IMpower150: A post hoc analysis of efficacy outcomes in patients with KRAS, STK11 and KEAP1 mutations

Mutations in the KRAS oncogene and STK11 and KEAP1 tumour suppressor genes are found in non-squamous NSCLC, frequently co-occur and lead to differential response to immune checkpoint inhibitors. In the randomised, phase III IMpower150 study, atezolizumab (A) + bevacizumab (B) + carboplatin/paclitaxel (CP) chemotherapy significantly prolonged PFS and OS vs BCP in patients (pts) with first-line non-squamous NSCLC. We evaluated the efficacy of A and/or B with CP in pts with and without the KRAS mutation and according to STK11/KEAP1 status in IMpower150. 1202 ITT pts were enrolled to receive ABCP, ACP or BCP. Doses were A, 1200 mg; B, 15 mg/kg; C, AUC 6 mg/mL/min and P, 200 mg/m2. Primary endpoints were OS and investigator-assessed PFS in ITT wild-type (WT; no EGFR/ALK alterations) pts (N = 1047). KRAS, STK11 and KEAP1 status were determined by ctDNA next-generation sequencing (Foundation Medicine, Inc). This post hoc analysis evaluated OS and PFS in sub-groups of pts by blood-based tumour mutational status (data cutoff: 13 Sep 2019). Among 920 mutation-evaluable ITT WT pts, 24.5% had KRASmut, 14.5% had STK11mut and 15.5% had KEAP1mut tumours. Within the KRASmut population, 44.9% of pts also had co-occurring mutations in STK11 and/or KEAP1. KRASmut, STK11mut and KEAP1mut tumours were generally associated with higher tumour mutation burden levels than tumours in pts WT for these mutations. PFS and OS outcomes with ABCP, ACP and BCP in pts with and without KRAS mutation and per STK11/KEAP1 status are shown in the table.Table: 1265PMutation StatusABCP Median, months nACP Median, months nBCP Median, months nABCP vs BCP HR 95% CIACP vs BCP HR 95% CIPFSKRASmut8.11804.8745.82710.420.29, 0.610.800.56, 1.13KRASWT8.362356.832347.032260.650.54, 0.790.820.67, 0.99KRASmut/STK11mut and/or KEAP1mut6.03343.2383.35290.490.28, 0.840.880.54, 1.46KRASmut/STK11WT and KEAP1WT15.21467.39366.9420.360.22, 0.590.640.39, 1.05OSKRASmut19.818011.73749.8710.500.34, 0.720.630.43, 0.91KRASWT18.9223519.4823418.232260.980.8, 1.210.90.72, 1.11KRASmut/STK11mut and/or KEAP1mut11.1347.93388.67290.60.34, 1.030.870.52, 1.45KRASmut/STK11WT and KEAP1WT26.184620.963610.68420.430.26, 0.720.430.25, 0.74 Open table in a new tab KRASmut pts treated with ABCP derived improvement in OS and PFS benefit compared with pts treated with BCP and showed numerical improvement vs pts treated with ACP. In KRASmut pts, ABCP provided survival benefit regardless of STK11 and KEAP1 status. The efficacy data from this exploratory analysis suggest that ABCP could be considered a treatment option for pts with KRAS mutations, regardless of STK11 or KEAP1 status.