Effect of hypofractionated radiotherapy plus GM-CSF on antitumor activity with PD-1/PD-L1 inhibitors in oligoprogressive advanced NSCLC: A prospective phase II study.

Abstract

e20638 Background: Oligoprogressive disease during PD-1/PD-L1 therapy is a challenging acquired resistance pattern in advanced NSCLC. Radiotherapy modulates antitumor immunity, and GM-CSF may enhance systemic immune responses. We hypothesized that combining hypofractionated radiotherapy (HFRT) with GM-CSF could restore antitumor activity and extend disease control in PD-1/PD-L1–refractory oligoprogressive advanced NSCLC. Methods: This prospective, single-arm phase II trial enrolled driver gene–negative patients with advanced NSCLC who developed oligoprogressive disease following first- or second-line PD-1/PD-L1 inhibitor therapy (ChiCTR2300069974). Progressive measurable lesions were treated with HFRT, predominantly delivered as 10–15 Gy in a single fraction (25 Gy in 5 fractions when clinically indicated). PD-1/PD-L1 inhibitors were resumed the day after radiotherapy and administered every 3 weeks, combined with subcutaneous GM-CSF (200 μg, days 1–7). The primary endpoint was objective response rate (ORR). Secondary endpoints included time to next treatment (TTNT), duration of response (DOR), overall survival (OS), and safety (CTCAE v5.0). Exploratory immune profiling was performed using peripheral blood cytokines and immune cell subsets. Results: As of December 31, 2025, 33 patients were treated. Median age was 68 years (range, 39–78), and 15.2% were female. Histologic subtypes included squamous cell carcinoma (42.4%), adenocarcinoma (39.4%), and other NSCLC subtypes (18.2%). The ORR was 42.4% (14/33), including 1 complete response (3.0%) and 13 partial responses (39.4%). Median TTNT was 10.3 months (95% CI, 7.0–13.7), and median DOR among responders was 11.4 months (95% CI, 2.6–20.3). Median OS was not reached at the time of analysis. Treatment-related adverse events (TRAE) occurred in 69.7% of patients and were predominantly grade 1–2. Grade 3 TRAE were observed in two patients (6.1%), with no grade ≥4 events. Exploratory immune analyses demonstrated post-treatment increases in IFN-γ, CD8⁺ T cells, and NK cells, supporting systemic immune reinvigoration. Conclusions: In patients with oligoprogressive, PD-1/PD-L1–refractory advanced NSCLC, HFRT combined with GM-CSF and continuation of PD-1/PD-L1 blockade demonstrated a clinically meaningful efficacy signal, durable disease control, and a favorable safety profile. These findings suggest that radiotherapy-based immune modulation may represent a viable strategy to overcome acquired immune resistance and warrant further randomized validation. Clinical trial information: ChiCTR2300069974. Key efficacy and safety outcomes. Parameter Result ORR 42.4% PR, n (%) 13 (39.4%) CR, n (%) 1 (3.0%) TTNT, months (95% CI) 10.3 (7.0–13.7) DOR among responders , months (95% CI) 11.4 (2.6–20.3) Any TRAE, n (%) 23 (69.7%) Grade 1–2 TRAE, n (%) 21 (63.6%) Grade 3 TRAE, n (%) 2 (6.1%) Grade ≥4 TRAE 0