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

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

June 04, 2007

Study Highlights Quality-of-Life Data


    CHICAGO, June 4 /Xinhua-PRNewswire/ -- 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
http://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.

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    For more information, please contact:

     Gregory L. Clarke 
     Lilly
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     Email:  [e-mail]

     Neil Hochman
     CPR Worldwide
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