Oncologic Drugs Advisory Committee

July 27, 2004

Briefing Material

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

 

 

 


 

Table of Contents

 

Executive Summary.................................................... 6

I.      Recommendations................................................................................ 6

A.    Recommendation on Approvability................................................. 6

B.    Recommendation on Phase 4 Studies and/or Risk Management Steps......................................................................................................... 6

II.    Summary of Clinical Findings.............................................................. 6

A.    Brief Overview of Clinical Program................................................ 6

B.    Efficacy............................................................................................ 6

C.    Safety............................................................................................... 7

D.    Dosing.............................................................................................. 7

E.     Special Populations.......................................................................... 7

Clinical Review........................................................... 8

I.      Introduction and Background.............................................................. 8

A.    Drug Established and Proposed Trade Name, Drug Class, Sponsor’s Proposed Indication(s), Dose, Regimens, Age Groups............................ 8

B.    State of Armamentarium for Indication(s)....................................... 9

C.    Important Milestones in Product Development............................. 10

D.    Other Relevant Information........................................................... 12

E.     Important Issues with Pharmacologically Related Agents............. 12

II.    Clinically Relevant Findings From Chemistry, Animal Pharmacology and Toxicology, Microbiology, Biopharmaceutics, Statistics and/or Other Consultant Reviews.................................................................................... 13

A.    Chemistry....................................................................................... 13

B.    Animal Pharmacology and Toxicology.......................................... 13

C.    Biopharmaceutics........................................................................... 13

D.    Statistics......................................................................................... 13

III.       Human Pharmacokinetics and Pharmacodynamics....................... 13

A.    Pharmacokinetics........................................................................... 13

B.    Pharmacodynamics........................................................................ 15

IV.       Description of Clinical Data and Sources...................................... 16

A.    Overall Data................................................................................... 16

B.    Listing of Submitted Clinical Trials................................................ 16

C.    Postmarketing Experience............................................................. 16

D.    Literature Review.......................................................................... 16

V.    Clinical Review Methods................................................................... 17

A.    How the Review was Conducted................................................... 17

B.    Overview of Materials Consulted in Review................................. 17

C.    Overview of Methods Used to Evaluate Data Quality and Integrity        17

D.    Were Trials Conducted in Accordance with Accepted Ethical Standards................................................................................................ 17

E.     Evaluation of Financial Disclosure................................................ 17

VI.       Integrated Review of Efficacy....................................................... 18

A.    Brief Statement of Conclusions...................................................... 18

B.    General Approach to Review of the Efficacy of the Drug............ 18

C.    Detailed Review of Trials by Indication........................................ 19

D.    Efficacy Conclusions..................................................................... 35

VII.      Integrated Review of Safety........................................................... 35

A.    Sponsor’s Conclusions................................................................... 35

B.    Description of Patient Exposure - Per Sponsor.............................. 35

C.    Methods and Specific Findings of Safety Review.......................... 36

D.    Adequacy of Safety Testing........................................................... 46

E.     Summary of Critical Safety Findings and Limitations of Data....... 46

VIII.    Dosing, Regimen, and Administration Issues................................. 47

IX.       Use in Special Populations............................................................. 48

A.    Evaluation of Sponsor’s Gender Effects Analyses and Adequacy of Investigation........................................................................................... 48

B.    Evaluation of Evidence for Age, Race, or Ethnicity Effects on Safety or Efficacy.................................................................................. 48

D.    Comments on Data Available or Needed in Other Populations..... 48

X.    Conclusions and Recommendations................................................... 49

A.    Conclusions.................................................................................... 49

B.    Recommendations.......................................................................... 50

 


Table of Tables

 

 

Table 1: Alimta Phase 2 Experience.............................................................. 10

Table 2: Principal Investigators and Address................................................. 20

Table 3:  Summary of Response Rate By Site - ITT Population.................... 23

Table 4 Patient characteristics....................................................................... 27

Table 5: Prior Therapies................................................................................. 28

Table 6: Confirmatory Analyses of Overall Survival – ITT Population......... 29

Table 7: Exploratory Analyses of Overall Survival – ITT Population........... 30

Table 8: Post-study Anticancer Drug Therapy - ITT Population................... 31

Table 9: Post-study Anticancer Drug Therapy - RT Population.................... 31

Table 10: Effect of Post-study chemotherapy on survival - RT Population.. 32

Table 11: No post-study chemotherapy. Last performance status................. 32

Table 12: Time to Progressive Disease (Months).......................................... 33

Table 13: Best Objective Tumor Response - QR Population......................... 34

Table 14: Duration of Response (Months)..................................................... 34

Table 15: Summary of treatment cycles......................................................... 36

Table 16: Distribution of Weekly Mean Dose per Patient............................. 36

Table 17:  TAES occurring in >=10% of patients.......................................... 38

Table 18: Serious adverse events................................................................... 39

Table 19: Deaths............................................................................................ 40

Table 20 SAE's............................................................................................... 41

Table 21: CTC Grade 3/4 Laboratory Toxicity.............................................. 42

Table 22: Percent of cycles with CTC Grade 3/4 Lab Toxicity..................... 42

Table 23: CTC Grade 3/4 Non-Laboratory Toxicity..................................... 43

Table 24 Transfusions.................................................................................... 44

Table 25 Hospitalizations............................................................................... 45

 

 


 

Table of Figures

 

Figure 1 Schema - Study H3E-MC-JMEI 19

Figure 2: Disposition of Patients. 26

Figure 3 Overall survival ITT Population. 30

Figure 4: Time to Progressive Disease (Months)- RT Group. 33


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 (Cmax) 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 2nd 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)

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 Analysesa of Overall Survival – ITT Population

 

 

 

Sponsor Analysis

FDA Analysis

Alimta

(N = 283)

Docetaxel

(N = 288)