Sorafenib in Combination with Oxaliplatin, Leucovorin, and Fluorouracil (Modified FOLFOX6) as First-line Treatment of Metastatic Colorectal Cancer: The RESPECT Trial

Abstract

Purpose: This randomized, double-blind, placebo-controlled, phase IIb study evaluated adding sorafenib to first-line modified FOLFOX6 (mFOLFOX6) for metastatic colorectal cancer (mCRC).Experimental Results: Of 198 patients randomized, median PFS for sorafenib plus mFOLFOX6 was 9.1 months versus 8.7 months for placebo plus mFOLFOX6 (HR ¼ 0.88; 95% CI, 0.64-1.23; P ¼ 0.46). There was no difference between treatment arms for overall survival. Subgroup analyses of PFS and overall survival showed no difference between treatment arms by KRAS or BRAF status (mutant and wild type). The most common grade 3/4 adverse events in the sorafenib and placebo arms were neutropenia (48% vs. 22%), peripheral neuropathy (16% vs. 21%), and grade 3 hand-foot skin reaction (20% vs. 0%). Treatment discontinuation because of adverse events was 9% and 6%, respectively. Generally, dose intensity (duration and cumulative doses) was lower in the sorafenib arm than in the placebo arm.Conclusion: This study did not detect a PFS benefit with the addition of sorafenib to first-line mFOLFOX6 for mCRC. KRAS and BRAF status did not seem to impact treatment outcomes but the subgroups were small. These results do not support further development of sorafenib in combination with mFOLFOX6 in molecularly unselected patients with mCRC.

The role of targeted therapy for gastrointestinal tumors

“…This study did not find a PFS benefit with the combination therapy. KRAS and BRAF status did not change this result [53].…”

“…In this Asiatic study, lapatinib has been evaluated in combination with paclitaxel versus paclitaxel alone in pretreated HER2 amplified aGCs. OS improvement was not statistically significant in the intention-to-treat population (11.0 vs 8.9 months; HR: 0.84; p = 0.2088) Sorafenib [53] VEGFR Tivozanib [54] Gastric cancer HER2 Lapatinib [66,67] EGFR Erlotinib [61,62] Gefitinib c-MET Foretinib [86] Rilotumumab [87,93] Onartuzumab [88] Hepatocellular carcinoma VEGFR, BRAF, KIT, RET, PDGFR Sunitinib Linifanib [55,56] FGFR Brivanib [57,58] EGFR Erlotinib [59] mTOR Temsirolimus [60] c-MET Foretinib [82] Tivantinib [83] Cabozantinib [84] MEK Selumetinib [89,90] IGF/IGFR Cixutumumab [91] The role of targeted therapy for GI tumors Review informahealthcare.com while in the Chinese subgroup of HER2-positive patients, this improvement was higher [67]. In many Phase II trials, the association of cetuximab with chemotherapy has been shown to have some efficacy [68,69] and based on the increase of RR in previous studies, Richards et al evaluated in a Phase II trial the combination of cetuximab and chemotherapy with docetaxel plus oxaliplatin (DOCOX) versus chemotherapy alone in patients affected with metastatic gastric and GEJ adenocarcinoma.…”

Protracted inhibition of vascular endothelial growth factor signaling improves survival in metastatic colorectal cancer: A systematic review

“…Unfortunately, both failed to improve prognosis in phase III randomized trials, even if sorafenib still maintains promise for pretreated KRAS mutant patients. [16][17][18] Other antiangiogenic molecules able to target multiple pathways are under investigation. Among these, nintedanib (BIBF 1120), a multi target TKI able to efficiently block VEGFR, FGFR and PDGFR, is one of the most promising, as it has already shown to improve survival in lung adenocarcinoma.…”

Anti-angiogenic agents in metastatic colorectal cancer

“…In phase 2, an encouraging response rate of 64.9% was noted with a PFS of 3.7 mo and a median OS of 8 mo [73] . However, in a subsequent phase Ⅱb study of 198 treatment naive mCRC patient, the combination of sorafenib and mFOLFOX4 was shown to offer no PFS or OS advantage over placebo (Table 3) [74] .…”