Sintilimab, SBRT and GM-CSF for Metastatic NSCLC: A Prospective, Multicenter, Phase II Trial

Abstract

PD-1/PD-L1 inhibitors have transformed the therapeutic landscape in metastatic non-small cell lung cancer (NSCLC). However, the objective response rate (ORR) remains limited in unselected population. Incorporating SBRT to PD-1/PD-L1 inhibitors may improve treatment efficacy and the anti-tumor immunity induced by SBRT may be enhanced by GM-CSF, which plays a pivotal role in dendritic cell differentiation and maturation. The current trial (NCT04106180) is the first prospective, multicenter, phase II study assessing the safety and efficacy of a PD-1 inhibitor (Sintilimab), SBRT and GM-CSF in metastatic NSCLC patients without sensitizing driver mutations. Metastatic EGFR/ALK negative NSCLC pts who had failed first-line standard chemotherapy were eligible. Pts received SBRT (8 Gy*3) to one lesion, followed by Sintilimab (200 mg d1, every 3 weeks) and GM-CSF (125 μg/m2 d1-d14, cycle 1) within 3 weeks after SBRT. Sintilimab would be given continuously until disease progression, unacceptable toxicity, or up to 35 cycles. Primary end point is ORR. Secondary end points are safety, out-of-field response rate, overall survival (OS), progression free survival (PFS). The trial was designed to enroll 56 patients and if ≥17 pts evaluated had an objective response, it was regarded as positive. By the time of 2022/10/30, the trial was early closed after 18 of the 51pts enrolled from 6 academic centers documented PR. The majority of pts were male, ECOG 1 and non-squamous NSCLC, having more than 5 lesions at baseline, with a median age of 62 (range, 32-74). The sites of SBRT included lung (n = 20), regional lymph node (n = 16), pleural nodule (n = 5), vertebra (n = 3), distant lymph node (n = 3), liver (n = 2) and others (n = 2). Treatment-related adverse event (TRAE) occurred in most pts and grade 3 TRAE occurred in 6 (11.8%) pts. No grade 4-5 TRAE occurred and the most common grade 3 TRAEs were ALT/AST elevation (n = 2), transient acute heart failure (recovered within 7 days) (n = 1), leucopenia/neutropenia (n = 2), pneumonitis (n = 1) and creatinine elevation (n = 1). With a median follow-up of 19.2 (range, 4.6-35.4) months, 49 pts had evaluable efficacy, with 18 PR, 15 SD and 16 PD. Median PFS and OS were 5.9 (95% CI, 3.9-9.2) and 16.2 (95% CI, 12.6-34.1) months, respectively. The results of biomarker testing will also be presented. Triple combination of Sintilimab, SBRT and GM-CSF is safe and shows promising efficacy in metastatic EGFR/ALK negative NSCLC.