INNOVAZIONI TERAPEUTICHE IN ONCOLOGIA MEDICA CAGLIARI …

1

INNOVAZIONI TERAPEUTICHE IN ONCOLOGIA MEDICACAGLIARI 23-24 GIUGNO 2005Policlinico Universitario - Cagliari

MULTI TARGETED ANTIFOLATE

Elena MassaCATTEDRA DI ONCOLOGIA MEDICA

UNIVERSITA’ DEGLI STUDI DI CAGLIARI

2

Chemical Structure of ALIMTA (pemetrexed disodium, LY231514)

N-[4-[2-(2-amino-3,4-dihydro-4-oxo-7H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-L-

glutamic acid ALIMTA

HO

Methotrexate

O

N

NNN

NH2

NH2

NN

O

OHOH

N

OHO

OHO

NHN

O N SO

H

LometrexolNHN N

O

NH2

N

OHO

OHO

O

H

H

NH

N N

O

NH2

N

OHO

OH

O

O

H

H

Raltitrexed

NHHN

NHN

NH

NHCOOH

COOH

O

O

NH2

TH-FA

Taylor et al., J Med Chem 35: 4450-4454, 1992

ALIMTA: Key Intracellular Enzyme TargetsALIMTA: Key Intracellular Enzyme Targets

55--FU, FU, RaltitrexedRaltitrexedALIMTA

MethotrexateMethotrexate

dUMPdUMP

1010--CHOCHO--THFTHF DHFDHF

GARGAR

fGARfGARAMP, GMPAMP, GMP

NADPHNADPH5,105,10--CH2CH2--THFTHF

GARFTGARFTGARFT DHFRDHFRDHFR

TSTSTS

dTMPdTMP DNADNA

PRPPPRPP

THFTHF NADP+NADP+

DNA, RNA DNA, RNA TS: thymidylate synthase DHFR: dihydrofolate reductaseGARFT: glycinamide ribonucleotide formyltransferase

4

ALIMTA ALIMTA vsvs Other AntimetabolitesOther Antimetabolites

PURINE SYNTHESISPURINE SYNTHESISPYRIMYDINE SYNTHESISPYRIMYDINE SYNTHESIS

DNA, RNA biosynthesisDNA, RNA biosynthesis

like 5- FU/Leucovorin like Raltitrexedlike 5- FU/Leucovorin like Raltitrexed like Methotrexatelike Methotrexate unlike any other

marketed drugunlike any other marketed drug

ALIMTA inhibits

ALIMTA inhibits

ALIMTA inhibits

DNADNA

TSTS GARFTGARFTDHFRDHFRALIMTA inhibits

ALIMTA inhibits

ALIMTA inhibits

ALIMTA inhibits

5

ALIMTA: Preclinical activityALIMTA: Preclinical activity

5-FUPaclitaxel

RT (concurrent)

GemcitabineCisplatin

CarboplatinOxaliplatinTaxotere

VinorelbineDoxorubicin

CyclophosphamideRT (sequential)

SynergisticSynergistic additive

Additive

Hanauske et al. The Oncologist 2001;6:363-373

6

Toxicity Before and After Addition of FA and BToxicity Before and After Addition of FA and B1212 to to ALIMTA StudiesALIMTA Studies

Death rate

(all studies; n=1169)

1.4%(all studies; n=504)

Any grade 4 hemtoxicity

grade 3/4Nonhem tox

22%(n=394)

11%(n=196)

Follow-up safety data from studies ...

Before FArestoration

After FA restoration

8.3% 1.4%(n=36) (n=148)

4.2%

7

Folic Acid/Vitamin BFolic Acid/Vitamin B12 12 Supplementation RationaleSupplementation Rationale

• Folic acid is a supplement in cereal products in the US to reduce the incidence of neural tube defects.

• Plasma homocysteine concentration is a sensitive marker of folate and vitamin B12 status.

• Plasma homocysteine concentrations are associated with an increased risk of coronary artery disease and cerebral vascular mortality.

• Folic acid supplementation reduces toxicity without affecting efficacy in patients receiving low-dose methotrexate for rheumatoid arthritis and with B12/B6, reduces the rate of coronary restenosis .

8

Vitamin Supplementation InterventionVitamin Supplementation Intervention

Folic Acid: 350 - 1000 µg orally daily beginning 1-2 weeks prior to first dose of ALIMTA and continuing while the patient remains on study

Vitamin B12: 1000 µg im prior to the first dose of ALIMTA and repeated every 3 cycles while the patient remains on study

Bunn, et al. Proc Amer Soc Clin Oncol 76a: (abstr 300) 2001

9

ALIMTA SAFETY SUMMARYALIMTA SAFETY SUMMARY• Folic acid and vitamin B12 supplementation results in a dramatic reduction

in drug-related death.

• Folic acid and vitamin B12 supplementation significantly reduces the number of episodes of grade 4 hematologic or grade 3/4 nonhematologic toxicity associated with ALIMTA.

• The improved safety profile of ALIMTA may be attributed to the decrease in Hcys levels achieved through folic acid and vitamin B12supplementation.

• While folic acid and vitamin B12 supplementation has significantly reduced Hcy levels in all patients, the effect appears to be more pronounced in patients whose baseline Hcys ≥12 µmol.

• Patients with baseline Hcys ≤12 µmol benefit more from the FA and vitamin B12 supplementation.

Bunn P, et al. Proceedings of ASCO 2001: 76a:A300

10

Phase I Trials of ALIMTA SinglePhase I Trials of ALIMTA Single--AgentAgentSchedule Dose MTD DL Effects Responses

(mg/m2)Wkly x 4 q 6 wks

q 3 Wkly

Daily x 5q 3 wks

10-40 40 neuts 2MR

50-700 700 neuts 4PR, 6MR

0.2-4.0 4.0 neuts 2MR

(mg/m2)

600/500 mg/m2 administered as a 10-minute IV infusion once every 21 days schedule taken into Phase II trials

Rinaldi D et al. JCO 13:2842-2850, 1995Rinaldi D et al. Cancer Chemother Pharmacol 44(5):372-380, 1999 McDonald AC et al.Clin Cancer Res 4(3):605-610, 1998

11

Phase I ALIMTA Combination StudiesPhase I ALIMTA Combination Studies

Completed Ongoing

ALIMTA + Paclitaxel

ALIMTA + Docetaxel

ALIMTA + Irinotecan

ALIMTA + Cyclophosphamide

ALIMTA + Radiation

ALIMTA + Epirubicin

*Studies completed prior to folic acid/B12 supplementation

ALIMTA + Cisplatin*

ALIMTA + Carboplatin*

ALIMTA + Oxaliplatin*

ALIMTA + GEMZAR*

ALIMTA + Vinorelbine

ALIMTA®

ACTIVITY IN PLEURAL MESOTHELIOMA

13

ALIMTA in Mesothelioma

ALIMTA vs BSC

ALIMTA Cisplatin vsCisplatin

ALIMTA Sigle agentALIMTA -CarboplatinALIMTA- Cisplatin

Regimen

ongoing

Vogelzang JCO2Phase IIIShin ASCO1Phase II

Huges, JCOThödtmann, JCO2Phase I

StatusNo of trials

14

Phase III, SinglePhase III, Single--Blinded Trial ofBlinded Trial of

ALIMTAALIMTA® ® ((pemetrexedpemetrexed) and ) and CisplatinCisplatinversusversus

CisplatinCisplatin AloneAlone

in in ChemonaiveChemonaive Patients with MalignantPatients with MalignantPleural Pleural MesotheliomaMesothelioma

Nicholas Vogelzang, et al. J Clin Oncol 2003; 21:2636–44

15

Initial Study DesignInitial Study Design

ALIMTA 500 mg/m2 + Cisplatin 75 mg/m2 (n=140)

Statistical Plan

•• Phase III singlePhase III single--blinded trialblinded trial•• Primary endpoint: survivalPrimary endpoint: survival•• 80% power to detect hazard ratio of .6780% power to detect hazard ratio of .67

(based on (based on α α = 0.05 level, two= 0.05 level, two--sided sided logranklogrank test)test)

RANDOMIZE

Stratified by:

•• PS, histology, PS, histology, gender, WBC, gender, WBC, disease disease measurabilitymeasurability

•• baseline baseline homocysteinehomocysteine,

Cisplatin 75 mg/m2 (n=140),

16

Final Study Design

ALIMTA + Cisplatin

Primary endpoint: survivalPrimary endpoint: survival

FinalFinalAnalysisAnalysis

58 pts58 pts

59 pts59 pts

No FA/BNo FA/B1212

CisplatinCisplatin

168 pts168 pts

163 pts163 pts

FA/BFA/B1212

ALIMTA + CisplatinRANDOMIZE

226 pts226 pts

222 pts222 pts

Nicholas Vogelzang, et al. J Clin Oncol 2003; 21:2636–44

17

MST = 12.1 MST = 12.1 mosmos

HRHR 0.770.77LogrankLogrank pp--valuevalue 0.0200.020

MST = 9.3 MST = 9.3 mosmos

ALIMTA + ALIMTA + CisplatinCisplatin (n=226)(n=226)CisplatinCisplatin (n=222)(n=222)

00 55 1010 1515 2020 2525 3030

100100Survival: All Eligible PatientsSurvival: All Eligible Patients

7575

5050

2525

00

% A

live

% A

live

MonthsMonths Method: KaplanMethod: Kaplan--MeierMeier

18

Survival: Fully Supplemented PatientsSurvival: Fully Supplemented Patients

MST = 13.3 MST = 13.3 mosmosMST = 10.0 MST = 10.0 mosmos



100

% A

live

% A

live

5050

2525

00

100

7575

00 55 1010 1515 2020 2525 3030MonthsMonths

19

TTPD: All Eligible PatientsTTPD: All Eligible Patients

Method: KaplanMethod: Kaplan--MeierMeier

% P

rogr

essi

on%

Pro

gres

sion

00 55 1010 1515 2020 2525 3030

100100

7575

5050

2525

00

MonthsMonths

MTPD = 5.7 MTPD = 5.7 mosmos

MTPD = 3.9 MTPD = 3.9 mosmos



20

TTPD: Fully Supplemented PatientsTTPD: Fully Supplemented Patients%

Pro

gres

sion

0 5 10 15 20 25

100

75

50

25

0

Months

MTPD = 6.1 mos

MTPD = 3.9 mos

HR 0.64Logrank p-value 0.008

ALIMTA + Cisplatin (n=168)Cisplatin (n=163)

21

Patient Treated with ALIMTA + Patient Treated with ALIMTA + CisplatinCisplatin

BaselineBaselineBaseline

Visit 4Visit 4Visit 4

22

Tumor Response Rates Tumor Response Rates

50

40

30

20

10

0n=225 n=222

41

17

n=167 n=163

46

20

n=58 n=59

29

8

p <0.001 ALIMTA/Cisp <0.001%

Cis(CI 38-53)

(CI 35-48)p =0.005

(CI 18-43)

(CI 14-27)(CI 12-22)

(CI 3-19)

Partially and no FA/B12FA/B12All Eligible

23

SSelected Grade 3/4 Toxicity (%) elected Grade 3/4 Toxicity (%)

All Patients

4

4

13

2

6

28

4

Alimta/CisNo=226 No=222

Cis

2NeutropeniaNeutropenia

0DiarrheaDiarrhea

0StomatitisStomatitis

4VomitingVomiting

1FebrFebr. . NeutNeut..

0PlateletsPlatelets

2Possible DRD

Alimta/Cis

Possible DRD

NO FA/B12

7

7

21

5

7

41

7No=58

CisNo=59

0

0

0

2

0

0

3

FA/B12

4

3

11

1

5

23

3

Alimta/CisNo=58

CisNo=59

3

0

0

4

1

0

2

24

Lung Function (Vital Capacity) by Treatment ArmLung Function (Vital Capacity) by Treatment Arm

p =0.324

p =0.034ALIMTA/Cis

Cis

p =0.002p =0.002

CycleCycle

VC (L

)

2.55

2.70

2.65

2.60

2.50

2.45

2.400 2 64

25

40

35

30

25

mm

Lung Cancer Symptom Scale: Lung Cancer Symptom Scale: DyspneaDyspnea

p =0.004

p =0.344p =0.476

ALIMTA/Cis

Cis

Worse

Better

Cycle0 2 4 6

26

Conclusions (1)Conclusions (1)

ALIMTA and cisplatin significantly improved survival compared to cisplatin alone

ALIMTA and cisplatin also significantly improved:

• Time to progressive disease• Tumor response rate • Lung function • Subjective indicators of quality of life

27


Following the sequential, non-random addition of folic acid and B12:

• The improved efficacy of ALIMTA and cisplatin over cisplatin was maintained

• There was strong evidence of reduction in toxicity (including drug related deaths)

• Improved efficacy in FA/B12 – supplemented patients may be due to the higher median number of cycles delivered

28


ALIMTA and cisplatin with FA/B12

should now be consideredstandard front-line therapy for patients with

malignant pleural mesothelioma

29

ALIMTA in NSCLCSingle Agent Studies

Two trials in previously untreated patients

Rusthoven et al, (NCIC), J Clin Oncol, 1999Clarke et al, (S.Africa/Australia), Ann Oncol 9:86, 1998

One trial in patients with one previous CT regimen

Postmus et al, Eur J Cancer, 35:249, 1999

No vitamin supplementation administered in these studiesNo vitamin supplementation administered in these studies

30

ALIMTA Single AgentALIMTA Single Agent in NSCLCin NSCLCResponseResponse

PostmusPostmusCDDP n/CDDP

Evaluable 30 51 44 35CR 0 0 0 1PR 7 9 2 4Overall RR 23.3%23.3% 14%14% 5% 14%5% 14%Med Surv 9.2m 7.2m 6.4m 4m

ClarkeClarkeRusthovenRusthoven

Rusthoven et al, (NCIC), J Clin Oncol ,1999Clarke et al, (S.Africa/Australia),Ann Oncol,1998; Data on file, 2001Postmus et al, Eur J Cancer, 35:249, 1999


31

Phase II ALIMTA in NSCLCCombination Studies with Cisplatin

Two Phase II combination trials in untreated NSCLC

Shepherd et al, Cancer, 92(3):595-600, 2001Manegold et al, Ann Oncol, 11(4):435, 2000


32

Phase II ALIMTA + Cisplatin in NSCLCPhase II ALIMTA + Cisplatin in NSCLCStudy DesignStudy Design

Treatment and Eligibility (both trials)

ALIMTA 500 mg/m2Cisplatin 75mg/m2 D1 Q21 daysD1 Q21 days

No prior ChemotherapyStage IIIB/IVPS 0,1 and 2Measurable disease

Manegold, et al. Ann Oncol 11(4):435-40, 2000. Shepherd, et al. Cancer, 92(3):595-600, 2001.

33

Phase II ALIMTA + Cisplatin in NSCLCPhase II ALIMTA + Cisplatin in NSCLCResultsResults

Shepherd ManegoldN° Evaluable 29 36PR 13 14SD 11 17RR 44.8% 38.9%Med Surv 8.9 mo 10.9 mo1-year Surv 49% 50%

No vitamin supplementatNo vitamin supplementation administered in these studieson administered in these studies

Shepherd, et al. Cancer, 92(3):595-600, 2001.Manegold, et al. Ann Oncol 11(4):435-40, 2000.

Randomized Phase III Trial of Randomized Phase III Trial of ALIMTA (ALIMTA (PemetrexedPemetrexed) vs. ) vs. DocetaxelDocetaxel inin

Patients with Locally Advanced or Patients with Locally Advanced or MetastaticMetastaticNSCLC Previously Treated with ChemotherapyNSCLC Previously Treated with Chemotherapy

Nasser Hanna, Frances Shepherd, Rafael Rosell, Jose Pereira, Filippo DeMarinis, Frank Fossella,

Louis Kayitalire, Sofia Paul, Lawrence Einhorn, Paul Bunn

HannaHanna N N etet al JCO 22:1589al JCO 22:1589--1597, 20041597, 2004

35

BackgroundBackground

Lung cancer is the leading cause of cancer-related death worldwide

1st-line chemotherapy offers a modest survival advantage over best supportive care (BSC)

Phase III studies have demonstrated docetaxelimproves 1 year survival by ~10-15% compared to BSC, ifosfamide or vinorelbine in the 2nd-line setting1,2

ALIMTA, a novel multi-targeted antifolate, shows activity as a single-agent in 1st-line and 2nd-line NSCLC

1 Fossella et. al., JCO 18(12):2354-2362, 20002 Shepherd et al., JCO 18(10):2095-2103, 2000

36

A Phase III Study of ALIMTA vs. A Phase III Study of ALIMTA vs. DocetaxelDocetaxel in in 22ndnd--line NSCLCline NSCLC

Primary Endpoint • Survival

Secondary Endpoints• Tumor Response Rate• Progression-free Survival• Toxicity


37

Inclusion/Exclusion CriteriaInclusion/Exclusion CriteriaInclusion

• Histological/cytological NSCLC • Stage III or IV NSCLC• Previously treated with only 1 regimen for metastatic disease• ECOG PS 0-2• Adequate end organ function

Exclusion• Symptomatic brain metastasis• Grade 3 or 4 peripheral neuropathy• Weight loss > 10% over previous 6 weeks• Uncontrolled pleural effusions

38

ALIMTA vs. ALIMTA vs. DocetaxelDocetaxel in 2in 2ndnd--line NSCLCline NSCLC

ALIMTA 500 mg/m2 i.v. q3wks (n=283)(folic acid 350-1,000 µg daily + vitamin B12 1,000 µg q 9wks; dexamethasone 4mg bid on d-1,d0,d+1)

Stratified by:

• ECOG PS 0/1 vs. 2• Stage III vs. IV• # of prior chemo• Best response to prior

chemo• Time since last chemo • Prior platinum• Prior taxane• Homocysteine level • Center

Docetaxel75 mg/m2 i.v. q3wks (n=288)(dexamethasone 8 mg bid on d-1,d0,d+1)

RANDOMIZED

39

Patient Characteristics (n=571) Patient Characteristics (n=571)

ALIMTA Docetaxel(n=283) (n=288)

Median Age (range) 59 (22-81) 57 (28-87)ECOG PS 0 or 1 (%) 88.3 87.0Stage IV (%) 74.9 74.7Homocysteine levels < 12 (%) 71.4 68.9Histology (%)

Adenocarcinoma 54.4 49.3Squamous 27.6 32.3

Best response to prior chemoCR/PR (%) 35.6 36.5

Time since last chemo< 3 mos 50.4 48.1> 3 mos 49.6 51.9

Prior taxane (%) 25.8 27.8 Prior platinum (%) 92.6 89.9

40

Response RatesResponse Rates

46,445,8

9,1 8,8

05

101520253035404550

CR and PR Stable Disease

Pemetrexed(n=264)

Docetaxel(n=274)

%

[CI=5.9,13.2] [CI=5.7,12.8]

41

ProgressionProgression--Free Survival (ITT)Free Survival (ITT)

0.00

0.25

0.50

0.75

1.00

0.0 2.5 5.0 7.5 10.0 12.5 15.0 17.5 20.0

Months

ALIMTA (n=283)Docetaxel (n=288)

% P

rogr

essi

on

MPFS = 2.9 mos

MPFS = 2.9 mos

ITT = intent to treatHR = hazard ratioCI = confidence intervalMPFS = median progression-free survival

HR 0.9795% CI of HR (0.82, 1.16)

42

Survival (ITT)Survival (ITT)ALIMTA (n=283)

Docetaxel (n=288)

Surv

ival

Dis

trib

utio

n Fu

nctio

n

MonthsITT = intent to treatHR = hazard ratioCI = confidence intervalMST = median survival time

0.00

0.25

0.50

0.75

1.00

0.0 2.5 5.0 7.5 10.0 12.5 15.0 17.5 20.0 22.5

MST 8.3 mos1-yr OS: 29.7%

HR 0.9995% CI of HR (0.82, 1.20)

MST 7.9 mos1-yr OS: 29.7%

43

Nonhematological Toxicities (% Patient)

NS1.115.904.9Neurosensory

NS2.524.30.412.8DiarrheaNS1.117.41.114.7Stomatitis

.02801.41.97.9ALT<.00137.737.76.46.4Alopecia

NS08.304.5EdemaNS01.801.1Weight Loss

RashPulmonary Tox

NS0.78.00.815.9NS1.42.100.8

NS1.112.01.516.2VomitingNS1.816.72.630.9Nausea

Fatigue NS5.435.95.334.0

P value1Grade

3/4Any

gradeGrade

3/4

ALIMTA (n=265)

Docetaxel(n=276)

Any grade

1 = applies to grade 3/4 toxicity only

44

Hematological Toxicities (Grade 3/4 % Patient) Hematological Toxicities (Grade 3/4 % Patient)

ALIMTA Docetaxel(n=265) (n=276) p value

Neutropenia 5.3 40.2 <.001

Febrile Neutropenia 1.9 12.7 <.001

Infection w/ gr 3/4 Neutropenia 0 3.3 .004

Anemia 4.2 4.3 1.00

Thrombocytopenia 2 <1 .116


45

Hospitalizations, Transfusions & Growth Factors Hospitalizations, Transfusions & Growth Factors ALIMTA Docetaxel(n=265) (n=276) p-value

Patients with > 1 hosp 31.7% 40.6% .032due to an adverse event

Total hospitalizations 1.5% 13.4% <.001 due to febrile neutropenia

G-CSF/GM-CSF 2.6% 19.2% <.001

Erythropoietin 6.8% 10.1% .169

Red blood cell 16.6% 11.6% .085Transfusions

46

Summary

• This is the largest phase III study ever reported for treatment in 2nd-line NSCLC

• ALIMTA and docetaxel have similar efficacy:

- response rates

- progression-free survival

- overall survival

47

SummarySummaryALIMTA had a more favorable hematological toxicity profile when compared with docetaxel:

− less severe neutropenia w/without fever and infections

− fewer hospitalizations

− less need for G-CSF/GM-CSF support

ALIMTA is an effective 2nd-line chemotherapy agent in NSCLC

48

Phase III ALIMTA Clinical TrialsPhase III ALIMTA Clinical Trials

ALIMTA + Cisplatin vs. Cisplatin in mesothelioma:−Completed; ALIMTA + Cisplatin showed survival advantage

ALIMTA vs. Docetaxel for 2nd Line NSCLC−Completed; ALIMTA showed equal efficacy but more favorable hematological toxicity profile

ALIMTA + GEMZAR vs. GEMZAR in Pancreatic Cancer−Completed accrual; awaiting data analysis

49

Conclusions IConclusions I

ALIMTA is an unique antifolate that inhibits several different enzymes in the DNA and RNA biosynthesis pathway

ALIMTA has activity in a number of solid tumors: NSCLC, pancreas, breast, colorectal, bladder and mesothelioma

In malignant pleural mesothelioma, a hard to-treat cancer, ALIMTA became the first agent that demonstrated superior survival and this represents a significant advance

In addition to survival benefits, ALIMTA also reduces disease-related symptoms and produces significantly higher objective response rates than the control arm in a phase III study

50

Conclusions IIConclusions II

ALIMTA is an effective 2nd-line chemotherapy agent in NSCLC

ALIMTA had a more favorable hematological toxicity profile when compared with control arm in a phase III study on 2nd line NSCLC

ALIMTA has an easy-to-control toxicity profile; physicians can deliver the planned course of therapy with simple folic acid and vitamin B12 supplementation

The antitumor activity of ALIMTA is retained or enhanced by folic acid and vitamin B12 supplementation

ALIMTA has a simple, brief outpatient administration and can easily be combined with other cytotoxic drugs

INNOVAZIONI TERAPEUTICHE IN ONCOLOGIA MEDICA CAGLIARI …

Documents

Transcript of INNOVAZIONI TERAPEUTICHE IN ONCOLOGIA MEDICA CAGLIARI …