scholarly journals Molecular Targets for Gastric Cancer Treatment and Future Perspectives from a Clinical and Translational Point of View

Cancers ◽  
2021 ◽  
Vol 13 (20) ◽  
pp. 5216
Author(s):  
Justus Körfer ◽  
Florian Lordick ◽  
Ulrich T. Hacker
Keyword(s):  
Gastric Cancer ◽  
Targeted Therapy ◽  
Molecular Characterization ◽  
Gastroesophageal Junction ◽  
Standard Of Care ◽  
Metastatic Gastric Cancer ◽  
Point Of View ◽  
Current Status ◽  
Molecular Alterations ◽  
Definition Of

Gastric cancer is a leading cause of cancer death worldwide. Systemic treatment comprising chemotherapy and targeted therapy is the standard of care in advanced/metastatic gastric cancer. Comprehensive molecular characterization of gastric adenocarcinomas by the TCGA Consortium and ACRG has resulted in the definition of distinct molecular subtypes. These efforts have in parallel built a basis for the development of novel molecularly stratified treatment approaches. Based on this molecular characterization, an increasing number of specific genomic alterations can potentially serve as treatment targets. Consequently, the development of promising compounds is ongoing. In this review, key molecular alterations in gastric and gastroesophageal junction cancers will be addressed. Finally, the current status of the translation of targeted therapy towards clinical applications will be reviewed.

A phase Ib/II, multicenter, open-label, dose-escalation, and dose-expansion study evaluating trastuzumab deruxtecan (T-DXd, DS-8201) monotherapy and combinations in patients with HER2-overexpressing gastric cancer (DESTINY-Gastric03).

2021 ◽  
Vol 39 (3_suppl) ◽  
pp. TPS261-TPS261
Author(s):  
Yelena Y. Janjigian ◽  
Natasha Viglianti ◽  
Feng Liu ◽  
Ariadna Mendoza-Naranjo ◽  
Liz Croydon
Keyword(s):  
Gastric Cancer ◽  
Dose Escalation ◽  
Topoisomerase I ◽  
Gastroesophageal Junction ◽  
Objective Response ◽  
Locally Advanced ◽  
Metastatic Gastric Cancer ◽  
Her2 Status ◽  
Open Label ◽  
Phase 1B

TPS261 Background: For patients (pts) with HER2-overexpressing metastatic gastric cancer, trastuzumab + chemotherapy is a standard first-line option but provides only a modest overall survival (OS) benefit vs chemotherapy. T-DXd is an antibody-drug conjugate consisting of an anti-HER2 antibody, cleavable tetrapeptide-based linker, and a membrane-permeable topoisomerase I inhibitor payload. Results from a phase 1 trial showed promising antitumor activity (confirmed objective response rate [ORR], 43.2%) in pts with heavily pretreated HER2+ metastatic gastric cancer who received T-DXd (5.4 or 6.4 mg/kg; Shitara K, et al. Lancet Oncol. 2019;20:827-836). Here we describe the phase 1b/2 DESTINY-Gastric03 trial (NCT04379596) evaluating T-DXd monotherapy and combinations in pts with HER2-overexpressing gastric cancer. Methods: This is an open-label, multicenter, 2-part, phase 1b/2 study in pts with HER2-overexpressing (immunohistochemistry [IHC] 3+ or IHC 2+/in situ hybridization positive) locally advanced, unresectable or metastatic gastric or gastroesophageal junction cancer. In part 1 (dose escalation), pts who had received prior trastuzumab-containing therapy will be assigned to 1 of 5 arms: (1) T-DXd + 5-fluorouracil (5-FU); (2) T-DXd + capecitabine (C); (3) T-DXd + durvalumab; (4) T-DXd + 5-FU or C + oxaliplatin (Ox); or (5) T-DXd + 5-FU or C + durvalumab. In part 2 (dose expansion), pts with no prior treatment for metastatic disease will be randomized across 4 arms: (1) T-DXd; (2) trastuzumab + 5-FU or C + Ox or cisplatin; (3) T-DXd + 5-FU or C ± Ox; or (4) T-DXd + 5-FU or C + durvalumab. In part 2, pts will be stratified by HER2 status. Primary endpoints are safety, determination of recommended phase 2 doses (part 1), and investigator-assessed confirmed ORR per RECIST v1.1 (part 2). Secondary endpoints include confirmed ORR (part 1), disease control rate, duration of response, progression-free survival (all per investigator), OS, safety (part 2), pharmacokinetics, and immunogenicity. Clinical trial information: NCT04379596.

scholarly journals Differences in outcome according to chemotherapy backbone and maintenance treatment in HER2 positive metastatic gastric cancer (GC) or gastroesophageal junction (GEJ)

2018 ◽  
Vol 29 ◽  
pp. viii225
Author(s):  
N. Martinez Lago ◽  
S. Candamio Folgar ◽  
C. Grande Ventura ◽  
M. Salgado Fernandez ◽  
J. De la Camara Gomez ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Maintenance Treatment ◽  
Gastroesophageal Junction ◽  
Metastatic Gastric Cancer ◽  
Her2 Positive

Pembrolizumab (MK-3475) for recurrent or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma: Multicohort phase II KEYNOTE-059 study.

2016 ◽  
Vol 34 (4_suppl) ◽  
pp. TPS184-TPS184 ◽  
Author(s):  
Charles S. Fuchs ◽  
Andrew E. Denker ◽  
Josep Tabernero ◽  
Eric Van Cutsem ◽  
Atsushi Ohtsu ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Phase Ii ◽  
Gastroesophageal Junction ◽  
Metastatic Gastric Cancer ◽  
Response Patterns ◽  
Prior Chemotherapy ◽  
End Point ◽  
Duration Of Response ◽  
Treatment Naïve ◽  
Ecog Ps

TPS184 Background: Pembrolizumab (pembro) is a humanized monoclonal antibody that targets the PD-1 receptor and prevents it from interacting with its ligands, PD-L1 and PD-L2. In the phase I KEYNOTE-012 trial, pembro showed an acceptable safety profile and promising antitumor activity in patients (pts) with PD-L1+ metastatic gastric cancer. The multicohort, phase II KEYNOTE-059 (NCT02335411) trial was designed to further evaluate pembro as monotherapy or in combination with 5-fluorouracil (5-FU) and cisplatin in pts with advanced gastric cancer. Methods: Patients ≥ 18 y who have relapsed or metastatic gastric or GEJ adenocarcinoma, ECOG PS 0-1, no active autoimmune disease or brain metastases, and no prior chemotherapy within 2 wk of the first dose of pembro are eligible. PD-L1 expression status will be determined by IHC using the 22C3 antibody (Merck). In cohort 1 (C1), up to 180 pts with any PD-L1 status whose disease progressed on ≥ 2 prior chemotherapy regimens, including a fluoropyrimidine and platinum doublet and, if HER2+, trastuzumab, will receive pembro 200 mg Q3W. In cohort 2 (C2), ~12 Asian and ~6 non-Asian, treatment-naive, HER2– pts of any PD-L1 status will receive pembro 200 mg Q3W + infusional 5-FU or capecitabine and 6 cycles of cisplatin. In cohort 3 (C3), ~25 treatment-naive pts with HER2–/PD-L1+ tumors will receive pembro 200 mg Q3W. Treatment may continue for up to 24 mo or until progression, intolerable toxicity, or investigator decision. Response will be assessed at wk 9 and every 6 wk thereafter per RECIST v1.1 and RECIST v1.1 adapted for immunotherapy response patterns. Treatment may be discontinued for eligible pts who have a CR. Eligible pts may continue treatment beyond initial RECIST-defined progression. AEs will be collected throughout the study and for 30 d thereafter (90 d for serious AEs) and graded per NCI CTCAE v4.0. The primary efficacy end point for C1 and C3 is ORR per RECIST v1.1 by central review; the primary end point for C2 is safety and tolerability of the combination. Secondary end points include PFS, OS, DCR, and duration of response. Enrollment in KEYNOTE-059 is ongoing and will continue until up to 223 pts are enrolled across all cohorts. Clinical trial information: NCT02335411.

scholarly journals Case report of the rapid achievement of sustained and long-term remission resulting from the use of ramucirumab plus paclitaxel in the second-line treatment of a patient with disseminated gastric adenocarcinoma

2018 ◽  
pp. 150-153
Author(s):  
T. A. Titova ◽  
N. S. Besova ◽  
V. A. Gorbunova ◽  
Yu. P. Kuvshinov ◽  
A. A. Filatov ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Advanced Gastric Cancer ◽  
High Efficiency ◽  
Performance Status ◽  
Gastroesophageal Junction ◽  
Growth Factor Receptor ◽  
Metastatic Gastric Cancer ◽  
Best Supportive Care ◽  
Serious Adverse Events ◽  
Endothelial Growth Factor

Ramucirumab is a monoclonal antibody targeting vascular endothelial growth factor receptor 2. In two randomised clinical trials Ramucirumab either alone or in combination with paclitaxel has been found to be safe and effective for patients with previously treated advanced gastric cancer. One of the serious adverse events associated with ramucirumab is bleeding.We report the case of a 56-year-old man with advanced gastric cancer located at the gastroesophageal junction with liver, pulmonary and multiple lymph node metastases, plevritis was treated with a paclitaxel plus Ramucirumab regimen. We demonstrate a case of a cardioesophageal junction bleeding due to the high efficiency of treatment. He was successfully treated with by applying only hemostatical therapy, but after stop the bleeding chemotherapy was not reintroduced. The partial response was maintained for approximately 10 months. The patient died on 28 November 2017.Chemotherapy with best supportive care for metastatic gastric cancer shown the improvement the performance status, help keep the cancer under control and help relieve symptoms during the time.

TOPGEAR: An international randomized phase III trial of preoperative chemoradiotherapy versus preoperative chemotherapy for resectable gastric cancer (AGITG/TROG/EORTC/NCIC CTG).

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. TPS4141-TPS4141 ◽  
Author(s):  
Trevor Leong ◽  
Mark Smithers ◽  
Michael Michael ◽  
Val Gebski ◽  
Alex Boussioutas ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Adjuvant Therapy ◽  
Phase Ii ◽  
Preoperative Chemotherapy ◽  
Gastroesophageal Junction ◽  
Phase Iii ◽  
Standards Of Care ◽  
Current Status ◽  
Quality Assurance Program ◽  
Resectable Gastric Cancer

TPS4141 Background: Optimal management of patients with resectable gastric cancer remains unknown. Since the INT0116 and MAGIC trials, there are 2 standards of care for adjuvant therapy: postoperative chemoradiotherapy (CRT) and perioperative ECF chemotherapy. The important question arising from these studies is whether CRT is superior to chemotherapy alone as adjuvant therapy. This randomized phase II/III trial will compare CRT to chemotherapy alone in the preoperative setting. Methods: Patients with resectable adenocarcinoma of the stomach or gastroesophageal junction will be randomized to receive either preoperative chemotherapy alone (ECFx3 as per MAGIC regimen) or preoperative CRT (ECFx2 followed by 45Gy of radiation with concurrent 5-FU). Following surgery, both groups will receive 3 further cycles of ECF. The trial is being conducted in two Parts; Part I (phase II component) will recruit 120 patients with the aim of demonstrating sufficient efficacy and safety of preoperative CRT, as well as trial feasibility. Part II (phase III component) will recruit a further 632 patients to provide a total of 752. The primary endpoint for Part I is pathological complete response rate, and for Part 2 it is overall survival. The trial includes formal quality of life and biological sub-studies. In addition, the trial incorporates a rigorous quality assurance program that includes real time central review of radiotherapy plans and central review of surgical technique. Current status: This study is an international, intergroup trial led by the Australasian Gastro-Intestinal Trials Group (AGITG), in collaboration with the Trans-Tasman Radiation Oncology Group (TROG), European Organisation for Research and Treatment of Cancer (EORTC) and the NCIC Clinical Trials Group. To date, 36 patients have been recruited from 20 sites in Australia and New Zealand; European and Canadian sites will commence recruitment in 2012.

Docetaxel, oxaliplatin, and capecitabine (DOX) combination chemotherapy for metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e15065-e15065 ◽  
Author(s):  
Luigi Di Lauro ◽  
Domenico Sergi ◽  
Franca Belli ◽  
Silvia Ileana Fattoruso ◽  
Maria Grazia Arena ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Combination Chemotherapy ◽  
Gastroesophageal Junction ◽  
Distant Metastases ◽  
Metastatic Gastric Cancer ◽  
Secondary Prophylaxis ◽  
Stage Design ◽  
Grade 3 ◽  
Ecog Ps ◽  
Disease Location

e15065 Background: So far, the prognosis of advanced gastric cancer is dismal. Combination chemotherapy of docetaxel (D), cisplatin (C) and fluorouracil (F) showed activity in metastatic gastric cancer, but this regimen was complicated by a high incidence of myelotoxicity. We performed a multicenter phase II trial substituting C with oxaliplatin (O) and F with capecitabine (X) in chemotherapy-naive patients (pts) with gastric or GEJ adenocarcinoma. Methods: Pts with measurable distant metastases received D 60 mg/mq iv, O 100 mg/mq iv on day 1 and X 500 mg/mq orally twice daily continuously, with cycles repeated every 3 weeks for a maximum of 8. G-CSF was used only as secondary prophylaxis. The primary endpoint was overall response rate (RR) according to RECIST. Toxicity was reported according to NCI-CTC v 3.0. Optimal Simon's two-stage design was employed with 6/15 responses required in the first stage to allow continuation to 46 pts. Results: 46 pts were enrolled: M/F 28/18; median age 66 years (32-75); median ECOG PS 1 (0-2); primary tumor resected/ unresected 16/30; disease location was gastric in 34 and GEJ in 12 pts; sites of disease were liver in 27, nodes in 25, peritoneum in 20, lung in 8 and bone in 5 pts. At the time of analysis all pts were evaluable for response and toxicity. In 46 pts, 3 CR and 21 PR were observed, for an overall RR of 52.1% (95% CI, 37.7%-66.5%). Responses were obtained in 15/27 pts (55%) with liver metastases. Disease remained stable in 14 pts (30.5 %). Median TTP was 6.8 months and median OS was 12.6 months. Grade 3/4 neutropenia, thrombocytopenia and anemia occurred in 41%, 4% and 9% of the pts, respectively. Febrile neutropenia was observed in 2 pts (4%). Other grade 3 toxicities included mucositis in 2 pts (4%), vomiting in 3 pts (6.5%) and diarrhea in 2 pt (4%). There were no severe neurotoxicity, nor treatment-related deaths. Conclusions: The DOX combination is an active and well tolerated novel chemotherapy regimen for treating metastatic gastric or GEJ adenocarcinoma and deserves further evaluation in randomized trials and, hopefully, in neoadjuvant setting.

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