148P - DESTINY-PanTumor02 study of trastuzumab deruxtecan (T-DXd) in patients (pts) with HER2-expressing solid tumors: Exploratory biomarker analyses of HER2 expression and gene amplification in tissue and plasma

Background

HER2 expression is prevalent in a range of solid tumors. Testing for HER2 is not routine outside breast and gastric cancers, and no HER2 assays are currently validated in all cancers. We evaluated the concordance between local and central HER2 immunohistochemistry (IHC) and between HER2 amplification in tissue and in baseline plasma circulating tumor DNA (ctDNA).

Methods

In this open-label, multicenter, multicohort, phase 2 study (NCT04482309), T-DXd (5.4 mg/kg q3w) was evaluated in pts with HER2-expressing (IHC 2+/3+ by local or central testing) locally advanced or metastatic disease after ≥1 systemic Tx or without Tx options. HER2 IHC status was assessed centrally using HER2 HercepTest™ (DAKO) and scored according to gastric-specific criteria. HER2 amplification was evaluated centrally using Ventana dual in situ hybridization (ISH) on archival tissue and detected in baseline plasma ctDNA using Guardant Health OMNI assay.

Results

Agreement between local and central HER2 IHC score was 59% for IHC 3+ and 55% for IHC 2+. HER2 amplification was 35% by ISH and 18% by ctDNA. The table shows concordance between HER2 status by ISH or IHC and ctDNA; agreement with HER2 focal amplification detected in plasma was 42% and 39%, respectively. Table: 148P

*HER2+: IHC3+ and IHC2+/ISH+ HER2-: IHC2+/ISH- and IHC1+/0 PPA and NPA were calculated excluding N/A samples (failed/unprofiled/undetectable ctDNA); CI calculated using Clopper-Pearson method CI, confidence interval; HER2amp, focal HER2 amplification; N/A, not available; NPA, negative percent agreement; PPA, positive percentage agreement

Conclusions

The moderate concordance between local and central HER2 IHC results can be ascribed to multiple factors, including different assays/algorithms, tumor heterogeneity, and inter-pathologist variability, highlighting the need for a standardized method to score HER2 across indications. Detection of HER2 amplification in plasma was accurate, as indicated by the low rate of false positives; however, sensitivity was poor. This suggests that ctDNA testing may help identify pts with HER2 amplification but is not yet a substitute for tissue-based HER2 ISH and IHC testing.

Clinical trial identification

NCT04482309.

Editorial acknowledgement

Under the guidance of authors and in accordance with GPP3, medical writing and editorial support was provided by Melanie Francis, MSc, of Helios Medical Communications, and was funded by AstraZeneca.

Legal entity responsible for the study

Daiichi Sankyo and AstraZeneca.

Funding

Daiichi Sankyo and AstraZeneca.

Disclosure

V. Makker: Financial Interests, Institutional, Funding, Study funding: Merck, Eisai, Clovis, Karyopharm, AstraZeneca; Financial Interests, Institutional, Funding, Study support: Zymeworks; Financial Interests, Institutional, Funding, Study Support: BMS, Duality, Faeth, Takeda; Non-Financial Interests, Principal Investigator: Merck; Non-Financial Interests, Advisory Role: Eisai, Clovis, Novartis, Lilly, Gsk, Karyopharm, Iteos, Faeth, Duality, ZYmeworks, Morphosys, Moreo. J. Lee: Financial Interests, Personal, Invited Speaker: AstraZeneca, Takeda, MSD, Roche; Financial Interests, Personal, Advisory Board: Eisai, GI Innovation; Financial Interests, Institutional, Local PI: Alkermes, AstraZeneca, BergenBio, Cellid, Clovis Oncology, Eisai, GI Innovation, ImmunoGen, Janssen, Merck, Mersana, MSD, Novartis, OncoQuest, Roche, Seagen, Synthon; Financial Interests, Personal and Institutional, Local PI: BeiGene; Financial Interests, Personal, Steering Committee Member: AstraZeneca, OncoQuest, Seagen, ImmunoGen, MSD; Financial Interests, Institutional, Research Grant: ONO, Takeda. D. Oh: Financial Interests, Personal, Advisory Board: AstraZeneca, Novartis, Genentech/Roche, Merck Serono , Bayer, Taiho, ASLAN, Halozyme, Zymeworks, BMS/Celgene, BeiGene, Basilea, Turning Point, Yuhan, Arcus Biosciences, IQVIA, MSD; Financial Interests, Institutional, Research Grant: AstraZeneca, Novartis, Array, Eli Lilly, Servier, BeiGene, MSD, Handok. A. Oaknin: Financial Interests, Personal, Advisory Board: AstraZeneca, Clovis Oncology, Deciphera Pharmaceuticals, Genmab, GSK, Immunogen, Mersana Therapeutics, PharmaMar, Merck Sharps & Dohme de España, SA, Agenus, Sutro, Corcept Therapeutics, EMD Serono, Novocure, Sattucklabs, Itheos, Eisai, F. Hoffmann-La Roche, Seagen, OneXerna Therapeutics, Inc, Regeneron, Sutro Biopharma; Financial Interests, Personal, Other, Travel and accomodation: AstraZeneca, PharmaMar, Roche; Financial Interests, Institutional, Funding: Amgen, AbbVie Deutschland, Advaxis Inc., Aeterna Zentaris, Aprea Therapeutics AB, Regeneron Pharmaceuticals, Clovis Oncology Inc, EISAI limited LTD, F. Hoffmann –La Roche LTD, Immunogen Inc, Merck, Sharp & Dohme de España SA, Millennium Pharmaceuticals Inc, PharmaMar SA, Tesaro Inc., Bristol Myers Squibb; Non-Financial Interests, Leadership Role, on behalf of GEICO: GCIG; Non-Financial Interests, Officer, Chair of Gynaecological Track ESMO 2019 . Scientific Track Member Gynaecological Cancers ESMO 2018 , ESMO 2020 , ESMO 2022 . Member of Gynaecological Cancers Faculty and Subject Editor Gyn ESMO Guidelines: ESMO; Non-Financial Interests, Leadership Role, ESMO GYN Co-Chair 2023 - 2025: ESMO; Non-Financial Interests, Leadership Role, Chair de Cervix Committee. 2022-2024: GCIG; Non-Financial Interests, Member: ESMO, ASCO, GCIG, SEOM, GOG. S.D. Puvvada: Financial Interests, Personal, Full or part-time Employment: AstraZeneca. F. Cecchi: Financial Interests, Personal, Full or part-time Employment: AstraZeneca. R. Mcewen: Financial Interests, Personal, Full or part-time Employment: AstraZeneca. F. Michelini: Financial Interests, Personal, Full or part-time Employment: AstraZeneca. F. Meric-Bernstam: Financial Interests, Personal, Other, Consultant: AstraZeneca, F. Hoffman-La Roche Ltd., Zymeworks, OnCusp Therapeutics; Financial Interests, Personal, Advisory Board, Advisory Board/Consultant: Seagen; Financial Interests, Personal, Advisory Board: Zentalis, Karyopharm, Biovica, Eisai, Protai, TheraTechnologies; Financial Interests, Personal, Other, Consulting: Tallac Therapeutics, Lengo Therapeutics, LOXO-Oncology, Black Diamond, Infinity Pharmaceuticals, AbbVie, GT Aperion, Ecor1; Financial Interests, Personal, Other, Consutling: Menarini Group; Financial Interests, Institutional, Other, Local PI / Research Grant: Aileron Therapeutics, Bayer Healthcare, CytomX Therapeutics Inc., Daiichi Sankyo Co. Ltd., eFFECTOR Therapeutics, Taiho Pharmaceutical Co.; Financial Interests, Institutional, Other, Local PI / Research Grant / Coordinating PI: AstraZeneca; Financial Interests, Institutional, Local PI: Calithera Biosciences, Curis Inc., Debiopharm International, Guardant Health Inc., Klus Pharma, Novartis; Financial Interests, Institutional, Other, Local PI / Steering Committee Member: Genentech Inc.; Financial Interests, Institutional, Research Grant: Takeda Pharmaceutical Co., Puma Biotechnology Inc., Repare; Other, Travel Support: Cholangiocarcinoma Foundation; Other, Travel support: European Organisation for Research and Treatment of Cancer (EORTC), European Society for Medical Oncology (ESMO).