Gemzar (gemcitabine hydrochloride), an investigational nucleoside analog from Eli Lilly and Company, for the treatment of advanced or metastatic pancreatic cancer, has been recommended to be cleared for full marketing by the Oncology Drug Advisory Committee (ODAC) of the Food and Drug Administration (FDA).
The committee of consultants to the FDA made its recommendation after reviewing and evaluating clinical data on the use of gemcitabine(Drug information on gemcitabine) in patients with advanced or metastatic pancreatic cancer. The committee's recommendations, while not binding, will be considered by the FDA in its final review of the New Drug Application (NDA) submitted by Lilly on February 1, 1995.
"We are pleased to learn of ODAC's recommendation concerning Gemzar. Gemzar is an innovative investigational drug that targets an unmet medical need in the United States," said August M. Watanabe, MD, a vice president of the company and president of Lilly Research Laboratories. "As the first newly discovered drug recommended for marketing for the treatment of advanced or metastatic pancreatic cancer in several decades, Gemzar offers the potential of providing new hope to pancreatic cancer patients."
"I want to congratulate the company on putting a lot of effort into a very difficult area [clinical benefit endpoints] in a manner that is conservative," said Richard Gelber, PhD, Professor of Pediatrics in the Division of Biostatistics, Dana Farber Cancer Institute, Boston, Massachusetts, and a member of ODAC.
Recognizing the unique needs associated with caring for pancreatic cancer patients, Lilly has worked with the FDA on a clinical endpoint with which to measure the efficacy of gemcitabine and the impact treatment has on patients.
This endpoint, termed "clinical benefit," is designed to quantitatively measure the effect of gemcitabine on patients' overall quality of life. The components include the patient's level of pain, need for pain medication, ability to perform daily activities and weight change. Taken together, data on clinical benefit provide researchers with a more complete view of patients' health and quality of life.
"Lilly's innovative clinical endpoints take into account not just a patient's survival time, but the quality of life during that time," explained F. Andrew Dorr, MD, medical research advisor, Lilly Research Laboratories. "These endpoints illustrate the benefits of drugs that provide improvements in disease-related symptoms and clinical well-being."
Clinical Data on Survival
The committee's decision was based on the presentation of results from two clinical trials. One Phase III, multicenter, randomized trial compared gemcitabine to 5 fluorouracil(Drug information on fluorouracil) (5-FU). The study measured survival, an overall estimate of clinical benefit and tumor shrinkage in patients who had not previously received chemotherapy.
In this study, 63 patients were treated with each compound. The 6 month survival rates were 46% and 31% for gemcitabine and 5-FU respectively, and the 1 year survival rates were 18% and 2% for gemcitabine and 5-FU respectively. There was an approximately one and a half month improvement in median survival in patients who received gemcitabine in this study.
In addition, 24% of patients who received gemcitabine experienced "clinical benefit" compared with 5% of patients treated with 5-FU. The partial response rate (50% or greater decrease in tumor size) for patients treated with gemcitabine was 5.4% compared with 0 patients treated with 5-FU. Disease stabilization (a decrease of less than 50% and an increase of less than 25% in tumor size) for patients treated with gemcitabine was approximately 39% compared with 19% for patients receiving 5-FU.
"This randomized study showed a 30% improvement in median survival, illustrating the potential benefit of Gemzar as the initial treatment for patients with advanced pancreatic cancer," according to lead investigator Malcolm Moore, Princess Margaret Hospital, Ontario, Canada, who presented the results to the committee.
A second Phase II trial included 63 patients who had not responded 5-FU treatment. Symptoms improved in 27% of patients, with a median survival time of 3.85 months, a 6 month survival rate of 31% and a 1 year survival rate of 4%. A partial response rate was observed in approximately 10% of patients, and disease stabilization was reported in approximately 30% of patients.
"This study demonstrates that objective criteria can be used to evaluate the clinical impact of therapies being evaluated for difficult to treat solid tumors like pancreatic cancer, a highly symptomatic disease that is difficult to assess by traditional tumor response parameters," according to lead investigator, Mace L. Rothenberg, MD, University of Texas Health Science Center, San Antonio, Texas.
Some of the side effects of gemcitabine include neutropenia, thrombocytopenia, and elevation of liver enzymes. Nausea, vomiting, rash and flu-like symptoms and traces of blood and protein in urine have been reported. In the Phase III trial comparing gemcitabine to 5-FU, the discontinuation rate for all adverse events for patients treated with gemcitabine was 14.3% compared to 4.8% of patients treated with 5-FU. In the Phase 11 trial of patients who had not responded to 5-FU, 3.2% of patients discontinued
gemcitabine therapy due to adverse events that were considered possibly drug-related. In an analysis of 979 patients treated with gemcitabine, there were five patient deaths possibly causally related to drug treatment.
Worldwide Regulatory Status
The FDA has authorized Lilly to make Gemzar available in the United States through a Treatment Investigational New Drug (IND) program since February 1995. Patients with advanced or metastic pancreatic cancer who meet certain medical criteria are eligible for the program.