Background: Overall survival (OS) is an optimal endpoint for evaluation of checkpoint inhibitors (CPI). Identification of early surrogates of OS is important to inform early clinical signals and treatment decisions. We evaluated C-reactive protein (CRP) in clinical trials with atezolizumab (anti-PD-L1 antibody). CRP is elevated in different inflammatory and malignant conditions and is often considered to be a marker of poor prognosis.

Materials and Methods: Serum from patients enrolled in the 2L+ NSCLC studies POPLAR and OAK (randomized phase 2 and phase 3 controlled trials of patients with non-small cell lung cancer (NSCLC) who progressed on post-platinum chemotherapy) was analyzed for CRP levels over time. Patients were binned by changes in CRP at 6 weeks post-treatment (C3D1; Cycle 3 Day 1) as compared to pre-treatment levels, by either greater than 1.5 fold, less than 1.5 fold or unchanged (within +1.5 fold).

Results: C3D1 decreases in serum CRP were associated with RECIST1.1 based responses to atezolizumab but not with docetaxel in the POPLAR study, and these findings were further validated in the OAK study. Patients with RECIST based disease progression (PD) demonstrated an increase in serum CRP as early as Cycle 2 (3 weeks post atezolizumab therapy). Notably, decrease in CRP levels was strongly associated with improved PFS and OS. Results from OAK are shown below (table). Furthermore, in patients with RECIST PD or stable disease (SD), decrease in on-treatment CRP also predicted long overall survival.

Conclusion: CRP is a soluble biomarker that is modulated post-atezolizumab treatment. This simple lab test may provide utility in informing OS benefit for CPIs and combinations.

C3D1 CRP fold change relative to pre-treatment HR CI p value HR CI p value 
ITT 0.75 0.62-0.91 0.004 0.74 0.6-0.91 0.0053 
CRP <1.5 FC 0.48 0.33-0.69 0.000095 0.49 0.32-0.75 0.0011 
CRP +1.5 FC 0.85 0.62-1.15 0.28 0.61 0.43-0.86 0.0049 
CRP>=1.5 FC 0.96 0.69-1.34 0.81 1.25 0.86-1.81 0.25 
C3D1 CRP fold change relative to pre-treatment HR CI p value HR CI p value 
ITT 0.75 0.62-0.91 0.004 0.74 0.6-0.91 0.0053 
CRP <1.5 FC 0.48 0.33-0.69 0.000095 0.49 0.32-0.75 0.0011 
CRP +1.5 FC 0.85 0.62-1.15 0.28 0.61 0.43-0.86 0.0049 
CRP>=1.5 FC 0.96 0.69-1.34 0.81 1.25 0.86-1.81 0.25 

Citation Format: Namrata Patil, Wei Zou, Simonetta Mocci, Vinita Gupta, Luciana Molinero, Alan Sandler, Marcus Ballinger, Susan Flynn, Marcin Kowanetz, Priti Hegde. On-treatment changes in CRP as a surrogate for overall survival for atezolizumab benefit in 2nd line NSCLC [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 5707.