CENTER FOR DRUG EVALUATION AND RESEARCH
`
`APPROVAL PACKAGE FOR:
`
`APPLICATION NUMBER
`
`21-462
`
`Medical Review(s)
`
`

`

`Division Director’s Memorandum
`
`Date:
`NDA:
`.
`Sponsor:
`Proprietary Name:
`
`:
`
`February 4, 2004
`21—462
`Eli Lilly and Company
`Alimta® (pemetrexed for injection)
`
`Administrative Historv
`
`~
`
`On July 8, 1992, the initial IND was submitted. The product received Orphan designation on
`August 28, 2001. On June 10, 2002, this application received Fast Track designation for
`malignant pleural mesothelioma and the Division accepted Lilly‘s plan for a rolling
`submission. The first parts of the NDA‘were submitted October 24, 2002 and the last .
`reviewable unit (CMC) was received on September 30, 2003. The PDUFA goal date for this
`priority review is March 30, 2004.
`'
`
`Proposed Indication
`ALIMTA in combination with Cisplatin is indicated for the treatment ofpatients with
`malignant pleural mesothelioma whose disease is either unresectable or who are otherwise
`not candidates for curative surgery.
`
`Available Therapies '
`No drug treatment has been shown to prolong survival in this setting.
`
`Clinical Review (see reviews by Dr. White, Dr. Hazarika, and Dr. Johnson)
`A single randomized clinical trial was conducted, entitled, “A Single—blind Randomized
`Phase 3 Trial of Alimta plus Cisplatin versus Cisplatin Alone in Patients with Malignant
`Pleural Mesothelioma.”
`
`This multi-center study included 88 principal investigators at a total of 88 study centers
`located in 20 countries. The primary objective was to compare survival in chemonaive
`patients with malignant pleural mesothelioma treated with Alimta plus Cisplatin combination
`therapy to survival in the same patient population treated with Cisplatin alone.
`
`A total of 574 patients were entered into the study (signed the informed consent document).
`Four hundred fifty~six of these patients were randomized to a treatment arm and 448 were
`treated and constitute the randomized and treated (RT) population.
`
`During this study, after about 25% of the randomized population had been treated, vitamin
`B12 and folic acid supplementation was found to reduce Alimta toxicities. At that time all
`patients in both treatment groups in the randomized trial were supplemented with vitamins.
`This resulted in three subgroups in each treatment arm regarding vitamin supplementation.
`These groups are never supplemented (NS), partially supplemented (PS) and fully
`
`

`

`NDA 21-462: Alimta
`Division Director’s Memo
`Page 2
`
`supplemented (FS). Patient totals for the Alimta/cisplatin group are RT 226, FS 168, PS or
`never supplemented 58, and for the cisplatin alone group are RT 222, FS 163 and PS or NS
`59. The FDA review focuses on all RT patients (the primary analysis) and the FS patients
`(the proposed labeled administration.)
`
`The primary efficacy analysis was comparison of survival between the study arms in the RT
`population. Differences were assessed using a two-sided log rank test. Because an interim
`analysis was conducted (resulting in a decision to continue the trial to planned completion),
`the comparison of survival was tested at the p=0.0476 level.
`
`In the RT patient analysis, the combination of Alimta and cisplatin demonstrated a
`statistically significant improvement in survival with median survivals of 12.1 versus 9.3
`months, respectively (p=0.020). This superiority in the combination arm was also
`demonstrated in the fully supplemented subgroup with median survivals of 13.3 and 10.0
`months in the combination and cisplatin alone groups, respectively (p=0.051). In an
`exploratory analysis, the effect on survival was larger in females (n=83, 15.7 vs. 7.5 months
`median survival) than in males (n=305, 11 months vs. 9.4 months).
`
`Pathologic diagnosis of malignant pleural mesothelioma may be difficult. Because of
`concern that some patients may have other kinds of cancer, a subgroup survival analysis was
`performed, including only the 303 patients with a histologic‘ diagnosis ofmalignant pleural
`mesothelioma confirmed by a central independent pathology review. This subgroup analysis »
`corroborates the primary survival analysis. The median survival times were 13 and 10.2
`months in the RT combination and cisplatin alone groups, respectively (p=0.06). The median
`survival times were 14.4 and 10.3 months in the RT fully supplemented combination and
`., cisplatin alone groups, respectively (p=0.058).
`
`Prior to the trial’s initiation, the FDA indicated to the Applicant that tumor response in this
`disease cannot be reliably assessed and that the FDA would not form primary efficacy
`decisions based on tumor response or tirne-to-tumor progression. Tumor response and time-
`to—progression were assessed, but the results were not interpretable. Tumor response criteria
`are not well established in pleural malignant mesothelioma. The tumor often grows in sheets
`rather than well demarcated spherical configurations. The tumor response assessments were
`inconsistent between the. study investigators and the two independent reviewers. The FDA
`review of the submitted films could confirm tumor response in only 47 of the 94 patients in
`the combination group for whom the Applicant claimed responses. Patients in the
`combination group did appear to have a better response rate and longer time-to-progression;
`however, numerical results for tumor response and time-to-progression are not included in
`.the product label.
`
`Patients were assessed with the Lung Cancer Symptom Scale (LCSS). Although there were
`statistically significant changes favoring the combination group in some components and in
`the overall score, none of the changes was judged to be clinically important. No claims
`regarding the LCSS were included in the label.
`
`Patients were also assessed during the study for pulmonary function by measuring slow vital
`capacity, forced vital capacity and forced expiratory volume in one seCond. There were
`
`

`

`NDA 2l-462: Alimta
`Division Director’s Memo
`Page 3
`
`statistically significant changes in the pulmonary function tests favoring the combination
`group. However, consultation from the FDA’s Division of Pulmonary Drug Products
`indicated that the reported mean changes were within the range of normal variation ofthe
`tests and are not considered clinically important.
`
`The Division of Pulmonary Drugs recommended forced vital capacity (PVC) as the most
`appropriate pulmonary function test in these patients because the disease effect is constrictive
`rather than obstructive. To further assess the effect of treatment on pulmonary function, the
`Oncology Drug Products Division performed the following two analyses intended to consider
`meaningful changes in pulmonary function using the electronic database.
`
`In the first analysis 337/448 (75%) of RT patients who had a baseline and at least one follow-
`up PVC, 26.6% and 21.3% of combination group patients had an increase over baseline FVC
`_of _>_ 400 m]. and Z 500 'mL, respectively, on at least one follow-up visit. The differences
`between the combination and cisplatin alone groups are statistically significant. However,
`the increases in PVC were maintained for at least 6 weeks in only about half of the
`combination group patients. The difference between treatment groups was no longer
`statistically significant.
`
`In the second analysis 28.4% and 17.2% of combination group patients had an increase from
`baseline FVC of Z 20% and Z 30% on at least one follow-up visit, respectively. The
`differences between the combination and cisplatin alone treatment groups are statistically
`significant. The increases in PVC were maintained for at least 6 weeks in only about half of
`the combination group patients. But the difference between treatment groups remains
`statistically significant.
`
`-
`
`_ Based on these two analyses, together with the overall mean increase, a labeling claim for a
`modest beneficial effect on pulmonary fiinction can be made.
`
`The adverse effects of the combination regimen are acceptable for chemotherapy drug
`products. The principal adverse effects that are greater with the combination than with
`cisplatin alone are myelosuppression, severe nausea and vomiting, and rash/desquamation.
`Patients in both groups were fatigued and had dyspnea and chest pain, probably related to the
`' underlying disease. Severe hematologic and gastrointestinal adverse effects are significantly
`reduced by supplementation with vitamin B 1 2 and folic acid without any decrement in
`efficacy.
`
`Alimta is eliminated primarily by the renal route. In clinical studies, patients with creatinine
`clearance Z 45 mL/min required no dose adjustments other than those recommended for all
`patients, although AUC’s were increased by about 50-60% in patients with CLcr of 45-50
`mL/min. Insufficient patient numbers with creatinine clearance below 45 mL/min have been
`treated to make dosage recommendations for this patient group. Alimta should not be
`administered to patients whose creatinine clearance is < 45 mL/min using the Cockcroft and
`Gault formula or GFR measured by Tc99m-DPTA serum clearance method.
`
`

`

`NDA 21-462: Alimta
`Division Director’s Memo
`Page 4
`
`Binstatistical Review (see Dr. Wang’s review)
`The results of the biostatistical review are presented in the table below and have been
`previously discussed in the clinical section.
`
`Primary Endpoint: Survival for RT Population (FDA Analvsis)
`RT Population
`PS Population
`PS+NS Population
`=448)
`(N=33l
`(N=1 l7
`Combo
`'
`Combo
`
`Combo
`
`Cis
`
`Cis
`
`Cis
`
`Patients dead'
`
`Survival time (months)
`Median
`‘
`,
`(95% CI)
`p;\'alueb
`Long-rank
`Wilcoxon
`
`(N=226)
`n (%)
`145 (64)
`
`(N=222)
`n (%
`159 (7'2)
`
`(N=168)
`n (%)
`95 (57)
`
`(N=]63)
`n (%)
`103 (63)
`
`(N=58)
`n (°/o
`50 (86)
`
`(N=59)
`n %)
`56 (95)
`
`_]2.-l
`(100,144)
`
`9.3
`(7.8, 10.7)
`
`13.3
`(114,149)
`
`10.0
`(8.4, 11.9)
`
`.
`' 9.5
`(8.1, 10.8)
`
`7.2
`(6.5, 9.9)
`
`'
`0.021
`0.028
`
`0.051
`0.039
`
`0.253
`0.440
`
`0.798
`0.758
`'
`0.766
`Hazard Ratio"
`
`95% CI for Hazard Ratio‘ (0.54.1.17) (0.61. 0.96) (0.57.1.0)
`
`
`' Results based on the analysis of data sets provided by the sponsor.
`Combo = combination ofcisplatin plus Alimta; Cis = single-agent cisplatin
`' Patients were died for different reasons: study disease related, study toxicity, and other causes.
`‘ b P-value is based on the test results for the two treatment groups.
`‘ Hazard Ratio is based on the proportional-hazardsmodel with the treatment as single independent variable.
`
`Chemistrv/Manufacturing and Controls Review (see Dr. Liang‘s review for details)
`'ALIMTA, pernetrexed (L-Glutamic acid, N—[4-[2-(2-amino-4,7—dihydro-4-oxo-lH—
`pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]—,disodium salt heptahydrate) drug substance,
`contains one chiral center and is a disodium salt containing seven water molecules of
`hydration (heptahydrate) in the solid state of the drug product. The molecular formula is
`C20H19N506Nag\.7H20, and the molecular weight is 597.49 daltons.
`
`
`2 and its structure is well
`_
`Pemetrexed drug substance is
`characterized. During the review process, several discrepancies related to stereoisomer
`control and correct USAN nomenclature were resolved.
`
`Alimta drug product is supplied in glass vials as a singleouse sterile lyophilized powder for
`intravenous infusion. Each — of Alimta contains
`r— pemetrexed disodium
`heptahydrate (equivalent to 500 mg pemetrexed free acid) and 500 mg of mannitol. Sodium
`hydroxide and, if necessary, hydrochloric acid are added to adjust the pH. Eli Lilly
`manufactures the drug product in Fegersheim, France.
`
`Each vial of Alimta is reconstituted with 20 mL of commercially available 0.9% Sodium
`Chloride Injection without preservatives to a concentration of 25 mg/mL of pemetrexed as
`free acid. This reconstituted pemeUexed solution must be further diluted to 100 mL with
`
`

`

`NDA 21-462: Alimla
`Division Director's Memo
`Page 5
`
`0.9% Sodium Chloride Injection prior to intravenous infusion. The final concentration of
`drug product solution to be administrated is 0.25 mg’mL pemetrexed as free acid.
`
`During the review process, deficiencies related to the control of drug product total impurities
`were resolved. The applicant agreed to restrict the limit for total impurities from NMT— Va
`to NMT _ °/o as an interim specification and to reevaluate the limit for total impurities
`within 24 months (or after ten commercial batches of drug product have been manufactured).
`
`/
`./
`/
`
`-
`
`raise clinical concern: Any impurity profile
`.' ‘ ‘range will be within current impurity limits.
`
`-—--
`
`within the specified
`-
`
`The drug substance, drug product, and the reconstituted drug product solution have adequate
`stability characteristics to support a 24-month shelf life for the drug product based'on primary
`and supportive stability data.
`
`Nonclinical Review (see Dr. Lee Ham’s review and Dr. Morse’s team leader memo)
`Alimta® (pemetrexed disodium) is a pyrrolopyrimidine antifolate. Although it’s mechanism
`of action is not fully understood, multiple non-clinical studies suggest pemetrexed exerts
`antineoplastic activity by interfering with folate-dependent metabolic processes essential for
`cell replication. After entrance into the cell (via reduced folate carrier [RFC] and membrane
`folate-binding protein [FBP]), pemetrexed is rapidly polyglutamated by folypolyglutamate
`synthetase. Both parent and polyglutamated pemetrexed act as competitive inhibitors of
`several folate—dependent enzymes, including thymidylate synthase (TS), dihydrofolate
`reductase (DHFR), and glycinamide ribonucleotide transferase (GARFT), which are key
`enzymes for de novo nucleotide biosynthesis. These actions are similar to methotrexate,
`which has inhibitory effects on thymidylate synthase (TS) and dihydrofolate reductase
`(DHFR).
`
`When tested in a series of in vitro and in viva (xenograft) models of cancer, pemetrexed
`demonstrated activity against a variety of tumor types, including leukemia (CCRF-CEM,
`Ll 210), lung (A549), mesothelioma (NCI-H2052 and MSTO-2l'lH), breast (MCF7), colon
`(GC3 and HCTS), and ovarian cancer (SKOVI).
`
`Non-clinical toxicity studies were conducted to determine the acute and repeat-dose effects
`when administered to mice, rats, and dogs. Toxicity studies included: single and repeat dose
`Studies of 2- and 6-weeks intraperitoneal (ip) dosing in mice, and 4- and 6-weeks, and 6-
`' months intravenous (iv) dosing in dogs. In single dose studies, pemetrexed demonstrated
`limited acute toxicity in mice and rats, but more extensive toxicity in dogs. Six week repeat
`dose studies were conducted using daily, twice weekly or weekly ip doses in mice and iv
`doses in dogs. Mice tolerated weekly ip doses of up to 944 mg/m2 (twice the clinical close)
`without death or toxicity, whereas weekly iv closing at 2099 mg/m2 (four times the clinical
`
`

`

`NDA 21-462: Alimta
`Division Director’s Memo
`' Page 6
`
`
`
`dose) resulted in the early termination of several dogs. Repeat-dose adverse effects at higher
`doses caused decreased food consumption, emesis, diarrhea, mucositis, decreased red cell
`parameters, leukopenia, neutropenia, and increased hepatic enzymes in dogs.
`In mice,
`weight loss and leukopenia were the predominant drug toxicities. Histopathologic indices
`generally occurred in the thymus, lymph nodes, GI tract, testis, bone marrow, and skin.
`
`Pemetrexed (intravenous) doses of 3 0.3 mg/m2 caused testicular atrophy and reduced
`fertility. Further, pemetrexed was embryotoxic and teratogenic in mice when administered at
`0.6 mg/mz. Pemetrexed caused no genetic damage in a standard battery of in vitro tests,
`mutation and clastogenicity assays, although, pemetrexed was clastogenic in the
`micronucleus assay. Carcinogenicity studies of pengetrexed disodium have not been
`conducted.
`
`Limited non-clinical investigations of “rescuing" agents" (leucovorin andthymidine) were '
`conducted with pemetrexed administration. Results suggest that the co-adrninistration of
`leucovorin (20 mgx’kg im days 5-10; 25 rug/kg im days 4, & 5, and 50 mg/kg iv day 4)
`reduced or reversed the toxicity of pemetrexed (50 mg/kg iv days 1 & 4) in dogs. Dogs
`given pemetrexed (50 mg/kg, iv days 0 & 3) with thymidine (8 mg/kg, days 4-7,
`administration as a continuous infusion) had no toxic alterations associated with pemetrexed
`compared to the saline-treated controls.
`
`AUC values for pemetrexed were approximately dose proportional following single ip or iv
`administration to mice, and iv administration to dogs and humans. Elimination half-life was
`significantly shorter in dogs and man when compared to mice. The PK profile was biphasic
`following radiocarbon tracer administration, with rapid tissue distribution following an iv
`dose and subsequent elimination (tissue levels generally did not persist beyond 3 hrs post-
`dose).
`
`Clinical Pharmacoloov and Biopharmaceutic Review (see Dr. Booth’s review)
`The pharmacokinetics of Alimta follow a 2-compartment model, and excretion is
`predominantly renal. Alirnta was not metabolized by any cytochrome P-450, nor did it
`inhibit any cytochrome P-450 isozyme. Total systemic clearance is 91.8 mL/min and is
`correlated with glomerular filtration rate and creatinine clearance (CLcr) (Cockcroft-Gault
`formula). 'The elimination half-life is 3.5 hours; accumulation was not noted. The
`pharmacokinetics were unaffected by sex, age or ethnicity.
`
`Cisplatin co-administration did not alter the Alimta’s pharmacokinetics or vice versa. Co-
`administration of carboplatin did not alter the pharmacokinetics of Alirnta, but the
`pharrnacokinetics of carboplatin may have been affected. Neither folic acid/vitamin B12 nor
`aspirin (1.3 mg/day) altered Alimta pharmacokinetics. However, ibuprofen increased Alirnta
`AUC by approximately 20% at a moderate dose of 1.6 gm/day. Renal impairment studies of
`Alimta as a single agent indicated that the Alimta AUC increased by 130% in patients with
`moderate renal impairment (CLcr 30-50 mL/min; n=6), suggesting that neutropenia might be
`exacerbated in these patients. These studies were not considered Sufficient to provide dosing
`recommendations for patients with CLcr < 45 mL/min.
`
`

`

`NDA 21-462: Alimta
`.
`Division Director’s Memo
`Page 7
`
`Labeling (see DMETS review)
`DMETS reviewed the draft container labels, carton, and insert labeling for Alimta and
`focused on safety issues relating to possible medication errors. DMETS recommended the
`following changes to minimize potential user errors.
`
`- Carton labeling (500 mg Single-Use Vial): Increase the prominence of the route of
`administration on the principal display panel by bolding or other means. Repeat the
`statement, “Caution: Cytotoxic Agent” on the principal display panel.
`_/
`
`C
`
`
`Data Inteoritv Issues (see Dr. Gan’s Clinical Inspection Summary)
`The Division of Scientific Investigation investigated four sites (University of Chicago
`Hospital, Chicago, IL; Texas Oncology, Dallas, TX; and sites in Milano, Italy and Hamburg,
`Germany) and found the data adequate for safety and efficacy evaluation.
`
`Tradename consultation
`
`The tradename, Alimta, is acceptable to DDMAC and DMETS (see DMETS review).
`
`Pediatric Considerations
`
`Malignant pleural mesothelioma does not occur in children.
`
`Conclusions and Recommendations: Approval
`The trial contained in this application demonstrates a survival advantage in patients with
`malignant pleural mesothelioma treated with Alimta plus cisplatin compared to those treated
`with single-agent cisplatin. These patients were either unresectable or were otherwise not
`candidates for curative surgery. No other drug, including cisplatin, has demonstrated a
`survival advantage in this life-threatening disease setting associated with a short survival.
`The Division has consistently accepted a survival improvement to demonstrate clinical
`benefit. Hence, this application was not presented to the Oncologic Drugs Advisory
`Committee (ODAC). The trial’s design allows demonstration of Alimta’s effect on the
`primary study endpoint (survival).
`
`Although a single randomized trial supports this NDA, this trial was multi-institutional with
`over 88 study centers enrolling over 574 patients and is the largest randomized study ever
`conducted in this disease. The primary efficacy analysis was confirmed in the randomized
`‘ and treated (RT) population as well as in a subset population--the fully vitamin supplemented
`group (F S). Although the Division did not allow specific numbers to be included in response»
`rate and time-to-progression analyses because of the inaccuracies and difficulties in
`
`

`

`NDA 21-462: Alimta
`Division Director‘s Memo
`Page 8
`
`measuring disease in mesothelioma patients, the Division acknowledges that the combination
`treatment group did appear to show an improvement in these secondary endpoints. An
`,
`additional secondary endpoint of improvement in pulmonary function (forced vital capacity)
`was also included in the product label.
`
`The safety profile of the proposed combination of Alimta plus cisplatin with vitamin
`supplement (and corticosteroids for skin rash prophylaxis) is consistent with other cytotoxic
`chemotherapy agents approved by the Division. The primary toxicities include
`myelosuppression, fatigue, nausea, vomiting, and dyspnea. The product label clearly advises
`physicians of specific vitamin use to reduce the toxicity. Hence, an acceptable risk-benefit
`relationship is noted with the combination. The recommended regulatory action is approval
`- ofNDA 21-462.
`
`Richard Pazdur, MD
`
`Director, Division of Oncology Drug Products
`
`

`

`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`---------------------------------------------------------------------------------------------------------------------
`
`Dianne Spillman3
`2/4/04 12:26:54 PM
`_ "(:30
`
`Richard Pazdur
`
`2/4/04 12:31:55 PM
`MEDICAL OFFICER
`
`

`

`ONCOLOGY DRUGS CLINICAL TEAM LEADER
`
`REVIEW OF NDA
`
`NDA 21462
`
`NAME OF DRUG
`
`Alimta (pemetrexed)
`
`APPLICANT
`
`Eli Lilly
`
`.
`
`CLINICAL TEAM LEADER John R. JohnsonM. D.
`
`DATE REVIEW COMPLETED ' December 10, 2003
`
`ADMINISTRATIVE
`
`8-28-01 Orphan Drug Designation
`6-10-02 Fast Track Designation
`10-24-02 Initial Rolling Submission
`9-30-03 Final Rolling Submission
`
`, PROPOSED INDICATION
`
`ALIMTA in combination with Cisplatin is indicated for the treatment of patients with
`malignant pleural mesothelioma whose disease is either unresectable or who are not
`' otherwise candidates for curative surgery.
`
`PRESENT ARMAMENTARIUM
`
`No treatment has been shown to prolong survival in this setting.
`
`CLINICAL TRIAL
`
`One randomized clinical trial was conducted.
`
`Title:
`
`A Single-blind Randomized Phase 3 Trial ofAlimta plus Cisplatin versus Cisplatin
`Alone in Patients with Malignant Pleural Mesothelioma
`
`This multicenter study included 88 principal investigators who entered patients at a total
`0f88 study centers located in 20 countries.
`
`

`

`Primary Objective:
`
`To compare survival in chemonaive patients with malignant pleural mesothelioma
`whose disease is either unresectable or who are otherwise not candidates for curative
`surgery when treated with Alimta plus cisplatin combination therapy to survival in the
`same patient population when treated with cisplatin alone.
`
`Secondary Objectives:
`
`To compare between the two treatment arms: (1) time-to-event efficacy measures,
`including: a) duration of response for responding patients, b) time to progressive disease,
`c) time to treatment failure; (2) tumor response rate; (3) clinical benefit response rate;
`(4) Lung Cancer Symptom Scale (LCSS) patient and observer scores; (5) pulmonary
`function tests; (6) lung density; (7) relative toxiCities; (8) to assess the impact of folic
`acid and vitamin B12 supplementation on toxicity; (9) pharrnacokinetic effects;
`(10) information regarding vitamin metabolite status in this patient population.
`
`.Treatment:
`
`Alimta plus cisplatin treatment arm: Alimta was administered at a dose of 500 mg/mz
`diluted in approximately 100 mL normal saline as a 10-minute intravenous infusion.
`Approximately 30 minutes after the administration of Alimta, cisplatin was administered
`at a dose of 75 mg/mz over 2 hours. Both drugs were administered on Day 1 ofa 21-day
`period. This 21-day period defined one cycle oftherapy.
`
`Cisplatin alone treatment arm: Approximately 100 mL normal saline was given as an
`intravenous infusion over approximately 10 minutes. Approximately 30 minutes after
`the administration ofnormal saline, cisplatin was administered at 75 mg.l’ni2 over 2 hours
`on Day 1 ofa 21-day period. This 21-day period defined one cycle oftherapy.
`
`Both treatment arms:
`
`:Dexamethasone 4 mg (or an equivalent corticosteroid) was taken by all patients orally
`twice a day 1 day before, on the day of, and 1 day after each dose of Alimta for primary
`prophylaxis against rash.
`
`:Folic acid and vitamin B12 for supplementation were standard components of therapy for
`all patients participating in the study from December 2, 1999 onwards. Folic acid 350
`to 1000 pg was administered orally daily, beginning approximately 1 to 3 weeks before
`the first dose of therapy and continued daily for 1 to 3 weeks after the patient
`discontinued treatment. A vitamin BIZ injection 1000 pg was administered
`intramuscularly approximately 1 to 3 weeks before the first dose of therapy and was
`repeated approximately every 9 weeks until the patient discontinued study therapy.
`
`

`

`Patient Population:
`
`A total of574 patients were entered into the study (that is,signed the Informed Consent
`Document). Four hundred fifty six of these patients were randomized to a treatment arm
`and 448 of thesepa'tients were treated and constitute the randomized and treated (RT)
`population.
`
`Initially no vitamin supplementation was given. Part way through the study it became
`apparent from other Alimta studies that Vitamin supplementation was beneficial from a
`safety standpoint. At that time all patients in both treatment groups in the randomized
`trial were supplemented with vitamins. This resulted in three subgroups in each
`treatment arm regarding vitamin supplementation. These groups are never supplemented
`(NS), partially supplemented (PS) and fully supplemented (FS). Results are reported for
`each group. This review will focus on all RT patients (the primary analysis) and the FS
`patients (the proposed labeled administration.)
`
`Alimta plus cisplatin: Total RT 226, Male 184, Female 42,
`Fully Supplemented (FS) 168, Partially Supplemented (PS) or
`Never Supplemented (NS) 58.
`
`Cisplatin alone: Total RT 222, Male 181, Female 41,
`Fully Supplemented (FS) 163, Partially Supplemented (PS) or
`Never Supplemented (NS) 59.
`
`Statistics:
`
`The primary etTicacy analysis was comparison of survival time between the study arms in
`the RT population. Differences were assessed using a two-sided log rank test. Because
`an interim analysis was conducted (resulting in a decision to continue the trial to planned
`completion), the comparison of survival was tested at the p=0.0476 level.
`
`APPEARS THIS WAY
`
`0N ORlGlNAL
`
`

`

`Patient Characteristics:
`
`The following Tables compiled by the Applicant show the disease and demographic
`factors for the study patients. These are well balanced between the treatment groups.
`
`Table JMCH.“ .3.
`
`Summary of Patient Characteristics
`RT Population by Supplementation Status
`H3E-MCJMCH
`
`
`
`
`pailmam
`.
`
`
`3209.!» :.
`loony ~ 29073)‘
`
`
`53 (89.8)
`54 (93.1)
`153 (93.9)
`150 ($9.3)
`
`
`
`I-fispanic
`5 (8.5)
`7 (4.3)
`l [l .7)
`10 (6.0)
`
`
`Asianl
`l (0.?)
`3 (1.8)
`M51)
`781)
`
`
`
`African
`0
`0
`0
`1 (0.6)
`
`Age
`'
`' Median
`6]
`fi2
`60
`60
`
`
`
`35
`19
`7 Minimum]
`29
`84
`
`
`
`35 77‘ B2
`
`
`
`’ Wain and East/sums: Asian have hm combined.
`
`:"tizfimsja '
`Y 121213)
`
`1
`
`

`

`Tabb JMCH.11 .5.
`
`Basollno ambn Factors Used for Randomlmtlon
`RT Populatk'm by Supplementation status
`HSE-MC-JMCH
`
`KPS
`
`
`
`26 (44.8)
`69 (42.3%)
`
`
`94 (5 7.7)
`32 (55.2)
`
`
`
`12 (20.7}
`62 (38.0)
`
`
`
`101 (52.11)
`46 (79.3)
`
`
`
`
`39 (55.1)
`117 (995)
`113' (59.3)
`
`’11:(185). :
`; 25(14.9)-.;'
`_:-__.2_5(153)
`
`
`'I':n:l.4(53)‘ ..
`I’M-IDA) ..
`. "ii-E3059 .
`,.
`18(43)
`I 12 ("1.1)
`'
`-'
`l (l7)-
`
`
`25 (43.1)
`GB (41 .7)
`
`
`
`33 (56.9)
`95 (5 8.3)
`
`
`
`311 (51.7)
`80(491) ~
`
`
`
`28 (48.3)
`.83 (511.9)
`
`
`
`
`44 (75 .9)
`124 (75.1)
`
`
`
`14 (24.1)
`39 (23.9)
`
`
`
`
`25 (43.1)
`68 (41.7)
`
`
`33 (56.9)
`95 (5 8.3)
`
`
`
`3611621)
`118 (72.4)
`
`
`22 (3 7.9)
`45 (27.5)
`
`
`
`Sn
`»
`
`Male
`136 (81 .n)
`. 48 (82 .8)
`134 (82.2)
`
`
`
`Female
`32 19.!
`
`
`.1 Amy; (salient was 1111881113 their evaluable disusemmmml 111 1118811118
`.
`'1 Pafisnts 302-3025 and 720-7209 mplimd 1118111112111 1135 at bulina, but outside anha 111:1ch
`défined windnw, 11m dalaam not included111 lbs) taming 11111211889.
`
`_ Law (580)
`High (290)
`
`83 (49.491)
`85 (511.5)
`
`Damn of Mmmbililyl
`Unidimmaimnl
`Bidimansicnal
`
`Hist-logic 8mm
`Epilhalml
`
`-
`
`-
`
`.
`
`WBC
`Low (<83 (3121)
`High [28.3 GIRL)
`
`Pull ll‘hflly?
`Low (<20 m)
`High (221) mm)
`
`6] (36.5)
`106 (53.5)
`
`72 (42. 9)
`96 (57.1)
`
`82 (49.4)
`84 (511.5)
`
`‘
`Annual: Cow“ '
`Low (<50 mg mu’p gqltlny)‘
`High (250mgmap dqldxy)
`
`,
`
`129 (76.8)
`39 (23.2)
`
`'
`
`078111831
`Low (<20 111111)
`. High (220 mm)
`
`Ilm-qsldné
`Low (<12 mm.)
`High (212111110111)
`
`'
`65 (39.8)
`100 (50 .2)
`
`119 (m .8)
`49 (29.2)
`
`-
`
`28 (47.5)
`31 (52 5)
`
`II (18.6)
`48 (8| .4)
`
`23 (39.0)
`36 (6| .0)
`
`33 (55.9)
`26 (44.1)
`
`45 (78.0)
`13 (22.0)
`
`24 (40.7)
`35 (59.3)
`
`38 (64.4)
`21 (355)
`
`

`

`Tabb JMCH.11.7.
`
`Summary at Baseline Disease Characteristics
`RT Population by Supplementation status
`H3E-Mc-JMCH
`
`Ding-um Ifllwolm
`
`Epithelial
`1 17 (69.6%)
`39 (1515. 1%)
`Mind
`25 (14.9)
`25 (15.3)
`11 (18.6)
`
`17 (10.4)
`Sarccmntnid
`14 (33)
`s (13.6)
`
`12 (7.1)
`10.7)
`
`7 (4:3)
`
`
`5 (3.1)
`
`
`27 (16.8)
`a (13.11)
`
`
`
`‘ 22 (37.9)
`49 (30.4)
`
`
`
`‘ 27(4616)
`13(453)
`
`
`3
`.:
`' f D?
`2 (11)
`
`
`
`
`
`
`
`s (4.8)
`7(42)
`27 (152)
`51 (50.5)
`. 74(443) .
`- _;:gg=:.;-f'5;. H116)
`
`.
`
`
`
`1 (1.7)
`1 (1.7)
`6 (113.2)
`19 (5220
`-32 (54.2)
`.-.:3"-;-;n'..~'1--
`
`:
`
`' 25 (14.9)
`1290.7)
`511 (54.5)
`14 (24.1)
`57139.9)
`1
`211 [44.8)
`
`
`
`
`3 600.3)
`13 (111.7)
`
`-
`
`905.3)
`22(12'5) '
`19 (32.2)
`47 (28.8)
`619(423)
`25 (42.4)
`
`
`25 (15.3)
`6(102)
`
`Efficacy Results:
`
`Survival
`
`In the all RT patients analysis the combination of Alimta and cisplatin demonstrates a
`statistically significant improvement in survival compared to cisplatin alone with median
`survivals of 12.1 versus 9.3 months, respectively (p=0.020). An ITT analysis on all
`randomized patients, including 8 patients not in the RT analysis, yields nearly identical
`results to the RT analysis. This superiority in the Alimta/cisplatin arm is also
`demonstrated in the fully supplemented subgroup with median survivals of 13.3 and 10.0
`months in the Alimta/cisplatin and cisplatin alone treatment groups, respectively
`(p=0.051).
`
`APPEARS THlS WAY
`0N ORlGlNAL
`
`

`

`All Randomized Treated Patients (448)
`
`Product-Limit Survival Fit
`Survival Plot
`
`
`0.8
`
`0.7
`
`
`
`0.6 —’
`
`-
`
`
`
`\ x‘i‘kL‘
`~_
`
`._
`
`22.!“
`.. R
`7%;
`
`g) 0.5—
`0.4—
`. 3
`‘0 0'3
`0.2
`0.1 —
`
`> E
`
`0.0 -
`
`‘0.1 _‘
`
`1
`
`.
`
`l
`
`i
`
`l
`
`I
`
`I
`
`I
`
`|
`
`1
`
`I
`
`1
`
`5
`
`20
`15 _
`10
`SURVIVAL TIME
`
`25
`
`30
`
`Time intervals are in months.
`
`M2 = Alimta/cisplatin (upper curve)
`M39 = cispaltin alone (lower curve)
`
`Summary
`Group
`M2
`M39
`Combined
`Quantiles
`Group
`M2
`M39
`Combined
`
`N Failed
`145
`159
`304
`
`N Censored
`81
`63
`144
`
`Mean
`13.5305 Biased
`11.485 Biased
`12.5648 Biased
`
`Median Time
`12.1
`9.3
`10.4
`
`Lower95%
`10
`7.3
`9.3
`
`Upper95%
`14
`10.7
`11.9
`
`Std Dev
`0.64943
`0.56377
`0.44228
`
`25% Failures
`6.1
`5.5
`5.9
`
`75% Failures
`19.7
`16.4
`18.9
`
`Tests Between Groups
`Test
`ChiSquare
`Log-Rank
`5.4033
`Wilcoxon
`4.8458
`
`DF
`1
`1
`
`Prob>ChiSq
`0.0201
`0.0277
`
`

`

`RT Fully Supplemented Patients (331)
`
`Product-Limit Survival Fit
`
`Survival Plot
`
`
`
`
`
`
`.
`
`*~
`
`'
`
`L
`
`_
`
`y
`
`m
`
`r '—**********
`
`.
`
`.
`
`|
`5
`
`0
`
` | 1
`
`.
`
`I
`10
`
`5
`
`20
`
`25
`
`1.0
`
`0.9
`
`0.8
`0.7
`
`30.6
`-E 0.5
`‘30.4
`0.3
`
`0.2
`
`0.1
`
`0.0
`
`SURVIVAL TIME
`
`
`Time intervals are in months.
`
`M2 = Alimta/cisplatin (upper curve)
`M39 = cispaltin alone (lower curve)
`
`Summary
`Group
`M2
`M39
`Combined
`Quantiles
`‘ Group
`M2
`- M39
`Combined
`
`N Failed
`95
`103
`198
`
`N Censored
`73
`60
`133
`
`-
`
`Mean
`12.8946 Biased
`11.1832 Biased
`12.1377 Biased
`
`Median Time
`13.3
`10
`11.9
`
`Lower95%
`11.4
`8.4
`10
`
`Upper95%
`14.9
`11.9
`13.3
`
`Std Dev
`0.57646
`0.55631
`0.41116
`
`25% Failures
`6.6
`5.4
`6
`
`75% Failures
`21.5
`17.3
`18.9
`
`Tests Between Groups
`Test
`ChiSquare
`Log—Rank
`3.8084
`Wilcoxon
`4.2649
`
`DF
`1
`1
`
`Prob>ChiSq
`0.0510
`0.0389
`
`Pathologic diagnosis of malignant pleural mesothelioma is sometimes difficult. Because
`of concern that some patients may have other kinds of cancer a subgroup analysis of
`survival was done including only patients with a histologic diagnosis of malignant pleural
`mesothelioma confirmed by central independent pathology review. This subgroup
`
`

`

`analysis supports the primary survival analysis. The median survival times were 13 and
`10.2 months in the RT Alimta/cisplatin and cisplatin alone treatment groups, respectively
`(p=0.06). The median survival times were 14.4 and 10.3 months in the RT