Rescue by radiotherapy and anti-CTLA4/PD-1 after failure of anti-PD-1 therapy in patients with metastatic NSCLC: the phase II RECLAIM trial

BACKGROUND: Response to anti-programmed cell death protein-1 (anti-PD-1) immunotherapy remains limited in patients with metastatic non-small cell lung cancer (NSCLC), whose tumors exhibit low or absent programmed death-ligand 1 (PD-L1) expression, and subsequent second-line therapy has poor efficacy. To address this limitation, we evaluated the efficacy and safety of combined ipilimumab and nivolumab (IPI/NIVO) with subablative radiotherapy (RT) in patients with metastatic NSCLC with negative or low PD-L1 expression, who had progressed on prior anti-PD-1 therapy. METHODS: This single-arm, prospective phase II trial aimed to enroll 30 evaluable patients with metastatic NSCLC exhibiting low (1-49%) or negative (<1%) PD-L1 tumor expression who had progressed after first-line anti-PD-1 therapy. Primary endpoints were safety, disease control rate (DCR), and objective response rate (ORR) at 6 and 12 weeks, assessed in non-irradiated tumor lesions. Treatment consisted of IPI 1 mg/kg every 6 weeks (Q6W) and NIVO 240 mg every 2 weeks for 6 weeks combined with subablative RT (3×8 Gy to 1-4 lesions). Thereafter, IPI 1 mg/kg Q6W and NIVO 360 mg every 3 weeks were continued. RESULTS: In 31 patients of the intention-to-treat population, ORR was 7% and 10% at 6 and 12 weeks, and reached 29% as the best response. DCR was 58% and 39% at 6 and 12 weeks. Overall survival (OS) differed significantly by best response, with a median OS of 3.1, 13.5 and 22.5 months for progressive disease, stable disease and partial/complete response (p<0.001). Baseline sum of longest diameters, together with age, blood inflammatory markers and albumin levels, were prognostic of treatment response. All patients experienced treatment-related adverse events (AEs), with grade 3 as the highest severity in eight patients (26%). Immune-related AEs led to treatment discontinuation in five patients (16%). Early T-cell activation in peripheral blood samples (day 8) was detectable and more pronounced in responders than in progressors. CONCLUSIONS: In patients with metastatic NSCLC and low or negative tumor PD-L1 expression, IPI/NIVO/RT was able to induce objective clinical responses in a subset of patients who had progressed after first-line anti-PD1 therapy. Treatment was associated with a strong T-cell activation, improved OS and an acceptable safety profile. TRIAL REGISTRATION NUMBER: 2020-001097-29.