HER2 and PD-L1 co-expression in patients with HER2-positive, trastuzumab-refractory gastric or gastroesophageal junction cancer

Up to 20% of patients with gastric cancer or gastroesophageal junction adenocarcinoma  (GC/GEJA) are HER2-positive. Combined expression of HER2 and PD-1/PD-L1 in GC was previously shown to have prognostic relevance, and seems to be associated with an improved efficacy of T-DXd in combination with an anti–PD-1 antibody. The DESTINY-Gastric03 (DG-03) trial evaluated concordance between local and central HER2 testing and overlap of PD-L1 and HER2 expression in GC/GEJA. In a subset of patients, the concordance rate between local and central HER2 testing was 64%. Substantial overlap between PD-L1 positivity and HER2 positivity (85%) supports combined administration of HER2-targeted agents and checkpoint inhibitors.

Up to 20% of patients with gastric cancer or gastroesophageal junction adenocarcinoma  (GC/GEJA) prove to be HER2-positive. In the DESTINY-Gastric01 trial, Trastuzumab Deruxtecan (T-DXd) was shown to improve the survival compared to standard chemotherapy in HER2-positive GC/GEJA in the ≥3L setting. In previous reports, up to 88% of HER2-positive GC/GEJA tumours were PD-L1 positive (combined positive score [CPS] ≥1). Interestingly, the combined expression of HER2 and PD-1/PD-L1 was shown to have prognostic relevance in GC, and preclinical data indicate improved efficacy of T-DXd in combination with an anti–PD-1 antibody. The ongoing DESTINY-Gastric03 (DG-03) trial, evaluated the concordance between local and central HER2 testing and the overlap of PD-L1 and HER2 expression in GC/GEJA

Study design

DG-03 is an open-label, phase 1b/2 study evaluating T-DXd-based combinations in patients with locally advanced/metastatic HER2-positive GC/GEJA (IHC 3+ or 2+/ISH positive). DG-03 is comprised of two parts. Part 1 (dose escalation) included patients with locally confirmed HER2-positive GC/GEJA who progressed on ≥1 prior trastuzumab-containing regimen. Part 2 (dose expansion) included patients with previously untreated, locally confirmed HER2-positive GC/GEJA. The status of HER2 was reassessed in a central laboratory and scored according to GC-specific criteria. HER2 gene amplification status and PD-L1 expression were centrally assessed. PD-L1 positivity was defined as having a CPS ≥1, in which CPS is the number of PD-L1–positive cells (tumour cells, lymphocytes, and macrophages) divided by the total number of viable tumour cells multiplied by 100.

Results

Analyses included 44 samples (twelve patients from part one and 32 from part two). Five samples were collected from metastatic sites (all before T-DXd treatment), while 39 samples were taken from primary tumours (28 before T-DXd treatment, eleven from archival tissue). Per local HER2 assessment, 37 patients were IHC 3+ while another seven were IHC 2+/ISH positive. Per central HER2 assessment, 27 patients were IHC 3+, one was IHC 2+ and HER2 amplified, four were IHC 2+ and not amplified, one was IHC 1+ and not amplified, and two were IHC 0 and not amplified. Nine patients had missing IHC/amplification data. As such, local and central HER2 testing demonstrated a concordance rate of 64% (28/44 samples), with 16% discordance (20% of the samples were not evaluable). In the DG 03 HER-2 positive cohort, 85% of patients had a CPS ≥1, which is a higher percentage than the overall population of GC/GEJCs with any HER2 status (67%).

Conclusions

In a subset of patients of the ongoing DG-03 trial, the concordance rate between local and central HER2 testing was acceptable at 64%, with 16% discordant results. There was a substantial overlap (85%) between HER2 positivity and PD-L1 positivity (CPS ≥1), which is consistent with previous reports. Substantial overlap between PD-L1 positivity and HER2 positivity supports combined administration of HER2-targeted agents and checkpoint inhibitors.

Reference

Janjigian Y, Rha S, Oh D, et al. 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. Presented at ESMO WGCI 2022; Abstract SO-7.