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Eli Lilly and Company

Clinical Data Suggest Potential Versatility of ALIMTA(R) (Pemetrexed for Injection)-Based Regimens in Lung Cancer

Chicago (ots/PRNewswire)

- Study Highlights Quality-of-Life Data
ALIMTA(R) (pemetrexed for injection) showed additional utility in
the treatment of the most diagnosed type of cancer(i), according to
data presented today at the 43rd Annual Meeting of the American
Society of Clinical Oncology (ASCO). Results from a Phase III study
suggest that a first-line ALIMTA-based regimen may deliver less
toxicity than a commonly used therapy in advanced non-small cell lung
cancer (NSCLC). ALIMTA is manufactured and marketed by Eli Lilly and
Company.
A prospective, randomized, multicenter Phase III study was
conducted to compare ALIMTA plus carboplatin with the commonly used
regimen of GEMZAR(R) (gemcitabine HC1 for injection) plus carboplatin
(ASCO Abstract # 7517(ii)). The study, conducted by the Norwegian
Lung Cancer Group, enrolled 446 chemonaive patients with either stage
IIIB or IV NSCLC. The primary purpose of the study was to evaluate if
the ALIMTA-carboplatin combination provided increased quality-of-life
benefits while offering comparable survival data. As such, the
primary endpoint was quality of life (defined in the study as
nausea/vomiting; dyspnea or a difficulty in breathing, and; fatigue)
and the secondary endpoint was overall survival.
Thus far, 384 patients have been analyzed for toxicity and there
were fewer patients in the ALIMTA arm who experienced Grade 3/4
thrombocytopenia or a low platelet level (48 vs. 107, p < .001);
leukopenia or a lowering of leukocyte white blood cells (44 vs. 89, p
< .001), and; granulocytopenia or a lowering of granulocyte white
blood cells (78 vs. 98, p=.02). More patients in the GEMZAR arm
received transfusion of platelets (5 vs. 19, p=.02). At this point,
no difference in survival has been observed.
"The patients in this study received a comparable quality-of-life
benefit whether they received ALIMTA and carboplatin or GEMZAR and
carboplatin," said Bjorn Henning Gronberg, M.D. of St. Olavs
University Hospital in Norway and the study's principal investigator.
"Patients on the ALIMTA arm also appeared to benefit from a lower
toxicity profile."
Additional data to be presented on Sunday, June 3rd at ASCO from a
Phase II, open-label, non-randomized trial will report on an
International Oncology Network Study evaluating the safety of a
triplet therapy in which bevacizumab (Avastin(R)) was added to the
combination of ALIMTA plus oxaliplatin (Eloxatin(R)) in patients with
advanced NSCLC (Abstract # 7700(iii)). Previous research has
indicated that oxaliplatin and ALIMTA, as single agents, have shown
activity in NSCLC, and ALIMTA has shown synergistic effects when
combined with platinum-based drugs.(iv,v) This preliminary study was
conducted to evaluate the efficacy and safety of the combination as
first-line treatment for NSCLC.
"We are pleased to see that ALIMTA has a synergistic effect with
platinum agents like carboplatin," said Richard Gaynor, M.D., vice
president, cancer research and global oncology platform leader for
Lilly. "We look forward to continued research on ALIMTA as a
chemotherapeutic foundation with targeted therapies and other
anti-cancer agents for the treatment of lung cancer.
"Lilly is aggressively investigating potential novel therapies in
other tumor types, as we are committed to providing patients with
therapeutic options that fight the cancer but do not compromise
quality of life."
Lilly also has studied ALIMTA plus cisplatin for the first-line
treatment of NSCLC. In the first quarter of 2007, a study of ALIMTA
plus cisplatin versus GEMZAR plus cisplatin met its primary endpoint
of non-inferiority relative to overall survival. Utilizing these
data, Lilly plans to submit ALIMTA for an indication for the
first-line treatment of NSCLC to the European Medicines Agency (EMEA)
later this year.
At ASCO, researchers will also present data that show ALIMTA as a
chemotherapeutic foundation to a variety of approved and
investigational targeted anti-cancer agents, including bevacizumab
(Avastin(R)), erlotinib (Tarceva(R)), cetuximab (Erbitux(R)) and
vandetanib (Zactima(TM)).
ALIMTA is an antifolate which interferes with a crucial process
that allows cancer cells to reproduce and spread. The most common
side effects when ALIMTA is used as monotherapy are disorders of the
blood and lymphatic system, gastrointestinal disorders, fatigue, rash
and desquamation or flaking of skin in scales. Myelosuppression is
usually the dose-limiting toxicity with ALIMTA therapy.
About Non-Small Cell Lung Cancer
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.
ALIMTA
Indications
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 1500 cells/mm3, the platelet count is > 100,000 cells/mm3 and
creatinine clearance greater than or equal to 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.
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.
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%); thrombsis/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.
GEMZAR
Indications
GEMZAR in combination with paclitaxel is indicated for the
first-line treatment of patients with metastatic breast cancer after
failure of prior anthracycline-containing adjuvant chemotherapy,
unless anthracyclines were clinically contraindicated.
GEMZAR is indicated in combination with cisplatin for the
first-line treatment of patients with inoperable, locally advanced
(stage IIIA or IIIB), or metastatic (stage IV) non-small cell lung
cancer.
GEMZAR is indicated as first-line treatment for patients with
locally advanced (nonresectable stage II or stage III) or metastatic
(stage IV)adenocarcinoma of the pancreas. GEMZAR is indicated for
patients previously treated with 5-FU.
GEMZAR in combination with carboplatin is indicated for the
treatment of patients with advanced ovarian cancer that has relapsed
at least 6 months after completion of platinum-based therapy.
Important Safety Information for GEMZAR
Myelosuppression is usually the dose-limiting toxicity with GEMZAR
therapy.
Contraindication
Known hypersensitivity to GEMZAR. Anaphylactoid reaction has been
reported rarely.
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 with the use of GEMZAR. 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.
Adverse Events
The most severe adverse events (grades 3/4) with GEMZAR plus
paclitaxel for the treatment of patients with MBC were neutropenia
(48%); alopecia (18%); leukopenia (11%); anemia (7%); fatigue (7%);
thrombocytopenia (6%); ALT elevation (6%); and neuropathy-sensory
(6%). The most common adverse events (all grades) were nausea (50%);
fatigue (40%); myalgia (33%); and vomiting (29%).
The most severe adverse events (grades 3/4) with GEMZAR for the
first-line treatment of patients with pancreatic cancer were
neutropenia (24%-26%); alkaline phosphatase elevation (16%-20%); AST
elevation (12%-17%); nausea/vomiting (12%-13%); ALT elevation
(10%-11%); anemia (10%); leukopenia (9%-10%); thrombocytopenia
(8%-10%); bilirubin elevation (4%-8%); and pain (2%-7%). The most
common adverse events (all grades) were AST (72%-78%); alkaline
phosphatase (71%-77%); anemia (65%-73%); ALT (72%); leukopenia
(64%-71%); nausea and vomiting (64%-71%); neutropenia (61%-62%);
thrombocytopenia (36%-47%); pain (10%-42%); fever (30%-38%);
proteinuria (10%-32%); constipation (10%-31%); diarrhea (24%-30%);
rash (24%-28%); and bilirubin (16%-26%).
The most severe adverse events (grades 3/4) with GEMZAR plus
cisplatin for the first-line treatment of patients with NSCLC were
neutropenia (57%-64%); thrombocytopenia (50%-55%); leukopenia
(29%-46%); anemia (22%-25%); nausea (27%); vomiting (23%);
nausea/vomiting (39%); neuromotor (12%); hypomagnesemia (7%);
neurohearing (6%); creatinine elevation (5%); alopecia (1%-13%); and
dyspnea (1%-7%). The most common adverse events (all grades) were
paresthesias (38%); hyperglycemia (30%); infection (18%-28%); and
constipation (17%-28%).
The most severe adverse events (grades 3/4) with GEMZAR plus
carboplatin for the treatment of patients with advanced ovarian
cancer were neutropenia (71%), thrombocytopenia (35%), leukopenia
(53%), anemia (28%), nausea (6%), vomiting (6%), and constipation
(7%). The most common adverse events (all grades) were RBC
transfusion (38%), alopecia (49%), neuropathy/sensory (29%), nausea
(69%), fatigue (40%), vomiting (46%), diarrhea (25%), and
constipation (42%).
See complete Warnings, Precautions, Adverse Reactions, and Dosage
and Administration sections in the accompanying full Prescribing
Information for safety and dosing guidelines.
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
    GEMZAR(R) (gemcitabine HCl for injection), Lilly
    bevacizumab (Avastin(R)), Genentech
    oxaliplatin (Eloxatin(R)), Sanofi Aventis
    erlotinib (Tarceva(R)), Genentech, OSI Pharmaceuticals
    cetuximab (Erbitux(R)), Bristol-Myers Squibb, ImClone, Merck
    vandetanib (Zactima(TM)), AstraZeneca
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 products under development, there are substantial
risks and uncertainties in the process of development,
commercialization, and regulatory review. There is no guarantee that
the products will receive additional regulatory approvals. There is
also no guarantee that the products will continue to be commercially
successful. For further discussion of these and other risks and
uncertainties, see Lilly's filing with the United States Securities
and Exchange Commission. Lilly undertakes no duty to update
forward-looking statements.
    (i)   Parkin DM, Bray F, Ferlay J, Pisani P, Global Cancer Statistics,
          2002. CA Cancer J Clin 2005;55;74-108.
    (ii)  Gronberg, BH. Pemetrexed+carboplatin vs. gemcitabine+carboplatin in
          the treatment of stage IIIB/IV non-small cell lung cancer. Abstract
          #7517, American Society of Clinical Oncology (ASCO) Annual Meeting
          2007.
    (iii) Heist RS, Auerbach M, et al. Phase II trial of oxaliplatin,
          pemetrexed, and bevacizumab in previously-treated advanced non-
          small cell lung cancer (NSCLC). Abstract #7700, American Society of
          Clinical Oncology (ASCO) Annual Meeting 2007.
    (iv)  Scagliotti GV, Kortsik C, Dark GG, et al. Pemetrexed combined with
          oxaliplatin or carboplatin as first-line treatment in advanced non-
          small cell lung cancer: a multicenter, randomized, phase II trial.
          Clin Cancer Res. 2005 Jan 15;11 (2 Pt 1):690-6.
    (v)   Zinner RG, Fossella FV, Gladish GW, et al. Phase II study of
          pemetrexed in combination with carboplatin in the first-line
          treatment of advanced nonsmall cell lung cancer. Cancer. 2005 Dec
          1;104(11):2449-56.
(Logo: http://www.newscom.com/cgi-bin/prnh/20031219/LLYLOGO )

Contact:

Gregory L. Clarke of Lilly, +1-317-276-5222, +1-317-554-7119
(mobile), gregory.clarke@lilly.com; or Neil Hochman of CPR Worldwide,
+1-212-453-2067, +1-516-784-9089 (mobile),
n.hochman@cprworldwideusa.com . Photo: NewsCom:
http://www.newscom.com/cgi-bin/prnh/20031219/LLYLOGO , PRN Photo
Desk, photodesk@prnewswire.com

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