AstraZeneca is to pitch its anticancer offering Iressa (gefitinib) head to head against Roche's Tarceva (erlotinib) in a bid to reinvigorate the profile of its once star offering and put some life back into sales, after a major clinical trial in 2004 showed no survival benefit over placebo.

Iressa reaped just $50 million during the first three months of this year, down 38% from the same period in 2005. In contrast, Roche's Tarceva, which was launched in the USA in November 2004, has seen phenomenal growth and - in the first quarter of this year alone - knocked up sales of 172 million Swiss francs, up 182%.

Iressa was cleared by the US Food and Drug Administration's accelerated approval system in 2003 on the back of Phase II data demonstrating a 10% response rate, but the UK pharmaceutical giant was required to conduct a large post-marketing study as a condition of its clearance.

The so-called Isel (Iressa Survival Evaluation in Lung cancer) trial put Iressa against placebo in almost 1,700 patients with advanced non-small cell lung cancer who had failed on previous chemotherapy, with the primary endpoint being survival. However, at the end of one year, just 27% of the Iressa group were still alive compared to 21% of placebo receivers - a non-significant result. AstraZeneca was allowed to keep the drug on the market, but its use has been severely restricted to existing patients, with no new cases permitted access to the therapy.

AstraZeneca goes FISH-ing

But, now, AstraZeneca says extensive analyses have shown a significant benefit to Iressa in certain subgroups of the patient population - particularly Asians, non-smokers and patients showing over-expression of the epidermal growth factor receptor as measured by FISH (fluorescent in situ hybridisation) - and hopes to demonstrate this in some 300 clinical trials.

One of these is the head to head study versus Tarceva. While the Isel trial showed an overall response rate of 8% among Iressa receivers, versus 1% for those given placebo, Tarceva's 731-patient BR21 study turned in 9% versus 1%. The differences appear small, but BR21 threw up a significant result, while Isel did not and AstraZeneca thinks this could be down to the fact that the patients enrolled in its trial were more resistant to treatment, with only 18% having responded to prior therapy compared to 40% of the BR21 cohort. In addition, 45% of its enrolees had seen disease progression versus 21% of participants in Roche's trial.

Specifically, the Phase II study will investigate the efficacy and tolerability of the two compounds in so-called FISH positive patients, those who have been identified as being good treatment responders. Alex Oldham, vice president and global product team leader for Iressa, told PharmaTimes World News that the company is making significant investments in the compound, having taken stock over the past couple of years, and is now moving forward to explore its use as a first-line therapy in Asian patients and to pull out the estimated 30% of Western patients who are FISH-positive and likely to respond to second-line treatment with the drug. It is also collaborating with a UK diagnostics company - as yet undisclosed - to standardise the FISH analysis into a readily-accessible tool that will help inform treatment decisions.

Meanwhile, AstraZeneca also has underway a Phase III survival study of Iressa versus Sanofi-Aventis' standard-of-care offering Taxotere (docetaxel) in advanced NSCLC - the second biggest study ever conducted in this condition, involving 1,440 patients - and a similar study in Japan. And planned studies include: IDENTIFY, which is due to start in the fourth quarter of 2006 and will look at Iressa versus Taxotere in FISH-positive patients with locally advanced or metastatic NSCLC; INVITE, which will enrol elderly chemotherapy-naïve patients to evaluate Iressa versus Pierre Fabre's Navelbine (vinorelbine); and IPASS, which recruited its first patient in April and this time will pitch Iressa against platinum-based doublet chemotherapy in NSCLC.

With new data comes new registrations and Dr Oldham suggested that AstraZeneca will consider filing additional dossiers “when it has convincing data,” including a resubmission in Europe and extending the treatment population in the USA to include new patients. We think it is possible to have a major cancer product in Iressa, said Dr Oldham, “if we can identify the 30% of the patient population that are FISH-positive.”