Hypofraction radiotherapy followed by immune checkpoint inhibitors for locally advanced non-small cell lung cancer: A phase I/II trial.

8058 Background: To explore the safety and primary efficacy of hypofraction radiotherapy followed by immune checkpoint inhibitors (ICI) for stage III locally advanced non-small cell lung cancer patients. Methods: Patients with stage III non-small cell lung cancer were enrolled to receive hypofraction radiotherapy (48-64Gy/12-16f) followed by ICI maintenance treatment. After the completion of radiotherapy, one-year maintenance ICI treatment was encouraged. The primary objective was to explore the toxicity of hypofractionated radiotherapy with immunotherapy. The secondary objective was survival outcome. We also performed multicolor immunohistochemistry (mIHC) of tumor tissues, peripheral blood single-cell RNA sequencing (scRNA-seq) and flow cytometry to characterize the immune microenvironment of enrolled patients. Results: According to the inclusion criteria, totally 51 patients were enrolled from June 2021 to January 2024. The median follow-up time was 28 months (8-22 months). After the completion of hypofractionated radiotherapy, 13 patients received no or less than 5 cycles of immunotherapy. All kinds of radiation-induced toxicity (≥ grade 3) occurred in 17 patients (33.3%). The rate of over grade 3 PBT injury and over grade 3 radiation-induced pneumonitis was 3.9% and 17.6% respectively, resulting in 11.8% of over grade 3 cough and 9.8% of over grade 3 dyspnea. No over grade 3 radiation-induced esophagitis occurred. The median progression-free survival (PFS) was 28 months with 1-year PFS rate of 72.1% and 2-year PFS rate of 54.7%. The median overall survival (OS) was not reached with 1-year OS rate of 84.0% and 2-year OS rate of 61.6%. In subgroup analysis, high-dose (60-64Gy/15-16f) group did not demonstrate survival benefit to low-dose group (48-52Gy/12-13f), but more grade III and higher toxicity (41.2% vs. 17.6%, p=0.002). In addition, mIHC, scRNA-seq and flow cytometry showed an increase in the number of anti-tumor immune cells in the treated tumor tissues, as well as an expansion of T-cell clones with cytotoxic T-cell phenotype and enhanced anti-tumor activity of neutrophils in the peripheral blood. Conclusions: Hypofraction radiotherapy (48-64 Gy/12-16f) with ICI treatment was safe and efficient. But the use of high dose (over 60Gy/15f) should be alerted due to its toxicity. Further, hypofraction radiotherapy can provide patients with an immune-activated tumor microenvironment that makes them respond better to immunotherapy. Clinical trial information: NCT05269485 . Clinical characteristic of total patients. Total patientsn=51 High-dose Subgroup (≥60 Gy)n=34 Low-dose Subgroup(<60 Gy)n=17 Statistical Method and p value Gender Male 48 (94.1%) 33 (97.1%) 15 (88.2%) χ 2 testp=0.255 Female 3 (5.9%) 1 (2.9%) 2 (11.8%) Age Median (Range) 69 (41-84) 65 (51-83) 70 (41-84) Independent sample t-testp=0.916 Clinical Stage II 4 (7.8%) 2 (5.9%) 2 (11.8%) Mann-Whitneyp=0.304 IIIA 11 (21.6%) 8 (23.5%) 3 (17.6%) IIIB 23 (45.1%) 13 (38.2) 10 (58.8%) IIIC 13(25.5%) 11 (32.4) 2 (11.8%) Pathology Squamous Cell Carcinoma 41 (80.4%) 29 (85.3%) 12 (70.6%) χ 2 testp=0.190 Adenocarcinoma 10 (19.6%) 5 (14.7%) 5 (29.4%) Tumor Location