Lapatinib with ECF/X in the first-line treatment of metastatic gastric cancer according to HER2neu and EGFR status: a randomized placebo-controlled phase II study (EORTC 40071)

Moehler, Markus; Schad, Arno; Maderer, Annett; Atasoy, Ajlan; Mauer, Murielle; Caballero, Carmela; Thomaidis, Thomas; John, Jestinah Mahachie; Láng, István; Cutsem, Éric Van; Freire, Joao; Lutz, Manfred P.; Roth, Arnaud

doi:10.1007/s00280-018-3667-8

Cited by 15 publications

(20 citation statements)

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“…Numerous EGFR-targeting phase II studies evaluated cetuximab (24-37), panitumumab (38,39), nimotuzumab (40,41), lapatinib (42,43), erlotinib (44,45), gefitinib (46), matuzumab (47), and icotinib (48) in mEGC patients ( Table 1). As a monotherapy in an unselected population, cetuximab had modest benefit with FIGURE 1 | Schematic of EGFR and its downstream pathways with monoclonal antibodies exerting their effects at the extracellular domain, and small molecule inhibitors inhibiting phosphorylation intracellularly.…”

Section: Targeting Egfr In Metastatic Egc (Megc)mentioning

confidence: 99%

Targeting EGFR in Esophagogastric Cancer

Maron

Janjigian

2020

Front. Oncol.

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Esophagogastric cancer (EGC) remains a major cause of cancer-related mortality. Overall survival in the metastatic setting remains poor, with few molecular targeted approaches having been successfully incorporated into routine care to-date: only first line anti-HER2 therapy in ERBB2-expressing tumors, second line anti-VEGFR2 therapy with ramucirumab in unselected patients, and pembrolizumab in PD-L1 expressing or MSI-H patients. EGFR inhibitors were extensively studied in EGC, including phase III trials with cetuximab (EXPAND), panitumumab (REAL3), and gefitinib (COG). All three trials were conducted in unselected populations, and therefore, failed to demonstrate clinical benefit. Here, we review previous attempts at targeting EGFR in EGC and potential future biomarkers for targeting this pathway in patients with EGFR-amplified tumors.

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Section: Targeting Egfr In Metastatic Egc (Megc)mentioning

confidence: 99%

Targeting EGFR in Esophagogastric Cancer

Maron

Janjigian

2020

Front. Oncol.

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“…The combination of lapatinib plus chemotherapy in 422 patients was associated with a mean PFS of 4.4 months (range: 1.7-6 months) and a mean OS of 11.6 months (range: 11-12.2 months. In one study, the median OS was not reached, and the OS was not reported in another one) [20][21][22]24]. In summary, the overall clinical and survival benefits of HER2targeting TKIs for lapatinib, dacomitinib, and neratinib were discouraging and not superior to standard-of-care chemotherapy or placebo.…”

Section: Discussionmentioning

confidence: 99%

“…Table 1 outlines a summary of phase II and III trials that explored HER2-targeting TKIs in the management of patients with HER2-positive GC/GEJC. Collectively, there were six published phase II and III clinical trials: two phase III trials and four phase II trials [20,21,22,24,32,35]. Among them, only two studies included sample sizes of more than 100 patients [20,22].…”

Section: Discussionmentioning

confidence: 99%

“…Among them, only two studies included sample sizes of more than 100 patients [20,22]. The setting of HER2-targeting TKI was first-line in two studies, second-line in three studies, and mixed (first-line and second-line) in one study [20,21,32,22,24,35]. Lapatinib was the most commonly reported HER2-targeting TKI (n = 4).…”

Section: Discussionmentioning

confidence: 99%

“…In 2018, Moehler et al (NCT01123473: a phase II trial) examined the efficacy of frontline lapatinib plus chemotherapy (lapatinib group, n = 5) versus placebo plus chemotherapy (placebo group, n = 5) in ten patients with metastatic HER2-positive GC [24]. HER2 positivity was confirmed by IHC plus FISH (stratum one) or IHC only (stratum two).…”

Section: Lapatinibmentioning

confidence: 99%

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The Use of Epidermal Growth Factor Receptor Type 2-Targeting Tyrosine Kinase Inhibitors in the Management of Epidermal Growth Factor Receptor Type 2-Positive Gastric Cancer: A Narrative Review

AlMazmomy

Al-Hayani

Alomari

et al. 2019

Cureus

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Gastric cancer (GC), including gastroesophageal junction cancer (GEJC), continues to be one of the most frequently diagnosed neoplasms globally. Moreover, GC/GEJC is a principal cause of neoplasm-related fatalities. Early-stage GC/GEJC has a favorable five-year overall survival (OS) rate with surgical resection. However, the vast majority of patients present with advanced inoperable or metastatic disease with a very unfavorable five-year OS rate. Such patients are left with very limited therapeutic options, such as systemic chemotherapy, targeted therapy, and immunotherapy, all of which can be performed as monotherapy or in various combinations. The molecular profiling of GC has revealed several personalized therapeutic vulnerabilities, one of which is the expression of epidermal growth factor receptor type 2 (EGFR2, also known as HER2). HER2 overexpression or amplification is present in a fair subset of patients with GC/GEJC and has been shown to correlate with poor clinicopathological prognostic outcomes. Generally, treatment schemes to tackle HER2 in HER2-positive GC/GEJC comprise the use of anti-HER2 monoclonal antibodies or HER2-targeting tyrosine kinase inhibitors (TKIs). In this study, we engage in a narrative review of the available phase II and III literature on the efficacy and safety of HER2-targeting TKIs in the management of HER2positive GC/GEJC.

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FOLFIRINOX for the Treatment of Advanced Gastroesophageal Cancers

et al. 2020

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IMPORTANCE Standard first-line regimens for patients with metastatic gastroesophageal adenocarcinomas have an approximate 40% objective response rate (ORR). The combination of leucovorin, fluorouracil, irinotecan, and oxaliplatin (FOLFIRINOX) has been efficacious as first-line therapy for other gastrointestinal cancers, such as pancreatic and colon cancers.OBJECTIVE To evaluate the clinical activity and safety of FOLFIRINOX as first-line treatment for patients with advanced gastroesophageal adenocarcinoma. DESIGN, SETTING, AND PARTICIPANTSThis is an open-label, single-arm phase 2 study of first-line FOLFIRINOX in patients with advanced gastroesophageal adenocarcinoma. Estimated sample size included 41 patients with ERBB2-negative disease with 90% power to detect an ORR of 60% or greater with α of .10. No enrollment goal was planned for ERBB2-positive patients, but they were allowed to receive trastuzumab in combination with FOLFIRINOX.INTERVENTIONS Starting doses were fluorouracil, 400 mg/m 2 bolus, followed by 2400 mg/m 2 over 46 hours; leucovorin, 400 mg/m 2 ; irinotecan, 180 mg/m 2 ; and oxaliplatin, 85 mg/m 2 . Trastuzumab was administered as a 6 mg/kg loading dose, followed by 4 mg/kg every 14 days in patients with ERBB2-positive disease. MAIN OUTCOMES AND MEASURESThe primary end point was ORR by the Response Evaluation Criteria in Solid Tumors, version 1.1. Secondary end points included safety profile, progression-free survival (PFS), overall survival (OS), and duration of response. RESULTSFrom November 2013 to May 2018, 67 patients were enrolled (median [range] age, 59.0 [34-78] years; including 56 [84%] men), and 26 of 67 (39%) had ERBB2-positive disease. Median follow-up was 17.4 months. The ORR was 61%(95% CI, 44.5%-75.8%) (25 of 41) in the ERBB2-negative group and 85% (95% CI, 65.1%-95.6%) (22 of 26) in the ERBB2-positive group, including 1 patient with complete response. For ERBB2-negative patients, median PFS was 8.4 months and median OS was 15.5 months; for ERBB2-positive patients, median PFS was 13.8 months and median OS was 19.6 months. Fifty-six patients (84%) had dose modifications or treatment delays. The most common toxic effects were neutropenia (91%, n = 61), diarrhea (63%, n = 42), peripheral sensory neuropathy (61%, n = 41), and nausea (48%, n = 32), with no unexpected toxic effects. CONCLUSIONS AND RELEVANCEThe FOLFIRINOX regimen with or without trastuzumab was associated with improved ORR and PFS in patients with advanced gastroesophageal adenocarcinoma in the first-line setting. This regimen may be a reasonable therapeutic option for patients with preserved performance status.

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Lapatinib with ECF/X in the first-line treatment of metastatic gastric cancer according to HER2neu and EGFR status: a randomized placebo-controlled phase II study (EORTC 40071)

Abstract: Central EGFR and HER2neu stratification by IHC and FISH can be used for further pan-HER strategies. Lapatinib with ECF/X was well tolerated, but did not show clear activity in patients with metastatic GC.

Cited by 15 publications

References 20 publications

Targeting EGFR in Esophagogastric Cancer

Targeting EGFR in Esophagogastric Cancer

The Use of Epidermal Growth Factor Receptor Type 2-Targeting Tyrosine Kinase Inhibitors in the Management of Epidermal Growth Factor Receptor Type 2-Positive Gastric Cancer: A Narrative Review

FOLFIRINOX for the Treatment of Advanced Gastroesophageal Cancers

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