HER2-positive Metastatic Gastric Cancer Research Articles

Abstract 2484: Association of artificial intelligence (AI)-based HER2 scoring with clinical outcomes to first-line trastuzumab plus chemotherapy in HER2-positive metastatic gastric cancer (mGC)

Abstract Background: Although trastuzumab plus chemotherapy is the treatment of choice for HER2-positive mGC, not all patients respond to the therapy. To date, there is no reliable and efficient biomarker that can predict the response to trastuzumab-based treatment. Methods: Clinical data and pathology slides from HER2-positive mGC patients treated with first-line trastuzumab and capecitabine/5-fluorouracil plus cisplatin were retrospectively collected. HER2 positivity was confirmed using standard methods with immunohistochemistry (IHC) and/or in situ hybridization. An AI-based model was applied to a single HER2 IHC-stained whole slide image (WSI) of each patient to identify and quantify the tumor cells with HER2 IHC staining intensity categories of 0, 1+, 2+, or 3+ on the slide. The proportion of tumor cells with 3+ staining intensity among total tumor cells (h3 percentage) in each slide was calculated and analyzed in relation to clinical outcomes. Results: A total of 160 cases were included in this analysis. Overall, the median progression-free survival (PFS) was 9.2 mo, and the overall survival (OS) was 18.9 mo. By standard IHC HER2 grading, 107 (66.9%) 3+ and 53 (33.1%) 2+ cases were included. The median AI-estimated h3 percentage in these patients was 14.8% (range 0 - 99.5%). The patients with their best tumor response of complete (CR) or partial response (PR) (44.4%) exhibited significantly higher h3 percentages (mean h3 percentage 46.6% in CR/PR vs. 29.4% in stable or progressive disease, p = 0.018). The h3 percentage exhibited strong associations as a continuous variable with longer PFS (hazard ratio [HR] 0.94 [95% confidence interval (CI) 0.90 - 0.99] for 10% change of h3 percentages, p = 0.015) or OS (HR 0.93 [95% CI 0.89 - 0.98] for 10% change of h3 percentages, p = 0.004). Notably, patients having a proportion of 3+ tumor cells at ≥ 90% (27/160, 16.9%) showed particularly longer PFS (median PFS 21.4 mo in ≥ 90% vs. 8.5mo in < 90%, p = 0.006) and OS (median OS 40.3 mo in ≥ 90% vs. 16.6 mo in < 90%, p = 0.004). Conclusion: AI-based models interpreting WSI can provide additive predictive information to HER2-positive mGC patients treated with trastuzumab plus chemotherapy. Citation Format: Minsu Kang, Yoojoo Lim, Hyeon Jeong Oh, Ji Ae Lee, Jin Won Kim, Ji-Won Kim, Sanghoon Song, Heon Song, Keun-Wook Lee. Association of artificial intelligence (AI)-based HER2 scoring with clinical outcomes to first-line trastuzumab plus chemotherapy in HER2-positive metastatic gastric cancer (mGC) [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 2484.

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.

Effect of HER2/CEP17 ratio on survival in metastatic HER2-positive gastric cancer, multicenter study.

HER2-positive metastatic gastric cancer is still a highly fatal disease despite advances. We aimed to investigate the relationship between HER2/CEP17 ratio and survival in patients with HER2-positive metastatic gastric cancer. A total of 99 patients from 8 different centers in Turkey were included in the study. Patients with HER2-positive metastatic gastric cancer and whose HER2/CEP17 ratio was examined were included in the study. Patients were divided into two groups according to HER2/CEP17 values, and survival analysis was performed. The median age was 64 (24-83) years. There were 74 (74.8%) male and 25 (25.2%) female patients. OS in the high HER2/CEP17 ratio group was 21.97months (95% CI: 16.36-27.58), and in the low ratio group was 16.17months (95% CI: 10.95-21.38) (p = 0.015). OS was 17.7months (95% CI: 7.02-28.37) in the high HER2 gene copy number group and 10.13months (5.55-14.71) in the group with low copy number (p = 0.03). PFS was 10.94months (95% CI: 7.55-14.33) in the group with high HER2 gene copy number and 7.56months (4.62-10.49) in the low copy number group (p = 0.06). Patients with both high HER2 gene amplification and high HER2/CEP17 ratio had better OS. The PFS of the group with high HER2 gene amplification was also better. To our knowledge, this is the first study in the literature showing that the HER2/CEP17 ratio affects survival in patients with metastatic gastric cancer.

In era of immunotherapy: the value of trastuzumab beyond progression in patients with trastuzumab-resistant HER2-positive advanced or metastatic gastric cancer.

For patients with human epidermal growth factor receptor-2 (HER2)-positive advanced or metastatic gastric cancer who have progressed on first-line trastuzumab therapy, the clinical value of the continuous use of trastuzumab beyond progression (TBP) is controversial. The present study was conducted to evaluate the efficacy and explore new treatment strategies of TBP for patients with trastuzumab-resistant HER2-positive advanced or metastatic gastric cancer in the era of cancer immunotherapy. Retrospective analysis. Patients with HER2-positive advanced or metastatic gastric cancer who have failed first-line treatment based on trastuzumab-targeted therapy from June 2019 to December 2020 were retrospectively analyzed. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), objective response rate (ORR), disease control rate (DCR), and safety. Survival curves of patients were estimated by the Kaplan-Meier method and compared using the log-rank test. In all, 30 patients received TBP with chemotherapy, immunotherapy, or anti-angiogenic therapy, and the other 26 patients received treatment of physician's choice without trastuzumab. The median PFS in the TBP and non-TBP population was 6.0 [95% confidence interval (CI) = 3.8-8.2] and 3.5 (95% CI = 2.2-4.8) months, respectively (p = 0.038), and the median OS was 12.3 (95% CI = 10.4-14.2) and 9.0 (95% CI = 6.6-11.4) months (p = 0.008). The patients who received TBP treatment had more favorable PFS and OS than the non-TBP population. In the TBP group, patients who received trastuzumab plus chemotherapy and immunotherapy had higher ORR (40.0% versus 16.7%), DCR (90.0% versus 50.0%), and showed a significant improvement in PFS (7.0 versus 1.9 m) compared to TBP with chemotherapy alone. Subgroup analysis suggested that patients with male, HER2 positive with immunohistochemistry score 3+ and PFS of first-line treatment less than 6 months had a greater benefit from TBP. The incidence of Grade 3-4 adverse events in the TBP and non-TBP groups was 43.3% and 38.5%. The continuous use of TBP improves PFS and OS in patients with trastuzumab-resistant HER2-positive advanced or metastatic gastric cancer with well-tolerated toxicity. In the era of immunotherapy, TBP combined with chemotherapy and immunotherapy may further enhance the clinical benefit and provide a new treatment strategy. This study is a retrospective study, which does not require clinical registration.

Immune checkpoint inhibitors enhanced the antitumor efficacy of disitamab vedotin for patients with HER2-positive or HER2-low advanced or metastatic gastric cancer: a multicenter real-world study

BackgroundNovel ADC drugs provide a new therapeutic strategy for gastric cancer.The present study aimed to analyze the clinical efficacy and drug toxicities of disitamab vedotin (RC48) plus immune checkpoint inhibitors(ICIs) and RC48 as third-line therapies and beyond for advanced and metastatic gastric cancer patients.MethodsThis was an observational multicenter real-world study.From August 2021 to January 2022,patients with HER2-positive or HER2-low advanced and metastatic gastric cancer and failed from two or more lines of prior therapy were enrolled and treated with RC48 plus ICIs or RC48. In this study, progression free survival(PFS) was the primary end point. Other evaluation indicators were objective response rate(ORR),disease control rate(DCR),overall survival(OS) and drug toxicities.Results45 patients were enrolled,of which 25 patients received RC48 plus ICIs,20 patients received RC48.Patients who received RC48 plus ICIs obtained better ORR (36.0% vs. 10.0%, P = 0.044) and DCR (80.0% vs. 50.0%, P = 0.034) compared with RC48,and simultaneously,the median PFS in RC48 plus ICIs group were superior to RC48 group(6.2 m vs. 3.9 m).The median OS was not reached.No statistically differences were found between HER2-positive and HER2-low group with respect to ORR (27.3% vs. 16.7%, P = 0.464),DCR (66.7% vs. 66.7%, P = 1.000),median PFS(5.7 m vs. 4.3 m, P = 0.299).The most common adverse events (AEs) were decreased white blood count,decreased neutrophil count,fatigue,hypoaesthesia and alopecia.Grade 3–4 AEs occurred in 7(35.0%) patients of RC48 group and 10(40.0%) patients of RC48 plus ICIs group,respectively.ConclusionCompared with RC48 monotherapy, ICIs plus RC48 demonstrated superior third-line and beyond therapeutic efficacy for HER2-positive or HER2-low advanced and metastatic gastric cancer patients with manageable safety.

Trastuzumab deruxtecan in patients with locally advanced or metastatic HER2-positive gastric cancer: a multicenter, open-label, expanded-access study

BackgroundTrastuzumab deruxtecan (T-DXd) is an antibody–drug conjugate that consists of an anti-human epidermal growth factor receptor 2 (HER2) antibody bound by a cleavable tetrapeptide-based linker to a cytotoxic topoisomerase I inhibitor. Prior to marketing approval in Japan in September 2020, this expanded-access study was conducted to provide T-DXd to previously treated patients with locally advanced or metastatic HER2-positive gastric or gastroesophageal junction adenocarcinomas.MethodsThis multicenter, open-label, expanded-access study was conducted between March 25 and September 25, 2020 at 17 Japanese sites. Previously treated patients with locally advanced or metastatic HER2-positive gastric or gastroesophageal junction adenocarcinomas received T-DXd 6.4 mg/kg via intravenous infusions at 3-week intervals. Serious adverse events (SAEs), all potential cases of interstitial lung disease (ILD)/pneumonitis, all liver-related events potentially meeting Hy’s Law criteria, and all cases of overdose were reported on the case report forms.ResultsA total of 64 patients were treated with T-DXd. Among the 17 (26.6%) patients with reported SAEs, 10 (15.6%) had SAEs related to T-DXd treatment. Febrile neutropenia was the most common SAE (n = 6). SAEs led to death in six patients; drug-related SAEs (sepsis and febrile neutropenia) led to death in one patient. Drug-related ILD, as determined by the external Adjudication Committee, occurred in three patients (Grade 1, Grade 2, and Grade 3: all n = 1).ConclusionThis expanded-access study provided T-DXd to a broader population of Japanese patients prior to marketing approval in Japan, bridging the gap between clinical trials and drug approval. No new safety concerns were identified.

Advances in the treatment of gastric cancer: 2022-2023.

To review 2022-2023 studies in gastric cancer. Important studies report the role of laparoscopic surgery in gastric cancer, the activity of immune checkpoint inhibitors in metastatic, locally advanced and adjuvant therapy in gastric cancer, and the effectiveness of zolbetuximab in claudin 18.2-positive metastatic disease. From the Japanese JLSSG0901 Trial, equivalent survival was reported for laparoscopically assisted versus conventional open gastrectomy. Adding nivolumab to adjuvant chemotherapy in resected stage III gastric cancer failed to improve 3-year disease-free survival over chemotherapy alone. Ipilimumab and nivolumab as preoperative therapy in MSI-high gastric cancer resulted in a high rate of pathologic complete response. Trastuzumab added to chemoradiotherapy and surgery in HER2-positive locally advanced esophageal and gastroesophageal junction adenocarcinoma did not improve overall survival over chemoradiotherapy and surgery alone. Adding pembrolizumab to trastuzumab/chemotherapy in metastatic HER2-positive gastric cancer improved antitumor response rate. Addition of zolbetuximab, an antibody targeting claudin 18.2, to first-line chemotherapy in metastatic claudin 18.2-positive gastric cancer improved overall survival. Immune checkpoint inhibition has a role in locally advanced MSI-high and metastatic gastric cancer. Laparoscopic gastrectomy is acceptable in gastric cancer. Zolbetuximab in metastatic gastric cancer will emerge as a new therapy option.

Statins enhance the efficacy of HER2-targeting radioligand therapy in drug-resistant gastric cancers

Human epidermal growth factor receptor2 (HER2) is overexpressed in various cancer types. HER2-targeting trastuzumab plus chemotherapy is used as first-line therapy for HER2-positive recurrent or primary metastatic gastric cancer, but intrinsic and acquired trastuzumab resistance inevitably develop over time. To overcome gastric cancer resistance to HER2-targeted therapies, we have conjugated trastuzumab with a beta-emitting therapeutic isotope, lutetium-177, to deliver radiation locally to gastric tumors with minimal toxicity. Because trastuzumab-based targeted radioligand therapy (RLT) requires only the extramembrane domain binding of membrane-bound HER2 receptors, HER2-targeting RLT can bypass any resistance mechanisms that occur downstream of HER2 binding. Leveraging our previous discoveries that statins, a class of cholesterol-lowering drugs, can enhance the cell surface-bound HER2 to achieve effective drug delivery in tumors, we proposed that the combination of statins and [177Lu]Lu-trastuzumab-based RLT can enhance the therapeutic efficacy of HER2-targeted RLT in drug-resistant gastric cancers. We demonstrate that lovastatin elevates cell surface HER2 levels and increases the tumor-absorbed radiation dose of [177Lu]Lu-DOTA-trastuzumab. Furthermore, lovastatin-modulated [177Lu]Lu-DOTA-trastuzumab RLT durably inhibits tumor growth and prolongs overall survival in mice bearing NCI-N87 gastric tumors and HER2-positive patient-derived xenografts (PDXs) of known clinical resistance to trastuzumab therapy. Statins also exhibit a radioprotective effect, reducing radiotoxicity in a mice cohort given the combination of statins and [177Lu]Lu-DOTA-trastuzumab. Since statins are commonly prescribed to patients, our results strongly support the feasibility of clinical studies that combine lovastatin with HER2-targeted RLT in HER2-postive patients and trastuzumab-resistant HER2-positive patients.

Comprehensive biomarker analysis of long-term response to trastuzumab in patients with HER2-positive advanced gastric or gastroesophageal adenocarcinoma

BackgroundA subgroup of patients with HER2-positive metastatic gastric and gastroesophageal junction cancers shows long-term response under trastuzumab maintenance monotherapy. Obviously, HER2 status alone is not able to identify these patients. We performed this study to identify potential new prognostic biomarkers for this long-term responding patient group. Patients and methodsTumour samples of 19 patients with HER2-positive metastatic gastric and gastroesophageal junction cancer who underwent trastuzumab treatment were retrospectively collected from multiple centres. Patients were divided into long-term responding (n = 7) or short-term responding group (n = 12) according to progression-free survival (PFS≥12 months vs. PFS < 12 months). Next-generation sequencing and microarray-based gene expression analysis were performed along with HER2 and PD-L1 immunohistochemistry. ResultsLong-term responding patients had significantly higher PD-L1 combined positive scores (CPS) and CPS correlated with longer progression-free survival. PD-L1 positivity (CPS ≥ 1) was further associated with an increased CD4+ memory T-cell score. The ERBB2 copy number as well as the tumour mutational burden could not discriminate between short-term and long-term responding patients. Genetic alterations and coamplifications in HER2 pathway associated genes such as EGFR, which were connected to trastuzumab resistance, were present in 10% of the patients and equally distributed between the groups. ConclusionThe study highlights the clinical relevance of PD-L1 testing also in the context of trastuzumab treatment and offers a biological rational by demonstrating elevated CD4+ memory T-cells scores in the PD-L1-positive group.

Second-line Therapy after Trastuzumab Failure in HER2-Positive Metastatic Gastric Cancer: A Real-life Data

Second-line Therapy after Trastuzumab Failure in HER2-Positive Metastatic Gastric Cancer: A Real-life Data

HER2 Copy Number and Resistance Mechanisms in Patients with HER2-positive Advanced Gastric Cancer Receiving Initial Trastuzumab-based Therapy in JACOB Trial.

In JACOB trial, pertuzumab added to trastuzumab-chemotherapy did not significantly improve survival of patients with HER2-positive metastatic gastric cancer, despite 3.3 months increase versus placebo. HER2 copy-number variation (CNV) and AMNESIA panel encompassing primary resistance alterations (KRAS/PIK3CA/MET mutations, KRAS/EGFR/MET amplifications) may improve patients' selection for HER2 inhibition. In a post hoc analysis of JACOB on 327 samples successfully sequenced by next-generation sequencing (NGS; Oncomine Focus DNA), HER2 CNV, HER2 expression by IHC, and AMNESIA were correlated with overall response rate (ORR), progression-free survival (PFS), and overall survival (OS) by univariable/multivariable models. Median HER2 CNV was 4.7 (interquartile range, 2.2-16.9). HER2 CNV-high versus low using the median as cutoff was associated with longer median PFS (10.5 vs. 6.4 months; HR = 0.48; 95% confidence interval: 0.38-0.62; P < 0.001) and OS (20.3 vs. 13.0 months; HR = 0.54; 0.42-0.72; P < 0.001). Combining HER2 CNV and IHC improved discriminative ability, with better outcomes restricted to HER2-high/HER2 3+ subgroup. AMNESIA positivity was found in 51 (16%), with unadjusted HR = 1.35 (0.98-1.86) for PFS; 1.43 (1.00-2.03) for OS.In multivariable models, only HER2 CNV status remained significant for PFS (P < 0.001) and OS (P = 0.004). Higher ORR was significantly associated with IHC 3+ [61% vs. 34% in 2+; OR = 3.11 (1.89-5.17)] and HER2-high [59% vs. 43% in HER2-low; OR = 1.84 (1.16-2.94)], with highest OR in the top CNV quartile. These biomarkers were not associated with treatment effect of pertuzumab. HER2 CNV-high assessed by NGS may be associated with better ORR, PFS, and OS in a JACOB subgroup, especially if combined with HER2 3+. The negative prognostic role of AMNESIA requires further clinical validation.

Pertuzumab, trastuzumab, and chemotherapy in HER2-positive gastric/gastroesophageal junction cancer: end-of-study analysis of the JACOB phase III randomized clinical trial

BackgroundDual-targeted anti-HER2 therapy significantly improves outcomes in HER2-positive breast cancer and could be beneficial in other HER2-positive cancers. JACOB’s end-of study analyses aimed to evaluate the long-term efficacy and safety of pertuzumab plus trastuzumab and chemotherapy for previously untreated HER2-positive metastatic gastric or gastroesophageal junction cancer.MethodsEligible patients were randomized 1:1 to pertuzumab/placebo plus trastuzumab and chemotherapy every 3 weeks. Primary endpoint: overall survival (OS). Secondary endpoints included progression-free survival (PFS), objective response rate (ORR), duration of response (DoR), and safety.ResultsThe intention-to-treat population comprised 388 patients in the pertuzumab arm and 392 in the placebo arm. The safety population comprised 385 and 388 patients, respectively. Median follow-up was ≥ 44.4 months. Median OS was increased by 3.9 months (hazard ratio 0.85 [95% confidence intervals, 0.72–0.99]) and median PFS by 1.3 months (hazard ratio 0.73 [95% confidence intervals, 0.62–0.85]) in the pertuzumab vs. the placebo arm. ORR was numerically higher (57.0% vs. 48.6%) and median DoR 1.8 months longer with pertuzumab treatment. There was a trend for more favorable hazard ratios in certain subgroups related to HER2 amplification/overexpression. Safety was comparable between arms, except for serious and grade 3–5 adverse events, and any-grade diarrhea, which were more frequent with pertuzumab.ConclusionsJACOB did not meet its primary endpoint. Nonetheless, the study continues to demonstrate some, albeit limited, evidence of treatment activity and an acceptable safety profile for pertuzumab plus trastuzumab and chemotherapy in previously untreated HER2-positive metastatic gastric or gastroesophageal junction cancer after long-term follow-up.Trial registration NCT01774786; https://clinicaltrials.gov/ct2/show/NCT01774786.

Retrospective Comparison of Chemotherapy Plus Anti-HER2 Therapies at First-line Treatment in Patients with Metastatic Gastric Adenocarcinoma

Aim: We aimed to compare the efficacy and the safety of cisplatin plus 5-FU plus trastuzumab and mFOLFOX-6 plus trastuzumab at first-line treatment in HER2-positive metastatic gastric cancer.&#x0D; Method: It was a retrospective observational monocentric study. Patients diagnosed with HER2-positive metastatic gastric adenocarcinoma between January 2013 and December 2020 in Dr AY Ankara Oncology TRH were screened. Patients treated at least one cycle of treatment with either CF-T or mFOLFOX-T were included. Survival outcomes and treatment compliance of patients were compared between groups.&#x0D; Results: Of 52 patients, 55.8% (n=29) of patients were treated with CF-T, and 44.2% (n=23) with mFOLFOX-T. The median age at diagnosis was 60 years (IQR: 52-70) in the CF-T and 64 years (IQR: 59-70) in the mFOLFOX-T groups. De novo metastatic disease comprised 96.6% (n=28) of patients in the CF-T and 69.6% (n=16) in the mFOLFOX-T groups (p=0.016). Both IHC3+ and ISH positivity were observed 82.8% (n=24) of patients in the CF-T and 56.5% (n=13) in mFOLFOX-T groups (p=0.038). The mPFS was 10.4 months (95% CI 8.7-12.2) in the CF-T and 6.5 months (95% CI 5.5-7.6) in the mFOLFOX-T groups (p=0.532). The mOS was 12.2 months (95% CI 11.3-13.2) in the CF-T and 12.5 months (95% CI 9.8-15.5) in the mFOLFOX-T groups (p=0.974). No statistically significant difference regarding at least one dose reduction (31.0% vs 21.7%, p=0.453) and at least one dose delay (24.1% vs 21.7%, p=0.838) was observed between groups.&#x0D; Conclusion: It was revealed that CF-T and mFOLFOX6-T had similar efficacy and tolerability in patients with HER2-positive metastatic gastric adenocarcinoma.

1206P HER2 copy number variation (CNV), HER2 expression and primary resistance mechanisms in patients (pts) with HER2-positive metastatic gastric or gastroesophageal junction cancer (mGC/GEJC) receiving first-line chemotherapy (CT) + trastuzumab (T) +/- pertuzumab (P) in the JACOB trial

In JACOB trial, P added to T-CT did not significantly improve overall survival (OS) in pts with HER2+ mGC/GEJC despite a 3.3 mos increase vs placebo. We previously showed a negative prognostic role of AMNESIA panel, including KRAS/PIK3CA/MET mutations and KRAS/EGFR/MET amplifications (Pietrantonio et al, CCR 2018), whereas higher HER2 CNV may be associated with better outcomes on T. These biomarkers may allow to better identify pts with higher benefit from HER2 inhibition. Among 780 pts enrolled in JACOB and 580 with available baseline tumor DNA, 327 samples were sequenced by Oncomine Focus DNA assay. In a post-hoc analysis, HER2 CNV, HER2 expression by IHC and AMNESIA were correlated with overall response rate (ORR), progression-free survival (PFS) and OS by uni-/multivariable models. Median HER2 CNV was 4.7 (IQR 2.2-16.9). By pooling treatment arms, HER2-high vs low status using the median as the cut-off value was associated with longer PFS (mPFS: 10.5 vs 6.4 mos; hazard ratio (HR)=0.48, 95%CI: 0.38-0.62; p<.001) and OS (mOS: 20.3 vs 13.0 mos; HR=0.54, 0.42-0.72; p<.001). Combining HER2 CNV and IHC improved the discriminative ability, with better outcomes restricted to HER2-high/HER2 3+ subgroup. AMNESIA positivity was found in 51 (16%), with unadjusted HR=1.35 (0.98-1.86) for PFS; 1.43 (1.00-2.03) for OS. HER2-high subgroup was enriched for AMNESIA-neg and HER2 3+ status. In multivariable models with main variables including treatment arm, only HER2 CNV status remained statistically significant for PFS (p<.001) and OS (p=.004). Higher ORR was significantly associated with IHC 3+ [61% vs 34% in 2+; odds ratio(OR)=3.11 (1.89-5.17)] and HER2-high [59% vs 43% in HER2-low; OR=1.84 (1.16-2.94), with highest OR in the top CNV quartile. The selected biomarkers were not associated with activity and efficacy of P added to T-CT. HER2-high CNV assessed by NGS is associated with significantly better ORR, PFS, OS in a pts subgroup from the JACOB trial, independent from treatment arm and especially if combined with HER2 3+.

Trastuzumab in combination with chemotherapy for HER2-positive metastatic gastric cancer patients underwent conversion therapy.

BackgroundConversion surgery is a treatment that aims for R0 resection of primary advanced gastric cancers (GCs) that have responded well to systemic chemotherapy. We investigated the role of conversion therapy in initially unresectable metastatic cancer with positive HER2 status that responded to chemotherapy plus trastuzumab.MethodsA total of 32 metastatic GC patients who underwent systemic chemotherapy plus trastuzumab sequenced by conversion surgery at Zhejiang Cancer Hospital between 2015 and 2020 were retrospectively reviewed.ResultsThe observed overall survival (OS) and progression-free survival (PFS) for all the patients were 30.2 and 25.1 months, respectively. The 1-year survival rate was 81.25%, and the 1-year PFS rate was 78.13%. Univariate and multivariate analyses demonstrated that liver metastasis (P=0.021), peritoneal metastasis (P=0.047), para-aortic lymph node metastasis (16a1/b2) (P=0.048), macroscopic type 4 (P=0.027), number of noncurative factors (P=0.011), Yoshida et al. category (P=0.021), and inductive chemotherapy cycles (P=0.025) were independent prognostic factors for OS.ConclusionsHER2-positive patients with potentially resectable disease had a remarkably good prognosis after conversion gastrectomy following trastuzumab treatment. Adequate selection of metastatic GC patients for conversion surgery is recommended.

First-line treatment of patients with HER2-positive metastatic gastric and gastroesophageal carcinoma

Fluoropyrimidine+cisplatin/oxaliplatin+trastuzumab therapy is recommended for the first-line treatment of human epidermal growth factor receptor 2 (HER2)-positive metastatic gastric adenocarcinoma. However, there is no comprehensive study on which platinum-based treatment should be preferred. This study aimed to compare the treatment response and survival characteristics of patients with HER2-positive metastatic gastric or gastroesophageal junction (GEJ) cancer who received fluorouracil, oxaliplatin, and leucovorin (mFOLFOX)+trastuzumab or cisplatin and fluorouracil (CF)+trastuzumab as first-line therapy. It was a multicenter, retrospective study of the Turkish Oncology Group, which included 243 patients from 21 oncology centers. There were 113 patients in the mFOLFOX+trastuzumab arm and 130 patients in the CF+trastuzumab arm. The median age was 62 years in the mFOLFOX+trastuzumab arm and 61 years in the CF+trastuzumab arm (p = 0.495). About 81.4% of patients in the mFOLFOX+trastuzumab arm and 83.1% in the CF+trastuzumab arm had gastric tumor localization (p = 0.735). The median progression-free survival (PFS) was significantly higher in the mFOLFOX+trastuzumab arm (9.4 months vs. 7.3 months, p = 0.024). The median overall survival (OS) was similar in both groups (18.4 months vs. 15.1 months, p = 0.640). Maintenance trastuzumab was continued after chemotherapy in 101 patients. In this subgroup, the median OS was 23.3 months and the median PFS was 13.3 months. In conclusion, mFOLFOX+trastuzumab is similar to CF+trastuzumab in terms of the median OS, but it is more effective in terms of the median PFS in the first-line treatment of HER2-positive metastatic gastric and GEJ cancer. The choice of treatment should be made by considering the prominent toxicity findings of the chemotherapy regimens.

Apatinib as a Third-Line Treatment for HER2-Positive Metastatic Gastric Cancer: A Multi-Center Single-Arm Cohort Study.

Treatment options are limited after the failure of first-and second-line treatments in patients with HER2+ metastatic gastric cancer (mGC). The present study aimed to explore the efficacy, safety, and prognostic factors of apatinib efficacy as a third-line therapy for patients with human epithelial growth factor receptor 2-positive (HER2+) mGC. A total of 59 HER2+ mGC patients who received apatinib as third-line therapy were retrospectively enrolled in this two-center, single-arm, cohort study; the clinical response, survival data, and adverse events were retrieved. The median progression-free survival (PFS) was 5.2 months (95% confidence interval [CI], 3.9-6.5), and the median overall survival (OS) was 8.2 months (95% CI, 6.6-9.8) Furthermore, forward stepwise multivariate Cox regression analysis showed that a higher Eastern Cooperative Oncology Group performance status score and multiple metastases were independently correlated with decreased PFS and OS (both P<0.05). The main adverse events were leukopenia (45.8%), hypertension (44.1%), thrombocytopenia (39.0%), hand-foot syndrome (37.3%), and elevated transaminase (33.9%). Grade 3 adverse events mainly included hypertension (5.1%) and neutropenia (5.1%); grade 4 adverse events did not occur. Apatinib is efficient and well tolerated in patients with HER2+ mGC as a third-line treatment, suggesting that it may be a candidate of choice for these patients.

450P Efficacy and safety of pyrotinib-based therapy in HER2-positive metastatic colorectal and gastric cancer: A retrospective study

Pyrotinib, an irreversible pan-Human epidermal growth factor receptor (HER）tyrosine kinase inhibitor, has shown its antineoplastic activity in HER2-positive metastatic breast cancer and HER2 mutation lung cancer. This retrospective study was designed to analyze the efficacy of pyrotinib-based therapy in HER2-positive metastatic colorectal and gastric cancer.

LBA55 Primary analysis of a phase II single-arm trial of trastuzumab deruxtecan (T-DXd) in western patients (Pts) with HER2-positive (HER2+) unresectable or metastatic gastric or gastroesophageal junction (GEJ) cancer who progressed on or after a trastuzumab-containing regimen

Overexpression and/or amplification of HER2 occurs in ∼20% of gastric or GEJ cancers. In DESTINY-Gastric01, the HER2-targeted antibody-drug conjugate T-DXd improved response and overall survival vs physician’s choice irinotecan/paclitaxel in pts from Japan/Korea with locally advanced or metastatic HER2+ gastric/GEJ cancer who progressed on ≥2L therapy including trastuzumab. Here, we report data from the single-arm, phase 2 DESTINY-Gastric02 trial, the first 2L study of T-DXd in Western pts with HER2+ gastric/GEJ cancer.

Treatment Patterns and Outcomes in Chinese Patients with Gastric Cancer by HER2 Status: A Noninterventional Registry Study (EVIDENCE).

Real-world safety and effectiveness data for trastuzumab plus chemotherapy treatment of patients with HER2-positive metastatic gastric cancer (mGC) in China are lacking. EVIDENCE was a prospective, multicenter, noninterventional registry study evaluating the safety and effectiveness of trastuzumab in five cohorts of Chinese patients with gastric cancer, stratified by HER2 status and trastuzumab treatment. Effectiveness was analyzed for cohorts I (HER2-positive, trastuzumab treated), II (HER2-positive, trastuzumab untreated), and IV (HER2-negative, trastuzumab untreated); trastuzumab-related adverse events (AEs) were analyzed for cohort I. Cohorts I, II, and IV included 174, 113, and 422 patients, respectively. Most patients received first-line chemotherapy (87.6%). Median overall survival (OS1) for first-line treatment was 22.3, 17.2, and 17.4 months in cohorts I, II, and IV, respectively. After excluding patients who had surgery, respective median OS1 was 19.9, 15.3, and 12.9 months. Respective first-line progression-free survival (PFS1) was 8.2, 6.9, and 6.2 months; and respective first-line response rates (RR) were 51.7%, 18.4%, and 32.8%. Cohort I was significantly favored over cohort II for propensity score-matched first-line median OS1 (hazard ratio [HR], 0.61), PFS1 (HR, 0.64), and RR (odds ratio, 4.93). Trastuzumab-related AEs, grade 3-5 AEs, serious AEs, and AEs with a fatal outcome occurred in 23.6%, 3.4%, 2.3%, and 0.6% of cohort I patients, respectively. Safety profiles were consistent with those known for trastuzumab and chemotherapy; trastuzumab treatment improved outcomes. Our study provides real-world data supporting first-line trastuzumab plus chemotherapy in Chinese patients with HER2-positive mGC. This prospective, noninterventional registry study aimed to provide safety and effectiveness data for the use of trastuzumab in combination with chemotherapy in Chinese patients with HER2-positive metastatic gastric cancer (mGC) from the real-world clinical setting. Trastuzumab plus first-line chemotherapy was shown to be safe and to improve outcomes when compared with patients treated with chemotherapy alone. Trastuzumab was effective within a range of treatment regimens; subgroup analysis showed that trastuzumab paired most effectively with the XELOX regimen. This study provides real-world clinical safety and effectiveness data supporting the use of trastuzumab in the treatment of Chinese patients with HER2-positive mGC.