Positive results for potent colorectal drugs

Despite being the second-leading cause of cancer-related deaths, colorectal cancer is very much the 'poor cousin' in terms of cancer publicity and thus, funding.

As a result of this, the majority of patients present in the latter stages of the disease, when the chances of curative treatment are greatly reduced. Studies in the UK have shown that a screening programme for colorectal cancer could reduce mortality by 15%, thus saving around 1,200 lives each year. However, in spite of colorectal cancer's relatively low profile, a recent study by independent market analyst Datamonitor1 has shown that approved innovative medications may increase median survival rates by as much as 30%, and raise the bar in terms of the accepted standard for colorectal cancer treatment in the future.

Lack of recognition

Currently only the US actively promotes a screening programme for colorectal cancer, however even within the US, the implementation has been hampered by a lack of compliance. Surprisingly, this has come not just from the general public but physicians as well, Datamonitor analyst and report author Kyung Lee says: 'Although there is insufficient data to determine which colorectal cancer screening test is best in terms of the balance of benefits and potential harms or cost-effectiveness, studies reviewed by the US Preventative Services Task Force indicate that colorectal cancer screening is likely to be cost-effective (less than $30,000 per additional year of life gained) regardless of the strategy chosen. Unfortunately, colorectal cancer has not received the level of publicity of breast or lung cancer, even though it has a well-defined, identifiable and treatable precursor lesion.'

Innovative agents

Current treatment is largely based around chemotherapy, which while effective, comes with well-publicized unpleasant side effects. However the approval of two innovative agents, BMS/Merck KgaA/ImClone's Erbitux (cetuximab) and in particular, Genetech/Roche's Avastin (bevacizumab) in February 2004 is likely to alter the treatment paradigm for colorectal cancer significantly, Lee says: 'In a pivotal trial, Erbitux demonstrated a 23% response rate in combination with irinotecan compared with 11% for irinotecan alone in second line treatment. In addition, the median time to progression was nearly three times as long for the Erbitux treatment than in the irinotecan-alone treatment.

'Although the survival benefit has yet to be confirmed, this represents a significant leap forward in terms of efficacy of second-line colorectal cancer therapy.'

Most impressively of all, Avastin has shown the greatest ever improvement in median survival rate seen in a Phase III trial for cancer, Lee says: 'The improvement of nearly five months in terms of median survival represents a 30% increase over the control treatment in a pivotal Phase III trial. Unsurprisingly, this unequivocal survival advantage is expected to appeal to both patients and physicians alike.'

While cytotoxic chemotherapy regimens have remained the mainstay of colorectal cancer treatment for many years, improvements in efficacy have been very slow and steady, Lee says. 'The addition of irinotecan or oxaliplatin to standard 5-FU/leucovorin in chemotherapy in recent years has appeased some of the unmet needs in the disease to a certain extent by improving treatment outcomes. However the benefits have meant an increase in toxicity, and thus an increase in the unpleasant side effects normally related to chemotherapy.'

Leap in efficacy will raise overall standards

But that was then, this is now. Lee comments: 'The clinical advantages of Avastin and Erbitux over traditional chemotherapy means that these drugs are expected to become the gold-standard first and second-line therapies for colorectal cancer within a relatively short period.'

However, as they become the standard agents for colorectal cancer, regulatory authorities are likely to demand that Avastin and Erbitux be used as controls in clinical trials for colorectal cancer in the future, Lee says. 'In effect, that means they will raise the standard for pipeline colorectal cancer drugs.

'Given the leap in efficacy that these drugs have demonstrated, especially in the case of Avastin, it may be difficult for some drugs currently in the development pipeline to show superior efficacy and/or toxicity profiles over Avastin and Erbitux. As a result, some drugs that may be approvable by today's standards may fail to gain approval once these drugs become the standard therapy for colorectal cancer, as Datamonitor expects.'

Working in combinations

Despite the difficult road to approval for pipeline drugs should Avastin and Erbitux become the standard, Datamonitor believes there will be increased opportunities for pipeline innovative drugs to be used in combination therapies. 'By targeting more than one pathway, clinical efficacy should theoretically increase without significantly adding toxicity,' Lee notes. 'This may be especially critical in patients with poor performance status and chemotherapy-refractory patients.'

Although the lack of approved innovative agents means that targeted drug combinations are not currently feasible, as more and more pipeline drugs are approved in the future, Datamonitor expects to see a trend towards a decrease in the use of cytotoxics in favour of innovative agents in combination with each other. Despite the limited number of approved agents, there is an ongoing Phase II trial of Avastin in combination with Erbitux for colorectal cancer. 'Whether the combination proves to be successful or not remains to be seen, but targeted drug combinations are set to be used increasingly in patients where chemotherapy is not a viable option,' Lee says. 'Therefore, Datamonitor believes that Avastin and Erbitux will form the core of clinical trials for pipeline drugs in the medium and long term, at the same time creating new marketing opportunities for other targeted agents.'

Taking on the champions

However Avastin and Erbitux will not have the market all to themselves. The approval of Avastin will increase confidence in other angiogenesis inhibitors. While it predicts sales of Avastin to reach $2bn by 2008, Datamonitor doesn't foresee Avastin having the market to itself for very long, with Novartis/Schering AG's PTK787 (vatalanib) the main competitive threat.

Datamonitor expects it to be approved by late 2006, by which time Avastin could be firmly established in the colorectal cancer market and it may be difficult for PTK787 to erode Avastin's market share. 'However PTK787 should, in theory have higher efficacy than Avastin, and be more effective in the second line than Avastin,' Lee says. 'Furthermore, PTK787's once-daily oral formulation will be popular with physicians and patients alike because of the added convenience and potential reduction in administration costs. Taking all this into account, we forecast that PTK787 will also be a blockbuster seller, giving Avastin a run for its money in the colorectal cancer treatment market.'