1572P - Impact of HER2 and PD-L1 co-expression in Claudin18.2 positive resectable gastroesophageal cancers

Background

The identification of CLDN18.2, HER2, and PD-L1 as targetable biomarkers has contributed to defining different molecular subsets of gastroesophageal adenocarcinoma (GEA) and developing tailored treatments in the unresectable space. However, the prevalence and significance of their co-expression in the resectable stages remain unclear.

Methods

We evaluated CLDN18.2, HER2 and PD-L1 in a cohort of resectable GEA with paired clinical and WGS data. CLDN18.2 (ab222512, Abcam), HER2 (ab16662, Abcam) and PD-L1 (E1L3N, Cell Signaling) were assessed by immunohistochemistry (IHC) on adjacent slides from FFPE tumor samples. Positivity was defined as 2+/3+ staining in ≥40% of tumor cells for CLDN18.2, in ≥10% (surgical samples) or any percentage of tumor cells (biopsies) for HER2, and as a combined positive score (CPS)≥1 for PD-L1. Tumor mutational burden (TMB) was calculated as the number of non-synonymous somatic mutations per mega-base from WGS. Fisher’s exact test or Mann-Whitney test was used to compare baseline characteristics and log-rank test to compare survival curves, with statistical significance set at p=0.05 (two-sided).

Results

Eighty-four patients with resected GEA (71% GEJC/20% GC; 77% after neoadjuvant chemotherapy) were evaluated. CLDN18.2 was overexpressed in 18%, HER2 in 19%, and PD-L1 in 31% of the cases. Clinicopathological characteristics and OS were similar across subgroups (all p>0.05), except for significantly more stage III disease at diagnosis in HER2+ve (OR 6.07, p=0.02) and PD-L1+ve (OR 7.91, p<0.01) compared to their negative counterpart. Among CLDN18.2+ve cases, 4 patients (27%) co-expressed HER2 and 6 (40%) PD-L1. CLDN18.2+ve/HER2+ve cases were all MSS, mostly PD-L1-ve (n=3/4), and their TMB was significantly higher compared to CLDN18.2+ve only (10.46 vs 5.62, p=002). TMB was not significantly different by PD-L1 status in the CLDN18.2+ve subgroup nor between CLDN18.2+ve and HER2+ve subgroups, taking co-expressors out.

Conclusions

Biomarker co-expression may be frequent in the CDLN18.2+ve subset, and CLDN18.2+ve/HER2+ve may reveal a genomically more complex subgroup. Evaluation in larger datasets is required to understand its biological significance and potential therapeutic implications.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

L. Rimassa: Financial Interests, Personal, Advisory Board, Consulting and advisory role: AstraZeneca, Basilea, Bayer, Exelixis, Genenta, Hengrui, Incyte, Ipsen, IQVIA, MSD, Nerviano Medical Sciences, Roche, Servier, Taiho, Zymeworks; Financial Interests, Personal, Invited Speaker, Lecture fees: AstraZeneca, Incyte, Roche, Servier; Financial Interests, Personal, Other, Travel expenses: AstraZeneca; Financial Interests, Institutional, Steering Committee Member: Exelixis, Incyte, Ipsen, Nerviano Medical Sciences, Roche; Financial Interests, Institutional, Coordinating PI, National (Italian) coordinating PI: AstraZeneca, BeiGene; Financial Interests, Institutional, Local PI: Agios, Eisai, FibroGen, Lilly, MSD, Zymeworks; Financial Interests, Institutional, Funding: Ipsen. R.C. Fitzgerald: Financial Interests, Personal, Advisory Board, Invited speaker and expert advisor: Medtronic; Financial Interests, Personal, Stocks/Shares, Shareholder in startup: Cyted Ltd; Financial Interests, Institutional, Advisory Board, Licensing fees for technology development and associated patents: Medtronic; Financial Interests, Personal, Other, Founder shares: Cyted Ltd; Non-Financial Interests, Leadership Role, Advisory: Cyted Ltd. E. Smyth: Financial Interests, Personal, Invited Speaker: Amgen, Bristol Myers Squibb, Imedex, Merck, Novartis, Prova Education, Servier, TouchIME, Elsevier, PeerVoice, Cor2Ed, Daiichi Sankyo; Financial Interests, Personal, Other, TSC: Amgen; Financial Interests, Personal, Advisory Board: Astellas, AstraZeneca, Bristol Myers Squibb, Bristol Myers Squibb, My Personal Therapeutics, Novartis, Roche, Servier, Zymeworks, Viracta; Financial Interests, Personal, Other, IDMC: BeiGene, Zymeworks; Financial Interests, Personal, Other, IDMC chair: Everest Clinical Research; Financial Interests, Personal, Officer: EORTC GI Clinical Trials Group; Financial Interests, Institutional, Local PI: Daiichi Sankyo, Merus, Basilea, MSD, Mirati; Financial Interests, Institutional, Coordinating PI: Roche, AstraZeneca, Amgen; Financial Interests, Institutional, Research Grant: Bristol Myers Squibb; Non-Financial Interests, Leadership Role, Trustee: UK & Ireland Oesophagogastric Group (UKIOG). All other authors have declared no conflicts of interest.