1360P - Combining immunotherapy and hybrid dose-fraction radiotherapy (Hybrid-RT) for driver-negative metastatic non-small cell lung cancer patients (NSCLC): A single-arm multi-center phase II study (NCT05348668)

Background

Radiotherapy can elicit significant immunostimulatory effects, including triggering immunogenic cell death (ICD) by stereotactic body radiotherapy (SBRT) and improving the tumor immune microenvironment (TME) by low-dose radiotherapy (LDRT). This trial is designed to validation the efficacy and safety of the combination of immune checkpoint inhibitors (ICI) with Hybrid-RT for metastatic driven-genes negative NSCLC.

Methods

All enrolled patients receive first-line ICI plus chemotherapy for 4-6 cycles referred to NCCN guidelines. Patients with disease partial response (PR) or stable disease (SD) would be included into our study. Definition of Hybrid RT: For SBRT-safe lesion, SBRT is given to each lesion, with a radiotherapy of 24Gy in 3 fractions or 50Gy in 4 to 5 fractions; For LDRT lesion: All lesions except SBRT-safe lesion were given low-dose radiotherapy of 6 to 15Gy (1.5Gy per fraction); For patients with stage III NSCLC after re-staging, primary tumor and regional metastatic lymph nodes receive a radiotherapy of 48Gy in 12 fractions The primary endpoint was median progression-free survival (mPFS), and secondary endpoints were treatment-related adverse events (TRAE). In addition, we explored the effects of hybrid RT plus ICI on anti-tumor immunity and its potential mechanisms in mouse model.

Results

From Mar 1, 2022 to Dec 30, 2023, a total of 78 patients were enrolled in this study. Median follow-up for all patients was 17.7 months (IQR 8·4–25·7). The mPFS was 11.8 months (IQR 6·9–23.8), with 1-year and 1.5-year PFS rates of 45.4% and 38.6%, respectively. mOS not yet reached. Serious TRAE occurred in 14.1% (grade ≥ 3, 11/78) of patients. The percentages of CD8⁺T cells, and M1-type macrophages in patient peripheral blood were significantly increased after Hybrid-RT. In the mouse model, Hybrid RT promote the infiltration of GZMB⁺CD8⁺T cells and M1 macrophages in TME, significantly enhancing the therapeutic response of ICI.

Conclusions

Combining ICI with Hybrid-RT is safe and promising in patients with metastatic driven-genes negative NSCLC. These results warrant validation in a randomised phase 3 trial.

Clinical trial identification

NCT05348668.

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.