Preclinical activity of MM-111, a bispecific ErbB2/ErbB3 antibody in previously treated ErbB2-positive gastric and gastroesophageal junction cancer.

2013 ◽  
Vol 31 (4_suppl) ◽  
pp. 48-48 ◽  
Author(s):  
Johanna Lahdenranta ◽  
Violette Paragas ◽  
Arthur J. Kudla ◽  
Ryan Overland ◽  
Victor M. Moyo ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Gastroesophageal Junction ◽  
Resistance Mechanism ◽  
Predictive Biomarkers ◽  
Her2 Overexpression ◽  
Multiple Time ◽  
Gastric Cancers ◽  
Treatment Regimens ◽  
Gastroesophageal Junction Cancer ◽  
Erbb3 Signaling

48 Background: ErbB2 (HER2) overexpression has been reported in 7-34% of gastric cancers. ErbB3 (HER3) is the preferred dimerization partner of ErbB2, and ErbB2/ErbB3 heterodimer activation is implicated in the progression and metastasis of ErbB2+ tumors. Activation of ErbB3 signaling is a postulated resistance mechanism to current ErbB2-directed therapies and select chemotherapies. In line with this research, ErbB3 levels are associated with poor prognosis in gastric cancers. MM-111 is a bi-specific antibody that docks to ErbB2 and inhibits ErbB3 signaling in cells that overexpress ErbB2. In this study, MM-111 was evaluated in ErbB2+ gastric cancer by testing the activity of MM-111 in ErbB2+ pre-clinical models of gastric cancer, and by assessing the prevalence of potentially predictive biomarkers in a panel of archived gastric and gastroesophageal junction (GEJ) tumors. Methods: MM-111 was tested in ErbB2+ gastric cancer xenografts that were either untreated or after tumors ceased to respond to trastuzumab/5-FU. Xenografts were analyzed at multiple time points for the expression of ErbB-receptor family members and their downstream signaling by Luminex -assays. Preclinical data indicate that ErbB2, ErbB3, and heregulin are predictive biomarkers for MM-111. In order to determine the prevalence of our potentially predictive biomarkers in gastric and GEJ cancers, we obtained commercially archived tumor tissue and assayed the tissue for ErbB2 and ErbB3 expression levels using quantitative IHC, and measured heregulin transcript levels by RT-PCR. Results: MM-111 synergizes with various treatment regimens in the 2nd line treatment setting in ErbB2+ gastric cancer xenografts. In our models, the combination of MM-111, trastuzumab, and paclitaxel is particularly effective after tumors progressed on trastuzumab/5-FU. MM-111 inhibits the activity of the ErbB –signaling axis in these models. In addition, 23% of GEJ tumor samples and 20% of gastric samples were positive for potentially predictive biomarkers. Conclusions: ErbB2+xenograft tumors that stop responding to trastuzumab-based therapies benefit from MM-111–based regimens.

Health-related quality of life (HRQOL) in patients (pts) with advanced gastric cancer/gastroesophageal junction cancer (GC/GEJC) or esophageal adenocarcinoma (EAC): Results of nivolumab plus chemotherapy (NIVO+chemo) versus chemo from CheckMate 649.

2021 ◽  
Vol 39 (28_suppl) ◽  
pp. 167-167
Author(s):  
Elena Elimova ◽  
Lucjan Wyrwicz ◽  
Steven I. Blum ◽  
Hong Xiao ◽  
Mingshun Li ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Gastroesophageal Junction ◽  
Well Being ◽  
Primary Analysis ◽  
Open Label ◽  
Cox Models ◽  
Study Objective ◽  
Gastroesophageal Junction Cancer ◽  
Patient Reported ◽  
Mean Differences

167 Background: CheckMate 649 (NCT02872116) is a randomized, open label phase 3 study in first line (1L) treatment of pts with advanced GC/GEJC/EAC. Primary analysis results showed statistically significant improvement in overall survival (OS) for NIVO+chemo vs. chemo in all randomized pts. We present HRQOL results for these pts, included as an exploratory study objective. Methods: HRQOL was assessed using EQ-5D-3L (EQ-5D) and Functional Assessment of Cancer Therapy–Gastric Cancer (FACT-Ga). Assessments were performed at baseline (BL), every 6 weeks during treatment and during follow-up. Change from BL EQ-5D Visual Analog Scale (VAS), Utility Index (UI) and FACT-Ga scores were analyzed using mixed models. Time to first symptom deterioration (TTSD), time until definitive deterioration (TuDD), and time to improvement (TTI) were estimated with Kaplan-Meier estimators and stratified Cox models; deterioration/improvement was based on prespecified meaningful change thresholds. Results: 1581 pts were randomized to NIVO+chemo (n = 789) or chemo (n = 792). Among 1359 pts with BL and post-BL patient-reported outcomes (NIVO+chemo, n = 693; chemo, n = 666), BL scores for FACT-Ga total were similar between treatment groups. Least squares mean differences from BL favored NIVO+chemo at most visits for EQ-5D, FACT-Ga total, and Gastric Cancer Subscale (GaCS), and were comparable for other subscales (not shown). TTI generally favored NIVO+chemo (most HR > 1) but was not significantly different between arms. TTSD was longer in NIVO+chemo arm compared with chemo alone (all HRs < 1), except for Emotional Well-Being (WB); only GaCS and FACT-Ga total were significantly different between arms. TuDD showed statistically significant delays in deterioration (HR with CI < 1) for all scores expect Social WB. Conclusions: Compared with chemo alone, the addition of NIVO to chemo maintained HRQoL with a decreased risk of symptom deterioration in patients with previously untreated advanced or metastatic GC/GEJC/EAC. Together with improved OS, these data support NIVO+chemo as a new 1L standard treatment for GC/GEJC/EAC. Clinical trial information: NCT02872116. [Table: see text]

scholarly journals Correction to: Developing real-world comparators for clinical trials in chemotherapy-refractory patients with gastric cancer or gastroesophageal junction cancer

2019 ◽  
Vol 23 (1) ◽  
pp. 142-142
Author(s):  
Ian Chau ◽  
Dung T. Le ◽  
Patrick A. Ott ◽  
Beata Korytowsky ◽  
Hannah Le ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Clinical Trials ◽  
Real World ◽  
Gastroesophageal Junction ◽  
Gastroesophageal Junction Cancer

ping real-world comparators for

Significance of accurate HER2 testing as a new biomarker in advanced gastric cancer.

2013 ◽  
Vol 31 (4_suppl) ◽  
pp. 106-106
Author(s):  
Tetsuya Kusumoto ◽  
Hajime Ohtsu ◽  
Hiroyuki Kawano ◽  
Koji Ando ◽  
Satoshi Ida ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Advanced Gastric Cancer ◽  
Gastroesophageal Junction ◽  
Tumor Biology ◽  
Japanese Patients ◽  
Her2 Expression ◽  
Her2 Positive ◽  
Her2 Testing ◽  
Gastroesophageal Junction Cancer ◽  
Her2 Heterogeneity

106 Background: The Trastuzumab for Gastric Cancer (ToGA) study is the first international trial to include Japanese patients with human epidermal growth factor 2 (HER2)-positive advanced or recurrent gastric or gastroesophageal junction cancer, which demonstrated that trastuzumab plus chemotherapy improved overall survival in the overall population (hazard ratio 0.74). HER2 testing in gastric cancer differs from testing in breast cancer due to inherent differences in tumor biology; gastric cancer more frequently shows HER2 heterogeneity and incomplete membrane staining. The aim of the present study was to evaluate the frequency of HER2-positive cases by application of the standard criteria in Japanese patients with advanced gastric cancer (AGC) and to investigate the relationships between HER2 expression and therapeutic responses. Methods: A total of 199 tumor samples were assessed for HER2 expression both by immunohistochemistry (IHC) and HER2 amplification by fluorescence in situ hybridization (FISH). HER2-positive status was defined as IHC2+ and FISH-positive or IHC3+. Objective responses were evaluated in the patients with AGC who were treated with chemotherapy plus trastuzumab or chemotherapy alone based on the HER2 expression status. Results: HER2-positive tumors were identified in 12 patients (5.5%), less than 28.1% in the Japanese subgroup analyses of ToGA study. The positive rates varied with histological type; 14%, 5.3% and 0.95% in the well, moderately and poorly differentiated adenocarcinoma, respectively. Although high concordance between the results of IHC and FISH in all samples was found, IHC2+ samples retested here showed FISH-negative. Of all 10 patients with AGC, 3 patients with HER2-positive tumor were treated with capecitabine/cisplatin plus trastuzumab, and partial response was found in 2 cases; response rates were 67%. Conclusions: Specific consideration and scoring modification are required before embarking on HER2 testing in gastric cancer. Accurate and reliable HER2 testing and scoring will allow appropriate selection of patients eligible for treatment with trastuzumab.

scholarly journals RAMUCIRUMAB THERAPY IN PATIENTS WITH ADVANCED GASTRIC AND GASTROESOPHAGEAL JUNCTION ADENOCARCINOMA: A SYSTEMATIC REVIEW

2017 ◽  
Vol 22 (3) ◽  
pp. 116-121
Author(s):  
V. A Gorbounova ◽  
N. S Besova ◽  
M. B Bychkov ◽  
S. V Orlov ◽  
L. M Kogoniya ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Gastroesophageal Junction ◽  
Locally Advanced ◽  
Growth Factor Receptor ◽  
Predictive Biomarkers ◽  
Antiangiogenic Agents ◽  
Gastroesophageal Cancer ◽  
Gastroesophageal Junction Adenocarcinoma ◽  
American Society ◽  
Endothelial Growth Factor

Objective. Gastric cancer is the fifth most common malignancy and the third leading cause of the cancer mortality worldwide. It is most often diagnosed at a locally advanced or metastatic stage. Angiogenesis has become an important target in the treatment of solid tumors, and antiangiogenic agents are a promising approach to cancer therapy. In this review, we summarize the current literature on the treatment of gastric and gastroesophageal cancer with ramucirumab, an antiangiogenic agent specifically targeting vascular endothelial growth factor receptor-2 (VEGFR-2). Material and methods. We conducted a systematic search in May 2016 of PubMed and relevant congress proceedings including the American Society of Clinical Oncology, the European Society for Medical Oncology, and the European Cancer Congress. Included studies were aimed to prospectively evaluate the efficacy and safety of ramucirumab in advanced gastric or gastroesophageal cancer. Results. Our search yielded 91 publications including 5 manuscripts and 6 congress abstracts meeting the predefined inclusion criteria. Included studies reported outcomes were related to ramucirumab in gastric cancer, published within the past 5 years. Conclusion. Second-line treatment with ramucirumab, either as monotherapy or in combination with paclitaxel, significantly improves the survival of patients with advanced gastric cancer. Ramucirumab is well tolerated and has an acceptable safety profile. Furthermore, the patient quality of life is maintained with delayed both symptom worsening and deterioration of the functional status. Studies are required to identify potential predictive biomarkers of ramucirumab efficacy.

A phase Ib study of IMU-131 HER2/neu peptide vaccine plus chemotherapy in patients with HER2/neu overexpressing metastatic or advanced adenocarcinoma of the stomach or gastroesophageal junction.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 4030-4030 ◽  
Author(s):  
Yee Chao ◽  
Thomas Yau ◽  
Marina Maglakelidze ◽  
Iurie Bulat ◽  
Suebpong Tanasanvimon ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
B Cell ◽  
Gastroesophageal Junction ◽  
Peptide Vaccine ◽  
Injection Site Reaction ◽  
Cell Vaccine ◽  
Her2 Overexpression ◽  
Breast Cancer Patients ◽  
Best Response ◽  
Dose Levels

4030 Background: Gastric cancer is the 5th most common cancer and the 3rd leading cause of cancer deaths. HER2/neu is overexpressed in 15% - 25% of patients with gastric cancer. Monoclonal antibodies against HER2/neu are effective but alternatives are needed due to cost and global availability. IMU-131 is a B-cell peptide vaccine composed of a fusion of 3 epitopes from the extracellular domain of HER2/neu conjugated to CRM197 with the adjuvant Montanide. Polyclonal antibodies against IMU-131 peptides elicit antitumor activity in vitro and a phase I study demonstrated safety and immunogenicity in Her-2 +/++ breast cancer patients. Methods: IMU-131 was given to patients with HER2/neu overexpressing gastric or gastroesophageal junction (GEJ) adenocarcinoma in an international open-label Phase 1b dose escalation trial performed in 14 Asian and Eastern European sites assessing safety, tolerability, and immunogenicity. Each patient received IMU-131 on Days 0, 14, and 35, accompanied by cisplatin and 5-fluorouracil or capecitabine every 21 days. Results: 14 patients were enrolled with advanced stage IIIb or IV with 10 HER2 overexpressing tumors (7 x HER2+++, 3 x HER2++ FISH positive) and 4 HER2++ expressing tumors. Mean age was 57 yo (range of 21 - 79) with ECOG scores of 0 or 1 in 7 patients each. There were 9 Asian and 5 Caucasian patients with 5 females and 9 males. Dose levels were 0.1, 0.3 and 0.5 mg with 3, 6, and 5 patients receiving those dose levels each. 11 patients received all 3 doses with 3 patients who received only 2 doses due to disease progression and 2 patients received a dose on day 182. Of the 14 patients dosed 11 were evaluable for tumor progression at day 56 and later. Of those patients, the best response was 1 CR, 4 PR,5 SD and 1 PD. In the 0.1 mg dose group the best response was 1 CR and 2 SD, with 2 PR, 2 SD and 1 PD in the 0.3 mg group and 2 PR and 1 SD in the 0.5 mg group. In patients with HER2 overexpression there was 1 CR, 4 PR, 2 SD and 1 PD, and in patients with HER2++ expression there was 3 SD. There were no SAEs related to IMU-131 and 1 patient had a mild injection site reaction. Conclusions: IMU-131 is a promising B-Cell vaccine against HER2. Further work in a controlled phase 2 trial is ongoing. Clinical trial information: NCT02795988.

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