RAINBOW: A global, phase III, randomized, double-blind study of ramucirumab plus paclitaxel versus placebo plus paclitaxel in the treatment of metastatic gastroesophageal junction (GEJ) and gastric adenocarcinoma following disease progression on first-line platinum- and fluoropyrimidine-containing combination therapy rainbow IMCL CP12-0922 (I4T-IE-JVBE).

Abstract

LBA7 Background: RAM is a human IgG1 monoclonal antibody VEGF-receptor 2 antagonist. We conducted a global, placebo-controlled, double-blind, phase III trial to evaluate the efficacy and safety of PTX +/- RAM in patients with metastatic GEJ or gastric adenocarcinoma who had disease progression on or within 4 months after first-line platinum- and fluoropyrimidine-based combination therapy. Methods: Pts received RAM (8 mg/kg IV q2w) or placebo (PL) plus PTX (80 mg/m2 d1, 8, 15 of a 4 week cycle) until disease progression, unacceptable toxicity, or death. Eligible pts had ECOG PS ≤ 1; and adequate organ function. The primary endpoint was overall survival (OS). Secondary endpoints included progression-free survival (PFS), objective response rate (ORR), time to progression (TTP), and safety. Results: From Dec 2010 to Sep 2012, 665 pts were randomized (RAM+PTX: 330; PTX: 335). Baseline characteristics were generally balanced between arms. The OS hazard ratio (HR) was 0.807 (95% CI 0.678, 0.962; p=0.0169). Median OS was 9.63m for RAM+PTX and 7.36m for PTX. The HR for PFS was 0.635 (95% CI 0.536, 0.752; p <0.0001). Median PFS was 4.40m and 2.86m. Median TTP was 5.5m RAM+PTX; 3.0m PTX (p <0.0001). ORR was 28% RAM+PTX;16% PTX (p=0.0001). Grade ≥ 3 adverse events (AEs) occurring in >5% of patients on RAM+PTX were: neutropenia (40.7% RAM+PTX;18.8% PTX), leukopenia (17.4% vs 6.7% ), hypertension (14.1% vs 2.4%), anemia (9.2% vs 10.3%), fatigue (7.0% vs 4.0%), abdominal pain (5.5% vs 3.3%), and asthenia (5.5% vs 3.3%). Febrile neutropenia was reported in 3.1% RAM+PTX; 2.4% PTX. Conclusions: The primary endpoint of improved OS was met. A statistically significant and clinically meaningful OS benefit of > 2 months was observed for RAM+PTX vs. PTX in gastric and GEJ cancer after progression on 1st-line therapy, as were significant benefits in PFS and ORR. Neutropenia was more frequently reported in the RAM+PTX arm but incidence of febrile neutropenia was comparable between arms. Clinical trial information: NCT01170663.

FGFR2 in gastric cancer: protein overexpression predicts gene amplification and high H-index predicts poor survival

“…3 Thus, after a decade of repeated failures of most targeted agents, except HER2, in showing survival benefits in gastric cancer, these positive trial results have opened a new era for exploring targeted agents for the treatment of gastric cancer. 4,5 Fibroblast growth factor receptors (FGFRs) are transmembrane tyrosine kinase receptors, and binding of ligands to FGFRs leads to activation of the downstream PI3K-AKT and MAPK-ERK pathways.…”

A systematic review and meta-analysis of randomized trials on the role of targeted therapy in the management of advanced gastric cancer: Evidence does not translate?

“…For anti-angiogenic agents, this limitation is often due to the lack of validated predictive biomarkers. 26,31,[33][34][35]37,39,52,[60][61][62][63][64] In other cases, in particular for the anti-EGFR agents, even if the prominent role of RAS/RAF mutational status in colon cancer has been widely recognized so far, it is conceivable that this information was unknown at the time of studies design. 27,30,51,[65][66][67] Therefore it is highlighted the need of new trials designed to investigate the relevance of RAS mutation in predicting response to anti-EGFR mAbs, in aGC.…”

“…[22][23][24] Recently, RCTs investigated the efficacy of the targeted therapy alone or in combination with chemotherapy, but results were mostly unsatisfactory. [25][26][27][28][29][30][31][32][33][34][35][36][37][38] While several RCTs demonstrated an improvement in terms of response rate (RR), and progression free survival (PFS) only one study reported a significant increase in terms of OS in a selected subgroup of patients in front-line treatment. 25 In that trial, patients were selected according to HER2 status (resulted to be overexpressed in 16-34% of patients with intestinal type and 2-7% of diffuse aGC), and subsequently treated with trastuzumab plus standard chemotherapy with a significant 2.7 months advantage in OS.…”

“…[25][26][27][28][29][30][31][32][33][34][35][36][37]44,[51][52][53][54][55][56][57][58][59] The TYTAN trial missed data about PFS. One trial missed results about OS.…”

Gastric cancer: past progress and present challenges

“…Recently, ramucirumab, a fully human IgG1 monoclonal antibody to VEGFR-2, has demonstrated single-agent activity in the second-line setting, both alone and in combination with weekly paclitaxel therapy, and two large randomised phase III trials have reported survival benefits [31,32]. Efforts to improve outcomes in the first-line setting by combining ramucirumab with combination chemotherapy (5-fluorouracil and oxaliplatin) have been less successful, with a recently reported randomised phase II trial failing to demonstrate an improvement in median progression-free survival from the addition of ramucirumab therapy [33].…”