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



    
    Study Highlights Quality-of-Life Data
    

    CHICAGO, June 2 /CNW/ -- 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 )

    




For further information:

For further information: 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


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