Development of Targeted Therapies in Asia
the Pharmacia Way

Dr Ivan Horak Vice President Clinical Oncology Pharmacia Corporation New Jersey, USA

Pharmacia is a global corporation, with research and development centres based throughout the world, in San Francisco, St Louis, and New Jersey in the USA, Milan in Italy, Singapore, and Tokyo in Japan. Asia is an important area for Pharmacia as there are high quality cancer centres in the region and ICH guidelines are acceptable for most of the region. Cancers unique to Asia, or that have a particularly high incidence in the region include gastric cancer, hepatocellular carcinoma, cancer of the uterine cervix, and nasopharyngeal cancer of undifferentiated pathology.

Asia's Contribution to Global Studies

It is important to investigate the effects of cancer drugs in different racial groups and Asia therefore has a significant role to play in new drug development, particularly for those cancers with a high incidence in the region. Recently, Asian cancer centres participated in a multicentre study of SU5416.031 for colorectal cancer. Unfortunately, there was no clear clinical benefit of this molecule, but Asia helped to facilitate early closure of the trial by enrolling more patients than expected and contributing 10% of the global total number of patients.

Ongoing Oncological Studies in Asia

Currently, there are several ongoing Asian studies of anti-cancer drugs developed by Pharmacia, mainly investigating aromasin and epirubicin. The first is a multicentre trial of aromasin versus tamoxifen for the first-line treatment of breast cancer. 700 patients will be recruited worldwide, and it is expected that up to 180 patients will be enrolled from The Philippines, Taiwan, Thailand, Malaysia, and Pakistan. Epirubicin is being investigated for gastric, bladder, and breast cancer in China, and is being studied as therapy for ovarian cancer in India. There is currently much activity in Korea, with epirubicin being investigated for non-Hodgkin's lymphoma, and gastric and bladder cancer, and a study of idarubicin as induction therapy for acute myeloid leukaemia is being performed. Epirubicin is also being studied for non-small cell lung cancer in Taiwan and is being investigated in combination with taxotere for preoperative breast cancer in Thailand.

In Hong Kong, an innovative trial of aromasin plus celecoxib as neoadjuvant treatment for breast cancer has started. This trial will investigate various biological parameters in the tissues to ascertain the mechanisms of action of these agents. Meanwhile, Singapore is involved in a trial of aromasin for adjuvant breast cancer being performed throughout Europe, the USA, and Asia.

Nemorubicin is a new third-generation anthracycline. This compound is currently being tested in a phase II programme for hepatocellular carcinoma in China (Table 1).

Table 1. Characteristics of nemorubicin.

Cancer Prevention and Treatment

It is highly unlikely that there will be a rapid cure for metastatic cancer in the near future. However, it is to be hoped that it will be possible to decrease the incidence or delay the development of cancer by ascertaining who is at risk and preventing premalignant changes. Cyclooxygenase 2 (COX 2) is an attractive target for this therapeutic approach since COX 2 is overexpressed at all stages of human colon carcinogenesis, from initial familial adenomatous polyposis (FAP) to metastatic disease. COX 2 is also overexpressed in other human epithelial cancers, including head and neck, bladder, colon, breast, pancreatic, and prostate cancer.

Celecoxib has been found to be an effective therapy for FAP and is now approved for this indication. Indeed, the number of colorectal polyps decreased dramatically when celecoxib was given to patients with FAP for 6 months. The drug has now been tested in more than 4000 patients with spontaneous adenomatous polyposis and Asia has played a significant role in these trials.

There are ongoing studies investigating the effect of this drug in early colorectal cancers (stages A and B), additional trials involving FAP for postmarketing surveillance, and a trial in non-polyposis colorectal disease that will soon be completed. Trials are planned for the future to investigate celecoxib for treatment of all stages of colorectal disease (Figure 1). There are also trials planned to investigate the role of celecoxib in breast cancer, both for prevention and treatment (Figure 2).

Figure 1. Future trials of celecoxib in colorectal carcinoma. Abbreviations: FAP = familial adenomatous polyposis; SAP = spontaneous adenomatous polyposis.


Figure 2 . Future trials of celecoxib in breast cancer. Abbreviations: DCIS = ductal carcinoma in situ.



Cancer Treatment in the Future

There is an ongoing learning curve related to novel therapeutics for cancer. In the future, it is hoped that the use of novel therapeutics will exceed the use of conventional cytotoxic therapy and change the pattern of the disease to that of a chronic, or even a curable, condition. The challenges now being faced include the following:

• the role of biomarkers in the development of targeted therapy, with particular reference to the selection of compounds and the selection of patients who may benefit from targeted therapy, and proof of the mechanism of action
• attaining clinically meaningful benefits from selective targeted therapies
• the role of preventive therapy and acceptable endpoints for regulatory committees

the problem of multiple pathways controlling the process of carcinogenesis in solid tumours, including angiogenesis, metastasis, cell proliferation, and apoptosis.

The major challenge of the 'postgenomic' era is not in target identification or validation, or combinatorial chemistry, but in understanding the biology of the target and translating this knowledge from the laboratory to the clinic for a more sophisticated individualised treatment schedule. Currently, a combination of cytotoxic agents improves the short-term outcome of patients with cancer. However, it is hoped that a combination of novel therapeutics will change the acute disease to a chronic condition that is more target-specific.

In the postgenomic era, therapy is expected to become more personalised. Diseases will be reclassified based on biological markers (genomics, proteomics). Patients will receive therapy tailored to personal biological markers. Biological markers may be used to identify disease predisposition to reduce risk and delay or prevent cancer progression.

This article is based on a presentation given by Dr Ivan Horak at the 7th Annual Scientific Symposium of the Hong Kong Cancer Institute Cancer Trials in Asia, Hong Kong China, 5-6 March 2002.