Association of tumour burden with the efficacy of programmed cell death-1/programmed cell death ligand-1 inhibitors for treatment-naïve advanced non-small-cell lung cancer. (January 2022)

• Record Type: Journal Article
• Authors: Suzuki, Shinichiro; Haratani, Koji; Hayashi, Hidetoshi; Chiba, Yasutaka; Tanizaki, Junko; Kato, Ryoji; Mitani, Seiichiro; Kawanaka, Yusuke; Kurosaki, Takashi; Hasegawa, Yoshikazu; Okabe, Takafumi; Tanaka, Kaoru; Akashi, Yusaku; Ozaki, Tomohiro; Nishio, Kazuto; Ito, Akihiko; Nakagawa, Kazuhiko
• Is Part Of: European journal of cancer. Volume 161(2022)
• Page Start: 44
• Page End: 54
• Publication Date: 2022-01
• Subjects: Non-small-cell lung cancer -- Tumour burden -- PD-1/PD-L1 inhibitor -- Resistance mechanism -- M2-type macrophage; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Cancer; Tumors; Electronic journals; Periodicals; Electronic journals; 616.994
• DOI: 10.1016/j.ejca.2021.11.011
• Languages: English
• ISSNs: 0959-8049

Abstract

Abstract: Background: Tumour burden (TB) is implicated in resistance to programmed cell death-1/PD-L1 inhibitor (immune checkpoint inhibitor [ICI]) therapy. However, whether TB contributes to such resistance in non-small-cell lung cancer (NSCLC) has remained unknown. Methods: A total of 260 treatment-naïve patients with advanced NSCLC who started ICI monotherapy (ICI cohort), platinum-doublet therapy (Chemo cohort) or ICI and platinum-doublet therapy (ICI+Chemo cohort) as first-line treatment were consecutively included. TB was estimated on the basis of the sum of the diameters of measurable target lesions as per Response Evaluation Criteria in Solid Tumours. Progression-free survival (PFS) in the ICI cohort was evaluated as per TB as a preplanned primary objective, with the analysis based on propensity score-weighted survival curves and estimation of restricted mean survival time (RMST). The Chemo cohort served as a control to determine whether TB is predictive of ICI treatment outcomes. The ICI+Chemo cohort was exploratory. The relation of TB to tumour immune status was assessed by immune-related gene expression profiling (irGEP) of pretreatment tumour tissue. Results: In the ICI cohort, patients with a low TB showed a significantly longer PFS than did those with a high TB (median, 17.9 vs 4.3 months; weighted hazard ratio, 0.32 [95% confidence interval, 0.19–0.53]). No such difference was apparent in the other cohorts. A significant difference in overall survival was also observed only in the ICI cohort. RMST-based analysis confirmed these results. The irGEP analysis implicated M2-type macrophages, angiogenesis and transforming growth factor–β as well as protumourigenic signalling pathways in ICI resistance conferred by a high TB. Conclusion: A high TB was associated with a poor outcome of ICI therapy for advanced NSCLC as a result of immunosuppressive phenotypes. Development of combination or novel treatment strategies for such disease is thus warranted. Highlights: The relation of NSCLC tumour burden to PD-1/PD-L1 inhibitor efficacy was evaluated. High tumour burden (HTB) was associated with resistance to ICI monotherapy. HTB was not associated with treatment outcomes for cytotoxic chemotherapy. HTB was associated with macrophage-related and protumourigenic gene expression. Patients with HTB may require more aggressive treatment than ICI monotherapy.