A phase II, open-label study evaluating the safety and efficacy of ramucirumab combined with mFOLFOX-6 as first-line therapy in patients (pts) with metastatic colorectal cancer (mCRC): CP12-0709/NCT00862784.

Abstract

533^ Background: Vascular endothelial growth factor (VEGF) and the VEGF receptor-2 (VEGFR-2) are overexpressed in CRC and mediate angiogenesis. Ramucirumab (RAM; IMC-1121B) is a fully human IgG1 MAb that inhibits binding of VEGF ligands to VEGFR-2 and inhibits VEGFR-2 activation and signaling. In preclinical CRC models VEGFR-2 inhibition confers antitumor activity. RAM was administered with mFOLFOX-6 as 1st-line therapy (rx) in mCRC. Methods: Eligible pts had mCRC with no prior chemo Rx (prior adjuvant rx was allowed), at least 1 measurable target lesion by RECIST v1.0, ECOG PS 0-1, and adequate organ function. Pts received RAM (8 mg/kg IV on D1), oxaliplatin (85 mg/m² IV on D1), folinic acid (400 mg/m² IV on D1), fluorouracil (5-FU, 400 mg/m² bolus followed by 2400 mg/m² continuous infusion over 46 hours on D1). Rx cycles were q2w and tumor assessments were q8w. Endpoints included progression-free survival (PFS), objective response rate (ORR), overall survival (OS), safety, and pharmacokinetics/immunogenicity. Sample size was based on an improved median (medn) PFS from 8 to 11 months (m). Results: 48 pts received therapy. All were white; 25 M/23 F; median age 60.5 y. ECOG PS was 0/1 in 30/18 pts. 42 pts (88%) had metastatic disease, with liver (79%) and lung (35%) as most frequent sites. 13 (27%) pts had liver-only mCRC. The most frequently observed RAM-related adverse events (AEs) included hypertension 46% (15% Grade [G] ≥3); diarrhea 31% (2% G≥3); and nausea and infusion-related reactions, each 19% (0% G≥3). 2 pts died on study due to acute MI or cardiopulmonary arrest. Medn PFS was 11.5 m (9-13 m 95% CI) with 1-yr PFS of 48% (32-62% 95% CI). ORR: 67% (52-80% 95% CI); disease control rate (DCR: CR+PR+SD): 94% (83-99% 95% CI; 5 pts had CR, 27 had PR and 13 had SD). Medn duration of response was 11.0 m (7-12 m 95% CI). One-year OS was 85% (72-93% 95% CI). As of 4/15/2011, 2 pts continued to receive rx, 20 had died and 28 (58.3%) remained alive. Conclusions: RAM combined with mFOLFOX-6 was reasonably tolerated in pts with mCRC. Median PFS exceeds 11 m. PFS, ORR, and DCR are encouraging and favor investigation of this regimen and of RAM in mCRC.

Angiogenesis in esophageal and gastric cancer: a paradigm shift in treatment

“…Combined with conventional cytotoxic agents, ramucirumab yielded promising results in patients with metastatic hepatocellular carcinoma, nonsmall-cell lung cancer and renal cell carcinoma with high RR and PFS [56]. A more recent Phase II study combined ramucirumab with FOLFOX chemotherapy to treat metastatic colorectal cancer and demonstrated a median PFS of 11.5 months, with an ORR of 67%, including 5 patients with complete response and 27 patients with a partial response [57]. Many ongoing studies, both Phase II and Phase III, are currently evaluating novel combination of ramucirumab with chemotherapy in various types of tumors, including gynecological cancers [56].…”

Ramucirumab: A Novel Antiangiogenic Agent

“…These studies were for patients with various solid tumors including GC [10], hepatocellular carcinoma, renal cell carcinoma [15], melanoma, non-smallcell lung carcinoma [16], colorectal cancer [17], ovarian cancer, breast cancer [18] and prostate cancer. Phase I trials have provided considerable safety data and some evidence of anti-tumor activity of ramucirumab.…”

Targeted inhibition of VEGF receptor 2: an update on ramucirumab

“…PSA response was seen in 22%, with a progression free survival and overall survival of 6.7 months and 13.0 months, respectively. In metastatic colorectal cancer, ramucirumab was combined with FOLFOX chemotherapy; this regimen demonstrated a median progression free survival of 11.5 months, with an ORR of 67%, including 5 patients with complete response and 27 with a partial response 46 .…”