Afinitor fails Phase III gastric cancer trial
This article was originally published in Scrip
Novartis's mTOR inhibitor everolimus (marketed as Afinitor) has failed to meet the primary endpoint in a Phase III study in advanced gastric cancer. The company had previously been hoping to file for its approval in this indication this year, having already obtained US and EU approval for its use in kidney cancer and neuroendocrine tumours of pancreatic origin. It had obtained orphan drug status in the gastric indication in both the EU and US last year. Novartis is also hoping to gain FDA and EMA approval of Afinitor in advanced ER+/HER2- breast cancer this year.
In a presentation at the American Society of Clinical Oncology's 2012 Gastrointestinal Cancers Symposium last week, results of the GRANITE-1 Phase III randomised, double-blind, multicentre study were revealed, showing that everolimus monotherapy did not significantly improve overall survival in patients with advanced gastric cancer who had previously been treated with one or two lines of systemic chemotherapy. This had been the primary endpoint of the 656-patient study; secondary endpoints included progression-free survival, overall response rate and safety.
Although Afinitor failed to meet the primary endpoint, the safety profile was consistent with previous cancer studies, and it was shown to improve progression-free survival.
Novartis is relying on the drug to help drive future growth as key blockbuster products like Diovan come off patent, and although the gastric cancer setback will be disappointing, it is unlikely to prove catastrophic. Analysts at Datamonitor predict that the product will become a blockbuster (ie, with sales exceeding $1 billion), but they had expected the gastric cancer indication to account for only around 5% of that total. In the fourth quarter, Afinitor's sales rose by 66% to $133 million, while for the full year they were up 82% to $443 million.
study details
In GRANITE-1, patients were randomised 2:1 to receive either oral everolimus 10mg/day plus best supportive care or placebo plus best supportive care. Randomisation was stratified by region (Asia versus rest of world) and previous lines of chemotherapy (one versus two). The final analysis was performed once 526 deaths had occurred.
656 patients from 23 countries were enrolled from July 2009 to December 2010. Median overall survival was 5.39 months with everolimus versus 4.34 months with placebo (HR, 0.90; 95% CI, 0.75-1.08; p=0.1244). Median progression-free survival per local investigator assessment was 1.68 months with everolimus versus 1.41 months with placebo (HR, 0.66; 95% CI, 0.56-0.78; p<0.0001). six-month="" pfs="" estimates="" were="" 12%="" with="" everolimus="" and="" 4.3%="" with="" placebo.="" both="" overall="" survival="" and="" progression-free="" survival="" were="" consistent="" across="" the="" various="" subgroups="" of="" patients.="" overall="" response="" rate="" (95%="" ci)="" was="" 4.5%="" (2.6-7.1%)="" with="" everolimus="" versus="" 2.1%="" (0.6-5.3%)="" with="">
The drug, also launched as Zortress/Certican to prevent transplant rejection, is already approved in the US and EU to treat renal cell carcinoma following vascular endothelial growth factor (VEGF)-targeted therapy and advanced progressive neuroendocrine tumours of pancreatic origin, and has been showing increasing promise in breast cancer as a boost to hormonal therapy (scripintelligence.com, 9 December 2011). It is also marketed to treat subependymal giant cell astryocytomas associated with tuberous sclerosis and is licensed to Abbott/Boston Scientific for use in drug-eluting stents.
Roche's VEGF-targeting monoclonal antibody Avastin (bevacizumab) also failed in a Phase III trial in gastric cancer (scripintelligence.com, 23 February 2010). Pfizer also markets an mTOR inhibitor for cancer, Torisel (temsirolimus), but there is no evidence that this is being studied in gastric cancer.