Abstract 1774: Progression-free survival curves suggest a dichotomous determinant of PD-L1 inhibitor efficacy
Authors: Stewart David J. , Bosse Dominick , Brule Stephanie , Robinson Andrew G. , Ong Michael , Hilton John F. 
Published: July 2017

Background: PD-L1 expression varies across tumors but does not accurately predict PD-L1 inhibitor efficacy. Some negative tumors respond and some positive tumors fail. PD-L1 inhibitor progression-free survival (PFS) curve shape in non-small cell lung cancer (NSCLC) suggests that a dichotomous (present vs absent) factor might drive sensitivity rather than it being driven by a continuous variable like PD-L1 expression. PFS curves may follow first order kinetics, with a straight line if log % PFS is plotted vs time. If the population had 2 distinct subgroups with differing rates of progression then one would expect an inflection point on the log-linear curve, and the curve would fit a 2-phase decay model in nonlinear regression analysis (NLRA). A more homogeneous population would not fit a 2-phase model.

Methods: We used arohatgi.info/WebPlotDigitizer/app/ to digitize published PFS curves, then GraphPad Prism5 for 2-phase NLRA, with the constraints Y0=100, plateau=0. To generate standardized 2-phase curves, we utilized 1) unselected NSCLC patients treated with epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) where we expected a high proportion of curves to fit a 2-phase model as only some patients would have a sensitizing EGFR mutation; 2) NSCLC EGFR mutant and wild type (WT) patients treated with EGFR TKIs, and patients treated with platinum-based chemotherapy, taxanes or placebo/best supportive care (BSC), where we expected a lower proportion of curves to fit 2-phase models; 3) PD-L1 PFS curves in NSCLC and other tumor types.

Results: With EGFR TKIs in unselected patients, 58 of 79 (73%) curves were fit by 2-phase models, vs 5 of 37 (14%) with EGFR TKIs in EGFR mutant patients (p&lt;0.0001), 13 of 27 (48%) in EGFR WT patients (p&lt;0.02), 4 of 37 (11%) with platinum-based therapy (p&lt;0.0001), 15 of 47 (32%) with a taxane (p&lt;0.0001), and 6 of 22 (27%) with placebo/BSC (p=0.0001). With PD-L1 inhibitors in NSCLC, 30 of 32 (94%) curves fit 2-phase models (p&lt;0.0001 vs each of EGFR TKIs in EGFR mutants, EGFR WTs, platinum and taxane chemotherapy and placebo/BSC). In other tumor types, 27 of 32 (84%) PD-L1 curves fit 2-phase models.

Conclusions: Most PD-L1 inhibitor PFS curves fit a 2-phase model. This is similar to what we observed with EGFR TKIs in unselected patients and different from EGFR TKIs in EGFR mutant and WT patients, and from chemotherapy or placebo/BSC. This leads us to hypothesize the existence of a dichotomous (present vs absent) factor such as a gene mutation, deletion or silencing that sensitizes tumors to PD-1/PD-L1 inhibitors. If found, such a dichotomous factor could prove to be a highly useful biomarker that could permit accurate prediction of PD-1/PD-L1 inhibitor efficacy. Since PD-1/PD-L1 inhibitor efficacy is higher in tumors with high PD-L1 expression, any sensitizing dichotomous factor might also drive PD-L1 expression.

Citation Format: David J. Stewart, Dominick Bosse, Stephanie Brule, Andrew G. Robinson, Michael Ong, John F. Hilton. Progression-free survival curves suggest a dichotomous determinant of PD-L1 inhibitor efficacy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1774. doi:10.1158/1538-7445.AM2017-1774