Studies Suggest Key Correlation Between Lung Cancer Subtype and Treatment Outcomes

Lilly Studies Predictive Factors to Better Target Patients for ALIMTA(R) (pemetrexed for injection) in the Treatment of Non-Small Cell Lung Cancer

BARCELONA, Spain, September 25, 2007 /PRNewswire-FirstCall/ -- In clinical research, patients with advanced non-small cell lung cancer (NSCLC) that are classified as having a non-squamous histology achieve statistically significant higher survival when treated in the second-line setting with ALIMTA(R) (pemetrexed for injection) when compared to histologically-similar patients treated with docetaxel. The data (ECCO Abstract # 6521)(1) were presented at the 14th European Cancer Conference (ECCO) in Barcelona. ALIMTA, manufactured and marketed by Eli Lilly and Company, is currently indicated for the second-line treatment of advanced NSCLC in more than 85 countries.

The retrospective analysis of Phase III data(2) consisted of 571 patients. The analysis showed that non-squamous patients treated with ALIMTA achieved a statistically higher overall survival compared to those treated with docetaxel (9.3 months and 8.0 months, respectively; hazard ratio 0.778 [95% CI 0.607- 0.997]). Conversely, the analysis suggested that patients with a squamous histology and treated with docetaxel had a statistically higher overall survival compared to those treated with ALIMTA (7.4 months and 6.2 months respectively; hazard ratio 1.563 [95% CI 1.079, 2.264]). Patients with a non- squamous histology represented the majority of the patients on the trial.

The retrospective analysis was driven by preclinical data that suggested patients with a lower expression of thymidylate synthase (TS) enzyme show an increased efficacy when treated with ALIMTA.(3,4) The histological type of NSCLC is determined by how the cancerous cells appear under a microscope. Two of the most common histological types of NSCLC are adenocarcinoma and large cell carcinoma (5) and constitute approximately 55 percent of all NSCLC diagnoses.(6) These two subgroups, and any other types not identified as squamous, were considered non-squamous for this analysis.

"This particular analysis suggests that histology may play an important role in determining patients who are most likely to receive a larger treatment result from ALIMTA," said Patrick Peterson, Ph.D., principal research scientist at Lilly and principal author of the analysis.

Patients on the ALIMTA arm were treated with ALIMTA (500 mg/meters squared) supplemented with vitamin B12 and folic acid. Patients on the docetaxel arm were treated with docetaxel (75 mg/meters squared).

Data from a second trial (ECCO Abstract # 6560)(7) detailed additional predictive factors for a patient's potential benefit from treatment with ALIMTA. In a Phase II prospective study, researchers in Japan evaluated the survival outcomes of 216 patients with locally advanced or metastatic NSCLC who were treated with ALIMTA in the second-line setting. The data suggested that favorable predictive factors for ALIMTA treatment in the second-line NSCLC setting could include the following: female patients; patients with adenocarcinoma histology; patients with a longer interval since their previous chemotherapy treatment; patients with good performance status, and; those diagnosed in the early clinical stage.

"Cancer treatment continues to move in the direction of tailoring therapies to meet the needs of the specific types of cancers and patients," said Richard Gaynor, M.D., vice president, cancer research and global oncology platform leader for Lilly. "Our goal is to further explore the biologic rationale for this observation in non-squamous histology and work toward developing a biomarker approach to determine when ALIMTA is the right drug for the right patient."

ALIMTA, as a single agent, was approved by both the European Medicines Agency (EMEA) and the U.S. Food and Drug Administration (FDA) in 2004 for the treatment of patients with locally advanced or metastatic NSCLC after prior chemotherapy. The effectiveness of ALIMTA in second-line NSCLC was based on the surrogate endpoint, response rate. There are no controlled trials demonstrating a clinical benefit, such as a favorable survival effect or improvement of disease related symptoms.

About Non-Small Cell Lung Cancer (NSCLC)

NSCLC is the most common type of lung cancer and represents 75-80 percent of all lung cancers. NSCLC has five-tier staging, starting at 0 and rising to the severity of stage IV. NSCLC can spread through the lymphatic system, penetrating the chest lining, ribs, and the nerves and blood vessels that lead to the arm. The liver, bones and brain are potential targets if the cancerous cells enter the blood stream.

About Lilly Oncology, a Division of Eli Lilly and Company

For more than four decades, Lilly Oncology has been collaborating with cancer researchers to deliver innovative treatment choices and valuable programs to patients and their physicians. Inspired by courageous patients living with cancer, Lilly Oncology is providing treatments that are considered global standards of care and developing a broad portfolio of novel targeted therapies to accelerate the pace and progress of cancer care. To learn more about Lilly's commitment to cancer, please visit www.LillyOncology.com.

About Eli Lilly and Company

Lilly, a leading innovation-driven corporation, is developing a growing portfolio of first-in-class and best-in-class pharmaceutical products by applying the latest research from its own worldwide laboratories and from collaborations with eminent scientific organizations. Headquartered in Indianapolis, Ind., Lilly provides answers -- through medicines and information -- for some of the world's most urgent medical needs.

    P-LLY


    ALIMTA(R) (pemetrexed for injection), Lilly

    docetaxel (Taxotere(R)), Sanofi-Aventis

This press release contains forward-looking statements about the potential of ALIMTA for the treatment of non-small cell lung cancer and reflects Lilly's current beliefs. However, as with any pharmaceutical product under development, there are substantial risks and uncertainties in the process of development, commercialization, and regulatory review. There is no guarantee that the product will receive additional regulatory approvals. There is also no guarantee that the product will continue to be commercially successful. For further discussion of these and other risks and uncertainties, see Lilly's filings with the United States Securities and Exchange Commission. Lilly undertakes no duty to update forward-looking statements.

ALIMTA

ALIMTA in combination with cisplatin is indicated for the treatment of patients with malignant pleural mesothelioma whose disease is unresectable or who are otherwise not candidates for curative surgery.

ALIMTA as a single agent is indicated for the treatment of patients with locally advanced or metastatic non-small cell lung cancer after prior chemotherapy. The effectiveness of ALIMTA in second-line NSCLC was based on the surrogate endpoint, response rate. There are no controlled trials demonstrating a clinical benefit, such as a favorable survival effect or improvement of disease-related symptoms.

Important Safety Information

Myelosuppression is usually the dose-limiting toxicity with ALIMTA therapy.

Contraindication

ALIMTA is contraindicated in patients who have a history of severe hypersensitivity reaction to pemetrexed or to any other ingredient used in the formulation.

Warnings

ALIMTA should not be administered to patients with a creatinine clearance <45 mL/min. One patient with severe renal impairment (creatinine clearance 19 mL/min) who did not receive folic acid and vitamin B12 died of drug-related toxicity following administration of ALIMTA alone.

ALIMTA can suppress bone marrow function, as manifested by neutropenia, thrombocytopenia, and anemia (or pancytopenia).

Patients must be instructed to take folic acid and vitamin B12 with ALIMTA as a prophylaxis to reduce treatment-related hematologic and GI toxicities.

Pregnancy Category D-ALIMTA may cause fetal harm when administered to a pregnant woman.

Precautions

Complete blood cell counts, including platelet counts and periodic chemistry tests, should be performed on all patients receiving ALIMTA.

Patients should not begin a new cycle of treatment unless the ANC is greater than or equal 1500 cells per millimeter cubed and the platelet count is greater than or equal to 100,000 cells per millimeter cubed and creatinine clearance is greater than or equal to 45mL/min.

Pretreatment with dexamethasone or its equivalent has been reported to reduce the incidence and severity of skin rash.

The effect of third space fluid, such as pleural effusion and ascites, on ALIMTA is unknown.

In patients with clinically significant third space fluid, consideration should be given to draining the effusion prior to ALIMTA administration.

Caution should be used when administering ibuprofen concurrently with ALIMTA to patients with mild to moderate renal insufficiency (creatinine clearance from 45 to 79 mL/min). Patients with mild to moderate renal insufficiency should avoid taking NSAIDs with short elimination half-lives for a period of 2 days before, the day of, and 2 days following administration of ALIMTA. In the absence of data regarding potential interaction between ALIMTA and NSAIDs with longer half-lives, all patients taking these NSAIDs should interrupt dosing for at least 5 days before, the day of, and 2 days following ALIMTA administration. If concomitant administration of an NSAID is necessary, patients should be monitored closely for toxicity, especially myelosuppression, renal and gastrointestinal toxicities.

Concomitant administration of nephrotoxic drugs or substances that are tubularly secreted could result in delayed clearance of ALIMTA.

It is recommended that nursing be discontinued if the mother is being treated with ALIMTA.

ALIMTA should be administered under the supervision of a qualified physician experienced in the use of antineoplastic agents.

Dose adjustments may be necessary in patients with hepatic insufficiency.

Dosing and Modification Guidelines

Dose adjustments at the start of a subsequent cycle should be based on nadir hematologic counts or maximum nonhematologic toxicity from the preceding cycle of therapy. Modify or suspend therapy according to the Dosage Reduction Guidelines in the full Prescribing Information.

Abbreviated Adverse Events

The most common adverse events (grades 3/4) with ALIMTA in combination with cisplatin for the treatment of patients with MPM were neutropenia (24%); leukopenia (16%); anemia (6%); thrombocytopenia (5%); infection without neutropenia (2%); fatigue (17%); thrombosis/embolism (6%); nausea (12%); vomiting (11%); dyspnea (11%); and chest pain (9%). The most common clinically relevant adverse events (all grades) were fatigue (80%); thrombosis/embolism (7%); nausea (84%); vomiting (58%); constipation (44%); anorexia (35%); stomatitis/pharyngitis (28%); diarrhea (26%); dyspnea (66%); chest pain (40%); and rash (22%).

The most common adverse events (grades 3/4) with ALIMTA for the treatment of patients with NSCLC were anemia (8%); leukopenia (5%); neutropenia (5%); thrombocytopenia (2%); infection without neutropenia (6%); fatigue (16%); thrombosis/embolism (3%); cardiac ischemia (3%); anorexia (5%); dyspnea (18%); and chest pain (7%). The most common clinically relevant adverse events (all grades) were fatigue (87%); anorexia (62%); nausea (39%); constipation (30%); vomiting (25%); diarrhea (21%); stomatitis/pharyngitis (20%); dyspnea (72%); chest pain (38%); neuropathy/sensory (29%); infection without neutropenia (23%); and rash (17%).

See complete Warnings, Precautions, Adverse Reactions, and Dosage and Administration sections in the accompanying full Prescribing Information for safety and dosing guidelines.

    (1) Peterson P, Park K, Fossella F, et al. Is Pemetrexed More Effective in

        Adenocarcinoma and Large Cell Lung Cancer than in Squamous Cell

        Carcinoma? A Retrospective Analysis of a Phase III Trial of Pemetrexed

        vs Docetaxel in Previously Treated Patients with Advanced Non-small

        Cell Lung Cancer (NSCLC). Abstract # 6521, 14th European Cancer

        Conference (ECCO).

    (2) Hanna N, Shepherd FA, Fossella FV, et al. Randomized phase III trial

        of pemetrexed versus docetaxel in patients with non-small cell lung

        cancer previously treated with chemotherapy. J Clin Oncol 2004;

        22:1589-97.

    (3) Sigmond J, Backus HH, Wouters D, et al. Induction of resistance to the

        multitargeted antifolate pemetrexed (ALIMTA) in WiDr human colon

        cancer cells is associated with thymidylate synthase overexpression.

        Biochem Pharmacol 2003; 66:431-38.

    (4) Ceppi P, Volante M, Saviozzi S, et al. Squamous cell carcinoma of the

        lung compared to other histotypes shows higher messenger RNA and

        protein levels for thymidylate synthase. Cancer 2006; 107:1589-96.

    (5) National Cancer Institute, "General Information About Non-Small Cell

        Lung Cancer", Modified Aug. 2, 2007.

        http://www.cancer.gov/cancertopics/pdq/treatment/

        non-small-cell-lung/patient  (Accessed Sept. 11, 2007).

    (6) American Cancer Society, "What is non-small cell lung cancer?",

        Modified Oct. 25, 2006.

        http://www.cancer.org/docroot/CRI/content/CRI_2_4_1x_What_Is_

        Non-Small_Cell_Lung_Cancer.asp?sitearea= (Accessed Sept. 18, 2007).

    (7) Okabe T, Nakagawa K, Kuboto K, et al. Prognostic factors affecting

        survival on pretreated patients with locally advanced or metastatic

        non-small cell lung cancer (NSCLC) - Subgroup analysis in a randomized

        Ph. II study of pemetrexed 500 mg/m2 and 1000 mg/m2. Abstract #

        P-6560, 14th European Cancer Conference.


    

CONTACT: Gregory L. Clarke of Eli Lilly and Company, + 1-317-554-7119(mobile), ; or Paul George of CPR Worldwide,+1-917-251-1038 (mobile), , for Eli Lilly andCompany gregory.clarke@lilly.com p.george@cprworldwideusa.com

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Posted: September 2007

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