Treatment proven to demonstrate significant survival improvement in patients with mCRC whose disease has progressed despite treatment with oxaliplatin-based regimen(2)
Sanofi and Regeneron Pharmaceuticals, Inc. have announced that they have launched ZALTRAP (aflibercept) which is licensed for use in combination with irinotecan/5-fluorouracil/folinic acid (FOLFIRI) chemotherapy for the treatment of adults with mCRC that is resistant to or has progressed after an oxaliplatin-based regimen.(1) Colorectal cancer is the second most common cause of cancer death in the UK.(3) In its advanced stages it can become difficult-to-treat and until now there have been limited treatment options available.(4)
ZALTRAP is a targeted biologic agent proven to significantly improve overall survival (OS) (13.5 vs 12.06 months in the control arm HR=0.817 (95% CI, 0.713 to 0.937; p=0.0032), progression free survival (PFS) (6.9 months vs 4.67 months in the control arm (HR=0.758 95% CI, 0.661 to 0.869; p=0.00007),and overall tumour response rate versus placebo plus FOLFIRI in patients with mCRC whose disease has progressed after an oxaliplatin-based regimen.(2) A consistent OS and PFS improvement was seen with ZALTRAP in pre-specified subgroups including both prior bevacizumab-treated (approximately 30%) and bevacizumab-naïve patients.(2)
Known as a Vascular Endothelial Growth Factor (VEGF)-Trap, ZALTRAP has a novel mode of action that binds to angiogenic factors VEGF-A as well as uniquely targeting VEGF-B and placental growth factor (PIGF).(5) ZALTRAP is a multiple anti-angiogenic agent5 and works by preventing the formation of new blood vessels within and around a tumour thereby stopping or slowing the spread of cancer.(6,7)
"MCRC isa difficult disease to treat. The goal in recent years has been to develop more targeted therapies which aim for high efficacy but with reduced side effects," commented Dr Rob Glynne-Jones, Consultant Clinical Oncologist, Macmillan Lead Clinician in Gastro-Intestinal Cancer, Northwood, UK.(4,8) "ZALTRAP is a novel agent which has produced results that extend life in the later stages of colorectal cancer and has the potential to significantly impact mCRC survival rates in the future."
Over time, ZALTRAP treated patients also sustained higher survival rates than placebo treated patients, with survival rates of 38.5% (95% CI, 34.3 to 42.7) for ZALTRAP vs 30.9 (95% CI, 26.9 to 34.8) for placebo at 18 months; 28.0% (95% CI, 23.7 to 32.4) for ZALTRAP vs 18.7% (95% CI, 14.9 to 22.5) for placebo after 24 months. At 30 months the improvement in survival was almost double for ZALTRAP with survival rates of 22.3% (95% CI, 17.8 to 26.8) vs 12.0% (95% CI, 8.0 to 16.0) for placebo.(2)
"We are delighted that ZALTRAP is now available in the UK for mCRC patients. The availability of ZALTRAP fulfills an importantunmet need. ZALTRAP has been proven to increase overall survival, progression-free survival and overall response rate, in combination with FOLFIRI, for advanced colorectal cancer patients who have previously been treated with oxaliplatin."(2) said Dr Antonio Saha, Colorectal Lead & Oncology Medical Advisor for Sanofi UK & Ireland. "At Sanofi we are committed to improving the understanding and treatment of all cancers and to ensuring that patients continue to benefit from advances in treatment."
The ZALTRAP launch in the UK follows the granting of MA from the European Commission in February 2013 for the 27 member states of the European Union. The decision to grant MA was based on results from the Phase III VELOUR study, a multinational, randomised, double-blind trial comparing FOLFIRI in combination with either ZALTRAP or placebo in the treatment of patients with mCRC. The study randomised 1,226 patients with mCRC who had previously been treated with an oxaliplatin-containing regimen.(2)
Mark Flannagan, CEO of Beating Bowel Cancer commented: "This is excellent news for bowel cancer patients. We welcome any new treatment which gives new hope to and improves the prospects of patients living with metastatic colorectal cancer in the UK. We await the results of the NICE Single Technology Appraisal with interest."
ZALTRAP was licensed in February 2013 for use in combination with irinotecan/5-fluorouracil/folinic acid (FOLFIRI) chemotherapy for the treatment of adults with mCRC that is resistant to or has progressed after an oxaliplatin-based regimen.(1) ZALTRAP is an angiogenesis inhibitor and targeted biologic agent proven to demonstrate significant survival improvement in patients with mCRC whosedisease has progressed after an oxaliplatin-based regimen.(2) ZALTRAP is a multiple anti-angiogenic agent,(2) and has a novel mode of action that works in a different way to other available treatments licensed for use in the UK.(5)
About the Phase III VELOUR Study
The VELOUR study was a multinational, randomised, double-blindtrial comparing FOLFIRI in combination with either ZALTRAP or placebo in the treatment of patients with mCRC.(2) The study randomised 1,226 patients with mCRC who previously had been treated with an oxaliplatin-based regimen.(2) Approximately 30 percent of patients in the trial received prior bevacizumab therapy.(2) The primary endpoint was an improvement in OS. Secondary endpoints included PFS, response to treatment, and safety.(2)
In the study, patients with mCRC previously treated with oxaliplatin were randomised to receive ZALTRAP or placebo in combination with the FOLFIRI regimen (irinotecan-5-fluorouracil-leucovorin).(2) The addition of ZALTRAP to the FOLFIRI regimen significantly improved OS (13.5 months median OS vs 12.06 months in the control arm; HR=0.817; p=0.0032), PFS (6.9 months median PFS vs 4.67 months in the control arm; HR=0.758; p=0.00007). The overall response rate in the ZALTRAP plus FOLFIRI arm was 19.8% vs. 11.1% for FOLFIRI alone (p=0.0001).(2)
A similar effect was seen with ZALTRAP therapy whether or not patients had received prior bevacizumab therapy.(2)
The most common adverse reactions (all grades, ≥20% incidence) reported at least 2% greater incidence for the ZALTRAP/FOLFIRI regimen as compared to the placebo/FOLFIRI regimen in order of decreasing frequency were leucopenia, diarrhoea, neutropenia, proteinuria, increased aspartate aminotransferase (AST), stomatitis, fatigue, thrombocytopenia, increased alanine aminotransferase (ALT), hypertension, weight loss, decreased appetite, epistaxis, abdominal pain, dysphonia, increased serum creatinine, and headache. The most common reported grades 3-4 reactions (≥5% incidence) reported at least 2% greater incidence for the ZALTRAP/FOLFIRI regimen as compared to the placebo/FOLFIRI regimen in order of decreasing frequency, were neutropenia, diarrhoea, hypertension, leucopenia, stomatitis, fatigue, proteinuria, and asthenia.(1)
Angiogenesis is the process by which new blood vessels are formed. Abnormal angiogenesis is a hallmark of cancer.(5) and essential for disease growth and metastasis.(7,9)
Tumours secrete growth factors(10,11) that result in the formation of new blood vessels and enable the tumour to grow,(10,12) inhibiting these angiogenic factors has become an important area of oncology research.(11,10)
The VEGF family includes proteins that promote angiogenesis by binding to VEGF receptors on endothelial cells within existing blood vessels.(5) One pathway to inhibit angiogenesis is to prevent circulating VEGF angiogenic growth factors from binding to their specific receptors.(13) VEGF-A (generally referred to as VEGF) is just one of the mediators contributing to angiogenesis and does not act alone; related growth factors in the VEGF family, VEGF-B and PlGF may contribute to tumour angiogenesis as well.(14,5)
About Colorectal Cancer
Colorectal cancer is the second most common cause of cancer death in the UK and more than 16,000people die each year.(3) Whilst colorectal cancer is a highly treatable disease if diagnosed early,(15) in its advanced stages it can becomes difficult-to-treat and until now there have been limited treatment options available.(4)