Safety and efficacy of sintilimab in combination with SBRT and LDRT in PD-L1 positive treatment naïve-stage IV non-small cell lung cancer: A phase I study (IHC study).

e21174 Background: Low dose radiation (LDRT) can potentially enhance the synergistic anti-tumor effect in metastatic NSCLC when combining with immunotherapy and SBRT. We previously reported the safety and tolerability of this new combination strategy. Here we presented the updated safety and efficacy data. Methods: This phase I study included a dose escalation phase (aimed to determine the optimal LDRT dose) and a dose expansion phase. Eligible patients had histologically or cytologically confirmed NSCLC, stage IV, PD-L1 positive (TPS ≥ 1%), and at least 2 extra-cranial tumor lesions. Patients received SBRT (30Gy/3f) to a small lesion and LDRT to a large lesion concurrently, followed by sintilimab (200mg i.v., q3w) started within 7 days after radiation completion until disease progression, unacceptable toxicities or reached a maximum of 24 months. Primary endpoints were safety and tolerability; secondary endpoints included objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). Results: Between 4/2019 and 10/2021, 29 patients were enrolled and treated. No dose limiting toxicities were observed during the dose escalation phase and 4Gy/2f was chosen as recommended LDRT dose for expansion phase. Most patients were male (89.7%) with adenocarcinoma (58.6%). 34.4% patients had PD-L1 TPS ≥ 50%. Until data cutoff (1/8/2022), the median follow-up was 15.5 (range: 1.2-32.5) months. Treatment-related adverse events (TRAEs) occurred in 96.6% patients (28/29) and 20.7% (6/29) were grade 3-4. Permanent discontinuation due to TRAEs occurred in 6.9% (2/29) patients. Eight patients experienced pneumonitis, including 1 grade 1, 6 grade 2 and 1 grade 3. No grade 5 TRAE was observed. 51.7% (15/29) patients had potential immune-related AEs. Of the 28 patients who received at least one tumor assessment, the ORR was 60.7% (95%CI:40.6%-78.5%) and the confirmed ORR was 57.1% (95%CI:37.2%-75.5%). The median duration of response was 13.6 months (95%CI:7.9-19.3), and 4 patients maintained response after reaching the maximum treatment of 2 years. The disease control rate (DCR) was 78.6% (95%CI: 59.1%-91.7%). The median PFS was 8.6 months (95%CI: 5.7-11.5), the 12-month PFS rate was 39.6%, and the median OS was not reach. 17 patients were enrolled in the LDRT 4Gy/2f does group and 16 were evaluable. The ORR was 62.5%, the confirmed ORR was 56.3%, and the DCR was 81.25%. The median PFS was 9.0 months. Exploratory analysis revealed that patients with lower neutrophil to lymphocyte ratio (NLR) had longer PFS. Conclusions: This is the first prospective phase I study to evaluate a new combination with SBRT, LDRT and anti-PD-1 therapy. The result suggested it was tolerable and feasible, with encouraging ORR and PFS. The strategy of adding SBRT and LDRT to immuno-based systemic therapy in treatment naïve metastatic NSCLC warranted further exploration. Clinical trial information: NCT03812549.