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Ramucirumab for the treatment of gastroesophageal cancers.

ABSTRACT: INTRODUCTION:In 2014, the U.S. Food and Drug Administration (FDA) approved ramucirumab for use in the second line setting of advanced or metastatic, gastric or gastroesophageal adenocarcinoma (GEAC) based on the result of Phase III clinical trials; REGARD and RAINBOW. AREAS COVERED:We briefly review the mechanisms of angiogenesis, anti-angiogenic therapy, and current status of advanced GEAC treatment then highlight the challenges and future prospects of novel molecular targeted agents. EXPERT OPINION:Although both the REGARD and RAINBOW trials met their primary endpoints of significantly prolonged overall survival (OS) and progression-free survival (PFS), the magnitude of the difference is still relatively modest. Given that ramucirumab alone has a marginal effect, a combination of paclitaxel and ramucirumab is strongly preferred as a second line therapy. To maximize the impact of ramucirumab in patients with GEAC, we can leverage the recent pharmacokinetics (PK) data of ramucirumab from the REGARD and RAINBOW trials. In addition, the quest for identifying biomarkers to select patients who are likely to benefit the most should continue. It is our firm belief that taxanes should no longer be added to the frontline regimens in most cases, given the success of the taxane/ramucirumab in the second line setting.

SUBMITTER: Shimodaira Y

PROVIDER: S-EPMC5001688 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Ramucirumab for the treatment of gastroesophageal cancers.

Shimodaira Y Y Elimova E E Wadhwa R R Shiozaki H H Charalampakis N N Planjery V V Rogers J E JE Song S S Ajani J A JA

Expert opinion on orphan drugs 20150525 6

<h4>Introduction</h4>In 2014, the U.S. Food and Drug Administration (FDA) approved ramucirumab for use in the second line setting of advanced or metastatic, gastric or gastroesophageal adenocarcinoma (GEAC) based on the result of Phase III clinical trials; REGARD and RAINBOW.<h4>Areas covered</h4>We briefly review the mechanisms of angiogenesis, anti-angiogenic therapy, and current status of advanced GEAC treatment then highlight the challenges and future prospects of novel molecular targeted ag ...[more]

PMID: 27570714

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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.

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).

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Ramucirumab for the treatment of gastroesophageal cancers.

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Ramucirumab for the treatment of gastroesophageal cancers.

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