HER2-positive Gastric Adenocarcinoma Research Articles

Sustained Clinical Complete Response after Discontinuation of Trastuzumab-deruxetecan Due to Interstitial Pneumonia for HER2-positive Gastric adenocarcinoma with Enteroblastic Differentiation (GAED): A Case Report.

Trastuzumab deruxtecan (T-DXd) has demonstrated remarkable efficacy as a third- or later-line chemotherapy for human epidermal growth factor receptor 2 (HER2)-positive advanced gastric and gastroesophageal junction adenocarcinomas. However, it may cause pneumonitis, and its efficacy in rare histologies such as gastric adenocarcinoma with enteroblastic differentiation (GAED) remains unclear. A 74-year-old woman with unresectable HER2-positive GAED and lung metastasis received T-DXd as a fifth-line chemotherapy. Treatment was discontinued after 15 cycles owing to drug-induced pneumonitis; however, the patient achieved a sustained complete response for 14 months without subsequent chemotherapy or the exacerbation of pneumonitis. T-DXd was effective in HER2-positive GAED.

Current management of gastric adenocarcinoma: a narrative review.

Gastric adenocarcinoma is a leading cause of cancer death worldwide. The management of this aggressive malignancy largely depends on tumor characteristics especially stage. Superficial early-stage gastric cancer can be safely managed by endoscopic resection, though clear negative deep and lateral margins must be obtained. Optimal surgical resection is an essential part of the treatment for locally advanced gastric adenocarcinoma, with perioperative and adjuvant therapies having significant impact on long-term outcomes. Chemoradiation is reserved for patients with suboptimal surgical resection. Recent therapeutic advances have prolonged survival in patients with metastatic gastric adenocarcinoma, include checkpoint inhibitors and biomarker-directed therapy. Targeted therapies in gastric adenocarcinoma include monoclonal antibodies directed against vascular endothelial growth factor (VEGF), vascular endothelial growth factor receptor-2 (VEGFR-2), and human epidermal growth factor receptor 2 (HER2). While anti-VEGF therapies were not found beneficial in the perioperative setting, the effectiveness of HER2 targeted agents in resectable HER2-positive gastric adenocarcinoma is being studied. Microsatellite instability (MSI) varies greatly in patients with gastric adenocarcinoma between 5-20% based on ethnic origin, tumour heterogeneity and staging. The role chemotherapy in the perioperative setting for patients with MSI-high tumors remains controversial while immunotherapy demonstrates promising results in preliminary studies. Immune checkpoint inhibitors in combination with chemotherapy has been shown to improve outcomes in patients with metastatic gastric adenocarcinoma who express programmed cell death 1 ligand 1 (PD-L1) and is now being investigated in the perioperative setting.

Anlotinib plus chemotherapy as first-line therapy for gastrointestinal tumor patients with unresectable liver metastasis: A multicenter, multicohort clinical trial (ALTER-G-001).

TPS229 Background: Liver metastases (LMs) are usually found in gastrointestinal tumors, such as colorectal cancer (mCRC), esophageal squamous cell carcinoma (ESCC) and gastric cancer. Currently, there is no formal option for such patients (pts) due to the different pathological characteristics, and more effective treatment regimens are needed. Anlotinib is an oral multi-targeted tyrosine kinase inhibitor targeting VEGFR1/2/3, FGFR1-4, PDGFRα/β and c-Kit, which effectively blocks tumor neovascularization and growth. Previous phase II clinical trials suggested that anlotinib plus chemotherapy as first-line therapy were well tolerated and showed clinical anti-tumor activity in mCRC and ESCC. It was demonstrated an objective response rate (ORR) of 76.7%, a disease control rate (DCR) of 93.3% and a median progression-free survival (mPFS) of 11.4 months in RAS/BRAF wild-type unresectable mCRC pts using anlotinib plus CAPEOX (ALTER-C002 trial, NCT04080843). Additionally, preliminary encouraging ORR (78.3%), DCR (93.5%) and mPFS (8.38 months) was observed in advanced ESCC pts treated with anlotinib plus cisplatin and paclitaxel (ALTER-E002 trial, NCT04063683). Based on these results, this multicohort, multicenter phase II ALTER-G-001 trial was launched to evaluate efficacy and safety of anlotinib plus chemotherapy as first-line therapy in gastrointestinal tumor pts with unresectable LMs. Methods: Previously untreated and histologically or cytologically confirmed gastrointestinal tumor pts with unresectable LMs were eligible, who will be divided into 3 cohorts, including mCRC (n = 45), ESCC (n = 31) and others (n = 25). Pts must be aged 18-75 years, with an ECOG PS of 0/1, adequate organ function, and at least one measurable LMs lesion according to RECIST v1.1. HER2-positive gastric adenocarcinoma, and pts with a high risk of bleeding, perforation or fistulas will be excluded. During first 6 cycles (3 weeks per cycle) of inducing treatment, mCRC pts will receive anlotinib (12mg, po, qd, d1-d14), oxaliplatin (130 mg/m2, iv, d1) and capecitabine (850 mg/m2, po, bid, d1-d14). ESCC pts will be treated with anlotinib, cisplatin (60-750 mg/m2, i.v., d1/d1-3) along with paclitaxel (135 mg/m2, i.v., d1) or docetaxel (75 mg/m2, i.v., d1). And pts in others cohort will receive anlotinib plus standard first-line chemotherapy. Then, pts without PD and LMs resection, will receive anlotinib and metronomic capecitabine (500mg, po. bid, d1-21, q3w) until PD or unacceptable toxicity. Primary endpoint is investigator-assessed ORR (RECIST 1.1). Secondary endpoints include duration of response (DoR), PFS, overall survival, DCR, radical resection rate for LMs and safety (NCI-CTCAE v5.0). Research sponsor: Chia Tai Tianqing Pharmaceutical Group Co., Ltd. Clinical trial information: ChiCTR2100050872.

HER2 Splice Site Mutation c.1899-1G>A as the Potential Acquired Resistance to Trastuzumab in a Patient with HER2-Positive Gastric Adenocarcinoma.

The addition of trastuzumab to chemotherapy regimen is the standard of care for human epidermal growth factor receptor 2 (HER2)-positive advanced gastric cancer; however, most patients eventually acquire trastuzumab resistance. Although some resistance mechanisms to trastuzumab-based regimens have been proposed, further understanding is required for developing therapeutic strategies to overcome the resistance. In the present work, we attempted to determine the possible resistance mechanism to trastuzumab in a patient with HER2-positive stage IV gastric adenocarcinoma. In this study, we first report the nucleotide change c.1899-1G>A at the intron 15 acceptor splice site promoting exon 16 deletion of HER2 as the potential mechanism of trastuzumab resistance in HER2-positive gastric adenocarcinoma. KEY POINTS: The combination of trastuzumab with chemotherapy is considered to be the standard therapy for HER2-positive advanced gastric cancer (GC), but most of the patients eventually acquire trastuzumab resistance. The mechanisms of resistance to trastuzumab in GC are poorly characterized. To the best of the authors' knowledge, this study is the first to implicate HER2 c.1899-1G>A, which results in exon 16 skpping, as the acquired resistance mechanism to trastuzumab in HER2-positive gastric adenocarcinoma. This work provides insights into the potential molecular mechanism of trastuzumab resistance, which is crucial in developing effective therapeutic strategies for HER2-positive GC patients refractory to trastuzumab.

Novel HER2-Directed Treatments in Advanced Gastric Carcinoma: AnotHER Paradigm Shift?

Simple SummaryMore than ten years after the first publication of the results of the ToGA phase III trial, active research avenues are exploring the role of novel agents targeting human epidermal growth factor receptor 2 (HER2). Preliminary reports have highlighted promising activity for several therapeutics, including the recently approved trastuzumab deruxtecan in pretreated GC patients. Herein, we discuss novel therapeutic opportunities in this setting.Human epidermal growth factor receptor 2 (HER2) is overexpressed and/or amplified in approximately 15–20% of gastric adenocarcinoma (GC) patients. In 2010, the landmark ToGA trial established the combination of trastuzumab plus chemotherapy as the first-line standard of care for HER2-positive GC patients with advanced disease. However, subsequent studies on HER2 targeted therapies in this setting failed to meet their primary endpoints, and not all HER2-positive GC patients benefit from targeted approaches. More recently, novel HER2-directed treatments have been investigated, including trastuzumab deruxtecan (T-Dxd); following the results of the DESTINY-Gastric01 study, T-Dxd received its first U.S. Food and Drug Administration (FDA) approval on 15 January 2021 for the treatment of adults with unresectable, locally advanced, or metastatic GC who have received a prior trastuzumab-based regimen. In this review, we discuss the current HER2-targeted treatments for GC in the advanced disease setting, mainly focusing on emerging new treatments and future research directions.

Perioperative trastuzumab, capecitabine and oxaliplatin in patients with HER2-positive resectable gastric or gastro-oesophageal junction adenocarcinoma: NEOHX phase II trial

IntroductionPerioperative chemotherapy improves overall survival (OS) and disease-free survival (DFS) compared with surgery alone in patients with resectable gastric adenocarcinoma (GA) or gastro-oesophageal junction adenocarcinoma (GEJA). The addition of trastuzumab to chemotherapy improves outcomes in patients with HER2-positive advanced gastric cancer (GC), and we aimed to explore its role in the perioperative setting. Material and methodsThis Spanish, multicentre, open-label phase II trial evaluated the efficacy and toxicity of perioperative capecitabine, oxaliplatin and trastuzumab (XELOX-T) in patients with HER2-positive resectable GA or GEJA. The primary end-point was 18-months DFS; and secondary end-points included pathological complete response (pCR) rate, R0 resection rate, OS and toxicity (NCT01130337). ResultsThirty-six patients were included. After three cycles of preoperative treatment, 14 patients (38% of the intention-to-treat population) had partial response and 18 (50%) had stable disease. Surgery was performed in 31 patients: 28 (90%) had R0 resection, three (9.6%) had a pCR and three (9.6%) died due to surgical complications. A total of 24 patients received post-operative XELOX-T, 22 of whom completed trastuzumab maintenance. Main grade III/IV toxicities included diarrhoea (33%), nausea and vomiting (8%). After a median follow-up of 24.1 months, 18-month DFS was 71% (95% confidence interval [CI], 53–83%); and an update after 102 months of follow-up showed a median OS of 79.9 months and a 60-month OS of 58% (95% CI, 40–73%). ConclusionsThese data suggest that perioperative XELOX-T in patients with HER2-positive GA and GEJA is feasible and active. Further investigation in randomised studies is warranted.

Safety and preliminary antitumor activity of the transforming growth factor beta (TGF-β) receptor I kinase inhibitor, vactosertib, in combination with paclitaxel in patients with metastatic gastric adenocarcinoma.

e16505 Background: Recent studies demonstrated that TGF-β signaling attenuation in combination with paclitaxel inhibits epithelial-to-mesenchymal transition and cancer stem-like cells features, especially in diffuse type. We are reporting dose finding part in phase 1b study evaluating the combination of vactosertib, a highly selective and potent TGF-β inhibitor, with paclitaxel as a second line treatment in patients with metastatic gastric adenocarcinoma (GA). Methods: Eligible patients (pts) are ≥19 years old, have ECOG status ≤1, and have progressed on the first line treatment of metastatic GA treated with the combination therapy of fluoropyrimidine and platinum, or trastuzumab containing combination therapy in HER2-positive GA. The primary objective is to assess the safety and recommended phase 2 dose (RP2D) of vactosertib given 5 days on/2 days off in combination with weekly paclitaxel 80 mg/m2. Three dose levels of vactosertib (100, 200, and 300 mg BID) were tested. Results: As of Jan. 25, 2020, 12 pts were enrolled to the study (6, 3, and 3 pts in 100, 200, and 300 mg BID, respectively) and finished the safety evaluation. Median age was 50 (range, 39-65), 50% were male, and 75% had gastrectomy (4 pts with subtotal gastrectomy; 5 pts with total gastrectomy). At all cohorts, no dose limiting toxicity was observed. The most frequently reported treatment related adverse events (AEs) were anemia (50.0%), anorexia (41.6%), fatigue (33.3%), and urticaria (33.3%). AEs were mostly grade 1 or 2 and manageable. One case of grade 3 anorexia was reported as a treatment-related severe adverse event. Among 6 evaluable patients in 200/300 mg BID cohorts, the best responses to treatment were partial response in 1 patient; 57% decrease from baseline, 16.7% of overall response rate, and 83.3% of disease control rate at 12 weeks. Median progression free survival of the RP2D cohort has not been reached yet. Updated safety, PK, efficacy and biomarker data will be presented at the meeting. Conclusions: The combination of vactosertib plus paclitaxel has been well tolerated. The anti-tumor activity of this combination in patients with metastatic GA is now under exploration in the phase 2a part of the study. Clinical trial information: NCT03698825 .

Re-evaluation of HER2 status in patients with HER2-positive advanced or recurrent gastric cancer refractory to trastuzumab (KSCC1604)

BackgroundAnti-HER2 therapy has not demonstrated a survival advantage in the second-line setting of patients with HER2-positive gastric cancer. We conducted this study to assess changes in HER2 status and to identify possible biomarkers for acquired resistance after the use of trastuzumab as the first-line therapy. Patients and methodsPatients with advanced or recurrent HER2-positive gastric adenocarcinoma who were diagnosed with progressive disease after the first-line trastuzumab-based therapy and developed pathologically confirmed adenocarcinoma within 3 months after completion of trastuzumab-based therapy were enrolled in this study. We collected re-biopsied samples from the HER2-positive patients who had developed resistance to trastuzumab and re-evaluated their HER2 status. Amplification of EGFR and c-met, as well as PIK3CA mutation, were comparatively analysed when samples were available. ResultsAmong 33 eligible patients, loss of HER2 was identified in 20 patients (60.6%) with refractory disease. Immunohistochemistry showed that the rate of HER2 overexpression was greatly reduced after therapy (pre-HER2 3+: 24 [72.7%] vs. post-HER2 3+: 13 [39.4%]). We found that the use of fixatives other than 10% neutral buffered formalin significantly reduced the HER2-positive rate. EGFR amplification, c-met amplification and PIK3CA mutation before and after trastuzumab-based therapy were observed in 10.3% and 3.8%, 17.9% and 4.2% and 4.0% and 4.2% of cases, respectively. ConclusionRe-evaluation of HER2 status is needed to determine the appropriate use of anti-HER2–targeted therapy after disease progression. Our results also highlight the importance of formalin fixation conditions for HER2 testing.

Current Targeted Therapies in HER2-Positive Gastric Adenocarcinoma.

Gastric cancer is one of the most common types of cancer in the world, usually diagnosed at an advanced stage. Despite the advances in specific anticancer agents' development, the survival rates remain modest, even in early stages. In 15%-20% of cases, the human epidermal growth factor receptor 2 (HER2) overexpression was identified. We conducted a general review to summarize the progress that has been made in the targeted treatment of HER2-positive esogastric junction or gastric adenocarcinoma. According to our findings, trastuzumab is the only validated anti-HER2 agent in locally advanced or metastatic disease and its adjuvant effectiveness is assessed in a RTOG phase III study. In a previously treated advanced disease, the maytansine derivate TDM 1 failed to be approved as a second-line regimen, and the tyrosine kinase inhibitor, lapatinib, shows modest results. The antiangiogenics have not been analyzed in specific populations and targeting the mesenchymal-epithelial transition factor (MET) receptor, overexpressed in up to 46% of the advanced disease, seems encouraging. Regarding the checkpoint inhibitors, based on KEYNOTE 059 multilevel ongoing trial, stratified according to the HER2 and programmed death-ligand (PD-L) 1 status, pembrolizumab was approved for third-line treatment of gastric or gastroesophageal junction adenocarcinoma.

Targeted therapies of HER2-positive gastric adenocarcinoma

Targeted therapies of HER2-positive gastric adenocarcinoma

Targeted therapies of HER2-positive gastric adenocarcinoma

Worldwide, gastric cancer is the fifth common cancer type and causes the third most cancer-associated deaths (1), mostly due to its commonly fatal outcome especially in locally advanced or metastatic disease. For over a decade, standard of care in metastatic disease was based on chemotherapy doublets or triplets containing platinum agents plus fluoropyrimidine in combination with either taxanes or anthracyclines (2). Molecular subtyping of gastric adenocarcinoma has identified promising protooncogenes as novel therapeutic targets (3). One of them is the human epidermal growth factor receptor 2 (HER2/ERBB2), detected in a subset of roughly 9% to 18% of gastric adenocarcinomas (4).