Abstract PD14-05: Genomic profiling and clinical outcomes with first-line atezolizumab and nab-paclitaxel in triple-negative breast cancer: An exploratory analysis from the phase 3 IMpassion130 trial
Authors: Emens Leisha , Molinero Luciana , Adams Sylvia , Rugo Hope S. , Schneeweiss Andreas , Diéras Véronique , Iwata Hiroji , Barrios Carlos , Winer Eric P. , Chang Ching-Wei , Chui Stephen Y. , Schmid Peter , Loi Sherene 
Published: February 2021

Abstract
Background: The clinical implications of genomic alterations in metastatic triple-negative breast cancer (mTNBC) have not been clearly addressed. In IMpassion130, atezolizumab (A) + nab-paclitaxel (nP) showed improved progression-free survival (PFS) and clinically meaningful overall survival (OS) benefit vs placebo (P) + nP in PD-L1+ mTNBC (Schmid, NEJM 2018). The goal of this exploratory study was to evaluate the prevalence of genomic alterations and their relationship with PD-L1 status and to determine whether a prognostic or predictive role for these factors exists for A + nP in a randomized dataset. Methods: Primary or metastatic tumor samples from patients in the IMpassion130 biomarker-evaluable population (BEP) were centrally evaluated for short variants (SV), copy number alteration (CNA) and rearrangements by using a targeted next-generation sequencing (NGS) panel (FoundationOne). PD-L1 status was evaluated using the VENTANA SP142 assay, with PD-L1 positivity defined by PD-L1-expressing immune cells on ≥1% of tumor area. Prognostic effects of genomic alterations were evaluated in the pooled population from both treatment arms. PFS and OS (co-primary endpoints) were analyzed by Cox proportional hazards models. ClinicalTrials.gov identifier: NCT02425891. Results: The BEP comprised 614 patients (68% of intent-to-treat population), 605 of whom received treatment. The most common pathogenic alterations were found in the following genes: TP53 (SV, 85%), MYC (CNA, 21%), PIK3CA (SV, 18%), PTEN (SV/CNA, 18%), RB1 (SV, 7%) and BRCA1 (SV, 9%). Primary tumors (n = 419), compared with metastatic tumors (n = 195), were more likely to bear alterations in BRCA1 (11.9% vs 5.6%) and less likely to have PIK3R1 alterations (4.8% vs 9.2%). TP53 loss-of-function mutations were associated with PD-L1+ status, whereas amplifications in VEGFA and CCND3 genes were significantly less associated; none of these alterations were linked with clinical outcomes favoring A + nP. Loss of RB1 (frequency 5%) was linked with reduced PFS and OS prognosis independent of treatment (hazard ratio [HR], 2.09 [95% CI: 1.42, 3.07] and HR, 1.98 [1.26, 3.11]), respectively), and CNA in CDKN2A (12%) and CDKN2B (11%) were associated with improved PFS and OS clinical activity in the A + nP arm vs the P + nP arm (HR PFS, 0.43-0.44 and HR OS, 0.47, respectively). Three of 584 microsatellite-evaluable samples (0.5%) had MSI-H status, which was not associated with PD-L1 status; all 3 MSI-H patients were from the P + nP arm. A total of 220 of 514 evaluable samples (42.8%) had PIK3CA/AKT1/PTEN-altered status, which was not significantly associated with PD-L1 status or A + nP clinical outcome. Conclusions: In this exploratory analysis using a targeted NGS panel, we show that tumors from patients with previously untreated mTNBC had similar genomic profiles at baseline as those published for early TNBC tumors. The few alterations that were linked to PD-L1 status were not linked to clinical outcome. CNA in cell cycle genes (e.g., RB1) had potential prognostic value, whereas CDKN2A and CDKN2B were potentially predictive of A + nP clinical benefit favoring A + nP. These data are hypothesis generating and require validation in an independent data set.
Citation Format: Leisha Emens, Luciana Molinero, Sylvia Adams, Hope S. Rugo, Andreas Schneeweiss, Véronique Diéras, Hiroji Iwata, Carlos Barrios, Eric P. Winer, Ching-Wei Chang, Stephen Y. Chui, Peter Schmid, Sherene Loi. Genomic profiling and clinical outcomes with first-line atezolizumab and nab-paclitaxel in triple-negative breast cancer: An exploratory analysis from the phase 3 IMpassion130 trial [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD14-05.