Expert Scientist Roche Innovation Center New York Little Falls, United States
Background: Many biomarkers have been proposed to be predictive of response to anti-PD1/anti-PD-L1 checkpoint inhibitors (CPI). However, conflicting observations and lack of consensus call for an assessment of their clinical utility in a large dataset. Using a combined dataset of clinical trials and real-world data (RWD), we assessed the predictive and prognostic utility of biomarkers for clinical outcome of CPI in NSCLC.
Objectives: To assess the association between tumor PD-L1, TMB and blood analytes with clinical outcomes in patients with advanced NSCLC following CPI therapy
Methods: Retrospective cohort study using 24152 patients selected from 71850 patients with advanced NSCLC from electronic health records and nine Roche atezolizumab trials. Patients were stratified into high and low biomarker groups. Correlation with treatment outcome in the different biomarker groups was investigated and compared between patients treated with CPI versus chemotherapy. Durable response was defined as having CR/PR without progression during the study period of 270 days.
Results: Standard blood analytes (e.g. albumin and lymphocyte) were just prognostic, having correlation with clinical outcome irrespective of treatment type. High expression of PD-L1 on tumors (≥ 50% tumor cell staining) were specifically associated with response to CPI (odds ratio [OR] 0.20; 95% CI = 0.13, 0.30; p< 0.001). The association was stronger in patients with non-squamous than squamous histology, with smoking history than non-smokers, and with prior chemotherapy than first line CPI. Higher tumor mutational burden (TMB) (≥ 10.44 mut/Mb) was also specifically associated with durable response to CPI (OR = 0.40; CI = 0.29, 0.54; p< 0.001). The combination of high TMB and PD-L1 expression was the strongest predictor of durable response to CPI (OR = 0.04; CI = 0.00, 0.18; p< 0.001). There was no significant association between PD-L1 or TMB levels with response to chemotherapy, suggesting a CPI-specific predictive effect.
Conclusions: Standard blood analytes had just prognostic utility, whereas tumor PD-L1 and TMB specifically predicted response to CPI in NSCLC. The combined high TMB and PD-L1 expression was the strongest predictor of durable response. PD-L1 was also a stronger predictor in patients with non-squamous histology, smoking history or prior chemotherapy.
