Clinical and laboratory predictors of immune checkpoint inhibitor efficacy in non-small cell lung cancer
Authors: P. Christopoulos, J. Kohlhäufl, F. Bozorgmehr, J. Kuon, M. Schneider, O. Neumann, S. Liersch, C. Heussel, H. Winter, F. Herth, S. Rieken, T. Muley, M. Meister, H. Bischoff, F. Lasitschka, A. Stenzinger, M. Thomas
Journal: Annals of Oncology (2018)

Background: Treatment with immune checkpoint inhibitors (ICI) prolongs overall survival (OS) and confers long-term disease control in 15-20% of non-small cell lung cancer (NSCLC) patients. Patient selection currently depends on the levels of PD-L1 expression, but correlation with outcome is weak. Methods: We retrospectively analyzed the clinical course of ICI-treated stage IV NSCLC patients at our institution. Results: A total of 453 patients were identified with a median age of 64 years having received nivolumab (57%), pembrolizumab (35%), PD-L1 inhibitors (7%) or PD1 blockade in combination with chemotherapy or CTLA4 inhibitors (1%). Progression-free survival (PFS) under ICI was significantly longer for patients receiving ICI in the first (21%, 7 months in median) compared to second (47%, 4 months in median) and later treatment lines (2 months in median, p < 0.001), for current and ex-smokers (91% of cases, p = 0.034), in case of adenocarcinoma (66%) compared to squamous cell carcinoma (28%) and other histologies (9%, p < 0.001), while age, sex and ECOG status at initial diagnosis had no influence. The total number of metastatic sites and the presence of liver metastases at start of IO treatment were associated with shorter ICI responses (p = 0.018 and p = 0.005, respectively), while metastases to other organs, especially brain, did not play a role. Blood markers, like the Lymphocyte-to-Neutrophile-Ratio (LNR) as well as CRP and LDH as indicators of inflammation and tumor load, had the highest discriminatory value (≥ 2x longer median PFS for cases with higher LNR or lower CRP or LDH, p < 0.0001 for each), while the occurrence of immune-related adverse events (irAE) conferred longer PFS (p < 0.001) as well as overall survival (OS) from the start of IO treatment (p < 0.01). PFS under ICI was similar for cases with PD-L1 <1% vs. 1-49% (14% and 34%, respectively), while cases with PD-L1 expression >50% had an ICI-PFS twice as long (p = 0.011). Conclusions: Several clinical and blood parameters appear to correlate with ICI benefit better than tissue PD-L1 expression levels in NSCLC patients and could be used along with molecular markers to improve predictive tools for lung cancer immunotherapy. Legal entity responsible for the study: Thoraxklinik Heidelberg. Funding: Has not received any funding. Disclosure: F. Bozorgmehr: Research funding: BMS; Travel grants: BMS, MSD. J. Kuon: Research funding: AstraZeneca, Celgene. C. Heussel: Consultation, lecture and other fees: Novartis, Siemens, Chiesi, Intermune, MEDA Pharma, Bracco, Pfizer, MSD, Roche, Lilly, AstraZeneca, Schering-Plough, Essex, Gilead; Ownership of GSK stocks. F. Herth: Advisory board fees and honoraria: Lilly, Roche, AstraZeneca, Novartis, Boehringer, Chiesi, Teva, Pulmonx BTG, Olympus; Research funding: Lilly, Roche, AstraZeneca, Novartis, Boehringer, Chiesi, Teva. T. Muley: Research funding, patents: Roche. A. Stenzinger: Advisory board honoraria: BMS, AstraZeneca, ThermoFisher, Novartis; Speaker's honoraria: BMS, Illumina, AstraZeneca, Novartis, ThermoFisher, MSD, Roche; Research funding: Chugai. M. Thomas: Advisory board honoraria: Novartis, Lilly, BMS, MSD, Roche, Celgene, Takeda, AbbVie, Boehringer; Speaker's honoraria: Lilly, MSD, Takeda; Research funding: AstraZeneca, BMS, Celgene, Novartis, Roche. All other authors have declared no conflicts of interest.