HER2-positive Advanced Gastric Cancer Research Articles

Inetetamab combined with S-1 and oxaliplatin as first-line treatment for human epidermal growth factor receptor 2-positive gastric cancer

BACKGROUND Patients with human epidermal growth factor receptor 2 (HER2)-positive advanced gastric cancer have poor outcomes. Trastuzumab combined with chemotherapy is the first-line standard treatment for HER2-positive advanced gastric cancer. Inetetamab is a novel anti-HER2 drug, and its efficacy and safety in gastric cancer have not yet been reported. AIM To evaluate the efficacy and safety of the S-1 plus oxaliplatin (SOX) regimen combined with inetetamab as a first-line treatment for HER2-positive advanced gastric cancer. METHODS Thirty-eight patients with HER2-positive advanced gastric cancer or gastroesophageal junction adenocarcinoma were randomly divided into two groups: One group received inetetamab combined with the SOX regimen, and the other group received trastuzumab combined with the SOX regimen. After 4-6 cycles, patients with stable disease received maintenance therapy. The primary endpoints were progression-free survival (PFS) and overall survival (OS), and the secondary endpoints were the objective response rate, disease control rate, and adverse events (AEs). RESULTS Thirty-seven patients completed the trial, with 18 patients in the inetetamab group and 19 patients in the trastuzumab group. In the inetetamab group, the median PFS was 8.5 months, whereas it was 7.3 months in the trastuzumab group (P = 0.046); this difference was significant. The median OS in the inetetamab group vs the trastuzumab group was 15.4 months vs 14.3 months (P = 0. 33), and the objective response rate was 50% vs 42% (P = 0.63), respectively; these differences were not significant. Common AEs included leukopenia, thrombocytopenia, nausea, and vomiting. The incidence rates of grade ≥ 3 AEs were 56% in the inetetamab group and 47% in the trastuzumab group (P = 0.63), with no significant difference. CONCLUSION In the first-line treatment of HER2-positive advanced gastric cancer, inetetamab and trastuzumab showed comparable efficacy. The inetetamab group showed superior PFS, and both groups had good safety.

Efficacy and safety of dual blockade of HER2 and PD-1 in patients with HER2-positive gastric cancer: a retrospective, multicentre study

Human epidermal growth factor receptor 2 (HER2) expression is one of the most important pathological characteristics of gastric cancer. The positive rate of HER2 expression in patients with gastric cancer is approximately 20%. The phase III Keynote-811 study revealed that anti-HER2 and anti-PD-1 therapy combined with chemotherapy could significantly improve the objective response rate as first-line treatment in patients with HER2-positive advanced gastric cancer. In the present study, we aimed to evaluate the efficacy of combination therapy with trastuzumab and PD-1 inhibitors in patients with advanced HER2-positive gastric cancer in a real-world setting. Seventy-two HER2-positive gastric cancer patients from three hospitals in China were retrospectively reviewed. These patients were treated with trastuzumab plus one anti-PD-1 agent with or without chemotherapy. The overall response rate, progression-free survival and overall survival were assessed according to the Response Evaluation Criteria in Solid Tumours (RECIST 1.1). From January 2018 to October 2021, 72 patients with HER2-positive gastric cancer received trastuzumab and a PD-1 inhibitor with or without chemotherapy as neoadjuvant chemotherapy, first-line therapy, second-line therapy or salvage therapy. The ORR was 54.2% for all patients and 79.4% for previously untreated patients. The median PFS and median OS were 10 months (95% CI: 8–13 months) and 26.1 months (95% CI: 18.5-NA months), respectively, for all patients. Grade 3 adverse effects occurred in approximately 25% of patients. Immune-related adverse effects occurred in approximately 12.5% of patients. Trastuzumab and PD-1 inhibitor combination therapy with or without chemotherapy achieved satisfactory survival outcomes in patients with HER2-positive gastric cancer with acceptable safety.

Real-world effectiveness and safety of trastuzumab-deruxtecan in Japanese patients with HER2-positive advanced gastric cancer (EN-DEAVOR study).

Trastuzumab-deruxtecan (T-DXd) was approved for the treatment of HER2-positive patients with advanced gastric cancer in Japan based on the results of the DESTINY-Gastric01 trial. This study aimed to collect real-world data and evaluate the effectiveness and safety of T-DXd. Patients aged ≥ 20years at the start of T-DXd administration with a histopathologically confirmed diagnosis of HER2-positive unresectable advanced or recurrent gastric or gastroesophageal junction (GEJ) adenocarcinoma that had worsened after chemotherapy were enrolled in this retrospective cohort study. Key outcomes included T-DXd treatment status, overall survival (OS), real-world progression-free survival (rwPFS), time to treatment failure (TTF), objective response rate and frequency of grade ≥ 3 adverse events (AEs). Of the 312 patients included in the analysis, 75.3% were male, the median (range) age was 70.0 (27.0-89.0) years, 12.2% had an ECOG PS ≥ 2, 43.3% had ascites and the initial T-DXd dose was > 5.4- ≤ 6.4mg/kg in 78.2% of patients. The median (95% confidence interval) OS, rwPFS and TTF (months) was 8.9 (8.0-11.0), 4.6 (4.0-5.1) and 3.9 (3.4-4.2), respectively. The response rate was 42.9% in patients with a target lesion. In total, 48.4% of patients experienced a grade ≥ 3 AE, 2.6% experienced grade 5 AEs and 60.9% experienced AEs leading to T-DXd dose adjustments (reduction: 36.9%, interruption: 34.0% or discontinuation: 23.7%). No new safety signals were detected. T-DXd was effective and had a manageable safety profile as a third- or later-line treatment for patients with HER2-positive gastric or GEJ cancer in Japanese clinical practice. UMIN000049032.

1442P Correlation between intratumor HER2 heterogeneity and circulating tumor DNA in HER2 positive advanced gastric cancer: A phase Ib trial of HER2 and PD-1 dual targeted therapy (Ni-High) substudy

1442P Correlation between intratumor HER2 heterogeneity and circulating tumor DNA in HER2 positive advanced gastric cancer: A phase Ib trial of HER2 and PD-1 dual targeted therapy (Ni-High) substudy

Management of HER2-positive and microsatellite instability-high advanced gastric cancer: a case report

Chemotherapy for advanced gastric cancer has progressed significantly in the past few decades. Biomarker-specific drugs, including anti-human epidermal growth factor receptor 2 (HER2) drugs for HER2-positive patients and immune checkpoint inhibitors for those with microsatellite instability-high (MSI-H), have become common. However, patients who are positive for HER2 and have MSI-H are extremely rare, and there are no established treatments for these patients. We present the case of a 75-year-old, male patient with gastric cancer with lymph node metastases and liver infiltration. Biomarker analysis revealed HER2 3 + , loss of MLH1, and MSI-H. After three cycles of S-1, oxaliplatin, and trastuzumab, the primary tumor and metastases shrank markedly. He subsequently underwent gastrectomy and hepatectomy as conversion surgery, achieving a pathologically complete response. He has been recurrence-free for seven months postoperatively. The present case demonstrated the efficacy of trastuzumab-containing chemotherapy followed by conversion surgery in a patient with HER2-positive, MSI-H, advanced gastric cancer.

Pembrolizumab in combination with trastuzumab for treatment of HER2-positive advanced gastric or gastro-esophageal junction cancer.

Gastric cancer remains a challenging malignancy with a high global mortality rate. Recent advances in targeted therapy and immunotherapy have shown promise in improving patient outcomes. This paper reviews the impact of incorporating targeted agents such as trastuzumab and immunotherapeutic agents like pembrolizumab into standard chemotherapy regimens for gastric cancer treatment. A comprehensive analysis was conducted on pivotal clinical trials, including KEYNOTE-590, KEYNOTE-811, and ToGA, focusing on their methodologies, patient populations, treatment regimens, and outcome measures. The review also explored emerging research avenues in precision medicine, particularly genomic sequencing and biomarker identification. To assess the efficacy and survival benefits of adding trastuzumab and pembrolizumab to standard chemotherapy in the treatment of gastric cancer and to outline future directions in gastric cancer research. Including trastuzumab and pembrolizumab in treatment regimens for human epidermal growth factor receptor 2 (HER2)-positive and PD-L1-expressing gastric cancers significantly improved progression-free and overall survival rates compared to chemotherapy alone. These findings highlight the potential of personalized therapy in enhancing treatment outcomes. Furthermore, ongoing research into the gastric cancer microenvironment and the role of the microbiome suggests novel targets for future therapeutic interventions. The integration of targeted and immunotherapeutic agents with traditional chemotherapy represents a pivotal shift in gastric cancer treatment, moving towards more personalized and effective regimens.

A randomized phase 2 study of HLX22 plus trastuzumab biosimilar HLX02 and XELOX as first-line therapy for HER2-positive advanced gastric cancer

Gastric cancer is the fifth most common cancer and the fourth most common cause of cancer death worldwide, yet the prognosis of advanced disease remains poor. This was a randomized, double-blinded, phase 2 trial (ClinicalTrials.gov: NCT04908813). Patients with locally advanced/metastatic HER2-positive gastric/gastroesophageal junction cancer and no prior systemic antitumor therapy were randomized 1:1:1 to 25mg/kg HLX22 (a novel anti-HER2 antibody)+ HLX02 (trastuzumab biosimilar)+ oxaliplatin and capecitabine (XELOX) (group A), 15mg/kg HLX22+ HLX02+ XELOX (group B), or placebo+ HLX02+ XELOX (group C) in 3-week cycles. Primary endpoints were progression-free survival (PFS) and objective response rate (ORR) assessed by independent radiological review committee (IRRC). Between November 29, 2021, and June 6, 2022, 82 patients were screened; 53 were randomized to group A (n= 18), B (n= 17), and C (n= 18). With 14.3months of median follow-up, IRRC-assessed median PFS was prolonged with the addition of HLX22 (A vs. C, 15.1 vs. 8.2months, hazard ratio [HR] 0.5 [95% confidence interval (CI) 0.17-1.27]; B vs. C, not reached vs. 8.2months, HR 0.1 [95% CI 0.04-0.52]). Confirmed ORR was comparable among groups (A vs. B vs. C, 77.8% vs. 82.4% vs. 88.9%). Treatment-related adverse events (TRAEs) were observed in 18 (100%), 16 (94.1%), and 17 (94.4%) patients, respectively. One (5.6%) patient in group C reported a grade 5 TRAE. Adding HLX22 to HLX02 and XELOX prolonged PFS and enhanced antitumor response in the first-line treatment of HER2-positive gastric cancer, with manageable safety. Shanghai Henlius Biotech, Inc.

Mechanisms of resistance to trastuzumab in HER2-positive gastric cancer.

Gastric cancer is one of the most prevalent cancers worldwide, and human epidermal growth factor receptor 2 (HER2)-positive cases account for approximately 20% of the total cases. Currently, trastuzumab + chemotherapy is the recommended first-line treatment for patients with HER2-positive advanced gastric cancer, and the combination has exhibited definite efficacy in HER2-targeted therapy. However, the emergence of drug resistance during treatment considerably reduces its effectiveness; thus, it is imperative to investigate the potential mechanisms underlying resistance. In the present review article, we comprehensively introduce multiple mechanisms underlying resistance to trastuzumab in HER2-positive gastric cancer cases, aiming to provide insights for rectifying issues associated with resistance to trastuzumab and devising subsequent treatment strategies.

The value of the radiological diameter-to-thickness ratio in patients with HER2-positive resectable advanced gastric cancer: implications for long survival and stage migration.

To investigate the clinical significance and stage migration effect of radiological diameter-to-thickness (DT) ratio in HER2-positive resectable advanced gastric cancer (HER2-p RAGC). 369 HER2-p RAGC patients were retrospectively enrolled and information on clinical pathological characteristics, radiological DT ratio, and outcomes [i.e., overall survival (OS) and progression-free survival (PFS)] was collected. Pearson's Chi-square and Student's t-test were employed to compare baseline characteristics. Clinical outcomes were estimated using Kaplan-Meier analysis and Log-rank test. Univariate and multivariate Cox regression models were utilized to analyze independent prognostic factors. HER2-p RAGC patients were stratified into two groups using a DT ratio cutoff value of 4.0 (p < 0.05). Patients with a DT ratio < 4.0 exhibited significantly longer OS (58.0 vs. 31.0months) and PFS (43.0 vs. 24.0months) than those with a DT ratio ≥ 4.0. DT ratio significantly predicted prognosis for N0 and II stage patients (p < 0.05). Patients with gastric body and antrum cancers demonstrated longer OS and PFS in the DT ratio < 4.0 group (p = 0.046, 0.017, 0.036 and 0.028). Multivariate Cox proportional hazard model identified age, pathological T category, pathological N category, pathological TNM category and DT ratio as independent prognostic factors. Notably, pStage II patients with a DT ratio ≥ 4.0 exhibited a similar prognosis to pStage III patients with a DT ratio < 4.0 (p = 0.418 for OS, 0.867 for PFS). Radiological DT ratio could evaluate the prognosis and detect higher malignant cases in HER2-p RAGC patients. Moreover, DT ratio might guide clinicians make postoperative strategies. Retrospectively registered.

Efficacy and safety of SOX regimen combined with inetetamab as first-line treatment for HER2-positive advanced gastric cancer.

e16028 Background: Patients with HER2-positive advanced gastric cancer have a poor prognosis. Trastuzumab combined with chemotherapy is the first-line standard treatment. Inetetamab is a novel anti-HER2 drug, and its efficacy and safety in gastric cancer have not been reported yet. Methods: Thirty-eight patients with HER2-positive advanced gastric cancer or gastroesophageal junction adenocarcinoma were randomly divided into two groups: one group received inetetamab combined with the SOX regimen, and the other group received trastuzumab combined with the SOX regimen. After 4-6 cycles, patients with stable disease received maintenance therapy. The primary endpoints were progression-free survival (PFS) and overall survival (OS), and the secondary endpoints were the objective response rate (ORR), disease control rate (DCR), and adverse events (AEs). Results: Thirty-seven patients completed the trial, with 18 patients in the inetetamab group and 19 patients in the trastuzumab group. In the inetetamab group, the median PFS was 8.5 months, compared to 7.3 months in the trastuzumab group (P = 0.046), indicating a significant difference. The median OS was 15.3 months vs. 14.3 months (P = 0.46), and the ORR was 50% vs. 42% (P = 0.63), with no significant differences between groups. Common AEs included leukopenia, thrombocytopenia, nausea, and vomiting. The incidence rates of grade ≥ 3 AEs were 56% in the inetetamab group and 47% in the trastuzumab group (P = 0.63), with no significant difference. Conclusions: In the first-line treatment of HER2-positive advanced gastric cancer, the efficacy of inetetamab and trastuzumab was comparable. The inetetamab group had superior PFS benefits, and both groups had good safety.

487P HER2DX ERBB2 mRNA assay following trastuzumab-based chemotherapy in HER2-positive (HER2+) advanced gastric cancer (AGC)

487P HER2DX ERBB2 mRNA assay following trastuzumab-based chemotherapy in HER2-positive (HER2+) advanced gastric cancer (AGC)

Trastuzumab deruxtecan in HER2-positive advanced gastric cancer: exploratory biomarker analysis of the randomized, phase 2 DESTINY-Gastric01 trial

Trastuzumab deruxtecan (T-DXd) showed statistically significant clinical improvement in patients with human epidermal growth factor receptor 2-positive (HER2+) gastric cancer in the DESTINY-Gastric01 trial. Exploratory results from DESTINY-Gastric01 suggested a potential benefit in patients with HER2-low gastric cancer. Spatial and temporal heterogeneity in HER2 expression or gene alteration, an inherent characteristic of gastric cancer tumors, presents a challenge in identifying patients who may respond to T-DXd. Specific biomarkers related to therapeutic response have not been explored extensively. Exploratory analyses were conducted to assess baseline HER2-associated biomarkers in circulating tumor DNA and tissue samples, and to investigate mechanisms of resistance to T-DXd. Baseline HER2-associated biomarkers were correlated with objective response rate (ORR) in the primary cohort of patients with HER2+ gastric cancer. The primary cohort had 64% concordance between HER2 positivity and HER2 (ERBB2) plasma gene amplification. Other key driver gene amplifications, specifically MET, EGFR and FGFR2, in circulating tumor DNA were associated with numerically lower ORR. Among 12 patients with HER2 gain-of-function mutations, ORR was 58.3% (7 of 12). ORR was consistent regardless of timing of immunohistochemistry sample collection. Further investigations are required in larger studies.

Recent Progress in Treatment for HER2-Positive Advanced Gastric Cancer.

Human epidermal receptor (HER) 2-positive advanced gastric cancer is one of the major subtypes of gastric cancer, accounting for ~20% of all cases. Although combination therapy with trastuzumab and chemotherapy provides meaningful survival benefit, clinical trials targeting HER2 have failed to demonstrate clinical benefits in first- or subsequent-line treatment. Trastuzumab deruxtecan, an antibody-drug conjugate, has shown positive results even in later-line treatment and has become new standard treatment. In first-line therapy, combination therapy with pembrolizumab and trastuzumab plus chemotherapy demonstrated a dramatic response rate. Therefore, the FDA rapidly approved it without waiting for the results of survival time. The emergence of combination therapy including immunotherapy with HER2-targeting agents and the development of HER2 targeting agents with or without immunotherapy have been advancing for treating HER2-positive gastric cancer. In this review, we will discuss the current status of treatment development and future perspectives for HER2-positive gastric cancer.

Abstract 3824: Efficacy of trastuzumab in combination with capecitabine and cisplatin vs 5-FU and cisplatin therapy for Korean patients with HER2-positive advanced gastric cancer Health Insurance Review and Assessment service (HIRA) data retrospective analysis

Abstract The combinations of oral fluoropyrimidines and cisplatin such as capecitabine and cisplatin (XP) or 5-FU and cisplatin (FP) are regarded as a standard therapy against HER-2 positive advanced gastric cancer (AGC). Trastuzumab-XP(HXP) and trastuzumab-FP(HFP) is the most common regimen against AGC in Korea. The aim of the present study is to evaluate the effectiveness of trastuzumab-XP vs trastuzumab-FP. Patients with HER2-positive AGC were assigned to the trastuzumabXP or trastuzumabFP group. We then retrospectively compared the efficacy and safety between both groups. As a first-line chemotherapy, trastuzumab in combination with XP or FP was administered to 2,399 patients: 1,913 with HXP and 486 with HFP. In the HXP group vs HFP group, median progression-free survival (mPFS), and median overall survival (mOS) were 8.02 vs 6.08 months (p &amp;lt;0.0001) and 13.27 vs 9.89 months (p &amp;lt;0.0001). In HFP group, mPFS and mOS were 10.15 vs 5.36 months (p &amp;lt;0.0001) and 15.15 vs 8.90 months (p &amp;lt;0.0001) in comparison HFP-H maintenance to HFP group. In HXP group, mPFS and mOS were 10.64 vs 13.44 vs 5.03 months (p &amp;lt;0.0001) and 20.14 vs 22.18 vs 9.10 months (p &amp;lt;0.0001) in comparison HXP-H maintenance, HXP-HX maintenance, and HXP group. Trastuzumab in combination with XP and HX maintenance is a potential first-line therapeutic option for patients with HER2-positive AGC. Citation Format: hyun woo Lee, Jang-Hee Kim, Seok Yun Kang, Tae Jun Park, Yong Won Choi. Efficacy of trastuzumab in combination with capecitabine and cisplatin vs 5-FU and cisplatin therapy for Korean patients with HER2-positive advanced gastric cancer Health Insurance Review and Assessment service (HIRA) data retrospective analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3824.

Abstract 6581: DX126-262 combined with chemotherapy (Cisplatin and 5-Fu) demonstrates promising antitumor efficacy in HER2-positive gastric cancer

Abstract Gastric cancer is a common malignant tumor of the digestive system, and its morbidity and mortality rank among the top five in the world. Although significant progress has been made in cytotoxic chemotherapy, immunotherapy and targeted therapy in recent years, the long-term prognosis of patients with advanced or metastatic gastric cancer is still poor. Trastuzumab combined with chemotherapy is the first-line standard of care (SOC) for HER2-positive advanced or metastatic gastric cancer. Two ADC drugs targeting HER2, DS-8201 and RC-48, have also been approved for the treatment of gastric cancer. However, their limited clinical benefits and occurrence of adverse events still present a significant challenge. Therefore, minimizing the off-target toxicity and collateral damage while achieving significant chemotherapy efficacy has become the focus of gastric cancer treatment. DX126-262 is a novel HER2-targeting antibody-drug conjugate (ADC), generated by conjugating a Tubulysin B analogue to a recombinant humanized anti-HER2 monoclonal antibody through a linker containing branched hydrophilic polyethylene glycol, using thiol-maleimide chemistry to achieve drug antibody ratio (DAR) of 3.8. Previous studies have confirmed that DX126-262 monotherapy showed excellent efficacy in HER2-positive gastric cancer NCI-N87 cells in vitro and in vivo. And the efficacy has also been demonstrated in clinical trials (now in phase II, CTR20211871). Based on above results, we intended to further explore whether combination therapy of DX126-262 with Cisplatin and 5-FU can improve the anti-tumor efficacy compared with SOC (Herceptin plus Cisplatin and 5-FU) or DS-8201 monotherapy. The triple-drug combination therapy demonstrated much better therapeutic efficacy than single drug (DX126-262, Cisplatin, 5-FU, Herceptin, or DS-8201) or double-drug combination (Cisplatin plus 5-FU) or SOC (Herceptin plus Cisplatin and 5-FU) on human gastric cancer cells in vitro and in vivo. Meanwhile, triple-drug combination therapy did not exhibit superimposed toxicity, judging by the body weight of mice and hemal biochemistry assays. These results suggested that DX126-262 plus Cisplatin and 5-FU might be a promising strategy for treatment of HER2-positive advanced or metastatic gastric cancer in clinic. Citation Format: Xiaobo Cai, Min Cao, Huihui Guo, Qingliang Yang, Xiangfei Kong, Yong Du, Zhicang Ye, Zhixiang Guo, Lingli Zhang, Lu Bai, Junxiang Jia, Yunxia Zheng, Yongxiang Chen, Miaomiao Chen, Wei Zheng, Jun Zheng, Wenjun Li, Yuanyuan Huang, Mengmeng Liu, Zhongliang Fan, Hangbo Ye, Yifang Xu, Binbin Chen, Meng Dai, Robert Y. Zhao. DX126-262 combined with chemotherapy (Cisplatin and 5-Fu) demonstrates promising antitumor efficacy in HER2-positive gastric cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6581.

Immunotherapy in Gastric Cancer: A Review

Globally, gastric cancer (GC) ranks fourth in terms of cancer-related mortality. Patients diagnosed with advanced gastric cancer (AGC) frequently have a median survival around 12-15 months, depending to the therapy. Immunotherapy is becoming an essential therapeutic strategy in medical oncology, and it is projected to make major advances to the way gastric cancer cure. The phase III ATTRACTION-2 showed that nivolumab, a monoclonal antibody targeting programmed cell death 1 (PD-1), substantially increased overall survival (OS) in patients with advanced gastric cancer (AGC) when given as a third- or later-line treatment, as compared to a placebo. Furthermore, nivolumab in combination with 5-fluorouracil and platinum as a first-line treatment increased OS in patients with human epidermal growth factor receptor-2 (HER2)-negative AGC in the international phase III CheckMate-649 investigation. Pembrolizumab, an additional anti PD-1 antibody, when used with trastuzumab and cytotoxic chemotherapy as first line treatment, demonstrated a substantial enhancement in the overall response rate among patients diagnosed with HER2-positive AGC. Hence, immune checkpoint inhibitors (ICIs) are crucial in the present management of GC. Current research is actively investigating alternative treatment following ICI combination therapy, including ICI rechallenge or combination therapy with drugs that have distinct mechanisms of action. Several clinical trials are presently being done to employ immunotherapy as a treatment option in the perioperative and postoperative settings for patients with early gastric cancer, based on the success of immunotherapy in treating advanced gastric cancer (AGC). This article gives an overview of the recent breakthroughs in immunotherapy.

Metabolic heterogeneity affects trastuzumab response and survival in HER2-positive advanced gastric cancer

BackgroundTrastuzumab is the only first-line treatment targeted against the human epidermal growth factor receptor 2 (HER2) approved for patients with HER2-positive advanced gastric cancer. The impact of metabolic heterogeneity on trastuzumab treatment efficacy remains unclear.MethodsSpatial metabolomics via high mass resolution imaging mass spectrometry was performed in pretherapeutic biopsies of patients with HER2-positive advanced gastric cancer in a prospective multicentre observational study. The mass spectra, representing the metabolic heterogeneity within tumour areas, were grouped by K-means clustering algorithm. Simpson’s diversity index was applied to compare the metabolic heterogeneity level of individual patients.ResultsClustering analysis revealed metabolic heterogeneity in HER2-positive gastric cancer patients and uncovered nine tumour subpopulations. High metabolic heterogeneity was shown as a factor indicating sensitivity to trastuzumab (p = 0.008) and favourable prognosis at trend level. Two of the nine tumour subpopulations associated with favourable prognosis and trastuzumab sensitivity, and one subpopulation associated with poor prognosis and trastuzumab resistance.ConclusionsThis work revealed that tumour metabolic heterogeneity associated with prognosis and trastuzumab response based on tissue metabolomics of HER2-positive gastric cancer. Tumour metabolic subpopulations may provide an association with trastuzumab therapy efficacy.Clinical trial registrationThe patient cohort was conducted from a multicentre observational study (VARIANZ;NCT02305043).

Efficacy and safety of trastuzumab deruxtecan and nivolumab as third- or later-line treatment for HER2-positive advanced gastric cancer: A single-institution retrospective study.

265 Background: Despite the difficulty of directly comparing trastuzumab deruxtecan (T-DXd) and nivolumab as third- or later-line treatment for HER2-positive advanced gastric cancer (AGC) in randomized trials, discussions regarding optimal treatment strategies are desired. Methods: This single-institution retrospective study aimed to describe the real-world efficacy and safety of T-DXd and nivolumab as third- or later-line treatment for patients with HER2-positive AGC treated between March 2016 and May 2022. Results: Overall, 58 patients (median age, 64 years; 69% male) were eligible (T-DXd group, n = 20; nivolumab group, n = 38). Most had HER2 3+ (72%) and presented with metastatic disease at diagnosis (66%). Response rates in the 41 patients with measurable lesions were 50% and 15% in the T-DXd and nivolumab groups, respectively. The T-DXd and nivolumab groups had a median progression-free survival of 4.8 months (95% confidence interval [CI], 3.3–7.0) and 2.3 months (95% CI, 1.5–3.5), median overall survival of 10.8 months (95% CI, 6.9–23.8) and 11.7 months (95% CI, 7.6–17.1), and grade 3 or greater adverse event rates of 50% and 2%, respectively. Overall, 64% received subsequent treatment. Among 23 patients who received both regimens, the T-DXd–nivolumab and nivolumab–T-DXd groups had a median overall survival of 14.0 months (95% CI, 5.0–not reached) and 19.3 months (95% CI, 9.5–25.1), respectively. Conclusions: T-DXd and nivolumab had distinctive efficacy and toxicity profiles as third- or later-line treatment for HER2-positive AGC. Considering the distinct features of each regimen might help clinicians personalize the optimal treatment approaches for patients with HER2-positive AGC.

Health-related quality of life (HRQOL) with pembrolizumab (pembro) plus trastuzumab (tras) and chemotherapy (chemo) in first-line HER2-positive (HER2+) advanced gastric cancer: KEYNOTE-811 trial results.

286 Background: In the phase 3 KEYNOTE-811 study (NCT03615326), first-line (1L) pembro with tras + chemo (pembro arm) yielded superior PFS and improved ORR with durable responses versus placebo (pbo) with tras + chemo (pbo arm) in pts with HER2+ metastatic gastric or gastroesophageal junction (G/GEJ) adenocarcinoma, notably in pts with PD-L1 combined positive score (CPS) ≥1. Key prespecified exploratory HRQOL outcomes supporting these data are presented. Methods: Pts with untreated histologically or cytologically confirmed advanced HER2+ G/GEJ adenocarcinoma, measurable disease per RECIST v1.1 by investigator, and ECOG PS of 0 or 1 were randomly assigned 1:1 to receive pembro 200 mg or pbo IV every 3 weeks (Q3W) with tras + chemo (cisplatin + 5-fluorouracil or capecitabine + oxaliplatin). HRQOL was evaluated in pts who received ≥1 dose of study treatment and completed ≥1 pt-reported outcome (PRO) assessment. End points were least squares mean (LSM) change from baseline, time to deterioration (TTD), and overall improvement/stability rate in prespecified subscales of EORTC QLQ-C30, QLQ-STO22, EuroQol EQ-5D-5L. LSM changes from baseline were analyzed at wk 24 when prespecified completion and compliance rates of ~60% and 80%, respectively, were met, based on review of blinded data. Results: In the PRO analyses, 685 pts were evaluable (345 pembro with tras + chemo; 340 pbo with tras + chemo). Median time from randomization to data cutoff (May 25, 2022) was 28.4 mo (range, 9.3-42.6). Completion rates were &gt;92% at baseline and &gt;55% at wk 24 for all assessments in both arms. Similar changes in PRO scores from baseline to wk 24 were observed for the pembro versus pbo arms (Table). Similar percentages of pts in each arm had improved or stable scores for the EORTC QLQ-C30 GHS/QOL and physical functioning scales and EORTC QLQ-STO22 subscales. TTD was similar between arms for all prespecified subscales. Conclusions: The addition of pembro to tras + chemo did not negatively affect HRQOL during treatment. Combined with safety and efficacy data, these results support the use of pembro with tras + chemo for first-line treatment of pts with HER2+ advanced gastric cancer. Clinical trial information: NCT03615326 . [Table: see text]

Retrospective cohort study to evaluate the efficacy and safety of T-DXd in HER2-positive unresectable advanced or recurrent gastric or gastroesophageal junction cancer: EN-DEAVOR study.

274 Background: Relatively limited clinical data exists for patients who receive T-DXd treatment in the 3L+ setting for HER2-positive unresectable advanced/recurrent gastric or gastroesophageal junction cancer. Insufficient data exists on real world patient populations that are likely to be excluded from clinical trials (e.g., elderly patients, those with significant co-morbidities). Therefore, this study was designed to evaluate the real-world clinical effectiveness and safety of T-DXd in patients with HER2-positive gastric cancer. Methods: This study (UMIN000049032) was a real-world, multicenter, non-interventional, retrospective cohort study conducted in Japan. Patients with HER2-positive unresectable advanced/recurrent gastric or gastroesophageal junction cancer treated with T-DXd were enrolled. The patients were first administered T-DXd between Sep 2020, when T-DXd became available for clinical use in Japan, and Sep 2021. We followed up on these patients' records until Sep 2022. The endpoints were overall survival (OS), real-world progression-free survival (rwPFS), time to treatment failure (TTF), objective response (ORR), adverse events (AEs) of Grade ≥3, and adverse events leading to dose reduction, interruption, or discontinuation. Results: A total of 318 patients were enrolled, and 312 patients were analyzed, excluding 6 patients due to double enrollment or miss-enrollment (median age 70 years, performance status 0 or 1/≥2 [87%/12%], 43% patients with ascites). Median OS, rwPFS, and TTF were 8.90 months, 4.57 months, and 3.94 months, respectively. Overall ORR was 32.7%; it was 43.8% in the 226 patients with a target lesion. Regarding safety, the incidence of Grade ≥ 3 AEs was 48.4%. A total of 190/312 (60.9%) patients treated with T-DXd experienced dose reduction, interruption, or discontinuation of T-DXd treatment due to AEs. The most common reasons for dose reduction or interruption were neutrophil count decreased, anorexia, and malaise, while the most common reasons for discontinuation were interstitial pneumonia, anorexia, malaise, and nausea. Conclusions: This study demonstrates the effectiveness and safety of T-DXd in the 3L+ setting in real-world patients with HER2-positive gastric or gastroesophageal cancer. No new safety signals were identified on the basis of this study.