Clinical Review for NDA 21-677

Executive Summary

I. Recommendations

A. Recommendation on Approvability

The Division of Oncology Drug Products (DODP), Center for Drug Evaluation and Research (CDER), FDA decision on approval is deferred pending discussion of the Oncologic Diseases Advisory Committee.

B. Recommendation on Phase 4 Studies and/or Risk Management Steps

Deferred

II. Summary of Clinical Findings

A. Brief Overview of Clinical Program

The safety and efficacy review is based on data provided in EDR \\CDSESUB1\N21677\ N-000\2003-11-03. The pivotal phase 3 trial was titled "A Phase 3 Trial of ALIMTA versus Docetaxel in Patients with Locally Advanced or Metastatic Non-Small Cell Lung Cancer (NSCLC) Who Were Previously Treated with Chemotherapy". Results of four supporting phase 2 NSCLC trials, two first-line and 2 second-line were also provided.

B. Efficacy

The sponsor claimed that survival of LY231514 treated patients was non-inferior to survival of docetaxel treated patients. FDA statistical analysis indicated that non-inferiority was not demonstrated. Even if non-inferiority was demonstrated, however, it would not be credible because of post-study chemotherapy. Thirty fewer docetaxel treated patients received post-study chemotherapy compared to LY231514 treated patients (randomized and treated population [RT]) Comparable findings were obtained with the ITT population. While 32% of LY231514 treated patients received post-study docetaxel it was observed that patients receiving any post-study chemotherapy drug(s) survived longer than those who did not. The majority of patients on both arms who did not receive post-study chemotherapy were performance status 0 or 1 at their last study visit and, conceivably, could have received additional treatment.

Response rate, time to progression and symptom improvement was comparable for the two study arms.

C. Safety

Safety testing was adequate. LY231514 produced significantly less neutropenia and less febrile neutropenia than did docetaxel. Myalgias, arthralgias and neurotoxicity were also significantly higher in the docetaxel arm. There were fewer hospitalizations and less need for granulocyte colony stimulating factors with LY231514 treatment but LY231514 patients spent more days in the hospital. LY231514 patients required more red blood cell transfusions. The incidence of fatigue, weight loss, nausea, vomiting and constipation were statistically significantly higher in the LY231514 arm. Other clinically significant AEs that were different between the treatment arms included increased alanine and aspartate aminotransferases (LY231514 higher incidence), skin rash (LY231514 higher incidence) and decreased creatinine clearance (LY231514 higher incidence.

There is also an issue regarding vitamin supplementation in LY231514 treated patients but ot in docetaxel treated patients. Twenty-nine percent of the latter patients had elevated homocysteinne (Hcys) levels. Hyperhomocysteinemia is risk factor for atherosclerotic disease in the coronary, cerebral, and peripheral arterial circulations. It also appears to be a risk factor for venous thromboembolism and for neuronal cell damage. Low dietary intake of vitamins B6, B12 and folic acid is the most prevalent cause of hyperhomocysteinemia. Vitamin B12 and folic acid supplementation have been shown to reliably reduce elevated Hcys levels and to reduce hematological and non-hematological toxicity of LY231514 treatment. Hcys was, in fact, better than baseline albumin (another predictor of toxicity) at predicting LY231514 toxicity. There is no reason to suspect that vitamin supplementation, if administered, would not have also reduced toxicity in hyperhomocysteinemic docetaxel treated patients

D. Dosing

The recommended dose of Alimta is 500 mg/m2 administered as an intravenous infusion over 10 minutes on Day 1 of each 21-day cycle. Patients receiving Alimta also received dexamethasone, for skin rash prophylaxis, and vitamin supplementation including a low-dose daily oral folic acid preparation (350 to 1000 µg folic acid) and vitamin B12 1000 µg i.m. during the week preceding the first dose of Alimta and every 3 cycles thereafter.

Patients receiving docetaxel also received dexamethasone to reduce the severity of fluid retention and hypersensitivity reactions.

E. Special Populations

1. Pediatrics LY231514 safety and efficacy have not been established in children.

2. Elderly - A statistically significant age by treatment interaction was observed for diarrhea (p=0.0496). Among patients > 65, docetaxel-treated patients experienced a significantly higher frequency of diarrhea compared with LY231514-treated patients (34% versus 13%, p=0.003). There was no difference in the incidence of diarrhea between the treatment arms among the younger patients.

3. Renal or Hepatic Impairment - In clinical studies, patients with creatinine clearance (Ccr) > 45 mL/min using the standard Cockcroft and Gault formula or GFR measured by Tc99m-DPTA serum clearance method required no dose adjustments other than those recommended for all patients. Insufficient numbers of patients with creatinine clearance below 45 mL/min have been treated to make dosage recommendations for this group of patients.

LY231514 is not extensively metabolized by the liver. Dose adjustments should be made based on CTC levels of hepatic impairment. Patients eligible for the study had to have a bilirubin less than or equal to the upper limit of normal (ULN), aspartate transaminase (AST) and alanine transaminase (ALT) <1.5 x ULN and alkaline phosphatase <5 x ULN.

4. Gender - There was no statistically significant gender by treatment interaction

5. Ethnicity - Approximately 70% of study patients were Caucasian. East and Southeast Asians comprised approximately 17% of the study population. Patients of African descent comprised 3% of the population. There was no significant difference in efficacy or safety results among these ethnic populations.

6. Pregnancy - Category D - LY231514 may cause fetal harm when administered to a pregnant woman.

Clinical Review

I. Introduction and Background

A. Drug Established and Proposed Trade Name, Drug Class, Sponsor’s Proposed Indication(s), Dose, Regimens, Age Groups

Established Name: ALIMTA^®

Proprietary Name: Pemetrexed for injection

Applicant: Eli Lilly and Company

Drug Class: Antifolate

Indication:

Current: Alimta in combination with cisplatin is indicated for the treatment of patients with malignant pleural mesothelioma whose disease is either unresectable or who are otherwise not candidates for curative surgery.

Proposed: 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

Dosage and Administration:

Current Label: The dose of Alimta is 500 mg/m2 administered as an intravenous infusion over 10 minutes on Day 1 of each 21-day cycle.

Proposed Label: Same

B. State of Armamentarium for Indication(s)

Prior to the 1980s available chemotherapy drugs demonstrated limited activity against NSCLC. In the 1980s, several agents were introduced, including cisplatin, mitomycin C, ifosfamide, vindesine, vinblastine, carboplatin, and etoposide. Response rates of these drugs as single agents ranged from 10% to 20%, with combinations resulting in response rates of 20% to 40%. Response rates to combinations of these drugs range from approximately 20% to 38%, with median survival times of 5 months to 10.8 months.

Vinorelbine is approved for first- line treatment of advanced NSCLC in several countries, including US, France, Italy, Spain, Germany, and UK, both as a single agent and in combination with cisplatin. As a single agent, it has shown response rates of 20% or higher. The combination of vinorelbine and cisplatin has, in some studies, resulted in improved response rates and survival advantages compared to either agent alone, with 1-year survival rates of 33% to 35% compared to 12% for cisplatin and 30% for vinorelbine. One study of vinorelbine plus cisplatin versus vinorelbine alone showed a higher response rate for the combination (43% versus 16%), but no advantage in median survival time ( 33 weeks for vinorelbine plus cisplatin versus 32 weeks for vinorelbine alone.

Gemcitabine and paclitaxel were both approved in 1998 in the US for use in combination with cisplatin for the first- line treatment of advanced NSCLC. In five Phase 2 trials of the gemcitabine/cisplatin combination, response rates ranged from 38% to 54% and median survival from 8.4 months to 14.3months. In a Phase 3 study of paclitaxel combined with cisplatin, without and with filgrastim, response rates were 27% and 32%, and median survival times were 9.5 and 10.5 months, respectively.

Historically, NSCLC has not responded well to second- line chemotherapy. In December 1999, however, docetaxel was approved in US for use in patients with locally advanced or metastatic NSCLC after failure of prior platinum-containing chemotherapy.

C. Important Milestones in Product Development

Single Agent NSCLC Phase 2 Study Results are summarized in Table 1.

Table 1: Alimta Phase 2 Experience

Study JMACa JMADb JMANc JMAOd JMAGe JMALf JMBRg

Site US US Canada Canada UK Aus/ S Africa Europe/ Aus

Tumor colorectal pancreas NSCLC colorectal breast NSCLC NSCLC

Pts 1st line 1st line 1st line 1st line Mixed 1st line 2nd line

No. Pts 41 35 30 29 36 42 80

Cycles

Median 4 2 3 3 4 4 2

Range 1-12 1- 12 1- 8 1- 8 1- 9 1- 9 1- 7

CR 1 1 0 0 1 0 1

PR 5 1 7 5 10 7 8 Overall RR

(%) 15.4 5.7 23 17 31 17 11.2

( 95% ( 4.1- ( 0.7- ( 9.9- ( 8- ( 16- ( 7- NA

CI, %) 26.7) 19.1) 42.3) 39.7) 46) 31)

a John et al. 1998 b Miller et al. 1998 c Rusthoven et al. 1999 d Cripps et al. 1997 e Smith et al. 1997 f Clarke et al. 1998 g unpublished data Abbreviation: NA = not available

One study (H3E- MC- JMBR), begun in 1997, looked at LY231514 in second- line treatment of NSCLC patients, some of whom had received a platinum-containing regimen. This study used a starting dose of 600 mg/m2 once every 21 days. However, due to unexpected toxicity (Grade 3 mucositis and Grade 4 vomiting and myalgia) the starting dose for all subsequent LY231514 trials, including Study JMBR, was reduced to 500 mg/m2. 80 patients were evaluable. The response rate was 11%.

Study JMAN, a multi- institutional completed in Canada, included chemo-naive patients. Seven partial responses were observed in 30 evaluable patients [23.3% (95% CI 9.9% to 42.3%)]. All responding patients were treated at the 500 mg/m2 dose level.

Study JMAL, in previously untreated NSCLC, carried out jointly between Australia and South Africa, enrolled 53 patients, with 42 evaluable for response at the time of the most recently published results. All patients received LY231514 600 mg/m2 every 3 weeks in this study. The partial response rate was 17% (7/42).

Study JMBR, a second- line NSCLC trial, was conducted in several European countries and in Australia (unpublished data). Patients had to have had failure of prior chemotherapy, as defined by disease progression during, or within 3 months after, the prior chemotherapy. Of the 80 evaluable patients, 42 had received platinum- containing prior regimens. All patients received a LY231514 starting dose of 500 mg/m2. The overall response rate was 11.2%. Overall median survival time is 5.8 months, with 21.3% of patients censored.

In 646 Phase 2 patients who have been treated on the once every 3 weeks schedule with Alimta 600 mg/m2 the most frequent, serious toxicity has been hematologic. CTC Grade 3 and 4 hematologic toxicity included neutropenia (23% and 24%, respectively) and thrombocytopenia (7% and 5%, respectively). The frequency of serious infection was low (CTC Grade 4 infection 2%). Likewise, despite thrombocytopenia serious episodes of bleeding have been rare (< 1%). While 6% of patients experienced CTC Grade 3 (3% with Grade 4) skin rash, prophylactic dexamethasone is reported to ameliorate or prevent the rash in subsequent cycles. Other Grade 3 and 4 non-hematologic toxicities included stomatitis, diarrhea, vomiting, and infection. As seen in clinical studies of other antifolates, transient Grade 3 and 4 elevations of liver transaminases are common but not dose limiting. There have been no cases of persistent transaminase elevation.

Toxicity at 600 mg/m2 has been compared to that at 500 mg/m2. For hematologic parameters there appears to be no difference between the incidence of Grade 3 and 4 toxicity or Grade 4 toxicity alone. For non-hematologic parameters there is also no difference except for rash, fatigue, and stomatitis, which appear to be less severe at 600 mg/m2. Of note, patients who were administered Alimta 500 mg/m2 in previous trials received concomitant dexamethasone after the onset of toxicity, whereas patients at the 600 mg/m2 dose level were given dexamethasone prophylactically. The reduced toxicity profile at the 600 mg/m2 dose level is thus likely a result of prophylactic corticosteroid administration, and is not considered a dose response effect of Alimta treatment.

Folic Acid and Vitamin B12 Supplementation

It is well established that toxicity induced by antifolate antimetabolites can be reversed and/ or prevented by treatment with folic acid or its reduced forms. An initial multivariate analysis was conducted in late 1997 to assess the relationship of metabolites of folic acid and vitamins B12 and B6, drug exposure, and other pre- specified baseline patient characteristics to toxicity following therapy with LY231514. Data were examined from 139 Phase 2 patients with various solid tumors who had been treated with LY231514 600 mg/m2 I.V. over 10 minutes once every 21 days. These patients had homocysteine (Hcys), cystathionine, and methylmalonic acid levels measured at baseline and once each cycle thereafter. This study demonstrated that toxicity resulting from LY231514 therapy appeared to be higher in patients with elevated pre- therapy Hcys levels, that elevated baseline Hcys levels (>10 µM) highly correlate with severe hematological and non-hematological toxicity and that Hcys was better than baseline albumin (another predictor of toxicity) at predicting LY231514 toxicity.

A second study also demonstrated that baseline Hcys was a highly statistically significant predictor of febrile neutropenia (p < 0.0001), Grade 4 neutropenia ( p= 0.0191), Grade 4 thrombocytopenia (p< 0.0001), and Grade 3 or 4 diarrhea ( p< 0.0001).

Hcys level has also been shown to be a sensitive indicator of folate and vitamin B12 status. Study results indicate that folic acid and vitamin B12 supplementation permits dose escalation by ameliorating LY231514 associated toxicity.

As of December 1999, all patients in LY231514 trials receive folic acid and vitamin B12 supplementation. There have been no deaths from LY231514 toxicity in the approximately 250 patients who have received folic acid and vitamin B12 with LY231514. In contrast, of 1,169 earlier patients who did not receive folic acid and vitamin B12, 3.9% died from causes at least possibly related to LY231514. Before vitamin supplementation was added to all LY231514 treatment regimens, 37% of patients experienced Grade 4 hematologic or Grade 3 or 4 non-hematologic toxicity. An analysis of 78 patients who have received vitamins along with LY231514 has shown that only 6.4% experienced such toxicity.

D. Other Relevant Information

None

E. Important Issues with Pharmacologically Related Agents

All antifolates tend to accumulate in third-space fluid collections and to be erratically released from these fluid collections. This may lead to severe toxicity. For patients with clinically significant pleural or peritoneal effusions (on the basis of symptoms or clinical examination) consideration should be given to draining the effusion prior to dosing.

II. Clinically Relevant Findings From Chemistry, Animal Pharmacology and Toxicology, Microbiology, Biopharmaceutics, Statistics and/or Other Consultant Reviews

A. Chemistry

No chemistry review was conducted for this NDA as there was no new data submitted

B. Animal Pharmacology and Toxicology

No animal pharmacology and toxicology review was conducted for this NDA as there was no new data submitted.

C. Biopharmaceutics

No animal pharmacology and toxicology review was conducted for this NDA as there was no new data submitted.

D. Statistics

See statistics section of review.

III. Human Pharmacokinetics and Pharmacodynamics

A. Pharmacokinetics

From the product label. No new information is submitted.

The pharmacokinetics of LY231514 administered as a single‑agent in doses ranging from 0.2 to 838 mg/m² infused over a 10‑minute period have been evaluated in 426 cancer patients with a variety of solid tumors. LY231514 has a steady‑state volume of distribution of 16.1 liters. In vitro studies indicate that LY231514 is approximately 81% bound to plasma proteins. Binding is not affected by degree of renal impairment. LY231514 is not metabolized to an appreciable extent. LY231514 is primarily eliminated in the urine with 70% to 90% of the dose recovered unchanged within the first 24 hours following administration. LY231514 total systemic clearance is 91.8 mL/min and the elimination half‑life from plasma is 3.5 hours in patients with normal renal function (creatinine clearance of 90 mL/min [calculated using the standard Cockcroft and Gault formula or measured glomerular filtration rate using the Tc99m‑DPTA serum clearance method]). Between patient variability in clearance is moderate at 19.3%. LY231514 total systemic exposure (AUC) and maximum plasma concentration (C_max) increase proportionally with dose. The pharmacokinetics of LY231514 are consistent over multiple treatment cycles.

Drug Interactions

Chemotherapeutic Agents — Cisplatin and carboplatin do not affect the pharmacokinetics of LY231514. Similarly, the pharmacokinetics of total platinum are unaltered by LY231514.

Vitamins — Coadministration of oral folic acid or intramuscular vitamin B₁₂ does not affect the pharmacokinetics of LY231514.

Drugs Metabolized by Cytochrome P450 Enzymes — Results from in vitro studies with human liver microsomes predict that LY231514 would not cause clinically significant inhibition of metabolic clearance of drugs metabolized by CYP3A, CYP2D6, CYP2C9, and CYP1A2.

Aspirin — Aspirin, administered in low to moderate doses (325 mg every 6 hours), does not affect the pharmacokinetics of LY231514.

Special Populations

Analyses to evaluate the effects of special populations on the pharmacokinetics of LY231514 included 287 patients with a variety of advanced tumor types from 10 single‑agent Phase 2 studies, 70 patients from the Phase 3 malignant pleural mesothelioma registration trial, and 47 patients from a Phase 1 renal study.

Geriatric — No effect of age on the pharmacokinetics of LY231514 was observed over a range of 26 to 80 years.

Pediatric — Pediatric patients were not included in clinical trials.

Gender — The pharmacokinetics of LY231514 were not different between male and female patients.

Race — The pharmacokinetics of LY231514 were similar in Caucasians and patients of African descent. Insufficient data are available to compare pharmacokinetics for other ethnic groups.

Hepatic Insufficiency — No effect of AST (SGOT), ALT (SGPT), or total bilirubin on the pharmacokinetics of LY231514 was observed. However, specific studies of hepatically impaired patients have not been conducted.

Renal Insufficiency — Pharmacokinetic analyses included 127 patients with reduced renal function. Total plasma clearance and renal clearance of LY231514 decrease as renal function decreases. On average, patients with creatinine clearance of 45 mL/min will have a 56% increase in LY231514 total systemic exposure (AUC) relative to patients with creatinine clearance of 90 mL/min.

B. Pharmacodynamics

From the product label. No new information is submitted.

LY231514 is an antifolate that exerts its antineoplastic activity by disrupting crucial folate‑dependent metabolic processes that are essential for cell replication. In vitro studies have shown that LY231514 behaves as a multi‑targeted antifolate by inhibiting thymidylate synthase (TS), dihydrofolate reductase (DHFR), and glycinamide ribonucleotide formyltransferase (GARFT), which are key folate‑ dependent enzymes for the de novo biosynthesis of thymidine and purine nucleotides. LY231514 is transported into cells by both the reduced folate carrier and membrane folate binding protein transport systems. Once in the cell, LY231514 is rapidly and efficiently converted to polyglutamate forms by the enzyme folyl polyglutamate synthase. The polyglutamate forms are retained in cells and are even more potent inhibitors of TS and GARFT. Polyglutamation is a time‑ and concentration‑dependent process that occurs in tumor cells and, to a lesser extent, in normal tissues. Polyglutamated metabolites have an increased intracellular half‑life resulting in prolonged drug action in malignant cells.

In vitro studies have also suggested that LY231514 may be active against certain tumor cells that are resistant to methotrexate, 5‑fluorouracil, and raltitrexed. Additionally, preclinical animal studies have suggested that folic acid and itamin B12 supplementation reduces the risk of severe drug‑induced toxicities while preserving the antitumor activity of LY231514.

Absolute neutrophil counts (ANC) following single‑agent administration of LY231514 to non‑vitamin‑supplemented patients were characterized using population pharmacodynamic analyses. Severity of hematologic toxicity, as measured by the depth of the ANC nadir, is influenced primarily by the magnitude of systemic exposure (AUC). A 5‑ to 6‑fold increase in LY231514 AUC produces a 5‑ to 6‑fold lowering of the ANC nadir. Though less pronounced than AUC, increased cystathionine or homocysteine concentrations correlate with a lowering of the ANC nadir, supporting the use of vitamin supplementation. There is no cumulative effect of LY231514 exposure on ANC nadir over multiple treatment cycles.

Time to ANC nadir also correlates with LY231514 systemic exposure (AUC), and varied from 8 to 9.6 days after LY231514 administration over a range of exposures from 38.3 to 316.8 mg·hr/mL. Return to baseline ANC occurs from 4.2 to 7.5 days following the nadir over the same range of exposures.

IV. Description of Clinical Data and Sources

A. Overall Data

Data derived primarily from a phase 3 study titled "A Phase 3 Trial of Alimta vs Docetaxel in Patients with Locally Advanced or Metastatic Non-Small Cell Lung Cancer (NSCLC) Who Were Previously Treated with Chemotherapy". This was a multicenter study conducted at 135 study centers. Five-hundred-seventy one patients comprised the intent-to-treat patient population. The primary objective of this study was to compare the overall survival following treatment with ALIMTA (LY231514) versus docetaxel in patients with locally advanced or metastatic (Stage IIIA, IIIB, or IV) non-small cell lung cancer (NSCLC) who were previously treated with chemotherapy. The first patient enrolled on 20 March 2001, the last on 06 February 2002.

B. Listing of Submitted Clinical Trials

One phase 3 trial of LY231514 vs Docetaxel in patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) who were previously treated with chemotherapy.

Supporting studies

Tax 317- Phase III docetaxel in previously treated NSCLC. Shepherd et al. J Clin Oncol 18:2095-2103, 2000.

Tax 320- Phase III docetaxel in previously treated NSCLC. Fossella et al. J Clin Oncol 18:2354-2362, 2000.

Two additional Randomized studies of docetaxel in 2^nd line NSCLC

Camps, IASLC 2003, oral presentation

Gridelli, IASLC 2003, oral presentation

C. Postmarketing Experience

None

D. Literature Review

Hanna N, Shepherd FA, Rosell R, Pereira JR, De Marinis F, Fosella FV, Kayitalire L, Paul S, Einhorn L, Bunn PA. 2003. A phase III study of LY231514 vs. docetaxel in patients with recurrent non-small-cell lung cancer (NSCLC) who were previously treated with chemotherapy. Proc Am Soc Clin Oncol. 22:622, 2003 Abstract # 2503.

Shepherd FA, Dancey J, Ramlau R, et al. Prospective randomized trial of docetaxel versus best supportive care in patients with non-small-cell lung cancer previously treated with platinum-based chemotherapy. J Clin Oncol. 2000;18:2095-103.

Fossella FV, DeVore R, Kerr RN, et al. Randomized phase III trial of docetaxel versus vinorelbine or ifosfamide in patients with advanced non-small-cell lung cancer previously treated with platinum-containing chemotherapy regimens. The TAX 320 Non-Small Cell Lung Cancer Study Group. J Clin Oncol. 2000;18:2354-62.

See also references at the end of the Appendix.

V. Clinical Review Methods

A. How the Review was Conducted

Databases provided by the sponsor were analyzed to independently confirm the sponsor's efficacy and safety results. Queries were sent to the sponsor to clarify issues that arose during the review. Any discrepancies between reviewer and sponsor were communicated to the sponsor to achieve mutually acceptable conclusions.

B. Overview of Materials Consulted in Review

The safety and efficacy review is based primarily on data provided in EDR \\CDSESUB1\N21677\ N_000\2003-11-03 and summarized in "Clinical Study Report: A Phase 3 Trial of ALIMTA versus Docetaxel in Patients with Locally Advanced or Metastatic Non-Small Cell Lung Cancer (NSCLC) Who Were Previously Treated with Chemotherapy". Results of four supporting phase 2 NSCLC trials, two first-line and 2 second-line were also provided.

C. Overview of Methods Used to Evaluate Data Quality and Integrity

Consistency of efficacy results (survival, time to progression, response rates was sought. Data from each of the 135 participating medical centers was reviewed to assure that results were relatively consistent at all sites. Pertinent NSCLC literature was reviewed to determine whether study results were consistent with expected results in a comparable patient population treated with other chemotherapy agents or with other treatment modalities

D. Were Trials Conducted in Accordance with Accepted Ethical Standards

Yes

E. Evaluation of Financial Disclosure

The sponsor has submitted certification that Eli Lilly and Company has not entered into any financial arrangement with any of its clinical investigators who participated in H3E-MC-JMEI with the exception of individuals listed below. This certification was signed on 9/25/03 by Binh Nguyen, M.D., Ph.D. Medical Director.

(Redacted Information (Table) per FOI)

* In some cases patients were consented but not enrolled in the trial.

VI. Integrated Review of Efficacy

A. Brief Statement of Conclusions

The sponsor claimed that survival of LY231514 treated patients was non-inferior to survival of docetaxel treated patients. FDA statistical analysis indicated that non-inferiority was not demonstrated. Even if non-inferiority was demonstrated, however, it would not be credible because of imbalances in post-study chemotherapy. Thirty fewer docetaxel treated patients received post-study chemotherapy compared to LY231514 treated patients (RT population). While 32% of LY231514 treated patients received post-study docetaxel it was observed that patients receiving any post-study chemotherapy drug(s) survived longer than those who did not. The majority of patients on both arms who did not receive post-study chemotherapy were performance status 0 or 1 at their last study visit and, conceivably, could have received additional treatment.

B. General Approach to Review of the Efficacy of the Drug

The efficacy review is based primarily on one multicenter trial. See Figure 1 for the schema of study H3E-MC-JMEI

Figure 1 Schema - Study H3E-MC-JMEI

C. Detailed Review of Trials by Indication

Table 2 lists the principal investigators and the corresponding participating institutions.

Table 2: Principal Investigators and Address

Trial Inv. Site Investigator Address

Country Ref #

Argentina 070 Rosenberg, Moises Hospital Ferrer, Finochietto 849, Ciudad De Buenos Aires,

Argentina 071 Bagnes, Claudia Hospital Dr. Tornu, Ex Combatientes De Malvinas 3002, Buenos Aires,

Argentina 072 Jovtis, Silvia Complejo Medico Churruca Visca, Uspallata 3400, Buenos Aires,

Argentina 073 Coppola, Federico Hospital Aleman, Av.Pueyrredon 1640, Buenos Aires,

Austria 050 Pirker, Robert Akh Wien Universitätskliniken, Währinger Gürtel 18-20, Wien,

Austria 051 Baumgartner, G Kh Der Stadt Wien Lainz, Wolkersbergenstraße 1, Wien,

Austria 052 Aigner, K Kh Der Elisabethinen Linz, Fadingerstraße 1, Linz,

Austria 053 Eckmayr, Josef Kh Der Barmherzigen Schwestern Wels, Grießkirchner Straße

Belgium 850 Van Steenkiste, J Univ Ziekenhuis Gasthuisberg Leuven,

Belgium 851 Bosquée, L Centre Hospitalier Régional De La Citadelle, Liège, B-4000,

Belgium 852 Rosier, Jean F Hopital De Jolimont, B-7100, Belgium

Brazil 011 Pereira, José R Instituto Arnaldo Vieira De Carvalho, Sao Paulo, 01221-020,

Brazil 033 Barrios, Carlos H Hospital São Lucas, Porto Alegre, RS, 90610-000,

Brazil ` 034 Malzyner, Artur Clínica De Oncologia Médica, São Paulo, SP, 01406-100,

Canada 200 Shepherd, FA Princess Margaret Hospital, Toronto, Ontario,

Canada 201a Stewart, David J Ottawa General Hospital,

Canada 203 Hirsh, Vera Royal Victoria Hospital, Montreal, Quebec,

Canada 204 Palmer, MC Cross Cancer Institute, Edmonton, Alberta,

Czech Rep 750 Roubec, Jaromir Fakultni Nemocnice S Poliklinikou,

France 301 Pujol, Jean-Louis Chu De Montpellier Hopital

France 302 Gervais, Radj Centre Francois Baclesse, Caen

France 303 Urban, Thierry Chu D'angers, Angers

France 305 Perol, Maurice Hopital De La Croix Rousse, Lyon

France 306 Depierre, Alain Hopital Saint Jacques,

France 310 Lafitte, Jean-Jaques Chru De Lille Hopital Calmette, Lille

France 311 Robinet, Gilles Hospital Du Morvan, Brest

France 314 Spaeth, Dominique Centre Alexis Vautrin, Vandoeuvre Les Nancy

Germany 400 Manegold, C Thoraxklinik Der Lva Baden, Heidelberg,

Germany 401 Mezger, Jorg St. Vincentius-Krankenhäuser, Karlsruhe,

Germany 402 Kortsik, Cornelius St. Hildegardis Krankenhaus, Mainz,

Germany 403 Saal, Johannes St Franziskus Hospital Waldstr. 17, Flensburg

Germany 404 Muller, Thomas Krankenhaus Hofheim Am Taunus, Hofheim

Germany 405 Hossfield, DK Universitäts Krankenhaus Eppendorf (Uke), Hamburg,

Germany 406 Welte, Tobias Universitätsklinikum Otto-Von Guericke, Magdeburg,

Germany 407 Huber, Rudolf M Klinikum Der Universitat Munchen,

Germany 408 Gatzemeier, Med U Krankenhaus Großhansdorf, Großhansdorf, D- 22927,

Germany 409 Von Pawel, J Fachklinik München-Gauting, Gauting D-82131,

Germany 410 Kaukel, E Allgemeines Krankenhaus Harburg, Hamburg, D-21075,

Germany 413 Jermann, Monika Universitätsspital Zürich, Zürich, Switzerland

Germany 414 Herrmann, R Kantonsspital Basel, Basel, CH-4031, Switzerland

Hungary 753 Kovacs, Gabor Orszagos Koranyi Tbc Es Pulmonologiai Intezet, Budapest, 1529,

Hungary 754 Magyar, P Semmelweis Medical University, Budapest, 1125,

India 001 Sharma, Atul Institute Rotary Cancer Hospital, New Delhi, 110029,

India 002 Sekhon, Jagdev S Dayanand Medical College, Punjab, 141001,

India 003 Nayak, RadheshyamSt. John Medical College, Bangalore, Karnataka, 560-034,

India 004 John, Subhashini Christian Medical College, Tamil Nadu, 632

India 006 Doval, DC Rajiv Gandhi Cancer Institute, Delhi, 110 085

India 009 Julka, PK All India Institute of Medical Sciences, New Delhi, 110 029,

Israel 351 Gottfried, Maya Meir Hospital, Kfar Saba, 44281,

Italy 500 De Marinis, F Azienda Ospedaliera S., Roma, 00149,

Italy 501 Rinaldi, M Istituti Fisioterapici Ospedalieri, Roma, 00144,

Italy 502 Crino, L Ospedale Bellaira, Bologna, 40139,

Italy 506 Adamo, V Universita Di Messina/Policlinico, Messina, 98100,

Korea 060 Bang, Yung-Jue Seoul National University Hospital, Seoul, 110-744

Korea, 061 Park, Keun-Chil Samsung Medical Center, Seoul, 135-710,

Korea 062 Kim, Joo-Hang Yonsei University Medical Center, Seoul, 120-752,

Pakistan 700 Zaidi, M Baquai Institute of Oncology, Karachi, 75510,

Pakistan 702 Shaharyar, Mayo Hospital, Lahore, 54000,

Pakistan 703 Ansari, Tariq Combine Military Hospital, Rawalpindi,

Pakistan 706 Siddiqui, Tariq The Aga Khan University, Karachi, 29667

Poland 007 Jassem, J Akademia Medyczna, Instytut Radioterapii, Gdansk, 80-211,

Poland 008 Roszkowski, K Instytut Gruzlicy I Chorob Pluc, Warszawa, 01-138,

Portugal 080 Jose De Melo, Maria Hospital De Pulido Valente, Lisboa, 1769-001,

Portugal 081 Bernardo, Manuela Hospital De Santo Antonio Dos Capuchos, Lisboa, 1169-050,

Portugal 082 Duro Da Costa, Jose Instituto Português De Oncologia Dr. Francisco Gentil, Lisboa, 1099-023,

Portugal 083 Teixeira, EncarnaçãoHospital De Santa Maria, Lisboa, 1649-035,

Portugal 084 Barata, Fernando Centro Hospitalar De Coimbra, Coimbra, 3040-853,

Portugal 086 Sanches, Evaristo Instituto Português De Oncologia Dr. Francisco Gentil, Porto 4200-072,

Portugal 087 Queiroga, Henrique Hospital De São João, Porto, 4200-319,

Portugal 088 Parente, Bárbara Centro Hospitalar De Vila Nova De Gaia, Gaia, 4434-502,

Portugal 089 Passos, Mario Centro Hospitalar Do Funchal, Funchal, 9004-514,

Russia 013 Garin, AM Blokhin Cancer Research Center, Moscow, 115478,

Russia 014 Lichinitser, MR Blokhin Cancer Research Center, Moscow, 115478

Russia 015 Gorbunova, VA Blokhin Cancer Research Center, Moscow, 115478

Singapore 020 Lim, Hong-Liang National University Hospital, Singapore, 119074,

Singapore 022 Leong, Swan-Swan National Cancer Center, Singapore, 169610,

South Africa 016 Abratt, RP Groote Schuur Hospital, Cape Town, 7925,

South Africa 017 Ruff, Paul Johannesburg General Hospital, Gauteng, 2193,

South Africa 023 Brennan, Sean East Cape Oncology Centre St. George's Hospital, Eastern Cape, 6001,

Spain 600 Rosell, R Hospital De Badalona Germans Trias I, Barcelona, 08915,

Spain 601 Esteban, Emilio Hospital Central De Asturias, Asturias, 33006,

Spain 603 Barceló Galíndez, J Hospital De Cruces, Vizcaya, 48903,

Spain 604 Felip, E Ciutat Sanitaria De La Vall De Hebron, Barcelona, 08035,

Spain 605 Garrido, Pilar Hospital Ramon Y Cajal, Madrid, 28034,

Taiwan 650 Tsai, Chun-Ming Taipei Veterans General Hospital, Taipei, 112,

Taiwan, 651 Chang, Gee-Chen Taichung Veterans General Hospital, Taiwan

Taiwan 652 Hsu, Hon-Ki Kaohsiung Veterans General Hospital, Taiwan

Taiwan 653 Wu, Ming-Fang Chung Shan Medical and Dental College, Taiwan,

Taiwan 654 Hsia, Te-Chun China Medical College Hospital, Taiwan,

Taiwan 655 Su, Wu-Chou National Cheng Kung University Hospital, Taiwan,

Taiwan 656 Yang, Chih-Hsin National Taiwan University Hospital, Taiwan,

Taiwan 657 Tsao, Thomas C Chang Gung Memorial Hospital, Taiwan

United States 100 Bhatia, Sumeet Community Care Center Inc., Indianapolis, IN 46202,

United States 101 Albain, Kathy Loyola Univ School of Medicine, Maywood, IL 60153,

United States 104 Scott, Miho Toi Hematology Oncology Associates, Fort Collins, CO 80528,

United States 105 Fossella, F MD Anderson Cancer Center, Houston, TX 77030,

United States 106 Figueroa, Jose A Joe Arrington Cancer Center, Lubbock, TX 79410,

United States 108 Beck, Joseph T Highland Oncology Group, Springdale, AR 72764,

United States 110 Shuster, Todd Lahey Clinc, Burlington, MA 01805,

United States 111 Desch, Christopher Hematology Oncology Associates, Richmond, VA 23226,

United States 112 Feldmann, John E Mobile Infirmary Medical Center, Mobile, AL 36607,

United States 114 Justice, GR Pacific Coast Hematolgy and Oncology, Fountain Valley, CA 92708,

United States 116 Liebmann, J New Mexico Hematology/Oncology Consultants, Albuquerque, NM 87109,

United States 117 Makalinao, Alex California Hematology Oncology Group, Torrance, CA 90505,

United States 120 Nimeh, NF Cleo Craig Cancer Research Clinic, Lawton, OK 73505,

United States 121 Schwartzberg, Lee The West Clinic, Memphis, TN, 38117

United States 123 Tezcan, Haluk North Idaho Cancer Center, Coeur D’Alene, ID 83814,

United States 126 Valdivieso, Manuel Univ of Texas Southwestern Med Center , Dallas, TX 75235,

United States 127 Dickman, E Primary Meridia Hillcrest Hospital, Mayfield Heights, OH 44124,

United States 129 Jazieh, Abdul-Rahman Cincinnati College of Medicine, Cincinnati, OH 45267,

United States 130 Peereboom, David Cleveland Clinic Foundation, Cleveland, OH 44195,

United States 131 Nattam, S Fort Wayne Hematology Oncology, Fort Wayne, IN 46815,

United States 132 Priego, VM Bethesda, MD, 20817,

United States 133 Webb, Timothy Primary Genesis Cancer Center, Hot Springs, AR 71913,

United States 134 Eisenberg, PD Marin Oncology Associates, Greenbrae, CA, 94904

United States 135 Dudek, Arkadiusz University of Minnesota Medical School, Minneapolis, MN 55455,

United States 136 Hart, Ronald Oncology of Wisconsin, Milwaukee, WI, 53215,

United States 137a Ellerton, JA Southern Nevada Cancer Research Foundation, Las Vegas, NV 89106,

United States 138 Mason, Bernard A Pennsylvania Oncology Hematology Assoc., Philadelphia, PA 19106,

United States 139 Larson, Tim Metro Minnesota CCOP, St. Louis Park, MN 55416,

United States 140 Kuebler, Phillip J. Columbus CCOP, Columbus, OH 43206,

United States 142 Arnold, Susanne University of Kentucky, Lexington, KY 40536,

United States 144 Eckardt, JR St John's Mercy Medical Center, St. Louis, MO 63141,

United States 146 Kennedy, Peter Metropolitan Oncology, Los Angeles, CA 90057,

United States 148 Malefatto, Jerry P. Oncology Associates of Bridgeport, Trumbull, CT 06611,

United States 149 Christiansen, Neal PSouth Carolina Oncology Associates, Columbia, SC 29203,

United States 154 Treat, Joseph Temple University, Philadelphia, PA 19140,

United States 155 Dobbs, Tracy W Baptist Regional Cancer Center, Knoxville, TN 37920,

United States 156 Perry, Michael C Ellis Fischel Cancer Center, Columbia, MO 65203,

United States 158 Bearden, James D Spartanburg Regional Healthcare System, Spartanburg SC, 29303

United States 160 Hanna, Nassar Indiana Cancer Pavilion, Indianapolis, IN 46202,

United States 161 Graziano, Stephen Regional Oncology Center, Syracuse, NY 13210,

United States 164 Lyss, Alan Missouri Baptist Medical Center, St. Louis, MO 63131,

United States 165 Rinaldi, DA Louisiana Oncology Associates, Lafayette, LA 70506,

United States 180 Ansari, R Memorial Hospital of South Bend, South Bend, IN 46601,

United States 182 Pennington, Ken Oncology Institute of Greater Lafayette, Lafayette, IN 47904,

United States 183 Fisher, William B. Medical Consultants, Muncie, IN 47304,

a Because of regulatory violations, this investigator was disqualified.

Table 3: Summary of Response Rate By Site - ITT Population

	Docetaxel			LY231514
Site	N	Responders	Response Rate (%)	N	Responders	Response Rate (%)
1 2 0 0 0	2	0	0	0
2 3 1	3	1	33	1	0	0
3	1	0	0	4	0	0
4	2	0	0	0
6	1	0	0	2	0	0
7	1	0	0	1	1	100
9	2	0	0	0
11	13	3	23	11	2	18
13	0			1	0	0
15	0			2	0	0
16	1	1	100	2	1	50
17	1	0	0	2	0	0
20	5	1	20	5	0	0
22	4	1	25	5	2	40
33	2	0	0	0
34	3	0	0	3	0	0
50	0			2	0	0
51	3	0	0	1	0	0
52	4	0	0	2	0	0
53	2	0	0	2	1	50
60	2	0	0	1	0	0
61	6	0	0	3	1	33
62	3	0	0	2	0	0
70	2	0	0	1	0	0
71	3	0	0	3	0	0
72	0			1	0	0
73	0			1	0	0
80	1	0	0	0
81	1	0	0	2	0	0
82	1	0	0	1	0	0
83	1	0	0	2	0	0
84	4	0	0	2	1	50
86	1	0	0	0
87	0			1	0	0
88	0			3	1	33
89	4	0	0	1	0	0
100	1	0	0	0
101	1	0	0	0
104	0			2	0	0
105	8	2	25	8	2	25
106	1	0	0	1	0	0
108	2	0	0	3	1	33
110	2	0	0	2	0	0
111	1	0	0	6	1	17
112	0			0
114	1	1	100	1	0	0
116	1	0	0	0
117	3	0	0	3	0	0
Docetaxel				LY231514
Site	N	Responders	Response Rate (%)	N	Responders	Response Rate (%)
120	1	0	0	0
121	1	0	0	0
123	1	0	0	0
126	1	0	0	0
127	1	0	0	0
129	1	0	0	1	0	0
130	0			1	0	0
131	3	0	0	1	0	0
132	1	0	0	0
133	1	0	0	0
134	0			2	0	0
135	3	1	33	2	1	50
136	0			1	0	0
138	1	0	0	0
139	0			4	0	0
140	2	0	0	2	0	0
142	1	0	0	0
144	0			1	0	0
148	1	0	0	0
149	1	0	0	0
152	2	0	0	1	0	0
155	1	0	0	1	0	0
156	2	0	0	4	0	0
160	5	0	0	2	0	0
161	3	0	0	2	0	0
164	3	1	33	3	0	0
165	2	0	0	0
180	0			1	0	0
182	1	0	0	0
183	0			1	0	0
200	3	1	33	6	1	17
201	1	0	0	2	1	50
203	2	1	50	1	0	0
204	0			2	0	0
301	2	0	0	2	0	0
302	7	0	0	2	0	0
303	0			1	0	0
305	1	0	0	1	0	0
306	1	1	100	0
310	0			1	1	100
311	1	0	0	1	0	0
314	1	0	0	0
351	2	0	0	0
400	6	1	17	2	0	0
401	0			2	0	0
402	3	0	0	5	1	20
403	4	0	0	0
404	4	0	0	4	0	0
405	3	0	0	3	0	0
406	1	0	0	2	0	0
		Docetaxel			LY231514
Site	N	Responders	Response Rate (%)	N	Responders	Response Rate (%)
407	1	0	0	0
408	6	0	0	8	1	13
409	10	1	10	7	1	14
410	2	0	0	3	0	0
413	2	0	0	3	0	0
414	5	0	0	7	0	0
500	10	1	10	10	0	0
501	0			1	0	0
502	0			1	0	0
506	0			0
600	4	0	0	2	0	0
601	1	0	0	2	0	0
603	1	0	0	1	0	0
604	2	0	0	3	0	0
605	0			1	0	0
650	5	2	40	3	0	0
651	3	1	33	4	0	0
652	1	0	0	1	0	0
653	3	0	0	4	0	0
654	4	0	0	2	0	0
655	0			2	0	0
656	4	1	25	2	1	50
657	4	2	50	9	0	0
700	0			2	0	0
702	5	0	0	4	0	0
703	1	0	0	1	0	0
706	1	0	0	0
750	1	0	0	3	0	0
753	3	0	0	1	0	0
754	6	0	0	3	1	33
800	3	0	0	1	0	0
801	1	0	0	1	0	0
803	0			1	0	0
850	1	0	0	1	0	0
851	1	0	0	1	0	0
852	2	0	0	1	0	0

Table 3 indicates that responses were relatively evenly distributed among sites and countries so that any one site did not unduly influence study results.

Study JMEI entered 698 patients at 135 investigational sites in 23 countries. Of these,

571 (81.8%) patients were randomly assigned (enrolled) to either the LY231514 arm or

the docetaxel arm. Figure 2 describes the disposition of patients who entered the trial.

Figure 2: Disposition of Patients

Patients who signed

IC document

N = 698

Not randomized n= 127

-inclusion criteria not met n=114

-reason unspecified n = 13

Randomized

N = 571

LY231514 Docetaxel

N = 283a n = 288 a

Treated non-treated n = 18 Treated non-treated n = 12

N = 265b PC not met = 7 n =276b PC not met = 2

Death from Systemic Dis =5 Death from S Dis =1

AE =3 Death from other =1

Personal conflict=2 Personal conflict=5

Prot. Violation =1 Lost to F/U=3

a = Intent to treat (ITT) population

b = randomized and treated (RT) subgroup

Table 4 presents the key patient characteristics by treatment arm. The two treatment arms were well-balanced with respect to demographic and disease characteristics.

Table 4 Patient characteristics

Variable

ALL (N=571)

LY231514

(N=283)

Docetaxel (N=288)

Sex: No. (%)

Female

Male

160 (28.0)

411 (72.0)

89 (31.4)

194 (68.6)

71 (24.7)

217 (75.3)

Origin: No. (%)

African Descent

Western Asian

Caucasian

East/Southeast A

Hispanic

Other

16 (2.8)

43 (7.5)

403 (70.6)

93 (16.3)

10 (1.8)

6 (1.1)

8 (2.8)

20 (7.1)

203 (71.7)

44 (15.5)

4 (1.4)

8 (2.8)

23 (8.0)

200 (69.4)

49 (17.0)

6 (2.1)

2 (0.7)

Age:

Mean

Median

58.24

58.00

58.44

59.00

58.05

57.00

Performance Status:

ECOG PS 0

ECOG PS 1

ECOG PS 2

100 (18.6)

374 (69.5)

64 (11.9)

52 (19.7)

182 (68.9)

30 (11.4)

48 (17.5)

192 (70.1)

34 (12.4)

Histological Subtype: Adenocarcinoma

Squamous

Other

301 (52.7)

171 (29.9)

99 (17.3)

158 (55.8)

78 (27.6)

47 (16.6)

143 (49.6)

93 (32.3)

52 (18.1)

Homocysteine

Low (< 12 Umol/L)

High (>= 12 Umol/L)

399 (70.1)

170 (29.9)

202 (71.4)

81 (28.6)

197 (68.9)

89 (31.1)

Stage Of Disease

Stage III

Stage IV

144 (25.2)

427 (74.8)

71 (25.1)

212 (74.9)

73 (25.3)

215 (74.7)

Prior Chemo Regimens

1 Regimen

2 Regimens

538 (94.2)

33 (5.8)

270 (95.4)

13 (4.6)

268 (93.1)

20 (6.9)

Prior Platinum

Had No Prior Platinum

Had Prior Platinum

50 (8.8)

521 (91.2)

21 (7.4)

262 (92.6)

29 (10.1)

259 (89.9)

Prior Taxane

Had No Prior Taxane

Had Prior Taxane

418 (73.2)

153 (26.8)

210 (74.2)

73 (25.8)

208 (72.2)

80 (27.8)

Best Response To Chemo Complete Response

Partial Response

Stable Disease

Progressive Disease

Unknown, NE, or Not Done

16 (2.8)

190 (33.3)

199 (34.9)

140 (24.5)

26 (4.5)

12 (4.2)

89 (31.4)

106 (37.5)

67 (23.7)

9 (3.2)

4 (1.4)

101 (35.1)

93 (32.3)

73 (25.3)

17 (5.9)

TIME SINCE LAST CHEMO

<3 mos since last chemo

>3 mos since last chemo

277 (49.2)

286 (50.8)

140 (50.4)

138 (49.6)

137 (48.1)

148 (51.9)

Table 5 indicates therapy received prior to enrollment into the current study.

Table 5: Prior Therapies

	LY231514 (N=283) n (%)	Docetaxel (N=288) n (%)
Prior surgery	64 (22.6)	67 (23.3)
Prior radiotherapy	125 (44.2)	131 (45.5)
Prior immunotherapy	1 (0.4)	1 (0.3)
Prior chemotherapy Adjuvant setting Neoadjuvant setting Locally advanced setting Metastatic setting	283 (100) 21 (7.4) 26 (9.2) 101 (35.7) 147 (51.9)	288 (100) 18 (6.3) 23 (8.0) 111 (38.5) 148 (51.4)
Metastatic setting One line of therapy Two lines of therapy	143 (50.5) 4 (1.4)	146 (50.7) 2 (0.7)

Primary Efficacy Analysis

Overall Survival

Analyses by FDA statisticians, Yong-Cheng Wang, Ph.D. and Rajeshwari Sridhara, Ph.D.

Overall survival was the primary efficacy endpoint of Study JMEI. Two statistical tests for the primary endpoint were defined in the protocol amendment: (1) Test for superiority of alimta relative to docetaxel (H₀₁: HR ³ 1), and (2) Test for non-inferiority based on a protocol-defined fixed margin (H₀₂: HR ³ 1.11). Since these two tests were pre-specified in the protocol, the analyses based on these two tests are presented below.

Table 6 summarizes the results of the superiority test and fixed margin non-inferiority test of the primary endpoint for ITT population. It failed to reach the significance level 0.05 in superiority test (p=0.9300; log-rank) and fixed margin non-inferiority test (p=0.2558).

Table 6: Confirmatory Analyses^a of Overall Survival – ITT Population

Sponsor Analysis

FDA Analysis

Alimta

(N = 283)

Docetaxel

(N = 288)

Application #	NDA 21-677
Drug Name	AlimtaÒ (pemetrexed)
Medical Reviewer Medical Team Leader	Martin H. Cohen, M.D. John R. Johnson,M.D.
Documents reviewed	EDR \\CDSESUB1\N21677\ N_000\2003-11-03