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Progress and challenges in HER2-positive gastroesophageal adenocarcinoma.

ABSTRACT: HER2 expression remains an important biomarker to guide the addition of the monoclonal antibody trastuzumab to first-line systemic chemotherapy in unresectable, metastatic gastroesophageal adenocarcinomas (GEA). However, in contrast to breast cancer, other HER2-targeted strategies to date have not improved outcomes in this molecular subtype of GEA. Since the initial development of HER2 biomarker testing guidelines, significant spatial intratumoral heterogeneity of HER2 overexpression has been recognized as a major characteristic of this disease. In this review, we aim to survey the seminal positive and negative trials investigating HER2-targeted agents for GEA. We also highlight emerging data on the genomic and temporal heterogeneity of molecular resistance alterations that have yielded further insight into the heterogeneity of therapeutic responses. We conclude with an overview of promising novel agents and strategies which may refine the therapeutic landscape.

SUBMITTER: Zhao D

PROVIDER: S-EPMC6525398 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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Progress and challenges in HER2-positive gastroesophageal adenocarcinoma.

Zhao Dan D Klempner Samuel J SJ Chao Joseph J

Journal of hematology & oncology 20190517 1

HER2 expression remains an important biomarker to guide the addition of the monoclonal antibody trastuzumab to first-line systemic chemotherapy in unresectable, metastatic gastroesophageal adenocarcinomas (GEA). However, in contrast to breast cancer, other HER2-targeted strategies to date have not improved outcomes in this molecular subtype of GEA. Since the initial development of HER2 biomarker testing guidelines, significant spatial intratumoral heterogeneity of HER2 overexpression has been re ...[more]

PMID: 31101074

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Project description:Since completion of the Trastuzumab for Gastric Cancer study, trastuzumab with doublet chemotherapy (a fluoropyrimidine and a platinum) has been the gold-standard first-line therapy for patients with locally advanced unresectable or metastatic human epidermal growth factor receptor 2-positive (HER2+) gastroesophageal adenocarcinoma (GEA). The safety and efficacy of 23 studies of first-line trastuzumab plus doublet chemotherapy, without checkpoint inhibitors (n = 19) or with checkpoint inhibitors (n = 4), conducted in patients with locally advanced unresectable or metastatic HER2+ GEA, including phase II/III, prospective, and retrospective observational studies, were summarized. In studies without checkpoint inhibitors, the median duration of trastuzumab treatment ranged from 19.5 to 39.0 weeks and from 15.3 to 30.0 weeks for chemotherapy. In studies with checkpoint inhibitors, the median duration of pembrolizumab/trastuzumab/chemotherapy was 30 weeks, and 18 weeks for chemotherapy. In studies without checkpoint inhibitors, treatment-emergent adverse events (TEAEs) of grade ≥3 ranged from 32% to 84%. Serious adverse events (SAEs) ranged from 15% to 39%. Adverse events resulting in discontinuation ranged from 0% to 30%. Treatment-related deaths occurred in 0%-9% of patients. In studies with checkpoint inhibitors, TEAEs of grade ≥3 were 57%. SAEs ranged from 31% to 38%. Adverse events resulting in discontinuation ranged from 5% to 24%. Treatment-related deaths occurred in 0%-3% of patients. In studies without checkpoint inhibitors, objective response rate (ORR) ranged from 39% to 82%, median progression-free survival (PFS) from 5.7 to 11.6 months, and median overall survival (OS) from 11.2 to 27.6 months. In studies with checkpoint inhibitors, ORR ranged from 39% to 86%, median PFS from 8.0 to 13.0 months, and median OS from 19.3 to 27.3 months. This review provides a historical benchmark on safety and efficacy of available first-line chemotherapy-based standard of care for patients with locally advanced unresectable or metastatic HER2+ GEA.

Project description:ImportanceDysregulation of the mesenchymal-epithelial transition (MET) signaling pathway is associated with poor prognosis in gastroesophageal adenocarcinoma (GEC). We report results of METGastric, a phase 3 trial of the MET inhibitor onartuzumab plus standard first-line chemotherapy for human epidermal growth factor receptor 2 (HER2)-negative, MET-positive, advanced GEC.ObjectiveTo determine whether the addition of onartuzumab to first-line fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) improves efficacy compared with mFOLFOX6 plus placebo in HER2-negative, MET-positive GEC.Design, setting, and participantsRandomized, double-blind, multicenter trial conducted from November 2012 to March 2014. Patients were 18 years or older with an adenocarcinoma of the stomach or gastroesophageal junction with metastatic disease not amenable for curative therapy. Tumor samples were centrally tested for MET expression using Ventana anti-Total c-MET (SP44) rabbit monoclonal antibody, HER2 status, and Lauren histologic subtype. MET-positive tumors were defined as at least 50% of tumor cells showing weak, moderate, and/or strong staining intensity (MET 1+/2+/3+, respectively) by immunohistochemistry.InterventionsPatients with HER2-negative, MET-positive GEC were enrolled and randomized 1:1 to receive mFOLFOX6 with or without onartuzumab (10 mg/kg).Main outcomes and measuresCo-primary end points: overall survival in the intent-to-treat (ITT) population and in patients with MET 2+/3+ GEC. Secondary end points: progression-free survival (PFS), overall response rate (ORR), and safety.ResultsEnrollment was stopped early due to sponsor decision, which was agreed with an independent data monitoring committee. At the data cutoff (April 25, 2014) there were 562 patients in the ITT population (n = 283 placebo plus mFOLFOX6 [median age, 58 y; 65% male]; n = 279 onartuzumab plus mFOLFOX6 [median age, 60 y; 67% male]); 109 (38.5%) and 105 (37.6%) of the ITT population were MET 2+/3+, respectively. Addition of onartuzumab to mFOLFOX6 did not significantly improve OS, PFS, or ORR vs placebo plus mFOLFOX6 in the ITT (OS hazard ratio [HR], 0.82; 95% CI, 0.59-1.15; P = .24; PFS HR, 0.90; 95% CI, 0.71-1.16; P = .43; ORR, 46.1% vs 40.6%) or MET 2+/3+ populations (OS HR, 0.64; 95% CI, 0.40-1.03; P = .06; PFS HR, 0.79; 95% CI, 0.54-1.15; P = .22; ORR, 53.8% vs 44.6%). Safety was as expected for onartuzumab.Conclusions and relevanceAddition of onartuzumab to first-line mFOLFOX6 did not significantly improve clinical benefits in the ITT or MET 2+/3+ populations.Trial registrationclinicaltrials.gov Identifier: NCT01662869.

Project description:ImportancePerioperative chemotherapy and surgery are a standard of care for operable gastroesophageal adenocarcinoma. Anti-HER2 therapy improves survival in patients with advanced HER2-positive disease. The safety and feasibility of adding lapatinib to perioperative chemotherapy should be assessed.ObjectivesTo assess the safety of adding lapatinib to epirubicin, cisplatin, and capecitabine (ECX) chemotherapy and to establish a recommended dose regimen for a phase 3 trial.Design, setting, and participantsPhase 2 randomized, open-label trial comparing standard ECX (sECX: 3 preoperative and 3 postoperative cycles of ECX with modified ECX plus lapatinib (mECX+L). This multicenter national trial was conducted in 29 centers in the United Kingdom in patients with histologically proven, HER2-positive, operable gastroesophageal adenocarcinoma. Registration for ERBB/HER2 testing took place from February 25, 2013, to April 19, 2016, and randomization took place between May 24, 2013, and April 21, 2016. Data were analyzed May 10, 2017, to May 25, 2017.InterventionsPatients were randomized 1:1 open-label to sECX (3 preoperative and 3 postoperative cycles of 50 mg/m2 of intravenous epirubicin on day 1, 60 mg/m2 intravenous cisplatin on day 1, 1250 mg/m2 of oral capecitabine on days 1 through 21) or mECX+L (ECX plus lapatinib days 1 through 21 in each cycle and as 6 maintenance doses). The first 10 patients in the mECX+L arm were treated with 1000 mg/m2 of capecitabine and 1250 mg of lapatinib per day, after which preoperative toxic effects were reviewed according to predefined criteria to determine doses for subsequent patients.Main outcomes and measuresProportion of patients experiencing grade 3 or 4 diarrhea with mECX+L. A rate of 20% or less was considered acceptable. No formal comparison between arms was planned.ResultsBetween February 2013, and April 2016, 441 patients underwent central HER2 testing and 63 (14%) were classified as HER2 positive. Forty-six patients were randomized; 44 (24 sECX, 20 mECX+L) are included in this analysis. Two of the first 10 patients in the mECX+L arm reported preoperative grade 3 diarrhea; thus, no dose increase was made. The primary endpoint of preoperative grade 3 or 4 diarrhea rates were 0 of 24 in the sECX arm (0%) and 4 of 20 in the mECX+L arm (21%). One of 24 in the sECX arm and 3 of 20 in the mECX+L arm stopped preoperative treatment early, and for 4 of 19 in the mECX+L arm, lapatinib dose was reduced. Postoperative complication rates were similar in each arm.Conclusions and relevanceAdministration of 1250 mg of lapatinib per day in combination with ECX chemotherapy was feasible with some increase in toxic effects, which did not compromise operative management.Trial registrationISRCTN.org identifier: 46020948; clinicaltrialsregister.eu identifier: 2006-000811-12.

Dataset Information

Progress and challenges in HER2-positive gastroesophageal adenocarcinoma.

Publications

Progress and challenges in HER2-positive gastroesophageal adenocarcinoma.

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