Analytical and clinical validation of oncomine Dx target (ODxT) test and local testing for identifying patients with HER2 (ERBB2)-mutant (HER2m) non–small-cell lung cancer (NSCLC) for treatment with trastuzumab deruxtecan (T-DXd) in DESTINY-Lung01/02 (DL-01/02).
Authors: Li Bob T. , De Langen Adrianus , Goto Koichi , Vitazka Patrik , Qi Zhenhao , Ha Thomas , Velasco Roth Anne Marie , Karnoub Maha , Feng Wenqin , Pereira Kaline , Shiga Ryota , Khambata-Ford Shirin , Goto Yasushi 
Published: June 2023

9033 Background: Based on the international DL-01 trial, the US Food and Drug Administration (FDA) approved the ODxT Test as a companion diagnostic (CDx) to identify patients (pts) with NSCLC harboring activating HER2 mutations who may benefit from T-DXd. The ODxT Test uses next-generation sequencing (NGS) to detect genomic alterations in formalin-fixed, paraffin-embedded tumor tissue. The accuracy of the ODxT Test by central testing and its agreement with clinical trial assays (CTAs; NGS, polymerase chain reaction, etc.) by local testing was evaluated using analytical and clinical validation data from DL-01 cohort 2 and DL-02 arm 1. Methods: ODxT Test and Illumina TruSight Tumor170 NGS assay results were compared for analytical accuracy in NSCLC samples from DL-01 and commercial vendors. Diagnostic agreement was assessed for DL-01/02 by concordance between the ODxT Test and CTAs. Clinical accuracy per objective response rate (ORR) and duration of response (DoR) to T-DXd were evaluated in all pts with HER2m NSCLC identified by ODxT Test vs CTA. Activating HER2 mutations included single nucleotide variants and exon 20 insertions. Pts received T-DXd 6.4 mg/kg in DL-01 or 5.4 mg/kg (FDA-approved dose) in DL-02 every 3 weeks. Results: NSCLC samples from DL-01 (n = 91), DL-02 (n = 102), and commercial vendors (n = 129) were individually assessed. The ODxT Test met requirements for analytical accuracy (≥90% agreement when excluding unknown results), with a positive percent agreement (PPA) of 100% and negative percent agreement (NPA) of 99.1% for detecting HER2 mutations. Clinical accuracy of the ODxT Test also met FDA requirements (excluding unknowns) for NPA (≥98%) and PPA (95% CI lower bound ≥85%). DL-01 PPA (95% CI) was 98.0% (89.2%-100%) and NPA was 100.0% (96.6%-100%); for DL-02, PPA was 96.7% (88.7%-99.6%) and NPA was 100% (96.6%-100%). In DL-01, confirmed ORR (95% CI) for pts with HER2m NSCLC identified by central ODxT Test was 58.3% (43.2%-72.4%) vs 54.9% (44.2%-65.4%) of pts identified by local CTA; median DoR (95% CI) was 12.0 mo (5.5 mo-18.2 mo) per the ODxT Test vs 9.3 mo (5.7 mo-14.7 mo) per CTA. In DL-02 (prespecified interim analysis early cohort), ORR (95% CI) was 53.6% (33.9%-72.5%) per ODxT Test vs 53.8% (39.5%-67.8%) per CTA; median DoR (95% CI) was not estimable (NE [NE-NE]) per the ODxT Test and NE (4.2 mo-NE) per CTA. Conclusions: This study demonstrates the analytical and clinical accuracy of the ODxT Test as a CDx for detecting activating HER2 mutations in NSCLC to identify pts who may benefit from T-DXd. A high level of agreement was also shown between the ODxT Test and CTAs. Clinical trials for HER2m NSCLC may successfully use a central testing assay as a CDx while allowing adequately validated local testing assays to expedite patient enrollment. Clinical trial information: NCT03505710 , NCT04644237 .