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Critical evaluation of ramucirumab in the treatment of advanced gastric and gastroesophageal cancers.

ABSTRACT: Gastric (GC) and gastroesophageal junction (GEJ) cancers are two global health problems with a relatively high mortality, particularly in the advanced stage. Inhibition of angiogenesis is now contemplated as a classic treatment preference for myriad tumor types encompassing renal cell carcinoma, non-small cell lung cancer, colorectal cancer, glioblastoma, and ovarian cancer, among others. Bevacizumab and ramucirumab have been widely investigated in GC and GEJ cancer, with some controversy about their therapeutic role. Ramucirumab is a monoclonal antibody for vascular endothelial growth factor receptor-2, with demonstrated activity both as a monotherapy and as a part of combination strategy in the management of advanced GC/GEJ cancer. In this review article, we present a critical evaluation of the preclinical and clinical data underlying the use of this drug in this indication. Moreover, we provide a spotlight on the future perspectives in systemic therapy for advanced GC/GEJ cancer.

SUBMITTER: ElHalawani H

PROVIDER: S-EPMC4524527 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Critical evaluation of ramucirumab in the treatment of advanced gastric and gastroesophageal cancers.

ElHalawani Hesham H Abdel-Rahman Omar O

Therapeutics and clinical risk management 20150728

Gastric (GC) and gastroesophageal junction (GEJ) cancers are two global health problems with a relatively high mortality, particularly in the advanced stage. Inhibition of angiogenesis is now contemplated as a classic treatment preference for myriad tumor types encompassing renal cell carcinoma, non-small cell lung cancer, colorectal cancer, glioblastoma, and ovarian cancer, among others. Bevacizumab and ramucirumab have been widely investigated in GC and GEJ cancer, with some controversy about ...[more]

PMID: 26251608

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Project description:BackgroundPlatinum/fluoropyrimidine regimens are the backbone of first-line chemotherapy for advanced gastric cancer (AGC). However response rates to first line chemotherapy range from 30 to 50% and disease progression occurs after 4-6 cycles. The optimal duration of first-line therapy is still unknown and its continuation until disease progression represents the standard. However this strategy is often associated with cumulative toxicity and rapid development of drug resistance. Moreover, only about 40% of AGC pts. are eligible for second-line treatment.MethodsThis is a randomized, open-label, multicenter phase III trial. It aims at assessing whether switch maintenance to ramucirumab plus paclitaxel will extend the progression-free survival (PFS) of subjects with HER-2 negative AGC who have not progressed after 3 months of a first-line with a platinum/fluoropyrimidine regimen (either FOLFOX4, mFOLFOX6 or XELOX). The primary endpoint is to compare Progression-Free Survival (PFS) of patients in ARM A (switch maintenance to ramucirumab and placlitaxel) versus ARM B (continuation of the same first-line therapy with oxaliplatin/fluoropyrimidine). Secondary endpoints are: overall survival, time-to-treatment failure, overall response rate, duration of response, percentage of patients that will receive a second line therapy according to arm treatment, safety, quality of life. Exploratory studies including Next-Generation Sequencing (NGS) in archival tumor tissues are planned in order to identify potential biomarkers of primary resistance and prognosis.DiscussionThe ARMANI study estimates if patients treated with early swich with ramucirumab plus paclitaxel received benefit when compared to those treated with continuation of first line therapy. The hypothesis is that the early administration of an active, non-cross resistant second-line regimen such as ramucirumab plus paclitaxel may prolong the time in which patients are progression-free, and consequently have a better quality of life. Moreover, this strategy may rescue all those subjects that become ineligible for second-line therapy due to the rapid deterioration of health status after the first disease progression.Trial registrationARMANI is registered at ClinicalTrials.gov ( NCT02934464 , October 17, 2016) and EudraCT(2016-001783-12, April 202,016).

Project description:ImportanceStandard 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.ObjectiveTo 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.InterventionsStarting doses were fluorouracil, 400 mg/m2 bolus, followed by 2400 mg/m2 over 46 hours; leucovorin, 400 mg/m2; irinotecan, 180 mg/m2; and oxaliplatin, 85 mg/m2. 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.Trial registrationClinicalTrials.gov Identifier: NCT01928290.

Dataset Information

Critical evaluation of ramucirumab in the treatment of advanced gastric and gastroesophageal cancers.

Publications

Critical evaluation of ramucirumab in the treatment of advanced gastric and gastroesophageal cancers.

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