HER-2 positive + PD-L1 expression

Background Recent results from the KEYNOTE-811 study showed that first-line pembrolizumab was superior to placebo with respect to progression-free survival (PFS) in combination with trastuzumab and chemotherapy in patients with HER2 positive metastatic gastric cancer (GC). Conclusions The high proportion of CD4 Tregs, CD8 Tex and the elevated exhausted score in the subgroup with PD-L1 negative in HER2 positive GCs suggesting immune exclusive environment compared to HER2 and PD-L1 coexpressing group. Considering increased expression of immune checkpoint proteins other than PD-1/PD-L1, for patients with HER2-positive and PD-L1 negative, combination therapy with other immune checkpoint inhibitors rather than anti-PD-1/PD-L1 may be suggested.

We conclude that certain parameters of poor prognosis such as high histologic grade of the tumour, presence of lymphovascular invasion, clinically positive axillary lymph nodes and high IC count correlate with PD-L1 expression in HER2-positive BC, but we did not find the potential of PD-L1 to predict response to anti-HER2 neoadjuvant treatment.

CLDN18 expression is generally maintained in PD and is relatively high even in double-negative tumors, making it a promising therapeutic target for PD-positive gastric cancer.

While the therapeutic implications of these observations remain unknown, these findings suggest that combination strategies targeting HER2 and PD-L1 might be directed toward distinct tumor subclones. The herein disclosed region-specific biomarker expression patterns may have important therapeutic and prognostic impacts, warranting further evaluation.

CLDN18.2-positive GC is associated with poor prognosis and worse immunotherapeutic outcomes. The combination of anti-CLDN18.2 therapy, anti-PD-L1/PD-1 therapy, and chemotherapy for GC requires further investigation.

P=N/A, N=80, Active, not recruiting, Ain Shams University | Recruiting --> Active, not recruiting | Trial completion date: Sep 2023 --> Mar 2024 | Trial primary completion date: Sep 2023 --> Mar 2024

P1, N=9, Enrolling by invitation, Base Therapeutics (Shanghai) Co., Ltd.

Our data demonstrated a link between IHC/ISH characteristics of GC and clinical outcomes. IHC/ISH based molecular classification may be helpful in predicting the survival.

Aberrant p53 in CCO is infrequent but associated with poor prognosis independent of stage. Presence of tumor budding could be a screening tool for p53 testing. High prevalence of HER2 and PD-L1 expression indicates the eligibility of patients with CCO for ongoing clinical trials using these therapeutic targets.

P=N/A, N=80, Recruiting, Ain Shams University | Not yet recruiting --> Recruiting

P=N/A, N=80, Not yet recruiting, Ain Shams University | Trial completion date: Apr 2023 --> Aug 2023 | Initiation date: Mar 2022 --> Aug 2022 | Trial primary completion date: Mar 2023 --> Aug 2023

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.

PD-L1 expression is upregulated in more than half of patients with GAC. Anti-PD-L1 treatment combined with anti-HER2 therapy may benefit patients with locally advanced GAC with HER2 overexpression.

P=N/A, N=80, Not yet recruiting, Ain Shams University