Anti-cancer Drug Development in Japan

Nagahiro Saijo, MD, of the National Cancer Center Hospital, Tokyo, discussed the unique aspects of anti-cancer drug development in Japan.

Dr. Saijo noted that Japanese clinical trials have greatly improved in quality and activity over the past decade. This improvement comes in part from the efforts of the Japan Clinical Oncology Group (JCOG).

As of May 2002, the group includes 150 hospitals and 260 active sites/investigators. Currently 14 phase III trials are open, 15 clinical trials are collecting follow-up data, and 18 clinical trials are in preparation. Investigators are enrolling approximately 600 patients a year.

Investigators in Japan have already contributed significantly to the development of modern chemotherapy regimens. Japanese research on irinotecan has led to advances in the treatment of colon cancer. Of the 150 abstracts on irinotecan presented at ASCO 2002, Japanese investigators presented 124. Major advances have also been made in non-small cell lung cancer and small cell lung cancer.

Japanese research was also instrumental in the development of oral fluorinated pyrimidines, including capecitabine, and uracil/tegafur (UFT). Japanese investigators presented approximately half the UFT presentations at ASCO this year.

Pivotal studies of UFT suggested that UFT-leucovorin may be an improvement over 5-fluorouracil (5-FU)/leucovorin in the treatment of metastatic colorectal cancer. Survival was equivalent to standard 5-FU/leucovorin, and there was a clinically significant improvement in patient safety.

Research continues on S-1, a novel oral fluoropyrimidine. In late phase II studies, investigators have reported response rates from 22% to 45% in a variety of cancers, including gastric, colorectal, breast, head and neck, and non-small cell lung cancer.

A randomized phase III study involving 450 patients (JCOG 9912) comparing S-1, 5-FU and irinotecan in advanced, inoperable or recurrent gastric cancer is currently underway.

Japanese investigators are contributing to the development of targeted therapies against cancer. These novel agents include UCN-01 and E-7070, both inhibitors of cyclin-dependent protein kinase; TAK-165, a tyrosine kinase inhibitor; and macromolecules.

In addition, Japanese investigators are very active in clinical trials of ZD1839 (Iressa®) via the first pivotal study of ZD1839 in non-small scale lung cancer. The trial included 210 patients, of which Japanese investigators enrolled 102 patients.

The Singapore/Hong Kong/Australia Anticancer Drug Development Consortium

John Eu-Li Wong, MD of the University of Singapore described the Singapore/Hong Kong/Australia Anticancer Drug Development Consortium. This unique collaborative group provides a platform for drug development activities in Asian and Caucasian patient populations simultaneously.

In comparing Asian and Caucasian patient populations, differences in patterns of disease can be studied leading to targeted drug development. Stomach, liver and nasopharyngeal cancers are more common in Asia than in the United States or in Europe. Yet, a large part of drug development in the United States and Europe has focused on colon, breast and lung cancer.

Phenotypic expression of disease can be different in Asian patient populations. In breast cancer patients for example, about 50% of postmenopausal Asian women are hormone-receptor positive, while 80% of Caucasian women are hormone receptor positive.

Dr. Wong described a study that demonstrates the advantage of comparing Asian patient populations and Caucasian patient populations in drug development trials.

Investigators enrolled 43 Asian and 23 Caucasian patients with advanced non-small cell lung cancer to receive the combination of docetaxel and carboplatin. Although differences in drug tolerability led to the need for decreased dosing of carboplatin in the Asian patients, the response rate was higher in this group. Multivariate analysis suggested ethnicity was a predictor of response.

Dr. Wong said other investigators groups should consider using the Consortium's joint drug development efforts as a model for international or regional collaborations.

Clinical Trials with New Anti-cancer Agents in Different Parts of the World

David R. Parkinson, MD, Novartis Pharmaceutical Corporation, said many people are frustrated that early drug development trials are seldom conducted outside the United States and Europe.

Pharmaceutical companies need to expand the patient base for clinical trials in order to accelerate accrual. At the same time they need to decrease trial expenses so that less prosperous countries may participate in drug development.

Japanese researchers recently attended a meeting sponsored by the American Association for Cancer Research. At the meeting, attendees discussed strategies to bridge clinical trial data from other parts of the world to Japan. This strategy has resulted in more rapid approvals of drugs in Japan.

Japanese medical oncologists expressed strong interest in participating in early drug development studies. Dr. Parkinson applauded recent changes that will facilitate drug development in Japan. There have been improvements in regulatory review and clinical trial accrual. Excellent investigators in strong institutions are available to participate in drug development trials.