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Presentation to the Oncologic Drugs Advisory Committee
Paolo Paoletti, MDVice President Clinical Research Oncology
27 July 2004Eli Lilly and Company
Alimta® (Pemetrexed) as a Second-Line Treatment for Patients with
Non-Small Cell Lung Cancer
2
Agenda Introduction Paolo Paoletti, MD
– Objectives of Presentation Vice President, Clinical Research Oncology, Eli Lilly and Company
Background Frances A. Shepherd, MD – 2nd-Line Treatment of NSCLC Professor of Medicine, University of Toronto
Scott Taylor Chair in Lung Cancer Research, President IASLC
Alimta Development Roy Herbst, MD, PhDChief, Thoracic Oncology, University of Texas M.D. Anderson Cancer Center
Clinical Efficacy Paul A. Bunn, Jr., MD– Pivotal Study JMEI Director, University of Colorado Cancer Center
Safety Profile Richard J. Gralla, MD– Pivotal Study JMEI President, Multinational Association of
Supportive Care in Cancer, Director IASLC
Conclusions Paul A. Bunn, Jr., MD
3
List of External ExpertsRobert Allen, MD
University of Colorado, United States
Donald Berry, PhD
University of Texas, MD Anderson, United States
Hilary Calvert, MD
University of Newcastle, United Kingdom
Scott Emerson, MD, PhD
University of Washington, United States
Nasser Hanna, MD
Indiana University, United States
Axel Hanauske, MD, PhD
Allgemeines Krankenhaus St Georg, Hamburg, Germany
Christian Manegold, MD
Thorax Klinik, Heidelberg, Germany
Giorgio Scagliotti, MD
University of Turin, Torino, Italy
4
Lilly Team
Medical
William John, MD
Louis Kayitalire, MD
Astra Liepa, PharmD
Binh Nguyen, MD, PhD
Paolo Paoletti, MD
Regulatory Affairs
Jeffrey Ferguson
Anne Kehely, MD
Debasish Roychowdhury, MD
John Worzalla
Statistics
Clet Niyikiza, PhD
Sofia Paul, PhD
Patrick Peterson, PhD
Jim Symanowski, PhD
Non-Clinical Studies
Ajai Chaudhary, PhD
Victor Chen, PhD
Vijay Reddy, PhD, DVM
Rebecca Wrishko, PhD
5
Provide evidence that Alimta is effective and safe.
Lilly intends to show that given its superior safety, Alimta has a better risk-benefit profile than docetaxel (Taxotere®) and provides clinical benefit to patients with non-small cell lung cancer (NSCLC).
Alimta is a novel, effective agent in the treatment of NSCLC– Demonstrates similar efficacy to docetaxel– Shows consistent results across all assessed endpoints and
subgroups – Estimated to retain 102% of docetaxel's benefit over BSC – Is superior to historical BSC
Alimta has an excellent safety profile – Has a superior safety profile to docetaxel
Alimta offers an effective and safer option in the treatment of second-line NSCLC
Objective of Presentation
6
Proposed Indication and Dosage Schedule
Alimta as a single‑agent is indicated for the treatment of patients with locally advanced or metastatic non‑small cell lung cancer (NSCLC) after prior chemotherapy
Dose: 500 mg/m2 iv, 10 minutes, Day 1 of each 21-day cycle
Folic Acid: 350-1000 µg orally daily; Vitamin B12 1000 µg im, q 3 cycles
Dexamethasone: 4 mg bid on d-1, d0, d+1
7
Development of Alimta in Second-Line Treatment of NSCLC
Consistent evidence of activity in seven Phase II studies
– Single agent (3 studies)
– In combination with platinum agents (4 studies)
– Both in 1st and 2nd-line
Supplementation with Folic Acid/B12 improved safety profile of Alimta
– Degree of toxicity reduction was not fully characterized
Decision to proceed with a Phase III study (JMEI) in 2nd-line treatment of NSCLC
8
Design of Global, Pivotal Study JMEI
Decision to run “Head to Head” trial of Alimta vs docetaxel
– Global study to support global registration
– BSC in 2nd-line NSCLC considered not feasible in US
– Combination chemotherapy not appropriate in 2nd-line setting
– Docetaxel only approved agent for treatment of 2nd-line NSCLC
Survival as a primary endpoint
– Limited historical data on the effect of docetaxel
– “Pure equivalency” study would require >4000 pts
9
Design of Global, Pivotal Study JMEI
Sample size of 520 patients allows for testing both superiority and non inferiority
Compare treatment arms by HR for survival
Protocol Specified:– Superiority
– 10% fixed margin NI (EU regulatory)
Statistical Analysis Plan Specified (prior to unblinding):– Percent Retention of the effect of docetaxel over BSC
– 50% retention – basis of approval for capecitabine (colorectal) and docetaxel (breast cancer)
– Percent Retention methodology published January 2003
10
JMEI first patient enrolled 20 March 2001
JMEI last patient enrolled 06 February 2002
Final Statistical Analysis Plan for 24 January 2003 JMEI approved
Unblinding of JMEI analysis data sets 30 January 2003
US fast track designation for 2nd- 23 July 2003line treatment of NSCLC
US NSCLC submission 04 November 2003
NSCLC 2nd Line and Mesothelioma 22 June 2004EU-CHMP positive opinion
Alimta Second-Line Treatment of NSCLC Global Development Timeline
11
Alimta in Combination with Cisplatin is Approved in the US for Mesothelioma – 04 February 2004
MST = 12.1 mo
HR: 0.77Log rank p-value = 0.020
MST = 9.3 mo
0 5 10 15 20 25 30
100
Months
75
50
25
0
Method: Kaplan-Meier
% A
live
Alimta+Cis (n=226)
Cis (n=222)
12
Seven Alimta Phase II studies show consistent evidence of activity
From this large Phase III randomized study in 2nd-line NSCLC, consistently similar efficacy results compared to docetaxel:
– All primary and secondary efficacy endpoints
– All subgroup analyses
Significantly better efficacy than historical BSC Alimta has a significantly better safety profile when
compared with docetaxel for clinically relevant events
Alimta is safe and effective and offers a superiorbenefit-to-risk profile compared to docetaxel
Why Alimta Merits FDA Approval as Second-Line Treatment for NSCLC
13
Points for Consideration
Docetaxel is effective in the 2nd-line treatment of NSCLC, but its use is limited by toxicity
– Results in the 288 patients receiving docetaxel in the JMEI trial confirms docetaxel’s survival effect and safety profile
The small size of the docetaxel vs BSC pivotal trial made non-inferiority designs and analyses very challenging.
Inevitable post study treatment may confound a survival endpoint; analysis of JMEI data suggest such a confounding effect is unlikely
Interpretation of the results we present must consider the whole body of evidence
14
Non-Small Cell Lung Cancer
Second-Line Treatment
Frances A. Shepherd, MD, FRCPC Scott Taylor Chair in Lung Cancer Research,
Princess Margaret Hospital
Professor of Medicine, University of Toronto
President, International Association for the Study of Lung Cancer
15
1997 ASCO Guidelines for NSCLC
“…there is no current evidence that either confirms or refutes that 2nd-line chemotherapy improves survival in … patients with advanced NSCLC.”*
* Treatment Guidelines For Unresectable NSCLC. JCO 15: 2996-3019, 1997.
16
6-11 mo.8-21%272Docetaxel
4-10 mo.0-23%112Paclitaxel
4-8 mo.0-21%201
3 mo.0-20%63Vinorelbine
Median Survival
Overall RRNAgent
Monotherapy for Previously Treated Patients With Advanced NSCLC
Gemcitabine
17
Study Design - TAX 317
NSCLCStratified by:
• ECOG PS (0,1 vs 2)
• Best response to prior platinum
(PD vs. non-PD)
• 10 Objective: survival
• No prior paclitaxel
RANDOMIZE
317A
Docetaxel 100 mg/m2, one-hour iv infusion on Day 1 q 21d Premedication:
Dexamethasone 8 mg x 10 doses, beginning 12 hours before docetaxel
By Protocol Amendment:
Docetaxel 75 mg/m2, one-hour IV infusion on Day 1 q 21d
Premedication: Dexamethasone 8 mg x 5 doses, beginning 12 hours before docetaxel
317B
Best Supportive Carewithout chemotherapy
18
Summary of Efficacy Results – TAX 317
Doc100 (n=49)
Doc75 (n=55)
BSC (n=49)
Partial Response 6% 6% —
TTPD — 2.8 mo 1.6 mo
Median Survival 5.9 mo 7.5 mo 4.6 mo
Log-rank p-value 0.780 0.010* —
One-Year Survival 19% 37% 12%
* 44% reduction in risk of death compared to BSC
19
Median 7.5 mo vs. 4.6 moLog-rank p = 0.010
1-year 37% vs. 12%Chi-square p = 0.003
Doc75 (n=55)
BSC75 (n=49)
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
0
3 6 9 12 15 18 21
Survival Time (months)
Cu
mu
lati
ve P
rob
abili
ty
Survival – TAX 317BDocetaxel 75mg/m2 vs BSC
20
TAX 317B Updated Survival (Number of Prior Regimens)
21
Study Design – TAX 320
RANDOMIZE
NSCLC Stratified by:
Best response to last platinum
(PD vs. non-PD)
ECOG PS (0,1 vs. 2)
10 Objective:
survival
Prior Paclitaxel allowed
Docetaxel 100 mg/m² iv q 3wksPremedication: Dexamethasone 8 mg x 5
doses, beginning 12 hours before docetaxel
Docetaxel 75 mg/m² iv q 3wksPremedication: Dexamethasone 8 mg x 5
doses, beginning 12 hours before docetaxel
Vinorelbine 30 mg/m² iv Days 1, 8, 15 q 3wks
- or - Ifosfamide 2 gm/m² iv (+ Mesna)
Days 1, 2, 3 q 3wks
Response assessment every 2 cycles
22
Summary of Efficacy Results – TAX 320
Doc100 (n=124)
Doc75 (n=124)
V/I (n=122)
Partial Response 11% 7% 1%
TTPD 1.9 mo 2.0 mo 1.8 mo
Median Survival 5.5 mo 5.7 mo* 5.6 mo
One-Year Survival 21% 32%** 19%
* Log-rank p=0.13
** Chi square p=0.05
23
Cu
mu
lati
ve P
rob
abili
ty
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
Survival Time (Mo)0 3 6 9 12 15 18 21
Doc100Doc75V/I
Doc75 vs. V / ILog-rank Test p= 0.121-Year 32% vs 19%
(p = 0.05, Chi-square)
Doc100 vs. V / ILog-rank Test p= 0.131-Year 21% vs 19%
Overall Survival – TAX 320
24
Docetaxel Toxicities (75 mg/m2) Regardless of Causality (per Label)*
Toxicity Any Grade 3/4
Neutropenia 84.1 65.3
Febrile Neutropenia n/a 6.3**
Infection 33.5 10.2
Diarrhea 22.7 2.8
Neurosensory 23.3 1.7
Alopecia 56.3 n/a
* Data combined from TAX 317 and TAX 320
** Grade 4 neutropenia with fever >38°C with iv antibiotics or hospitalizationn/a = Not Applicable
25
Opioid Analgesic Use – TAX 317BChange from Baseline
p=ns p<0.001 p<0.001
20%
13%
5%
49%
35%
18%
0%
10%
20%
30%
40%
50%
60%
Ongoing atBaseline
Additional Opioid Analgesic
Newly-started Opioid Analgesic
Per
cen
tag
e o
f P
atie
nts
Doc75BSC75
26
Weight Loss During TreatmentPercent of Patients with Weight Loss > 10%
5 %
8 %
0%
5%
10%
15%
20%
25%
T75 V/I
TAX 317B TAX 320
2 %
25 %
0%
5%
10%
15%
20%
25%
T75 BSC75
p<0.001 p=ns
27
Performance Status Evaluation
Performance Status (ECOG)
Cycle 1
Cycle 2
Cycle 3
Mean Across Cycles 1-3Last Assessment
TAX 317B TAX 320
Better forBSC75
Better forDoc75
Better forV/I
Better forDoc75
-1.0 -0.8 -0.6 -0.4 -0.2 0.0 0.2 0.4 0.6 0.8 1.0 -0.6 -0.5 -0.4 -0.3 -0.2 -0.1 0.0 0.1 0.2 0.3 0.4 0.5 0.6
28
Showed that 2nd-line chemotherapy could prolong survival in NSCLC
Showed that 2nd-line chemotherapy could improve performance status and symptom control in NSCLC
Showed that 2nd-line chemotherapy did not have a negative impact on QoL in NSCLC
Led to the approval of docetaxel 75 mg/m2 for the 2nd-line treatment of NSCLC in 1999
These Landmark Trials …
29
Current ASCO Guidelines for NSCLC
“Docetaxel is recommended as 2nd-line therapy for patients with advanced or metastatic NSCLC with adequate performance status who have progressed on 1st-line platinum-based therapy.”*
* ASCO Treatment of Unresectable NSCLC Guideline. JCO 22-: 330-353, 2004
30
Current Second-Line Treatment of NSCLC
Patients benefit from treatment with docetaxel
Safer or more effective alternatives to docetaxel are needed
Unmet medical need
– Performance status and toxicity of 1st-line therapy may preclude docetaxel use
– Increased use of 1st-line docetaxel
No other approved options
There is a need for additional options in second-line treatment of NSCLC
31
Roy Herbst, MD, PhDChief and Associate Professor, Thoracic Oncology, University of Texas
M. D. Anderson Cancer Center
Alimta Development
32
NHO
HO2CCO2H
NHN
NH
O
NH2
Alimta (Pemetrexed)Chemical Structure
N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-
pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-L-
glutamic acid
Alimta (Pemetrexed)
Folic Acid
N
NNH
N
NHO
NH2
NH
O CO2H
CO2H
33
GARFT RNA & DNA Synthesis
AMP
GMP
DHFRTS
DNA Synthesis
IMPPRPP + Gln
10-CHO-FH4
5, 10-CH2-FH4
FH4dUMP
FH2
dTMP
Cel
lM
emb
ran
e
Alimta-Glun
Alimta
FPGS
Folate Carriers (mainly
RFC)
Alimta
Alimta Mechanism of Action
34
Alimta Preclinical Results in Non Small Cell Lung Cancer
Tumor Graft DoseIn vivo %
Tumor Inhibition
LX-1 Lung 300100
7562
Tumor Cell Lines In vitroIC50 (nM)
NSCLC LX-1 4NSCLC H460 60NSCLC H23 50NSCLC A549 156
35
First-Line NSCLC Monotherapy – Alimta and Docetaxel Efficacy
N Evaluable RegimenDose
(mg/m2)Response Rate (%)
Median Survival
Fossella 41 Docetaxel 100 33 10.8 mo
Gandara 80 Docetaxel 100 16 7.0 mo
Alexopoulos 60 Docetaxel 100 25 7.4 mo
Miller 20 Docetaxel 75 25 NR
Roszkowski* 137 Docetaxel 100 13 6.0 mo
Clarke1 57 Alimta 600 16 7.2 mo
Rusthoven1** 30 Alimta 500 23 9.2 mo
* Phase III study ** Dosage amended from 600 mg/m2 due to toxicity1 No Vitamin Supplementation
36
First-Line NSCLC Combination – Alimta Phase II Studies
Manegold et al. (2000)*
Shepherd et al. (2001)*
Scagliottiet al. (2003)
Koshy et al. (2003)
N 36 29 39 50
Alimta (mg/m2)
Combination (d1 q21d)
500
Cisplatin75 mg/m2
500
Cisplatin 75 mg/m2
500
CarboplatinAUC 6
500
CarboplatinAUC 6
Response Rate
Median Survival
1-Year Survival
Median TTPD
39%
10.9 mo
50%
6.3 mo
45%
8.9 mo
49%
NR
31.6%
10.5 mo
NR
5.7 mo
29%
13.5 mo
55.8%
4.8 mo
* Before vitamin supplementation
37
Second-Line NSCLC Monotherapy –Alimta Phase II Study (N=79)
Smit et al. (2003)*
100%
66%
Relapsed < 3 mo
Relapsed < 1 mo
Response Rate
Median Survival
1-Year Survival
Median TTPD
8.9%
5.7 mo
23%
2.0 mo
* Before vitamin supplementation
38
Alimta Safety Profile
As with most antifolates, the primary toxicity is hematologic
Early data showed that high serum homocysteine levels – a surrogate for functional folate and/or B12
deficiency – correlated with higher levels of toxicity
A decision was made to supplement all patients with folic acid and vitamin B12
This resulted in decreased toxicity with no detrimental effect on efficacy
39
0
20
40% Without FA/B12 (N=246)
With FA/B12 (N=220)
Or
G3/
4 Non
hem
Tox
Toxicity in Patients With and Without FA/ Vitamin B12 Supplementation
P=<0.0001
P =<0.0001
P =0.0053 P =0.026
* No toxic death reported
*
40
Summary of the Development of Alimta
Alimta has shown activity in NSCLC
– Single agent 1st and 2nd-line
– Combination with platinum agents in 1st-line
Safety of Alimta has been well characterized
– Toxicity significantly reduced after Folic Acid / B12
– Very low incidence of neutropenia, febrile neutropenia, and other non-hematologic toxicities
A pivotal Phase III study in the treatment of 2nd-line NSCLC was indicated
41
Pivotal Study JMEI
Randomized Phase III Study of Alimta vs Docetaxel in Patients with Locally
Advanced or Metastatic NSCLC Previously Treated with Chemotherapy
Paul A. Bunn, Jr., MD Grohne/Stapp Professor & Director, University of Colorado Cancer Center Executive Director, International Association for the Study of Lung Cancer
42
Study Design
Patient Characteristics
Survival
Survival Analysis
– Alimta vs docetaxel
– Alimta vs historical BSC
Other Secondary Endpoints
Toxicity
Conclusion
Outline of Presentation
43
Alimta (N=283) 500 mg/m2 iv q3wks
(folic acid 350-1000 µg daily + vitamin B12 1000 µg q 9wks;
dexamethasone 4 mg bid on d-1, d0, d+1)
Balanced for:
ECOG PS 0/1 vs 2
Stage III vs IV
No. of prior regimens (1 or 2)
Best response to prior chemo
Time since last chemo
(< or > 3 mo)
Prior platinum Prior taxane
Homocysteine level (< or > 12 µm)
Center
Phase III Study of Alimta vs Docetaxel in 2nd-Line NSCLC
RANDOMIZE
Docetaxel (N=288)75 mg/m2 iv q3wks
(dexamethasone 8 mg bid on d-1, d0, d+1)
44
Primary Endpoint:
– Overall Survival HR
Major Secondary Endpoints:
– Progression-Free Survival
– Time to Progressive Disease
– Tumor Response Rate
– Toxicity
– Lung Cancer Symptom Scale
JMEI: Endpoints
45
Definition of Populations
Intent to treat (ITT): All randomized patients,
regardless of therapy. Primarily used for
efficacy analyses.
Randomized and Treated (RT): All randomized
patients who received at least one dose of
chemotherapy. Primarily used for safety
analyses.
46
Inclusion Criteria– Histologic/cytologic Stage III or IV NSCLC
– Only 1 regimen for metastatic disease
– ECOG PS 0-2
– Adequate end organ function
Exclusion Criteria– Symptomatic brain metastasis
– Grade 3 or 4 peripheral neuropathy
– Weight loss > 10% over previous 6 weeks
– Uncontrolled pleural effusions
– Prior docetaxel therapy
JMEI: Inclusion/Exclusion Criteria
47
JMEI: Baseline Characteristics (ITT)
Percent of PatientsAlimta
(N=283)Docetaxel(N=288)
ECOG PS 2 11.4% 12.4%
Stage IV 74.9% 74.7%
Median Age, years (range)
Male
59 (22-81)
68.6%
57 (28-87)
75.3%
HistologyAdenocarcinomaSquamous
54.4%27.6%
49.3%32.3%
Homocysteine levels <12 μm 71.4% 68.9%
48
JMEI: Baseline Characteristics (ITT)
Percent of PatientsAlimta
(N=283)Docetaxel(N=288)
Best Response to Prior ChemoCR/PR 35.6% 36.5%
< 3 mo since Last Chemo 50.4% 48.1%
Prior Taxane 25.8% 27.8%
Prior Platinum 92.6% 89.9%
49
JMEI: Treatment Delivered (RT)
Alimta(N=265)
Docetaxel(N=276)
No Treatment Delivered (ITT-RT) 18 12
Patients Received > 4 Cycles 136 139
No. Cycles, Median (range) 4 (1-20) 4 (1-14)
Planned Dose Intensity 96.6% 94.4%
Dose Delays 19.8% 17.8%
Dose Reductions* 1.2% 5.6%
* p<0.001
50
MST 8.3 mo1-yr OS: 29.7%
MST 7.9 mo1-yr OS: 29.7%
MST = median survival time * Test of superiority and 10% non-inferiority not statistically significant
JMEI: Survival (ITT)
0 181512963 21
1.00
0.75
0.50
0.25
0.00
Su
rviv
al D
istr
ibu
tio
n
Months
HR 0.99
95% CI of HR (0.82, 1.20*)
Alimta (N=283)
Docetaxel (N=288)
51
Interpreting the Efficacy of Alimta Relative to BSC
Retention method was used to estimate the percent of
docetaxel benefit over BSC retained by Alimta
– 95% CI for %-retention pre-specified in the Analysis Plan
– Based on TAX 317B (75 mg/m2 docetaxel randomized vs BSC)
– Accounts for variability (sample size) in TAX 317B and JMEI
– Allows for a survival comparison of Alimta to historical BSC
– Assumes a reasonable comparability of TAX 317B and JMEI
52
Patient Demographics for TAX 317 and JMEI
TAX 317 Data (N=204)
JMEI (N=571)
Performance status (2) 15% 12%
Stage IV 79% 75%
Median Age, years 61 58
Male 67% 72%
Best response to prior chemo (other than CR/PR)
65% 64%
Prior taxane 0% 27%
Prior platinum 100% 91%
Number of prior chemo (2) 25% 6%
53
JMEI Docetaxel (N=288) 1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
0
3 6 9 12 15 18 21
Survival Time (months)
Cu
mu
lati
ve P
rob
abili
ty
TAX 317 Docetaxel (N=55)
JMEI: Survival with TAX 317 (ITT)
HR (Alimta vs BSC) 0.55
95% CI: 0.33, 0.90
p-value= 0.019
JMEI Alimta (N=276)
TAX 317B BSC
(N=49)
54
JMEI: Overall Survival
* Percent retention based on TAX 317 (B) results
JMEI 95% CI
0%
0.70 1.400.82
157% 52%
Alimta superior to BSC*
1.33
1.20
102%Percent Retention*
Hazard Ratio
Alimta vs docetaxel
78%
1.11
Alimta within 10% margin of docetaxel
Alimta retains >50% of docetaxel benefit*
1.211.00
Alimta superior to docetaxel
0.99
55
JMEI: Overall Survival
ITT Population RT Population
Alimta(N=283)
Docetaxel (N=288)
Alimta (N=265)
Docetaxel (N=276)
Events 206 203 192 198
NI p-value for testing 50% retention
0.047 0.036
95% CI of estimated percent of efficacy retained by Alimta
(52%, 157%) (58%, 168%)
50% retention non-inferiority test based on point estimate of control effect (HR docetaxel/BSC = 0.555)
56
Stage of disease (III vs IV)
Performances status (0 or 1 vs 2)
Time since last chemotherapy ( 3 vs 3 mo)
Best response to prior chemotherapy (CR/PR vs SD vs PD/unknown)
Prior taxane use (Yes vs No)
Prior platinum use (Yes vs No)
Prior chemotherapies (1 vs 2)
JMEI: Stepwise Cox Multiple Regression Survival Model
57
Variable p-value HR
(95% CI for HR)
Performance Status (0 – 1 over 2)
< 0.001 0.25 (0.19, 0.34)
Time since last chemotherapy ( 3 mo over 3 mo)
0.004 0.74 (0.60, 0.90)
Stage of Disease (III over IV) 0.026 0.77 (0.60, 0.97)
Cox Multiple Regression Model
JMEI: Factors Predictive of Survival
58
JMEI: Adjusted Overall Survival (ITT)
0.70 1.400.76
JMEI 95% CI
Hazard Ratio 0.93
Alimta within 10% margin of docetaxel
3.6 days1.11
1.13
HR 0.93
95% CI of HR (0.76, 1.13)
p-value vs 1.11 = 0.051
59
JMEI: Survival Analyses for Key Subgroups
N Evaluable HRAdjusted
HR Prior Platinum 521 1.03 0.95 No Prior Platinum 50 0. 74 0.91
No Prior Taxane Prior Taxane
418153
1.030.97
0.970.84
Performance Status 0 or 1 474 1.00 0.99 Performance Status 2 64 0.75 0.73
Stage III 144 1.01 1.11 Stage IV 427 0.99 0.89
< 3 mo since last chemo 277 1.06 0.97 > 3 mo since last chemo 286 0.92 0.90
No treatment differences within subgroups
60
Primary Endpoint:
– Overall Survival HR
Major Secondary Endpoints:
– Progression-Free Survival (PFS)
– Time to Progressive Disease (TTPD)
– Tumor Response Rate
– Toxicity
– Lung Cancer Symptom Scale
JMEI: Endpoints
61MPFS = median progression-free survival
JMEI: Progression-Free Survival (ITT)
HR 0.97
95% CI of HR (0.82, 1.16)
MPFS = 2.9 mo
MPFS = 2.9 mo
0 181512963 21
1.00
0.75
0.50
0.25
0.00
Su
rviv
al D
istr
ibu
tio
n
Months
Alimta (N=283)
Docetaxel (N=288)
62
JMEI: Time to Disease Progression (ITT)
1.00
0.75
0.50
0.25
0.00
Su
rviv
al D
istr
ibu
tio
n F
acto
r
0 181512963 21
Alimta (N=283)
Docetaxel (N=288)
Months
MTTPD = 3.4 mo
MTTPD = 3.5 mo
HR 0.97
95% CI of HR (0.80, 1.17)
MTTPD = median time to disease progression
63
Type
No. of Patients in Each Arm (%)
Alimta (N=265)
Docetaxel (N=276)
1 Chemotherapy 126 (47.5) 107 (38.8)Platinum 9 (3.4) 15 (5.4)Docetaxel 85 (32.1) 11 (4.0)Paclitaxel 4 (1.5) 3 (1.1)Vinorelbine 6 (2.3) 25 (9.1)Gemcitabine 17 (6.4) 32 (11.6)Other chemo 22 (8.4) 34 (12.3)Gefitinib 5 (1.9) 21 (7.6)
JMEI: Post Study Chemotherapy Received (RT)
64
JMEI: Survival by Post Study Chemotherapy Group (RT)
Patient PopulationAlimta
(N=265) MSDocetaxel (N=276) MS
No post-study chemo 139 6.2 mo 169 5.0 mo
Any post-study chemo 126 9.8 mo 107 10.8 mo
Post-study docetaxel therapy
85 9.6 mo 11 10.1 mo
Other chemotherapy 41 10.6 mo 96 11.2 mo
65
JMEI: Post Progression Survival
Alimta (N=213)
Docetaxel (N=208)
HR 1.01
95% CI of HR (0.81, 1.27)MST 4.5 mo
MST 4.5 mo
Surv
ival
Dis
tribu
tion
Func
tion
0.00
0.25
0.50
0.75
1.00
Post Progression Survival
0.0 2.5 5.0 7.5 10.0 12.5 15.0 17.5 20.0
STRATA: trt_01=Docetaxel trt_01=LY231514
1.00
0.75
0.50
0.25
0.00
Su
rviv
al D
istr
ibu
tio
n F
acto
r
0 1512.5107.552.5 17.5 20
Post Progression Survival
66
JMEI: Response Rates
0
10
20
30
40
50
9.1% (CI 5.9, 13.2) 8.8%
(CI 5.7, 12.8)
45.8%(CI 39.7, 52.1)
46.4%(CI 40.3, 52.5)
Complete and partial response
Stable Disease
Alimta (n=264)
Docetaxel (n=274)
67
Statistically Significant Grade 3/4 CTCToxicities Regardless of Causality (RT)
Percent of Patients
Toxicity Alimta
(N=265)Docetaxel(N=276) p-value
Febrile Neutropenia 1.9 12.7 <0.001
Neutropenia 5.3 40.2 <0.001
Infect w Gr 3/4 Neutropenia
0 5.8 <0.001
Diarrhea 0.4 4.0 0.006
Alopecia (all grades) 11.3 42.4 <0.001
ALT 2.6 0.4 0.034
68
Benefit of Alimta in Second-Line NSCLC
Survival of Alimta compared to docetaxel:
– Overall survival is similar
– Retains 102% of docetaxel benefit (over BSC)
– Internal consistency within subgroups
– No cross-over or other post-study chemotherapy effect
Superior survival to historical BSC
Similar response rate to docetaxel
Similar PFS and TTPD to docetaxel
Superior safety profile to docetaxel
69
Safety Results and Patient Reported Outcomes
Richard J. Gralla, MDPresident, Multinational Association of Supportive
Care in Cancer
JMEI Randomized Trial:Alimta vs Docetaxel in Second-Line
NSCLC
70
Primary Endpoint:
– Survival
Major Secondary Endpoints:
– Progression-Free Survival
– Time to Progressive Disease
– Tumor Response Rate
– Toxicity
– Lung Cancer Symptom Scale
JMEI: Endpoints
71
Patient Reported Outcomes:Evaluation Methods in the JMEI Trial
Lung Cancer Symptom Scale (LCSS)
– Well validated with published psychometrics *
– Patient (9 items) & Observer (6 items) forms– Developed for clinical trials and patient management– Used in many randomized, multicenter trials in lung cancer
Evaluation
– Patients completed the instrument weekly while on trial
– 85% of patients adequately completed the PRO evaluation
* Reference: Hollen et al Cancer, 1994.
72
Maximum Symptom Improvement from Baseline for Patients with CR/PR vs SD vs PD
-5
0
5
10
15
20
25A
no
rex
ia
Fa
tig
ue
Co
ug
h
Dy
sp
ne
a
He
mo
pty
sis
Pa
in
AS
BI
CR/PR (n=42)
SD (n=231)
PD (n=211)
ASBI = Average Symptom Burden Index De Marinis et al, Proc ASCO 2004
73
Maximum Symptom Improvement from Baseline for Patients with CR/PR + SD
0
5
10
15
Anorexia Fatigue Cough Dyspnea Hemoptysis Pain ASBI
Pemetrexed (n=133)Docetaxel (n=140)
All between-arm comparisons were not statistically significant
ASBI = Average Symptom Burden Index De Marinis et al, Proc ASCO 2004
74
Primary Endpoint:
– Survival
Major Secondary Endpoints:
– Progression-Free Survival
– Time to Progressive Disease
– Tumor Response Rate
– Toxicity
– Lung Cancer Symptom Scale
JMEI: Endpoints
75
Docetaxel Toxicities (75 mg/m2) Regardless of Causality (per Label)*
Toxicity Any Grade 3/4
Neutropenia 84.1 65.3
Febrile Neutropenia - 6.3**
Infection 33.5 10.2
Asthenia 52.8 18.2
Nausea 33.5 5.1
Vomiting 21.6 2.8
Stomatitis 26.1 1.7
Diarrhea 22.7 2.8
Neurosensory 23.3 1.7
Hypersensitivity 5.7 2.8
Fluid Retention 35.5 2.8
Rash 19.9 0.6
Alopecia 56.3 -
* Data combined from TAX 317 and TAX 320
** ANC Grade 4 with fever >38°C with iv antibiotics and/or hospitalization
76
Percent of Patients
EventAlimta
(N=265)Docetaxel(N=276) p-value
On-study deaths*: Regardless of causality Drug-related
11.71.1
14.5 1.8
NS NS
Patients with 1 or more SAE: Regardless of causality Drug-related
37.410.2
43.523.9
NS<0.001
Patients with 1 or more TEAE: Regardless of causality Drug-related
97.778.1
98.685.9
NS0.025
JMEI: Adverse Events (RT)
* On-study or within 30 days of discontinuation
77
JMEI: Summary of Deaths
On-Study*Deaths Alimta Docetaxel p-value
Study drug related 3 5 0.725
Study disease related 18 26 0.276
Other 10 9 0.818
Total 31 40 0.374
Number of patients
* On-study or within 30 days of discontinuation
78
JMEI: Adverse Events (RT) NCI Common Toxicity Criteria v2 – Example: Neutropenia
Neutrophils/mm3 Risk / Impact
Grade 1 > 1500 < 2000 None
Grade 2 > 1000 < 1500 Very Low
Grade 3 > 500 – 1000 Moderate
Grade 4 < 500 Very High
79
Percent of Patients
Toxicity Alimta
(N=265)Docetaxel(N=276) p-value
Neutropenia 5.3 40.2 <0.001Febrile Neutropenia
1.9 12.7 <0.001
Infection with Gr 3/4 Neutropenia
0 5.8 <0.001
AnemiaThrombocytopeniaCreatinineALTAST
7.5 1.90.0
2.6 1.1
6.20.70.0
0.4 0.4
0.6100.277
1.0 0.034 0.364
Bilirubin 0.8 0.0 —
JMEI: Grade 3/4 Lab Toxicities (NCI-CTC) Regardless of Drug Causality (RT)
80
Percent of Patients
ToxicityAlimta
(N=265) Docetaxel
(N=276) p-value
Fatigue 15.8
16.7 0.817
Nausea 3.8
2.5 0.466
Vomiting 1.5 1.4 1.0Stomatitis 1.1 1.1 1.0Diarrhea 0.4 4.0 0.006Neurosensory 7.5 9.8 0.365Hypersensitivity 0.0 1.8 0.062Fluid Retention 0.4 0.4 1.0Rash 0.0 0.0 1.0Alopecia (all grades) 11.3 42.4 <0.001
JMEI: Gr 3/4 Non-Lab Toxicities (NCI-CTC) Regardless of Drug Causality (RT)
81
Percent of Patients
ToxicityAlimta (N=265)
Docetaxel (N=276) p-value
All Grade 1 26 23.9 0.620
All Grade 2 29.4 25.0 0.288
All Grade 3 18.1 30.4 <0.001
All Grade 4 5.3 34.1 <0.001
JMEI: Lab Toxicities (NCI-CTC) Regardless of Drug Causality (RT)
82
JMEI: Transfusions and Growth Factors (RT)
Percent of Patients
Alimta (N=265)
Docetaxel (N=276) p-value
Red Blood Cell Transfusions
16.6 11.6 0.108
Erythropoietin 6.8 10.1 0.169
G-CSF/GM-CSF 2.6 19.2 <0.001
83
Percent of Patients
ToxicityAlimta
(N=265)Docetaxel(N=276) p-value
All Grade 1 95.1 92.0 0.165
All Grade 2 93.6 93.8 >0.999
All Grade 3 60.0 68.1 0.060
All Grade 4 14.3 22.5 0.020
JMEI: Non-Lab Toxicities Regardless of Drug Causality (RT)
84
JMEI: Hospitalizations (RT)
Percent of Patients
Alimta (N=265)
Docetaxel (N=276) p-value
Any Hospitalizations 48.7 52.9 0.345
>1 Hospitalization due to AE 31.7 40.6 0.032
All drug-related hospitalization
Any drug-related hospitalization
Due to febrile neutropenia
7.2
1.5
21.7
13.4
<0.001
<0.001
Due to other drug-related AEs 6.4 10.5 0.092
85
Toxicity-Free (Any Grade 4) Survival Curve
Su
rviv
al D
istr
ibu
tio
n F
un
ctio
n
0.00
0.25
0.50
0.75
1.00
Toxicity Free Survival Time (Months)
0.0 2.5 5.0 7.5 10.0 12.5 15.0 17.5 20.0 22.5
Alimta (n=265)
Docetaxel (n=276)
MTFS 7.5 months; 1yr TFS 27.8%
MTFS 2.3 months; 1 yr TFS 16.0%
HR 0.5795% CI of HR (0.47, 0.69)
86
JMEI: Safety Conclusions
From a safety standpoint, Alimta represents a superior treatment option in the second line treatment of NSCLC
— Significantly less neutropenia and febrile neutropenia*
— Significantly less alopecia and diarrhea*
— Significantly fewer drug-related serious adverse events*
— Fewer on-study deaths
— Significantly fewer hospitalizations due to adverse events
— Less use of supportive care
* p < 0.006
87
Overall Conclusions
Paul A. Bunn, Jr., MD
Grohne/Stapp Prof. & Director, University of Colorado Cancer Center Exec. Director, International Association for the Study of Lung Cancer
88
Treatment Options in Second-Line NSCLC
Alimta provides a safe and effective 2nd-line option for NSCLC patients and this
is especially important because:
Advanced stage NSCLC patients are living longer and better lives, therefore more receive 2nd-line therapy
Docetaxel is the only approved compound for 2nd-line NSCLC
Docetaxel safety profile limits its use in 2nd-line
89
Evidence for Clinical Benefit of Alimta in 2nd-Line NSCLC (RT): Safety
Alimta(N=265)
Docetaxel(N=276)
Febrile Neutropenia 1.9% 12.7%
G-CSF/GM-CSF 2.6% 19.2%
Grade 3/4 Diarrhea 0.4% 4.0%
Alopecia (all grades) 11.3% 42.4%
Drug-induced AE hospitalization
7.2% 21.7%
Alimta is safer with respect to clinically important toxicities
90
Toxicity Comparison of Safety Database for Single
Agent Alimta* Regardless of Drug Causality
Other Alimta SA** (N=207)
JMEI(N=265)
Gr. 3/4 Neutropenia 14.0 5.3
Febrile Neutropenia 1.8 1.9
Gr. 3/4 Platelets 3.7 1.9
Gr. 3/4 Anemia 2.4 7.5
Alopecia (any grade) 11.6 11.3
Gr. 3/4 Diarrhea 3.0 0.4
Toxic Deaths 0 1.1
* With vitamin supplementation
** Single Agent
91
Direct Comparison to Docetaxel
– HR=0.99 (0.93 adjusted)
– Median Survival (8.3 mo vs 7.9 mo)
– One-Year Survival (29.7% vs 29.7%)
– Internal consistency of subgroups
Indirect Comparison to BSC
– Preserves at least 50% of docetaxel’s benefit over BSC
– Superior to historical BSC
– Consistent Alimta survival results across 1st and 2nd line trials
Evidence for Clinical Benefit of Alimta in 2nd Line NSCLC: Survival
92
Evidence for Clinical Benefit of Alimta in 2nd Line NSCLC: Response, TTP
Direct Comparison vs. docetaxel Time to Tumor Progression (3.4 mo vs 3.5 mo) Progression-Free Survival (2.9 mo vs 2.9 mo) Response Rate (9.1% vs 8.8%) Over 50% of Alimta and docetaxel patients had improved
or stable symptoms
Indirect Comparison to BSC Comparable Overall response rates and median time to
progression between Alimta trials Superior response rates and TTPD
93
Consistency of Survival Results in Randomized Studies in 2nd-Line NSCLC
0
8
Me
dia
n S
urv
iva
l (m
o)
Do
c 7
5 m
g/m
2
Do
c 7
5 m
g/m
2
Do
c 7
5 m
q 2
1d
Do
c 75
mg
/m2
Do
c 7
5 m
q 2
1d
Do
c 3
3.3m
w
Do
c 3
6m
w
Vin
/Ifo
s
Ali
mta
50
0 m
g/m
2 q
21
d
TAX 317BN=104
TAX 320N=248
GridelliN=220
CampsN=254
JMEIN=571
JBR21N=364
BS
C
Erl
oti
nib
150
mg
q d
P
lac
eb
o a
nd
BS
C
Alimta produces survival equivalent to the best docetaxel results and superior to BSC
4
2
6
94
Alimta Clinical Benefit
Alimta merits full approval as a single agent for the treatment of patients with locally advanced or metastatic NSCLC after prior chemotherapy based on:
– Superior PFS and survival compared to BSC
– Similar OR, PFS and survival compared to docetaxel
– Superior safety profile as compared with docetaxel.
Making available a safer effective treatment will improve the physicians’ ability to make treatment decisions for patients with this devastating disease.
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