Abstract 5708: Associations between soluble immune checkpoint molecules and overall survival in advanced non-small cell lung cancer (NSCLC) patients treated with either anti-PD-1/-L1 monoclonal antibodies or single-agent chemotherapy
Authors: Tarhoni Imad A. , Fughhi Ibtihaj , Gerard David , Basu Sanjib , Fhied Cristina , Lie Wen-rong , Russell Donna , Batus Marta , Thakar Nisha , Bonomi Philip , Fidler Mary , Borgia Jeffrey 
Published: August 2018

Background: While several of the KEYNOTE trials showed that NSCLC patients whose tumors expressed high levels of the programmed death ligand-1 (PD-L1) were more likely to have superior survival with pembrolizumab compared to chemotherapy, other trials failed to confirm the predictive value of PD-L1 tissue expression. And with response rates for PD-1/-L1 directed immunotherapy approximating 20%, development of improved molecular diagnostics to accurately identify patients likely to have long-term disease control is needed. The goal of the current study is to evaluate potential relationships between a panel of soluble immune checkpoint molecules and disease control in NSCLC patients treated with PD-1/-L1 monoclonal antibodies. Method: Pretreatment sera from 128 cases of advanced NSCLC that failed frontline chemotherapy were evaluated for 16 soluble checkpoint molecules and immune regulators using the Human Immuno-Oncology Checkpoint Protein Panel (MilliporeSigma). This panel consists of the following targets: BTLA, CD27, CD28, TIM-3, HVEM, CD40, GITR, GITRL, LAG-3, TLR-2, PD-1, PD-L1, CTLA-4, CD80/B7-1, CD86/B7-2, and ICOS. All patients tested received either PD-1/-L1 targeting checkpoint inhibitors (nivolumab, atelizumab, or pembrolizumab; n=79) or single-agent chemotherapy (n=49). All kits were processed according to manufacturer-defined protocols and read using a Luminex® FLEXMAP 3D®. Finally, statistical relationships were determined using the Log-Rank test in relation to overall survival, defined as the interval from diagnosis to last follow up or death. Results: Pretreatment sera from 128 cases of NSCLC were evaluated for 16 soluble checkpoint molecules and immune regulators using the Luminex immunobead platform. In analysis of the cohort, lower levels of CD80/B7-1 were found to have significant association (p=0.0372) with superior overall survival. Patients who received PD-1/L1-directed immunotherapy, however, demonstrated low circulating levels of the T-cell associated molecules CD28 and CD80/B7-1, which were associated with superior overall survival (p=0.0178 and 0.036, respectively), whereas low circulating levels of the tumor-associated molecules LAG-3 and CD86/B7-2 were associated with an inferior overall survival (p=0.009 and 0.0278, respectively). There were no significant associations (all p&gt;0.05) identified in the cohort that received chemotherapy alone. Conclusion: These findings suggest that soluble immune-checkpoint molecules may identify advanced NSCLC patients most likely to benefit from anti-PD-1/-L1 immunotherapy. Prospective study of these biomarkers is planned to determine if they have predictive value for anti-PD-1/-L1 therapy and to explore implications for developing combination immunotherapy regimens.

Citation Format: Imad A. Tarhoni, Ibtihaj Fughhi, David Gerard, Sanjib Basu, Cristina Fhied, Wen-rong Lie, Donna Russell, Marta Batus, Nisha Thakar, Philip Bonomi, Mary Fidler, Jeffrey Borgia. Associations between soluble immune checkpoint molecules and overall survival in advanced non-small cell lung cancer (NSCLC) patients treated with either anti-PD-1/-L1 monoclonal antibodies or single-agent chemotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5708.