XX (a PD-1 Inhibitor), Stereotactic Body Radiotherapy and Granulocyte-Macrophage Colony Stimulating Factor as Second-Line Therapy for Advanced Non-Small Cell Lung Cancer: Safety Run-In Results of a Prospective, Multicenter, Phase II Trial

Abstract

<h3>Purpose/Objective(s)</h3> Several PD-1/PD-L1 inhibitors have been approved, with or without chemotherapy, in advanced non-small cell lung cancer (NSCLC). However, the objective response rate (ORR) remains limited in unselected population. Accumulating data indicated that adding SBRT to PD-1/PD-L1inhibitors could improve treatment efficacy in NSCLC and the anti-tumor immune response induced by SBRT may be enhanced by GM-CSF, which plays a pivotal role in dendritic cell differentiation and maturation. Nevertheless, the safety and efficacy of triple combination of XX (a PD-1 inhibitor), SBRT and GM-CSF in advanced NSCLC remain unknown. <h3>Materials/Methods</h3> This is a prospective, multicenter, phase II study. Eligible patients (pts) were advanced EGFR/ALK negative NSCLC pts who had failed first-line standard chemotherapy. Pts received SBRT (8 Gy*3) to one lesion, followed by XX (200 mg d1, every 3 weeks) and GM-CSF (125 μg/m2 d1-d14, cycle 1) within 3 weeks after SBRT. XX would be given continuously until disease progression, unacceptable toxicity, or up to 35 cycles. To determine the tolerability of the triple combination therapy, a safety run-in phase was conducted in the first 20 enrolled pts by monitoring the dose-limiting toxicities (DLTs). Primary end point is ORR. Secondary end points are safety, out-of-field response rate, overall survival (OS), progression free survival (PFS). Here, we report the preliminary results of the safety run-in phase. <h3>Results</h3> From 2019/10/16 to 2020/8/8, 20 pts were enrolled from 3 academic centers. The majority of pts were male, smoker, ECOG 1 and non-squamous NSCLC, with a median age of 61 (range, 32-71). Baseline brain, liver and bone metastasis were present in 2, 4 and 8 pts, respectively. All of the pts had more than 5 lesions at baseline, and the sites of SBRT included lung (n = 11), mediastinal lymph node (n = 5), liver (n = 1), abdominal lymph node (n = 1), pleural nodule (n = 1) and vertebra (n = 1). There were no DLTs. Treatment-related adverse event (TRAE) occurred in 18 pts. The most common TRAEs were fatigue (50%), fever (30%), and ostealgia (20%), and all were grade1. Only 2 grade 3 TRAEs were observed. 1 pt had G3 ALT and AST elevation, and the other experienced transient (recovered within 7 days) acute heart failure which was considered GM-CSF related. No grade 4 or 5 AE occurred. Median follow-up was 7.9 (range,1.6-16.5) months by data cut-off (2021/02/28). Partial response occurred in 7 and stable disease in 5 pts, the confirmed ORR was 35%. Median PFS was 6.9 (95% CI, 2.76-NA) months with 12 events and 1-year OS rate was 75.0% (95% CI, 58.2%-96.6%). <h3>Conclusion</h3> Triple combination of XX, SBRT and GM-CSF is safe and shows promising efficacy as a novel second-line treatment for advanced EGFR/ALK negative NSCLC. The trial continues to recruit participants.