Kim IH, et al. J Gastric Cancer. 2025 Jan;25:e11. https://doi.org/10.5230/jgc.2025.25.e11

Immune checkpoint inhibitors targeting programmed death protein 1 (PD-1) receptor and its ligand, PD-L1, have recently led to significant and durable improvements in the clinical outcomes of some types of cancers including lung cancer. Areas covered: Pembrolizumab was approved by the US FDA for the treatment of advanced or metastatic NSCLC whose disease has progressed after other treatments and with tumors that express PD-L1. In the phase I KEYNOTE-001 trial, the overall response rate (ORR) was 19.4%, the median progression-free survival (PFS) and overall survival (OS) were 3.7 months and 12.0 months for 495 unselected NSCLC patients. Strong PD-L1 expression (≥ 50%) was associated with higher ORR, longer PFS, and longer OS. The phase II/III randomized KEYNOTE-010 trial demonstrated that pembrolizumab improved OS versus docetaxel in patients with previously treated NSCLC. Expert opinion: Pembrolizumab, demonstrated durable response and prolonged OS especially in NSCLC patients with high expression of PD-1, thereby suggests a new treatment paradigm. However, many issues remain to be explored, including the identification of other robust biomarkers that can accurately predict the immune-responsiveness of tumors. Along with the identification of predictive biomarkers, further understanding of the tumor microenvironment is necessary to improve treatment outcomes through combinations of immunotherapy or combined with other targeted therapies.

The COVID-19 pandemic is changing rapidly and requires different strategies to maintain immunization. In Korea, different COVID-19 vaccines are recommended and available for various populations, including healthcare workers (HCWs) at high risk of SARS-CoV-2 infection. We plan to evaluate the adverse events (AEs) and immunogenicity of the BNT162b2 and ChAdOx1 vaccines in HCWs at a single center. This cohort study included HCWs fully vaccinated with either BNT162b2 or ChAdOx1. Blood samples were taken eight weeks after the second vaccination with both COVID-19 vaccines and six months after the second vaccination from participants with the BNT162b2 vaccine. The primary endpoint for immunogenicity was the serum neutralizing antibody responses eight weeks after vaccination. The secondary endpoint was the incidence of various AEs within 28 days of each vaccination. Between 16 March and 23 June 2021, 115 participants were enrolled (65 in the ChAdOx1 group and 50 in the BNT162b2 group). Significantly higher surrogate virus neutralization test (sVNT) inhibition was observed in participants vaccinated with two doses of BNT162b2 (mean (SD) 91.4 (9.68)%) than in those vaccinated with ChAdOx1 (mean (SD) 73.3 (22.57)%). The effectiveness of the BNT162b2 vaccine was maintained across all age and gender categories. At six months after the second dose, serum antibody levels declined significantly in the BNT162b2 group. The main adverse events, including fever, myalgia, fatigue, and headache, were significantly higher in the ChAdOx1 group after the first dose, whereas, after the second dose, those AEs were significantly higher in the BNT162b2 group (p < 0.05). Two doses of either the ChAdOx1 or the BNT162b2 COVID-19 vaccine resulted in very high seropositivity among the HCWs at our center. The quality of the antibody response, measured by sVNT inhibition, was significantly better with the BNT162b2 vaccine than with the ChAdOx1 vaccine. There was no significant association between neutralizing antibody response and AE after each vaccination in our cohort.

Purpose: Adding pembrolizumab to first-line fluoropyrimidine (5-FU)/platinum chemotherapy plus trastuzumab improves outcomes in advanced HER2+ gastroesophageal adenocarcinomas, but the benefit is largely confined to dual HER2+ and PD-L1+ patients. To assess the contributions of components, we conducted a phase II trial evaluating 5-FU/platinum/trastuzumab and added pembrolizumab in cycle 2 in patients with metastatic HER2+ disease. Patients and Methods: Treatment-naïve patients with advanced HER2+ gastroesophageal cancer underwent a baseline biopsy and received a single dose of 5-FU/platinum with trastuzumab followed by repeat biopsy. Pembrolizumab was added, and a third biopsy was performed after six cycles. The primary endpoint was the objective response rate. Secondary endpoints included progression-free and overall survival. Exploratory biomarker analysis and dynamic changes in HER2 and PD-L1 were prespecified. Results: Sixteen patients were enrolled. The objective response rate was 69%, and the median progression-free survival was 11.9 months. Serial whole-exome, single-cell RNA, T-cell receptor sequencing, and spatial transcriptomics from pretreatment and on-treatment samples revealed early trastuzumab-induced NK cell infiltration in HER2+ tumor beds and an increase in Fc receptor gamma III expression in macrophages, suggesting that trastuzumab directs Fc receptor–mediated antibody-dependent cytotoxicity. This favorable remodeling was enhanced by the addition of pembrolizumab, primarily in PD-L1+ samples. We observed TGF-β signaling in HER2-negative tumor regions, which was associated with nonresponder status. Conclusions: These data highlight the biology of intratumoral heterogeneity and the impact of tumor and immune cell features on clinical outcomes and may partly explain the lesser magnitude of pembrolizumab benefit in HER2+ and PD-L1–negative subgroups.

The activities of bispecific antibodies against VEGF and PD-1 have reinvigorated interest in dual VEGF and PD-1 targeting across solid tumors. However, the tumor and immune features influencing tumor response remain largely unknown. We conducted a single-arm phase II trial evaluating dual VEGFR2 and PD-1 targeting with ramucirumab and pembrolizumab in pretreated PD-L1+ gastric cancer. Twenty-six patients were enrolled between June 2021 and May 2023. Nine patients received anti–PD-1 therapy before trial enrollment. There were no complete responses, but six patients had a partial response, for an objective response rate of 23%. The median progression-free survival was 2.7 months, and the median overall survival was 10.9 months. Grade ≥3 treatment-related adverse events occurred in 39% of patients. Digital spatial profiling of serial primary tumor biopsies revealed distinct tumor microenvironment phenotypes between responders and nonresponders. Responders were characterized by higher baseline tumoral VEGF signaling, baseline enrichment in antigen processing and presentation in the immune compartment, shorter distances between tumor and immune cell populations, and greater on-treatment vascular normalization coupled to cytotoxic T-cell infiltration. Nonresponders had greater baseline hypoxia and platelet-derived growth factor scores, significantly upregulated TGFβ in immune cell regions, and greater distances between tumor and immune cells and immune cells and vessels. Paired peripheral blood mass cytometry revealed lower proportions of myeloid-derived suppressor cells in responders. Together, these data highlight on-treatment remodeling under the therapeutic pressure of dual VEGF and PD-1 blockade and suggest features associated with the durable benefit seen in a subset of patients.