Considering two out of three phase III studies to report so far on AstraZeneca’s lung cancer pill Zactima failed to meet their primary endpoint, it would appear that regulatory approval next year is a slim possibility.
However, full results released at this year’s Asco provided reasons for optimism. The trial that was a success, Zodiac, generated a highly significant improvement in progression free survival, whilst the other studies contained signs of activity. Importantly, the drug also scored well on quality of life measures, something that doctors are increasingly looking for in patients with a poor prognosis, a message that emerged strongly from this year's meeting.
Zactima is a novel oral targeted agent which blocks both VEGFr and EGFr pathways; pivotal trials so far have pitted it in a second line setting in non-small cell lung cancer.
The largest and most successful trial, Zodiac, looked at Zactima in combination with Taxotere, against Taxotere alone. Median progression free survival (PFS), the primary endpoint, was 17.3 weeks and 14 weeks respectively, whilst objective response rate, disease control rate and time to deterioration of symptoms were all significantly improved. No statistical improvement in overall survival (OS) was seen, although a positive trend was recorded and data is still being collected.
A similar but much smaller study called Zeal which used Alimta instead of Taxotere failed to generate a significant improvement in PFS; 17.6 weeks against 11.9 weeks; or OS. However there was a trend in favour of the combination, and again objective response rate and time to deterioration of symptoms were significantly improved.
Why Zodiac was a success and Zeal was not is an important question, considering the similarities. Possible reasons are that the size of Zeal, which only recruited 534 patients against Zodiac’s 1,391, was too small to reach statistical significance. The investigators also posited that histology could be playing a part; if data from squamous lung cancer patients were discounted, the outcome was much stronger.
A third trial, called Zest, pitted a much higher dose of single agent Zactima against Tarceva, in the second line. Although the trial failed to generate significant improvements in PFS and OS, a non-inferiority analysis found the agents to have similar efficacy.
Quality of life
Clearly regulators will scrutinise this efficacy data closely, and although two out of three primary endpoints were missed, clear evidence of activity has been seen in a patient population with few treatment options left available. This will go in the drug’s favour, as will data gathered on safety, and quality of life.
Side effects were seen with Zactima, most commonly rash, diarrhoea and hypertension and neutropenia. Importantly, no bleeding events were seen, a side effect of VEGFr inhibitor Avastin, which prevents its use in squamous lung cancer. However, in the Zodiac trial patients appeared to suffer fewer symptoms of traditionally associated with chemotherapy, namely nausea, vomiting and anaemia. As well as suggesting that patients might be able to tolerate higher doses of chemotherapy, this had the effect of improving patients’ quality of life.
Numerous doctors reviewing results from studies at Asco this year stressed how important this is when it comes to treating very sick patients; as well as living longer, doctors want their patients to live better (ASCO - New lung cancer treatment strategy has sceptics as well as fans, June 3, 2009).
In reviewing the Zodiac data, Dr Martin Edelman, Professor of Medicine at the University of Maryland, found this particularly encouraging. “Compared to earlier trials that only presented progression free survival advantage, we have clear evidence of patient benefit in terms of quality of life,” he said in his address to the conference.
Whilst conceding that quality of life measures can be hard to collect reliably, he concluded that: “I feel that the improved PFS with concordant improvement in quality of life, assuming that there is adequate amount of data, support the potential use of vandentanib (Zactima) in combination with docetaxel as second line therapy.”
Of course, a biomarker to identify optimal patients for Zactima would be the ideal. Dr Roy Herbst, who conducted the Zodiac study, said he suspected patients with an EGFR might benefit more, although the minimal tumour tissue recovered did not allow for statistically rigorous analysis.
Whilst financial analysts have expressed concern about the approvability of the drug, the majority have pencilled in launch next year. Still, consensus for 2012 sales has come down 35% in the last 12 months, and currently sits at $184m, according to EvaluatePharma; the biggest downgrades followed top line results from these phase III studies announced in November.
In terms of Astra’s late-stage pipeline, Zactima is pretty important; other than Synagis follow-on Numax and diabetes pill Onglyza, both of which are already filed for approval, the drug is the company’s second most valuable phase III asset. Given concerns about the group's ability to replace sales as its precipitous patent cliff approaches, success for this drug is important for sentiment as well as profits.
AstraZeneca plans to file the data from all three studies in both the US and Europe within the next month. The filing for Zactima certainly looks stronger with this quality of life data, a measure that is often lacking from phase III trials, and considering the mixed efficacy data could well improve the drugs chance of winning approval.