ODAC Recommends Full Approval for Gemzar for Pancreatic Cancer

September 1, 1995

Gemzar (gemcitabine hydrochloride), an investigational nucleoside analog from Eli Lilly and Company, for the treatment of

Gemzar (gemcitabine hydrochloride), an investigational nucleosideanalog from Eli Lilly and Company, for the treatment of advancedor metastatic pancreatic cancer, has been recommended to be clearedfor 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 recommendationafter reviewing and evaluating clinical data on the use of gemcitabinein patients with advanced or metastatic pancreatic cancer. Thecommittee's recommendations, while not binding, will be consideredby 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 concerningGemzar. Gemzar is an innovative investigational drug that targetsan unmet medical need in the United States," said AugustM. Watanabe, MD, a vice president of the company and presidentof Lilly Research Laboratories. "As the first newly discovereddrug recommended for marketing for the treatment of advanced ormetastatic pancreatic cancer in several decades, Gemzar offersthe potential of providing new hope to pancreatic cancer patients."

"I want to congratulate the company on putting a lot of effortinto a very difficult area [clinical benefit endpoints] in a mannerthat is conservative," said Richard Gelber, PhD, Professorof Pediatrics in the Division of Biostatistics, Dana Farber CancerInstitute, Boston, Massachusetts, and a member of ODAC.

Recognizing the unique needs associated with caring for pancreaticcancer patients, Lilly has worked with the FDA on a clinical endpointwith which to measure the efficacy of gemcitabine and the impacttreatment has on patients.

This endpoint, termed "clinical benefit," is designedto quantitatively measure the effect of gemcitabine on patients'overall quality of life. The components include the patient'slevel of pain, need for pain medication, ability to perform dailyactivities and weight change. Taken together, data on clinicalbenefit provide researchers with a more complete view of patients'health and quality of life.

"Lilly's innovative clinical endpoints take into accountnot just a patient's survival time, but the quality of life duringthat time," explained F. Andrew Dorr, MD, medical researchadvisor, Lilly Research Laboratories. "These endpoints illustratethe benefits of drugs that provide improvements in disease-relatedsymptoms and clinical well-being."

Clinical Data on Survival

The committee's decision was based on the presentation of resultsfrom two clinical trials. One Phase III, multicenter, randomizedtrial compared gemcitabine to 5 fluorouracil (5-FU). The studymeasured survival, an overall estimate of clinical benefit andtumor shrinkage in patients who had not previously received chemotherapy.

In this study, 63 patients were treated with each compound. The6 month survival rates were 46% and 31% for gemcitabine and 5-FUrespectively, and the 1 year survival rates were 18% and 2% forgemcitabine and 5-FU respectively. There was an approximatelyone and a half month improvement in median survival in patientswho received gemcitabine in this study.

In addition, 24% of patients who received gemcitabine experienced"clinical benefit" compared with 5% of patients treatedwith 5-FU. The partial response rate (50% or greater decreasein 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 approximately39% compared with 19% for patients receiving 5-FU.

"This randomized study showed a 30% improvement in mediansurvival, illustrating the potential benefit of Gemzar as theinitial treatment for patients with advanced pancreatic cancer,"according to lead investigator Malcolm Moore, Princess MargaretHospital, Ontario, Canada, who presented the results to the committee.

A second Phase II trial included 63 patients who had not responded5-FU treatment. Symptoms improved in 27% of patients, with a mediansurvival time of 3.85 months, a 6 month survival rate of 31% anda 1 year survival rate of 4%. A partial response rate was observedin approximately 10% of patients, and disease stabilization wasreported in approximately 30% of patients.

"This study demonstrates that objective criteria can be usedto evaluate the clinical impact of therapies being evaluated fordifficult to treat solid tumors like pancreatic cancer, a highlysymptomatic disease that is difficult to assess by traditionaltumor 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-likesymptoms and traces of blood and protein in urine have been reported.In the Phase III trial comparing gemcitabine to 5-FU, the discontinuationrate for all adverse events for patients treated with gemcitabinewas 14.3% compared to 4.8% of patients treated with 5-FU. In thePhase 11 trial of patients who had not responded to 5-FU, 3.2%of patients discontinued

gemcitabine therapy due to adverse events that were consideredpossibly drug-related. In an analysis of 979 patients treatedwith gemcitabine, there were five patient deaths possibly causallyrelated to drug treatment.

Worldwide Regulatory Status

The FDA has authorized Lilly to make Gemzar available in the UnitedStates through a Treatment Investigational New Drug (IND) programsince February 1995. Patients with advanced or metastic pancreaticcancer who meet certain medical criteria are eligible for theprogram.