Phase II clinical trial of atezolizumab (A) in advanced non-small cell lung cancer (NSCLC) patients (pts) previously treated with PD1-directed therapy.

Abstract

TPS9105 Background: While inhibition of the PD1 axis is associated with improved response rates vs cytotoxic therapy in pts with previously treated NSCLC, the majority of pts will not benefit from objective response. Anti-PD1 and PD-L1 antibodies block distinct inhibitory pathways, possibly resulting in different clinical outcomes. While anti-PD1 antibodies block PD1 binding to PD-L1 and PD-L2, they do not affect the inhibitory signal of the PD-L1/B7.1 interaction. This trial is critical to establishing the clinical activity of sequencing PD-L1 inhibition in pts previously treated with PD1 directed and identifying candidate biomarkers of response and resistance to PD1/PD-L1 directed therapies. Methods: In this phase II clinical trial, pts with advanced NSCLC with stable or progressive disease on anti-PD1 therapy (nivolumab or pembrolizumab) will be treated with A1200 mg day 1 of a 21-day cycle until disease progression, unacceptable toxicity or death. The kinetics of response to anti-PD1 therapy can be variable and in some cases characterized by pseudo-progression. In order to account for variable response kinetics to PD1 therapy, pts will be enrolled in 3 parallel cohorts based on best overall response (BOR) to PD1 therapy (stable disease; progressive disease; complete or partial response followed by progressive disease). The primary objective is BOR to A. Secondary endpoints include duration of response, progression free survival, overall survival, and safety. 37 pts will be enrolled per cohort. A Simon 2-stage design will be employed with a stopping rule for futility if 0 of the first 11 evaluable patients within a cohort have a confirmed objective response in Stage 1. A promising result would be if ≥3 responses are seen at the conclusion of stage 2. This design has 80% power to detect a true response rate of 15% in each cohort (null rate 2%; alpha 0.05). Mandatory biopsies at time of enrollment, archival tumor pre-PD1 directed therapy, and optional biopsy at the time of progression on A will be collected for exploratory studies of immune biomarkers of response and resistance. Clinical trial information: NCT03014648.