ALIMTA(R) (pemetrexed for injection) Receives European Approval for Histologically-Based Use in First-Line Treatment of Most Common Lung Cancer

INDIANAPOLIS, April 11 /PRNewswire/ --

- Approval Marks Third European Indication for ALIMTA

Eli Lilly and Company (NYSE: LLY) today announced that European health authorities have approved the use of ALIMTA(R) (pemetrexed for injection) for a histologically-based use in the first-line treatment of advanced non-small-cell lung cancer (NSCLC), the most common form of lung cancer. This approval - the third for pemetrexed in Europe - follows an initial positive opinion issued by the European Medicines Agency's (EMEA) Committee for Medicinal Products for Human Use (CHMP) on February 21, 2008.

The EMEA specifically approved pemetrexed in combination with cisplatin as a first-line treatment for NSCLC patients with other than predominantly squamous cell histology. Histology is the microscopic study of tissue and NSCLC is classified by its histology. Previously, all histologies were treated similarly.

"This approval opens the door for a novel, tailored approach based on histology or tissue type," said Richard Gaynor, M.D., vice president of cancer research and global oncology platform leader for Lilly. "Our hope is that this study provides physicians with a powerful tool for choosing the right drug for the right patient that leads to optimal treatment results."

The approval in first-line NSCLC is based on a Phase III randomized study that evaluated pemetrexed plus cisplatin versus GEMZAR(R) (gemcitabine HCl for injection) plus cisplatin. The 1,725-patient study, the largest Phase III clinical trial undertaken in the first-line setting of NSCLC, met its primary endpoint of non-inferiority relative to overall survival(1).

However, when it came to survival by histology, the study found, in a pre-planned histological analysis, that patients with either adenocarcinoma or large-cell carcinoma had a clinically relevant improvement in overall survival when treated with the pemetrexed regimen in the first-line setting. In comparison, patients with squamous cell histology were found to have a more favorable overall survival when treated with the gemcitabine regimen.

The lead investigator of the study, Giorgio Scagliotti, M.D., Department of Clinical and Biological Sciences Thoracic Oncology Unit, University of Torino, Orbassano, Italy, said the approval of pemetrexed plus cisplatin in a first-line setting marked an important step forward in treating the world's leading cause of cancer deaths.

"This study provides further evidence of the need to use a tailored approach to treating lung cancer patients, rather than simply using a particular medicine because of the treatment stage," said Dr. Scagliotti.

Data from the first-line NSCLC study was presented at the Presidential Symposium at the 12th World Conference on Lung Cancer (WCLC) in Seoul, Korea, on September 5, 2007, and at the Presidential Symposium III at the 14th Annual European Cancer Conference (ECCO) on September 24, 2007, in Barcelona, Spain.

This regulatory approval paves the way for launches in Europe and applies to all 27 countries of the European Union, as well as Norway, Iceland, and Liechtenstein.

Pemetrexed as Second-Line NSCLC Treatment

In regard to the second-line indication for pemetrexed in NSCLC, the EMEA has approved a change in the indication to patients with other than predominantly squamous cell histology. This decision was based on a retrospective analysis of Phase III data in patients treated with either pemetrexed or docetaxel second-line that showed NSCLC patients with other than predominantly squamous cell histology had improved survival when treated with pemetrexed as compared to docetaxel, whereas patients with squamous cell histology treated with docetaxel had improved survival compared to pemetrexed. Data from this trial was presented at ECCO on September 25, 2007, in Barcelona(2).

Notes to Editor

About ALIMTA (pemetrexed for injection)

Pemetrexed is currently indicated in combination with cisplatin in more than 85 countries for the treatment of patients with malignant pleural mesothelioma (MPM) whose disease is unresectable or who are otherwise not candidates for curative surgery. Pemetrexed is also approved as a second-line, single agent for the treatment of patients with locally advanced or metastatic NSCLC after prior chemotherapy. This latest approval is for pemetrexed in combination with cisplatin as a first-line treatment for NSCLC patients with other than predominantly squamous cell histology.

About Non-Small-Cell Lung Cancer (NSCLC)

NSCLC is the most common type of lung cancer and represents 85 to 90 percent of all lung cancers(3). NSCLC has five-tier staging, starting at 0 and rising to the severity of stage IV(4). 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 bloodstream.

According to the World Health Organization (WHO) Cancer Report, lung cancer is the world's most common cancer and the leading cause of cancer death for men and women. More than 1 million people die from lung cancer each year(5).

NSCLC is defined as a group of histologies, that is, tumor types differentiated by cellular structure. The most common NSCLC histology types are squamous (or epidermoid) carcinoma, adenocarcinoma, and large-cell carcinoma. These histologies are often classified together because to date, approaches to diagnosis, staging, prognosis, and treatment have been similar(6).

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.

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

GEMZAR(R) (gemcitabine HCl for injection), Lilly

This press release contains forward-looking statements about the potential of ALIMTA and GEMZAR 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.

Important Safety Information for ALIMTA

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 > or = 1500 cells/mm(3) and the platelet count is > or = 100,000 cells/mm(3) and creatinine clearance is > or = 45 mL/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.

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

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.

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 (% incidence)

The most common adverse events (grades 3/4) with ALIMTA versus docetaxel, respectively, for the treatment of patients with NSCLC were anemia (8 vs 7); leukopenia (5 vs 28); neutropenia (5 vs 40); thrombocytopenia (2 vs 1); ALT elevation (3 vs 1); febrile neutropenia (2 vs 13); infection without neutropenia (6 vs 4); infection/febrile neutropenia - other (2 vs 1); fatigue (16 vs 17); thrombosis/embolism (3 vs 3); cardiac ischemia (3 vs 1); anorexia (5 vs 8); dyspnea (18 vs 26); and chest pain (7 vs 8). The most common clinically relevant adverse events (all grades) with ALIMTA versus docetaxel, respectively, were fatigue (87 vs 81); anorexia (62 vs 58); nausea (39 vs 25); constipation (30 vs 23); vomiting (25 vs 19); diarrhea (21 vs 34); stomatitis/pharyngitis (20 vs 23); edema (19 vs 24); dyspnea (72 vs 74); chest pain (38 vs 32); neuropathy/sensory (29 vs 32); infection without neutropenia (23 vs 17); anemia (33 vs 33); fever (26 vs 19); and rash (17 vs 9).

The most common adverse events (grades 3/4) with ALIMTA in combination with cisplatin versus cisplatin alone, respectively, for the treatment of patients with MPM were neutropenia (24 vs 4); leukopenia (16 vs 1); anemia (6 vs 0); thrombocytopenia (5 vs 0); infection without neutropenia (2 vs 0); infection with grade 3/4 neutropenia (1 vs 0); infection/febrile neutropenia - other (1 vs 0); febrile neutropenia (1 vs 0); fatigue (17 vs 13); thrombosis/embolism (6 vs 4); nausea (12 vs 6); vomiting (11 vs 5); dyspnea (11 vs 7); and chest pain (9 vs 6). The most common clinically relevant adverse events (all grades) with ALIMTA in combination with cisplatin versus cisplatin alone, respectively, were neutropenia (58 vs 16); leukopenia (55 vs 20); anemia (33 vs 14); thrombocytopenia (27 vs 10); fatigue (80 vs 74); thrombosis/embolism (7 vs 4); nausea (84 vs 79); vomiting (58 vs 52); constipation (44 vs 39); anorexia (35 vs 25); stomatitis/pharyngitis (28 vs 9); diarrhea (26 vs 16); dyspnea (66 vs 62); chest pain (40 vs 30); and rash (22 vs 9).

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

Important Safety Information for GEMZAR

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

Contraindication

Known hypersensitivity to GEMZAR.

Warnings

Infusion times of GEMZAR longer than 60 minutes and more frequent than weekly dosing have been shown to increase toxicity.

Pulmonary toxicity has been reported. In cases of severe lung toxicity, GEMZAR therapy should be discontinued immediately and appropriate supportive care measures instituted.

Hemolytic Uremic Syndrome (HUS) and/or renal failure have been reported following one or more doses of GEMZAR. Renal failure leading to death or requiring dialysis, despite discontinuation of therapy, has been rarely reported. The majority of the cases of renal failure leading to death were due to HUS.

Serious hepatotoxicity, including liver failure and death, has been reported very rarely in patients receiving GEMZAR alone or in combination with other potentially hepatotoxic drugs.

GEMZAR is Pregnancy Category D. GEMZAR can cause fetal harm when administered to a pregnant woman.

Precautions

Use caution in patients with pre-existing renal impairment or hepatic insufficiency. Administration of GEMZAR may exacerbate underlying hepatic insufficiency.

The optimum regimen for safe administration of GEMZAR with therapeutic doses of radiation has not yet been determined in all tumor types. GEMZAR has radiosensitizing activity and radiation recall reactions have been reported.

It is not known whether GEMZAR or its metabolites are excreted in human milk.

The effectiveness of GEMZAR in pediatric patients has not been demonstrated.

The toxicities of GEMZAR observed in pediatric patients were similar to those reported in adults.

GEMZAR clearance is affected by age as well as gender.

Patients receiving therapy with GEMZAR should be monitored closely by a physician experienced in the use of cancer chemotherapeutic agents.

Monitoring and Dosage Modifications

Dosage adjustments for hematologic toxicity may be required.

Serum creatinine, potassium, calcium, and magnesium should be monitored during combination therapy with cisplatin.

Patients should be assessed with a CBC, including differential and platelet count, prior to each dose of GEMZAR. Modify or suspend therapy according to the Dosage Reduction Guidelines in the full Prescribing Information.

Hepatic and renal function (including transaminases and serum creatinine) should be evaluated prior to therapy with GEMZAR and periodically thereafter.

Abbreviated Adverse Events (% incidence)

The most severe adverse events (grades 3/4) with GEMZAR plus cisplatin for the first-line treatment of patients with NSCLC in comparative trials of a 28-day regimen (GEMZAR plus cisplatin versus cisplatin alone) and a 21-day regimen(GEMZAR plus cisplatin versus etoposide plus cisplatin), respectively, were neutropenia (57 vs 4, 64 vs 76); thrombocytopenia (50 vs 4, 55 vs 13); leukopenia (46 vs 3, 29 vs 43); anemia (25 vs 7, 22 vs 15); nausea 28d (27 vs 21); vomiting 28d (23 vs 19); nausea/vomiting 21d (39 vs 26); neuromotor 28d (12 vs 3); hypomagnesemia 28d (7 vs 2); neurohearing 28d (6 vs 6); creatinine elevation 28d (5 vs 3); and dyspnea (7 vs 5, 1 vs 0). The most common adverse events (all grades) of the 28-day regimen (GEMZAR plus cisplatin versus cisplatin alone) and the 21-day regimen (GEMZAR plus cisplatin versus etoposide plus cisplatin), respectively, were anemia (89 vs 67, 88 vs 77); leukopenia (82 vs 25, 86 vs 87); neutropenia (79 vs 20, 88 vs 87), thrombocytopenia (85 vs 13, 81 vs 45), lymphocytopenia 28d (75 vs 51); hematuria (15 vs 13, 22 vs 10); creatinine 28d (38 vs 31), hyperglycemia 28d (30 vs 23); hypomagnesemia 28d (30 vs 17); nausea 28d (93 vs 87); vomiting 28d (78 vs 71); nausea and vomiting 21d (96 vs 86); alopecia (53 vs 33, 77 vs 92); neuromotor 28d (35 vs 15); constipation (28 vs 21, 17 vs 15); neurohearing 28d (25 vs 21); paresthesias 21d (38 vs 16); and infection (18 vs 12, 28 vs 21).

The most severe adverse events (grades 3/4) with GEMZAR plus carboplatin versus carboplatin, respectively, for the treatment of patients with advanced ovarian cancer were neutropenia (71 vs 12), thrombocytopenia (35 vs 11), leukopenia (53 vs 7), anemia (28 vs 11), nausea (6 vs 3), vomiting (6 vs 3), and constipation (7 vs 3). The most common adverse events (all grades) were neutropenia (90 vs 58); leukopenia (86 vs 70); anemia (86 vs 75); and thrombocytopenia (78 vs 57); RBC transfusion (38 vs 15), alopecia (49 vs 17), neuropathy/sensory (29 vs 27), nausea (69 vs 61), fatigue (40 vs 32), vomiting (46 vs 36), diarrhea (25 vs 14), and constipation (42 vs 37).

The most severe adverse events (grades 3/4) with GEMZAR plus paclitaxel versus paclitaxel, respectively, for the treatment of patients with MBC were neutropenia (48 vs 11); alopecia (18 vs 22); leukopenia (11 vs 2); anemia (7 vs 4); fatigue (7 vs 2); thrombocytopenia (6 vs 2); ALT elevation (6 vs 1); and neuropathy-sensory (6 vs 3). The most common adverse events (all grades) were alopecia (90 vs 92); anemia (69 vs 51); neutropenia (69 vs 31); neuropathy-sensory (64 vs 58); nausea (50 vs 31); fatigue (40 vs 28); myalgia (33 vs 33); vomiting (29 vs 15); and thrombocytopenia (26 vs 7).

The most severe adverse events (grades 3/4) with GEMZAR versus 5-FU for the first-line treatment of patients with pancreatic cancer and data reported from a single agent safety database, respectively, were neutropenia (26 vs 5, 24); alkaline phosphatase elevation (16 vs 17, 20); AST elevation (12 vs 2, 17); nausea/vomiting (13 vs 5, 12); ALT elevation (10 vs 0, 11); anemia (10 vs 0, 10); leukopenia (10 vs 2, 9); thrombocytopenia (10 vs 2, 8); bilirubin elevation (4 vs 9, 8); and pain (2 vs 0, 7). The most common adverse events (all grades), defined as reported in > 25% of patients, were AST elevation (72 vs 52, 78); alkaline phosphatase elevation (71 vs 64, 77); anemia (65 vs 45, 73); ALT elevation (72 vs 38, 72); leukopenia (71 vs 15, 64); nausea and vomiting (64 vs 58, 71); neutropenia (62 vs 18, 61); thrombocytopenia (47 vs 15, 36); pain (10 vs 7, 42); fever (30 vs 16, 38); proteinuria (10 vs 2, 32); constipation (10 vs 11, 31); diarrhea (24 vs 31, 30); rash (24 vs 13, 28); and bilirubin elevation (16 vs 25, 26).

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

(1) Scagliotti G, Purvish P, et al. Phase III study of pemetrexed plus cisplatin versus gemcitabine plus cisplatin in chemonaive patients with locally advanced or metastatic non-small cell lung cancer (NSCLC). Abstract PRS-3, 12th World Conference on Lung Cancer (WCLC) 2007. Journal of Thoracic Oncology, Vol 2 No 8, Supplement 4, Page S306, August 2007. (2) Peterson P, Park K, et al. Is pemetrexed more effective in patients with non-squamous histology? A retrospective analysis of a phase III trial of pemetrexed vs docetaxel in previously treated patients with advanced nonsmall cell lung cancer (NSCLC). Abstract P#6521, The European Cancer Conference 2007 (ECCO 14). European Journal of Cancer Supplements, Vol 5 No 4, Page 363. (3) American Cancer Society, "What Is Non-Small Cell Lung Cancer?," October 15, 2007, American Cancer Society, http://www.cancer.org/docroot/CRI/content/CRI_2_4_1x_What_Is_Non Small_Cell_Lung_Cancer.asp?rnav=cri, (February 21, 2008). (4) American Cancer Society, "How Is Non-Small Cell Lung Cancer Staged?" October 15, 2007, American Cancer Society, www.cancer.org/docroot/CRI/content/CRI_2_4_3x_How_Is_Non Small_Cell_Lung_Cancer_Staged.asp?rnav=cri, (February 21, 2008). (5) World Health Organization, Gender in Lung Cancer and Smoking Research, Department of Gender, Women and Health, 2003, http://www.who.int/gender/documents/en/lungcancerlow.pdf . (6) National Cancer Institute, "Non-Small Cell Lung Cancer Treatment (PDQ(R)) Health Professional Version," December 14, 2007, National Cancer Institute, www.cancer.gov/cancertopics/pdq/treatment/non-small cell-lung/HealthProfessional/page2, (February 14, 2008).

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