Abstract
ObjectivesThe SWORD trial is the first multicenter, single arm, phase II study assessing the safety and efficacy of a PD-1 inhibitor (Sintilimab), stereotactic body radiotherapy (SBRT) and granulocyte–macrophage colony stimulating factor (GM-CSF) in advanced non-small cell lung cancer (NSCLC) without sensitizing driver mutations. A safety run-in phase was conducted to determine the tolerability of the experimental treatment.Materials and methodsTwenty metastatic NSCLC patients who failed first-line chemotherapy were enrolled, and they received SBRT (8 Gy × 3) to one lesion, followed by Sintilimab (200 mg d1, every 3 weeks, until disease progression, unacceptable toxicity, or up to 35 cycles) and GM-CSF (125 μg/m2 d1-d14, cycle 1) within 2 weeks after SBRT. In addition, blood and tissue samples were serially collected for translational research.ResultsMedian age of the patients was 61 and all of them had more than 5 lesions at baseline. 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). No patients had dose-limiting toxicities (DLTs) and 18 patients experienced treatment-related adverse event (TRAE). The most common TRAEs were fatigue (50%), fever (30%), and ostealgia (20%), and they all were grade 1. Only 2 grade 3 TRAEs were observed, including elevation of liver enzymes in one and transient acute heart failure in another. No grade 4 or 5 AE was observed.ConclusionSintilimab, SBRT and GM-CSF for advanced NSCLC is safe with manageable TRAEs and the trial continues to recruit participants.Trial registration ClinicalTrials.gov, NCT04106180. Registered 26 September 2019, SBRT in Combination With Sintilimab and GM-CSF for the Treatment of Advanced NSCLC-Tabular View-ClinicalTrials.gov.
Highlights
Over the last decade, immune checkpoint inhibitors, inhibitors of the programmed cell death1(PD-1)/programmed cell death ligand-1(PD-L1) axis, have transformed the therapeutic landscape in advanced non-small cell lung cancer (NSCLC) without driver mutations
Radiotherapy, especially stereotactic body radiotherapy (SBRT), is repeatedly found to enhance anti-tumor immunity and has the potential to synergize with immunotherapy in NSCLC [8, 9]
A safety run-in phase is conducted to determine the tolerability of this novel triple combination therapy by monitoring dose-limiting toxicities (DLTs) in the first 20 enrolled patients and we reported the results
Summary
Immune checkpoint inhibitors, inhibitors of the programmed cell death1(PD-1)/programmed cell death ligand-1(PD-L1) axis, have transformed the therapeutic landscape in advanced non-small cell lung cancer (NSCLC) without driver mutations. An individual patient-level meta-analysis of the Pembro-RT trial and MDACC study [21], demonstrated that adding radiotherapy, especially SBRT, to Pembrolizumab, significantly improved outof-field (abscopal) response rate (ASR, 41.7% vs 19.7%, p = 0.0039), PFS (9.0 months vs 4.4 months, p = 0.0450) and OS (19.2 months vs 8.7 months, p = 0.0004) in patients with pretreated metastatic NSCLC [22]. These results need to be verified in further clinical trials enrolling patients from different races and genetic backgrounds. The reported efficacy of combining SBRT and PD-1/PD-L1 inhibitor remains unsatisfactory, and novel partners with non-redundant molecular mechanisms are demanded
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