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Translated from Rev Prescrire June 2015; 35 (380): 413 regorafenib (Stivarga°) and gastrointestinal stromal tumours after treatment failure Radiological improvement but major adverse effects

Regorafenib had no impact on over- assessment by an independent commit- Selected references from Prescrire’s literature • search. all survival in a placebo-controlled tee) was 4.8 months in the regorafenib In response to our request for information, trial in 199 patients, but adverse group versus 0.9 months in the placebo Bayer Healthcare provided us with no doc- effects were frequent and serious. group (p <0.0001) (3,4). umentation on its product. Symptomatic care is a more reason- 1- Prescrire Editorial Staff “Imatinib and inoperable or metastatic gastrointestinal stromal tumours. able choice. Frequent and often serious adverse Longer follow-up confirms the overall survival effects. The known adverse effects of benefit”Prescrire Int 2011; 20 (114): 61-63. Imatinib, an inhibitor of regorafenib are frequent, often severe 2- Prescrire Editorial Staff “Regorafenib. Metastat- ic colorectal cancer in treatment failure: may pro- various tyrosine kinases, and sometimes fatal, including: liver long survival by a few weeks” Prescrire int 2014; 23 prolongs survival by a damage; bleeding; hypertension, isch- (145): 8-11. few years in patients with aemic heart disease, cardiac arrhyth- 3- EMA - CHMP “Extension of indication variation NOT ACCEPTABLE assessment report for Stivarga. EMEA/H/C/002573/ inoperable or metastatic mia; mucocutaneous damage, including II/0001” 26 June 2014: 62 pages. gastrointestinal stromal tumours. Suni­ palmoplantar erythrodysaesthesia and 4- Demetri GD et al. “Efficacy and safety of rego- rafenib for advanced gastrointestinal stromal tinib, another tyrosine kinase inhibitor, is mucositis; gastrointestinal perforation tumours after failure of imatinib and sunitinib: an an option if imatinib fails. Tailored symp- and fistulae; infections; hypothyroidism; international, multicentre, prospective, ran- tomatic treatment is an alternative (1). multiorgan hypersensitivity reactions domised, placebo-controlled phase 3 trial (GRID)” Lancet 2013 ; 381 (9863): 17 pages. Regorafenib (Stivarga°, Bayer Phar- (DRESS); and leukoencephalopathy 5- European Commission “SPC-Stivarga” ma) inhibits tyrosine kinases involved in (2,5,6). Regorafenib interacts with many 16 December 2014: 25 pages. 6- Prescrire Editorial Staff “Regorafenib: Dress” angiogenesis and tumour growth (2). It other drugs (2). Prescrire Int 2015; 24 (156): 20-21. has been authorised for patients with This trial provided no additional infor- unresectable or metastatic gastrointes- mation on the adverse effect profile of tinal stromal tumours after failure of ima­ regorafenib (3). Serious adverse effects tinib and sunitinib. occurred in 61% of patients in the regor­ afenib group and 14% of those in the No proven survival advantage. Clin- placebo group. Most of these effects ical evaluation of regorafenib in this set- consisted of palmoplantar erythrodyses- ting is based on a randomised, double-­ thesia, hypertension or diarrhoea. Trial blind, placebo-controlled trial in investigators attributed three deaths to 199 patients who also received symp- regorafenib: one due to cardiac arrest, tomatic treatment (3-5). one due to acute liver failure, and one Median survival was similar in the two due to azotaemia and metabolic acid­ groups, about 17 months (3). Interpret­ osis (3). ation of this result is difficult as 85% of patients in the placebo group received In practice. In patients with unresect- regorafenib when their cancer pro- able or metastatic gastrointestinal stro- gressed (3,4). The median time to death mal tumours in whom imatinib and suni­ or radiological progression (blinded tinib have failed, the only proven advantage of regorafenib is that it delays radiological progression by about 4 months. Regorafenib has no proven impact on overall survival. This improve- tablets regorafenib ment in a surrogate endpoint is out- Stivarga° weighed by very frequent and often severe adverse effects, resulting in an • 40 mg of regorafenib per tablet unfavourable harm-benefit balance. cytotoxic drug; inhibitor of It is more reasonable to propose multiple tyrosine kinases symptomatic care rather than expose patients to the adverse effects of regor­  New indication: “(...) treatment of adult afenib. patients with unresectable or metastatic ©Prescrire gastrointestinal stromal tumors (GIST) who progressed on or are intolerant to prior treatment with imatinib and sunitinib”. [EU centralised authorisation]

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