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
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 (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