Squamous cell lung cancer (SqCLC) is a type of non-small cell lung cancer strongly associated with cigarette smoking and with known targetable mutations, however some patients do not have matching targeted drugs. The S1400I Phase III randomized LungMap sub-study of nivo+ipi versus nivo accrued 275 (252 eligible) previously-treated patients with stage IV SqCLC and absence of matched mutations (NCT02154490).Here, to investigate the longitudinal (baseline, C2 week 3, C4 week 7, C5 week 9) serum protein changes associated with treatment or response, we performed Olink proximity extension assay in 160 patients (561 samples) using an immuno-oncology panel of 92 analytes. We utilized mixed linear and joint models to identify differentially expressed proteins between treatment arms (nivo vs. nivo+ipi), response and quantify the effect of other potential prognostic factors. This approach quantifies the effect of covariates such as smoking status, demographics, prior radiation therapy, and metastases. We jointly modeled expression and survival to identify changes in proteins over time. The thresholds for significance in differentially expression tests were a log fold change of at least 0.5 and a false discovery rate of under 0.05 (FDR as a multiple testing adjustment method). The joint models used thresholds of log fold change of more than 1 and hazard ratio of more than 1. Results revealed increases in 40 serum proteins after treatment with either nivo alone or combined with ipi, including CXCL9, CXCL10, CXCL11, CXCL13, IL6, IL8, IL10, IFNg, and soluble PD-L1 and PDCD1. nivo+ipi treatment showed greater increases in IL8 and CXCL13 post-treatment compared to nivo alone. In addition, circulating IL6, CXCL13, and MIC-A/B were higher in patients with stable or progressive disease compared to those with objective response after treatment. The joint model revealed a worse hazard ratio with increases in 10 soluble proteins, including IL6, IL8, and CXCL13. Finally, for patients with similar values of IL8, those treated by combination had a better survival outcome than those treated by nivo alone. Using a data-modeling approach, we identified significant longitudinal changes in 40 serum proteins out of 92 tested in patients with SqCLC treated with nivo or nivo+ipi. Increases in serum inflammatory markers IL6 and CXCL13 were associated with worse disease. Although overall survival was not statistically different between arms, our modeling approaches suggested that IL-8 monitoring may help identify patients benefiting more from the combination vs. nivo alone.

Citation Format: Edgar Gonzalez-Kozlova, Hsin-Hui Huang, Mary Redman, Roy Herbst, Scott Gettinger, Luda Bazhenova, Hui Xie, Manishkumar Patel, Kai Nie, Jocelyn Harris, Kimberly Argueta, Karen Kelly, Ethan Cerami, James Lindsay, Joyce Yu, Roshni Biswas, Stephen Van Nostrand, Radim Moravec, Diane Marie Del Valle, Seunghee Kim-schulze, Sacha Gnjatic. Dynamic changes in circulating protein levels reveal an association between ipilimumab and nivolumab combination treatment (SWOG Lung-MAP S1400I trial) with outcomes in squamous cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5026.