Clinical outcomes and post-progression retreatment in patients with metastatic NSCLC who complete two years of treatment with immune checkpoint blockade.
Authors: Ricciuti Biagio , Gariazzo Eleonora , Gorria Teresa , Thummalapalli Rohit , Citarella Fabrizio , Gandhi Malini Marion , Elkrief Arielle , Pecci Federica , Alessi Joao Victor Machado , Di Federico Alessandro , Makarem Maisam , Saini Arushi , Aldea Mihaela , Baena Espinar Javier , Cortellini Alessio , Schoenfeld Adam Jacob , Aboubakar Nana Frank , Mezquita Laura , Metro Giulio , Awad Mark M. 
Published: June 2024

8633

Background: Immune checkpoint inhibition (ICI) has significantly improved survival in patients (pts) with metastatic non-small cell lung cancer (NSCLC). While ICI duration is commonly limited to two years, the optimal duration of ICI and post-progression treatment outcomes in pts who received at least two years of ICI are unknown. Methods: We conducted an international, multi-center study of pts with metastatic NSCLC treated with ICI for at least two years to characterize clinical outcomes and post-progression treatment patterns. Log-rank tests were used to test for differences in event-time distributions, and Cox proportional hazards models were used to estimate HRs. Results: We identified 255 pts with metastatic NSCLC treated with ICI alone (N=210, 82.3%) or ICI + chemotherapy (N=45, 17.7%) for least two years. Median age was 63.0, 42.4% were women, 93.0% had history of tobacco use, 79.2% had adenocarcinoma histology, 61.4% had a PD-L1 TPS ≥50%. From the start of ICI, the median time to progression (mTTP) was 6.9 years (95%CI 4.9-NR) and the median overall survival (mOS) was 9.5 years (95%CI 8.0-NR). Pts wo achieved a complete/partial response to ICI had a significantly longer mTTP (HR 0.41, P<0.01) and mOS (HR 0.30, P<0.01) compared to those with a best objective response of stable disease. Patients with high PD-L1 ≥50% (HR 0.6, P=0.02 vs PD-L1 <50%), very high tumor mutational burden (TMB) ≥20 mut/Mb (HR 0.7, P=0.03, vs <20 mut/Mb) and ever smoking status (HR 0.52, P=0.04, vs never smokers) had also significantly longer mTTP. There was no difference in mTTP (HR: 0.98, P=0.94) and mOS (HR: 0.61, P=0.06) between pts who stopped ICI at two years of treatment (N=112) and those who continued ICI beyond two years (N=143). Among 96 pts who progressed after ICI, 33.3% (N=32) received local ablative therapies (surgery or radiation), 9.3% (N=9) pts received systemic chemotherapy and 31.2% (N=30) pts received ICI retreatment. Among those retreated with ICI, the response rate was 63%, mTTP and mOS from the date of start of ICI retreatment were 22.7 (95%CI 11.2-NR), and 41.7 months (19.3-NR), respectively. Clinico-genomic predictors of response to ICI retreatment included higher TMB at baseline (15 vs 7.6 mut/Mb, P<0.001), adenocarcinoma histology (94.4% vs 50.0%, P=0.01), and longer ICI treatment duration prior to retreatment (31.2 vs 24.5 months, P=0.02). Conclusions: Pts who received a minimum of two years of treatment with ICI experienced unprecedented long-term survival. There was no difference in outcomes between pts who stopped at two years compared to those who continue therapy. After completing two years of initial ICI therapy, a large fraction of pts who subsequently experience disease progression and are retreated with ICI experience an objective response, particularly those with longer duration of prior ICI treatment, higher TMB, and adenocarcinoma histology.