a new strategy for LAESCC. Phase III clinical trial is ongoing to confirm the present results. This trial was registered in ClinicalTrials.gov (NCT03671265).