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Lung cancer is the leading cause of cancer death, accounting for more than one million new cases world-wide annually. In the US alone, lung cancer accounts for more than 25% of all cancer deaths, and by the end of 2005 it is estimated that 163,510 Americans will die from this silent killer; this is more than breast, colorectal and prostate cancers combined.

Lung cancer can be broadly divided into two main types, characterised by the type of cells that make up the tumour: non-small cell lung cancer (NSCLC) and small cell lung cancer. Approximately 80% of all cases are NSCLC, of which 25-30% present as locally advanced disease and 40-50% metastatic disease. Treatment options include surgery, to remove the lobe or lung affected, chemotherapy and radiotherapy.

The evolution of NSCLC treatment options

During the 1980s, platinum-based combination chemotherapies, such as cisplatin-based regimens, emerged as standard care. A large meta-analysis of cisplatin-based chemotherapy estimated a modest but significant increase in median survival of 1.5 months and an increase in one-year survival of 10% over standard care.

The 1990s saw the introduction of second-generation platinum-based regimens that included third-generation cytotoxic compounds (see table 1) and a steady improvement in terms of median survival and one-year survival rates. For example, in one trial, patients with previously untreated advanced NSCLC treated with Navelbine (vinorelbine) and cisplatin saw a median survival of 40 weeks compared with 31 weeks for patients treated with cisplatin alone, and one-year survival was increased by a further 5%

Table 1: Third-generation cytotoxics

Source: IMS LifeCycle R&Dfocus

At the 11th World Conference on Lung Cancer, held in Barcelona in July 2005, Lilly presented results from the GINEST (Gemzar In Neoadjuvant Early Stage Trials) project, designed to evaluate Gemzar (gemcitabine) in early stage (I and II) NSCLC. The programme included two randomised Phase II trials, which enrolled a total of 83 patients. Preliminary results demonstrated that Gemzar-based therapy (whether including a platinum or non-platinum agent) administered prior to lung resection was well tolerated, and quality of life was reported to have improved or stabilised in 76% of patients at six-month follow up. Additionally, one patient had a confirmed pathological complete response and overall one-year survival was 74%.

The next step

Our knowledge of the processes involved in tumor growth, survival and progression has increased dramatically in recent years and efforts are now focused on the development of therapies that specifically interfere with these processes. A number of new targeted therapies are starting to become available, through the FDA’s Fast Track accelerated approval procedure, for NSCLC. The first of these, developed for recurrent/refractory NSCLC, was Iressa (gefitinib), an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, launched in the US in May 2003 by AstraZeneca. This was closely followed by the launch of Tarceva (erlotinib), a HER1/EGFR tyrosine kinase inhibitor developed by OSI with partners Genentech and Roche, in November 2004.

In large Phase III trials Tarceva demonstrated a 42.5% improvement in median survival and a 41% improvement in one-year survival rates compared with placebo. Preliminary analysis of the ISEL (Iressa Survival Evaluation in Lung cancer) trial, however, showed that despite statistically significant improvements in tumor shrinkage and time to disease progression this did not translate into a significant survival benefit.

Consequently, following discussions with the FDA, AstraZeneca has revised the labelling of Iressa, which is now indicated only for use in patients who are benefiting or have previously benefited from Iressa therapy. Following discussions with the EMEA, AstraZeneca has also withdrawn its MAA, submitted in January 2005, seeking European approval of Iressa for NSCLC.

One explanation for this unexpected phenomenon came with the identification of specific mutations in the tyrosine kinase domain of the EGFR that may convey treatment resistance in certain patient populations.

According to IMS MIDAS Quantum, for the 12 months to March 2005, Iressa ranked eighth in the 'all other antineoplastics' class (L1X), with a market share of 4%, and fixed-rate dollar growth of 41%; 2004 Iressa sales reached $389 million, according to AstraZeneca. Subsequent to the release of the ISEL trial results, Morgan Stanley revised their estimates on future sales; the analysts had anticipated sales reaching $945 million by 2010, but now anticipate 2005 sales of just $120 million. The failure of Iressa to show a survival benefit clearly creates an opportunity for Tarceva; Morgan Stanley expect Tarceva to take the majority of the US and European market opportunities for this class of drug.

Targeted therapies: the way forward

Despite this early setback there are a large number of alternatives already in late-stage development (see table 2). Of note is AstraZeneca’s Zactima (vandetanib), an orally-available dual VEGFR-2/EGFR tyrosine kinase inhibitor, which is expected to enter Phase III evaluation for NSCLC by the end of 2005. The advantage of this compound is that it targets two key pathways: tumor growth by inhibition of VEGF-dependent angiogenesis and tumor progression by inhibiting EGFR-dependent tumor cell proliferation. Promising data from two Phase II trials of Zactima were presented at the Barcelona conference – most significantly, results from the first part of a two-part Phase II study involving 168 patients with locally advanced or metastatic NSCLC showed that the estimated median time to progression in Zactima-treated patients was 11.9 weeks, compared with 8.1 weeks for Iressa.

Table 2: A selection of targeted therapies in development for NSCLC

Source: R&Dfocus

Another hope is ImClone Systems, Bristol-Myers Squibb and Merck KGaA's Erbitux (cetuximab), a chimaeric monoclonal antibody against erbB-1 EGFR, available in a number of markets world-wide for colorectal cancer. Phase II data for Erbitux presented at the 41st annual meeting of the American Society of Clinical Oncology in May 2005, evaluating the activity of Erbitux as a single agent in NSCLC, showed that median time to disease progression was 2.3 months, median survival was 8.1 months, and six-month and one-year survival rates were 63% and 43%, respectively.

What does the next decade hold?

Despite these advances five-year survival rates remain as low as 15% in the US and 10% in Europe. This, coupled with the fact that at least 80% of all lung cancer cases are caused by smoking, highlights that the need for more effective treatment options is as crucial today as it was 20 years ago. Despite various awareness campaigns and task forces trying to address the issue, smoking is still prevalent, with 45 million smokers in the US alone; as many as 46 million former smokers also represent a huge reservoir of people at risk from this disease. The large number of products in late-stage development for NSCLC reflects this need and hope can be taken from the products currently in development that are producing encouraging clinical data, such as Zactima.

There is still a great deal of work to be done, however. Whilst our knowledge of tumour biology has increased on one level, the importance of individual genotypic and phenotypic characteristics are also becoming apparent, as seen with Iressa. Already vast quantities of abnormalities have been identified that convey treatment sensitivity or resistance. But the true functional significance of these and how they can be used to enhance or inform treatment remains relatively unexplored.

This article was written by Kay Moorcroft, an Editor for IMS LifeCycle R&D focus, which tracks the progress of drugs in development.

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