MARF Doctor Hails Alimta as "A New Standard Therapy" for Treating Mesothelioma; Lilly Makes Drug Available through Expanded Access Program. Indianapolis, Indiana, November 14, 2002"

INDIANAPOLIS, INDIANA (November 14, 2002: )--

As previously reported, ALIMTA® (pemetrexed) is an antifolate chemotherapy drug which has shown dramatic results in improving the median survival for advanced mesothelioma patients when compared to other drugs. On November 14, 2002, the directors and science advisors of the Mesothelioma Applied Research Foundation ( MARF ) met with other groups interested in this form of cancer to discuss the development of ALIMTA in mesothelioma. According to a published source (Scrip, July 2002) the drug has been granted fast-track approval status by the FDA, but more importantly the drug's developer, Eli Lilly and Company, has made the drug available through an Expanded Access Program in cooperation with the US Food and Drug Administration (discussed below).

Three MARF doctors presented lectures at the conference: Dr. Nicholas Vogelzang and Dr. Hedy Kindler of the University of Chicago Cancer Research Center, and Dr. Harvey Pass of the Karmanos Cancer Center. Chris Hahn, Executive Director of MARF, also presented a slide show about MARF's peer-reviewed grant system, a summary of the four grants it has awarded since 2000, and MARF's advocacy and education programs. At the meeting, MARF also announced the two winners of its 2002 round of $100,000 grants, which you can read about here. To date, MARF has awarded over $600,000 in research grants.

Dr. Vogelzang's lecture was entitled "A New Standard Therapy for the Treatment of Malignant Mesothelioma." He began by requesting a moment of silence for a 42 year-old young man who bravely fought the disease but died the very same week in bed curled up with his son. The somber moment was a reminder that mesothelioma does not respect rank, power, intelligence, beauty or courage, nor does it have much respect for the best available surgical, radiation, immunotherapy and chemotherapy treatment regimens.

Currently Available Chemotherapy Drugs

The response rate of mesothelioma to commercially available single agent chemotherapy ranges from Gemcitabene at 12% to Vinorelbine at 24% ( see attached chart ). Depending on the dosage, Cisplatin has registered a response rate between 13% and 36% ( see attached chart ). Although there is no real "standard of care" for mesothelioma for a number of reasons, Cisplatin has been considered a "standard therapy." The antifolate family of drugs, however, have produced higher response rates, topped by Methotrexate, at 41% (see attached chart , but also note that the definition of "response" is not always the same among different studies). Note that MARF Science Advisory Board member Dr. Eric Vallieres of the University of Washington School of Medicine typically administers Methrotrexate and Vinblastine to patients prior to performing an extra-pleural pneumonectomy.

For a summary of other novel drug compounds that are currently involved in clinical trials in the U.S. at various institutions, please see the attached chart here. Note also there is a Phase II clinical trial using Gleevec, which is a PDGF inhibitor (platelet derived growth factor), ongoing at the University of Chicago. Note also that "Tarceva" is a "close cousin" to Iressa.

Results of Randomized Phase III Trial

As presented by Dr. Vogelzang at the American Society of Clinical Oncology (ASCO) meeting in May 2002, the Alimta randomized Phase III clinical trial involved 448 patients from multiple sites in over 30 countries. The average age was 61. Half of the patients received Alimta/Cisplatin, and the other half received Cisplatin alone. Most of the patients enrolled were classified at stage III and IV and thus considered "inoperable." There were at least three categories for which data was presented: Cisplatin alone, Alimta/Cisplatin in combination without vitamin supplementation, and Alimta/Cisplatin with vitamin supplementation. As I understood it, patients given Folic Acid and B-12 supplements experienced less toxicity, but the issue confronting the investigators was at what point does too much folic acid/b-12 interfere with the drug's efficacy.

In the final analysis, the best results were recorded for the patient class who received vitamin supplementation, as they were able to undergo more cycles of treatment because they could tolerate it better. The principal side effect was neutropenia or a lowered white blood cell count, an effect that was reduced with vitamin supplementation.

The data below are available on the ASCO website at www.asco.org . Once at the home page for ASCO, click on the following words "Meetings and Education" then "Virtual Meetings" then "Virtual Lectures" then "General Oncology" then "3. Plenary Session - Dr. Nicholas J. Vogelzang MD."

In terms of lung function, over time patients in the Alimta/Cisplatin group recorded improved lung function, whereas the patients in the Cisplatin only group experience increased shortness of breath. Similarly, the Alimta/Cisplatin patients experienced less pain.

According to Dr. Vogelzang, the Alimta/Cisplatin regimen "significantly improved survival" and warranted consideration as "standard front line therapy" for patients with pleural malignant mesothelioma (see Conclusions ). My first question had to do with those patients who were advised by their doctor that they were late stage and therefore unresectable. If an "unresectable" patient took Alimta/Cisplatin and showed response could he then be eligible for the EPP or pleurectomy / decortication?

Dr. Vogelzang made two points: first, this issue will be explored in a phase III clinical trial that will be underway in the near future at the University of Chicago, which recently hired a thoracic surgeon. Secondly, the Alimta/Cisplatin regimen would be considered a "standard front line therapy" for those patients, even if early stage, who did not wish to undergo surgery. One audience member suggested that the regimen for this patient group (not favoring surgery) should be considered the "current best chemotherapy treatment," to avoid the impression that it is superior to another regimen, such as multi-modal surgery/chemotherapy/radiation in varying degrees and order.

At the outset of his lecture, Dr. Vogelzang noted that the median survival time (MST) for pleural mesothelioma patients who underwent either extra-pleural pneumonectomy (EPP) or pleurectomy / decortication was about 15 months. I am assuming that those patients also had either chemotherapy or radiation or both. The median survival time for Alimta/Cisplatin patients (with vitamin supplementation) was 13.3 months. Of note, the median survival of those stage I/II patients in the study was 16 months, which on paper looks better than the 15 months MST quoted above, but in order to compare oranges to oranges we would need to break down the surgery numbers for Stage 1 and II patients. Staging is everything. As I've heard doctors debate many times, without a large multi-group randomized phase III trial it's difficult to say whether any aggressive therapy is superior to simply doing nothing.

Certainly the data presented at ASCO show that Alimta/Cisplatin is superior to other currently available drugs, whether single agent or in combination, but it remains to be seen whether Alimta/Cisplatin plus surgery regimen will send the survival curve even higher and farther to the right.

Surgery, Chemo, Radiation: Is Timing Everything?

It is beyond the scope of this report, but I wondered at the timing issue. That is, is it better to undergo chemotherapy first and measure response, if any, as done at the University of Washington, or undergo the surgery first (if eligible), and opt for intracavitary chemotherapy during the procedure or afterwards? If afterwards, how much later, and should radiation precede or follow the chemotherapy cycles?

As Dr. Pass pointed out in his lecture, we can't cure mesothelioma through surgery alone, and it's certainly the case that we can't cure mesothelioma with chemotherapy alone, either. Most will agree that the long term survivors have generally undergone several treatment modalities. Dr. Pass also mentioned that Dr. David Sugarbaker at Brigham and Women's Hospital in Boston is expected to soon publish the results of his trial using hyperthermic chemotherapy infusion intraoperatively (Gemzar).

Alimta's Expanded Access Program: "Available, Tolerable and Pivotal"

Many patients have asked their doctors to obtain Alimta "off-protocol" or on a "compassionate use" basis, while the FDA is still deciding whether to approve the drug for commercial use. Because in earlier clinical trials Alimta has shown promise over other available drug therapies, Lilly and the FDA reached an agreement on making Alimta available on an expanded access, or compassionate use, basis to medically eligible patients with malignant pleural mesothelioma. Lilly has sought to answer the needs of mesothelioma patients by making Alimta relatively easy to obtain. The key word here is "relatively" since from a community hospital doctor's perspective -- with limited staff, time and resources -- it's never truly easy to fill out the paperwork required by the FDA.

According to a news release on the Business Wire at http://www.businesswire.com/webbox/bw.070902/221902229.htm , expanded access programs are designed to make investigational agents available at the earliest opportunity for the treatment of patients with diseases for which no comparable or satisfactory alternative drug or other therapy is available. Under such programs, patients are given access to an agent that is not yet commercially available, although the sponsor is actively pursuing marketing approval.

The FDA agreed to the expanded access program for Alimta based on preliminary review of results from clinical trials. Included in the review were the results of a Phase III trial presented May 20 at the annual meeting of the American Society of Clinical Oncology. Findings showed that patients treated with a combination of Alimta and Cisplatin survived longer and experienced less pain and shortness of breath than those treated with Cisplatin alone. In this trial, the most common side effect associated with Alimta and Cisplatin was a decrease in infection-fighting white blood cells (technically know as neutropenia). Under the expanded access program, Alimta will be available free of charge to patients with MPM who meet medical eligibility criteria.

For more information on the expanded access program, physicians may call toll-free 1-800-347-9503 (patients are asked to work through their physicians). The service which administers the program has hired registered nurses to field the calls. The nurses can also recommend patients to a list of doctors and hospitals who are administering Alimta. The service will provide the doctor with clinic/hospital certification forms, regulatory forms and other administrative forms. To qualify to treat patients under the program, doctors will need to obtain Internal Review Board (IRB) approval. For doctors who do not have easy access to an IRB, approval can be obtained through a centralized IRB that has been assembled by the expanded access program (this might even be easier and less time consuming than waiting to get IRB approval at a mega-hospital).

Additionally, information on this trial can be found at www.ClinicalTrials.gov , a service of the National Institutes of Health.

Progress: Slowly But Surely

On behalf of MARF, I want to thank Eli Lilly for their work on Alimta and commitment to mesothelioma. It is encouraging to know that a major pharmaceutical company has taken such a great interest in an orphan disease like mesothelioma, a tumor so resistant to treatment it has widely been considered "incurable."

As Dr. Pass has written, "Mesothelioma is an incredibly challenging malignancy to deal with. The small number of cases in the United States, the lack of uniform standards of care for its treatment, the prevailing sense of nihilism, and the litigious association with the disease are all barriers to a unified approach for disease eradication." Eli Lilly and Company is to be commended for investing an enormous amount of time and money (estimated at over $100 million) to develop a promising drug for mesothelioma.

Roger G. Worthington, Esq.
November 18, 2002

*** POSTED ON NOVEMBER 20, 2002 ***