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Co-occurring HER2 and PD-L1 expression in patients with HER2-positive trastuzumab-refractory gastric cancer (GC)/gastroesophageal junction adenocarcinoma (GEJA): Biomarker analysis from the trastuzumab deruxtecan (T-DXd) DESTINY-Gastric03 trial
Background
In up to 20% of patients (pts), GC/GEJA is HER2 positive. T-DXd is an antibody-drug conjugate composed of a humanized anti-HER2 monoclonal antibody, tetrapeptide-based cleavable linker, and topoisomerase I inhibitor payload. In the DESTINY-Gastric01 trial, T-DXd improved survival vs standard chemotherapy in HER2-positive GC/GEJA in the ≥3L setting. In previous reports, up to 88% of HER2-positive GC/GEJA tumors were PD-L1 positive (combined positive score [CPS] ≥1; Janjigian Nature 2021). Combined expression of HER2 and PD-1/PD-L1 in GC has been shown to have prognostic relevance (Lian Dig Liver Dis 2022), and preclinical data indicate improved efficacy of T-DXd in combination with an anti–PD-1 antibody. In the ongoing DESTINY-Gastric03 (DG-03) trial, we evaluated concordance between local and central HER2 testing and overlap of PD-L1 and HER2 expression in GC/GEJA.
Methods
DG-03 (NCT04379596) is a 2-part, open-label, phase 1b/2 study of T-DXd combinations in pts with locally advanced/metastatic HER2-positive GC/GEJA (IHC 3+ or 2+/ISH positive). Part 1 (dose escalation) includes pts with locally confirmed HER2-positive GC/GEJA that progressed on ≥1 prior trastuzumab-containing regimen. Part 2 (dose expansion) includes pts with previously untreated, locally confirmed HER2-positive GC/GEJA. HER2 status was reassessed in a central laboratory using HER2 DAKO HercepTest™ and scored according to GC-specific criteria (Bartley Arch Pathol Lab Med 2016). HER2 gene amplification status and PD-L1 expression were centrally assessed using FoundationOne® (F1CDx) and a verified IHC assay (PD-L1 IHC 22C3 pharmDx; Agilent Technologies), respectively. PD-L1 positivity was defined as CPS ≥1, where CPS is the number of PD-L1–positive cells (tumor cells, lymphocytes, and macrophages) divided by the total number of viable tumor cells multiplied by 100. A qualified pathologist performed cell counts and CPS categorization.
Results
Analyses included 44 samples (12 pts from part 1; 32 from part 2) with data available at the time of analysis. Five samples were collected from metastatic sites, all before T-DXd treatment. Thirty-nine samples were from primary tumors (28 before T-DXd treatment; 11 from archival tissue). Per local HER2 assessment, 37 pts were IHC 3+ and 7 were IHC 2+/ISH positive. Per central HER2 assessment, 27 pts were IHC 3+, 1 was IHC 2+ and HER2 amplified, 4 were IHC 2+ and not amplified, 1 was IHC 1+ and not amplified, and 2 were IHC 0 and not amplified; 9 had missing IHC/amplification data (eg, insufficient tumor cells [ < 100] on tissue section for HER2 IHC assessment/insufficient tumor content collected for NGS). Local and central HER2 assessment demonstrated 64% (28/44 samples) concordance and 16% discordance; 20% of samples were not assessable. Among 27 HER2-positive pts, 23 had PD-L1 CPS ≥1, 3 had CPS < 1, and 1 had insufficient tumor cells present for PD-L1 testing.
Conclusions
In a subset of pts in the ongoing DG-03 trial, the discordance rate between local and central HER2 testing (16%) and substantial overlap (85%) between HER2 positivity and PD-L1 positivity (CPS ≥1) were consistent with previous reports. Discordance may be attributed to tissue heterogeneity. Substantial overlap between PD-L1 positivity and HER2 positivity supports combined administration of HER2-targeted agents and checkpoint inhibitors.
Clinical trial identification
NCT04379596.
Editorial acknowledgement
Medical writing support was provided by ArticulateScience, LLC, and funded by AstraZeneca in accordance with Good Publication Practice (GPP3) guidelines (http://www.ismpp.org/gpp3). The authors retained full control of the content and made the final decisions for all aspects of this abstract.
Legal entity responsible for the study
AstraZeneca.
Funding
This study is funded by AstraZeneca Pharmaceuticals. In March 2019, AstraZeneca entered into a global development and commercialization collaboration agreement with Daiichi Sankyo for trastuzumab deruxtecan (T-DXd; DS-8201).
Disclosures
Y. Janjigian: Advisory / Consultancy: Bristol-Myers Squibb, Merck Serono, RGENIX, Eli Lilly, Daiichi-Sankyo, Pfizer, Bayer, Imugene, Merck, Zymeworks, Seagen, Basilea Pharmaceutica, AstraZeneca, Michael J. Hennessy Associates, Paradigm Medical Communications; Research grant / Funding (institution): NCI, Department of Defense, Cycle for Survival, Fred's Team, RGENIX, Bayer, Genetech/Roche, Bristol-Myers Squibb, Eli Lilly, Merck; Shareholder / Stockholder / Stock options: RGENIX. W. Zhong: Full / Part-time employment: Astrazeneca, Astrazeneca, Astrazeneca. E. Croydon: Full / Part-time employment: AstraZeneca. F. Cecchi: Full / Part-time employment: ASTRAZENECA, ASTRAZENECA, ASTRAZENECA. All other authors have declared no conflicts of interest.
