P3.02c-073 Evidence Suggesting a Dichotomous “Present vs absent” Determinant of PDL1 Inhibitor Efficacy in Non-Small Cell Lung Cancer (NSCLC): Topic: IT Biomarkers

Abstract

NSCLC survival and progression-free survival (PFS) curves often follow first-order kinetics (Stewart, Lung Cancer 2011;71:217). We hypothesized that the number of curve decay phases reflects number of biologically distinct subpopulations with distinct rates of progression or death that are determined by dichotomous (present vs absent) factors. In NSCLC, some PDL1-negative patients respond to PDL1 inhibitors, while some PDL1 strongly-positive patients do not. We used “arohatgi.info/WebPlotDigitizer/app/” to digitize published NSCLC PDL1-inhibitor PFS curves and used GraphPad Prism5 for nonlinear regression analyses (one-phase and two-phase decay; constraints:Y0=100, plateau=0). 26 of 28 curves fit 2-phase decay models with R2>0.90, with distinct “fast progression” (FP) and “slow progression” (SP) subgroups. In studies with PFS curves for different PDL1-expression groups, patients with higher PDL1 tended to have a larger SP subgroup, although some with low PDL1 had slow progression and some with high PDL1 had fast progression (see Table). 1) PFS-curve nonlinear regression analysis identified 2 distinct subgroups (FP/SP) with differing degrees of benefit from PDL1 inhibitors. 2) Some PDL1-low patients had SP while some PDL1-high patients had FP, although there was a trend to more SP with PDL1-high than PDL1-low. 3) The observation of 2 distinct subpopulations leads us to hypothesize that there is a dichotomous variable (eg, gene mutation, deletion, amplification or silencing) driving PDL1 inhibitor benefit. The trend to higher benefit with high PDL1 expression, but inexact prediction of benefit by PDL1 expression is similar to the published trend seen with response vs PDL1 expression, and suggests that this dichotomous variable is linked to but distinct from PDL1 expression. 4) The published observation that high mutation burden is associated with PDL1 inhibitor benefit suggests that high mutation burden increases the probability of presence of a putative dichotomous favorable factor. We observed similar outcomes in other tumor types.