First-Line Chemotherapy in Advanced or Metastatic Non-Small Cell Lung Cancer (NSCLC) - PowerPoint PPT Presentation

Loading...

PPT – First-Line Chemotherapy in Advanced or Metastatic Non-Small Cell Lung Cancer (NSCLC) PowerPoint presentation | free to download - id: 598e7b-MWNlM



Loading


The Adobe Flash plugin is needed to view this content

Get the plugin now

View by Category
About This Presentation
Title:

First-Line Chemotherapy in Advanced or Metastatic Non-Small Cell Lung Cancer (NSCLC)

Description:

First-Line Chemotherapy in Advanced or Metastatic Non-Small Cell Lung Cancer (NSCLC) Thoracic Tumors Lung Cancer Globally, 1.4 million new cases each year1 The ... – PowerPoint PPT presentation

Number of Views:145
Avg rating:3.0/5.0
Slides: 40
Provided by: Patti47
Learn more at: http://www.mednet.co.il
Category:

less

Write a Comment
User Comments (0)
Transcript and Presenter's Notes

Title: First-Line Chemotherapy in Advanced or Metastatic Non-Small Cell Lung Cancer (NSCLC)


1
First-Line Chemotherapy in Advanced or
Metastatic Non-Small Cell Lung Cancer (NSCLC)
2
Thoracic Tumors
  • Lung Cancer
  • Globally, 1.4 million new cases each year1
  • The leading cause of cancer death worldwide1
  • Approximately 80 of lung cancer cases are NSCLC2
  • NSCLC
  • Includes adenocarcinoma, squamous cell carcinoma,
    large cell carcinoma, and bronchoalveolar
    carcinoma histologies3,4
  • Predominant histologic type has shifted from
    squamous cell to adenocarcinoma in past 2
    decades5
  • In advanced or metastatic disease, 5-year
    survival rate is lt56

1Kamangar et al. J Clin Oncol 200624(14)2137-50
. 2Felip et al. Ann Oncol 200516(Suppl
1)i28-i29. 3Travis et al. IARC Press 2004
9-124. 4Travis et al. J Clin Oncol 2005
23(14)3279-87. 5Gabrielson. Respirology
200611533-8. 6 Breathnach et al. J Clin Oncol
200119(6)1734-42.
3
NSCLC Diagnosis and Staging
  • History and Physical Exam
  • Diagnostic tests1
  • Chest x-ray/CT
  • Biopsy (bronchoscopy, transthoracic needle
    biopsy, thoracoscopy, thoracotomy)
  • Histopathology
  • Staging tests1
  • CT chest/abdomen
  • PET scan2
  • Brain MRI2
  • Mediastinoscopy3-6

NSLC, non-small cell lung cancer CT, computed
tomography PET, positron emission tomography
MRI, magnetic resonance imaging
1Ginsberg et al. Lippincott-Raven2001925-81. 2
Pieterman et al. N Engl J Med 2000343(4)254-61.
3Detterbeck et al. Chest 2007 2(3Suppl)202S-220S
4Whiitson et al. Ann Thor Surg
200784(3)1059-65 5De Leyn et al. Eur J
Cardiothorac Surg 200732(1)1-8 6Kim and
Bosquee. J Thor Oncol 20072 Suppl 2259-67.
4
Staging of Lung Cancer Primary Tumor (T)
Primary Tumor (T)1 Primary Tumor (T)1 TNM Staging TNM Staging
T0 No evidence of primary tumor IA T1N0M0
Tis Carcinoma in situ IB IIA T2N0M0 T1N1M0
T1 Tumor 3 cm and not involving the mainstem bronchus IIB T2N1M0 T3N0M0
T2 Any of following Tumor gt3 cm, involves mainstem bronchus 2 cm from carina, invades visceral pleura, associated with lobar atelectasis or obstructive pneumonitis not involving entire lung IIIA T3N1M0
T3 Direct invasion chest wall, diaphragm, mediastinal pleura, pericardium, mainstem bronchus lt2 cm from carina, or associated with atelectasis or obstructive pneumonitis of entire lung IIIB T4N0M0 T4N1M0 T4N2M0
T4 Tumor any side with direct invasion medistinum, heart, great vessels, trachea, esophagus, vertebrae, carina, or satellite nodules in same lobe or associated with malignant effusion T1N3M0 T2N3M0 T3N3M0 T4N3M0
IV Any T Any N M1
TNM T, primary tumor N, regional lymph nodes
M, distant metastasis
1Mountain. Semin Surg Oncol 200018(2)106-15.
5
Staging of Lung Cancer Regional Lymph Nodes (N)
and Distant Metastasis (M)
Regional Lymph Nodes (N)1 Regional Lymph Nodes (N)1 TNM Staging TNM Staging
N0 No regional nodal metastasis IA T1N0M0
N1 Metastasis to ipsilateral peribronchial and/or ipsilateral hilar lymph nodes or intrapulmonary nodes involved, including by direct primary tumor extension IB IIA T2N0M0 T1N1M0
N2 Metastasis to ipsilateral mediastinal and/or subcarinal lymph nodes IIB T2N1M0 T3N0M0
N3 Metastasis to contralateral mediastinal, contralateral hilar, ipsilateral or contralateral scalene or supraclavicular lymph nodes IIIA T3N1M0
Distant Metastasis (M)1 Distant Metastasis (M)1 IIIB T4N0M0 T4N1M0
M0 No distant metastasis T4N2M0 T1N3M0 T2N3M0
M1 Distant metastasis present or metastatic nodules in nonprimary tumor lobe T3N3M0 T4N3M0
IV Any T Any N M1
TNM T, primary tumor N, regional lymph nodes
M, distant metastasis
1Mountain. Semin Surg Oncol 200018(2)106-15.
6
NSCLC Treatment
  • Treatment approach based upon
  • Diagnosis (histologically or cytologically
    confirmed)
  • Prognostic Factors disease stage, gender, PS,
    recent weight loss1-5
  • Other comorbidities
  • Treatment options
  • Surgery, chemotherapy, XRT, other agents,
    supportive care
  • Treatment goals to improve PFS, OS, and QoL
  • Improve PFS and OS
  • Measurable tumor response, by Response Evaluation
    Criteria in Solid Tumors (RECIST)6
  • Prolong time-to-disease progression
  • Use therapy with most favorable toxicity profile
  • Improve QoL7

NSCLC, non-small cell lung cancer PS,
performance status XRT, radiation therapy PFS,
progression-free survival OS, overall survival
QoL, quality of life
1Jiroutek et al. 1998. www.asco.org. 2Brudage et
al. Chest 2002122(3)1037-57. 3Mountain. Semin
Surg Oncol 200018(2)106-15. 4Ginsberg et al.
Lippincott-Raven2001925-81. 5Oken et al. Am J
Clin Oncol 19825(6)649-55. 6Therasse et al. J
Natl Cancer Inst 200092(3)205-16. 7 de Marinis
et al. J Thorac Oncol 20083(1)30-6.
7
Prognostic Factors Influencing Survival in NSCLC
  • Stage of disease at diagnosis1-4
  • Performance status (PS)1,4,5
  • Recent weight loss2,4
  • Gender2,4

1Jiroutek et al. 1998. www.asco.org 2Brudage et
al. Chest 2002122(3)1037-57. 3Mountain. Semin
Surg Oncol 200018(2)106-15. 4Ginsberg et al.
Lippincott-Raven2001925-81. 5Oken et al. Am J
Clin Oncol 19825(6)649-55.
8
Current Treatment for First-Line Advanced and
Metastatic NSCLC
  • Chemotherapy for Stage IIIB-IV
  • Standard first-line therapy Platinum doublet
    combinations using cisplatin or carboplatin1,2
  • Agents studied in combination with cisplatin or
    carboplatin include pemetrexed, gemcitabine,
    paclitaxel, docetaxel, vinorelbine, irinotecan3-7
  • May be administered with radiation for Stage III
    patients1,2
  • Results expected8-10
  • Median survival 7.4 to 9.9 months
  • 1-year survival 31 to 43

1Pfister et al. J Clin Oncol 200422330-53.
2NCCN, 2008. 3Manegold et al. Ann Oncol
200011(4)435-40. 4Shepherd et al. Cancer
200192(3)595-600. 5Scagliotti et al. Clin
Cancer Res 200511(2 Pt 1)690-6. 6Zinner et al.
Cancer 2005104(11)2449-56. 7Sandler et al. J
Clin Oncol 2000 18(1)122-30. 8Schiller et al. N
Engl J Med 2002346(2)92-8. 9Scagliotti et al. J
Clin Oncol 2002204285-91. 10Le Chevalier et al.
Lung Cancer 200547(1)69-80.
9
First-Line Treatment for Advanced and Metastatic
NSCLC-Background
  • In advanced (Stage IIIB or IV) NSCLC, doublet
    combinations of platinum compounds (cisplatin or
    carboplatin) with gemcitabine, vinorelbine, or
    taxanes (paclitaxel or docetaxel) are standard
    treatment1,2
  • When compared, in phase III studies, these
    doublets had comparable efficacy but showed
    differences in toxicity profiles3-6
  • Cis/Gem is an effective, widely-used reference
    regimen for the first-line treatment of advanced
    NSCLC7

Cis/Gem, cisplatin/gemcitabine
1Pfister et al. J Clin Oncol 200422330-53.
2NCCN 2007. 3Schiller et al. N Engl J Med
200234692-8. 4Scagliotti et al. J Clin Oncol
2002204285-91. 5Kelly et al. J Clin Oncol
2001193210-8. 6Fossella et al. J Clin Oncol
2003213016-24. 7Le Chevalier et al. Lung Cancer
200547(1)69-80.
10
Comparison of Four First-Line Doublets
Randomized Phase III Study in NSCLC
Outcomes of Treatment Groups Pac 135 Cis 75 q 21 days Gem 1000 Cis 100 q 28 days Doc 75 Cis 75 q 21 days Carb AUC 6 Pac 225 q 21 days
Sample size (n) 288 288 289 290
Median survival, months 7.8 8.1 7.4 8.1
1-year survival , 31 36 31 34
2-year survival , 10 13 11 11
ORR, 21 22 17 17
All patients were disease stage IIIB or IV
and ECOG performance status 0-2, N1155 No
significant differences found between treatment
arms Units mg/m2 Pac, paclitaxel Cis,
cisplatin Gem, gemcitabine Doc, docetaxel
Carb, carboplatin AUC, area under curve
ORR, overall response rate ECOG, Eastern
Cooperative Oncology Group
Schiller et al. N Engl J Med 200234692-8.
11
Comparison of Three First-Line Doublets
Randomized Phase III Study in NSCLC
Outcomes of Treatment Groups Vin 25 Cis 100 q 7/28 days Gem 1250 Cis 75 q 21 days Carb AUC 6 Pac 225 q 21 days
Sample size (n) 201 205 201
Survival median, months 9.5 9.8 9.9
1-year survival, 37 37 43
ORR, 30 30 32
All patients were disease stage IIIB or IV and
ECOG performance status 0-2, N607 No
significant differences found between treatment
arms units mg/m2 Vin, vinorelbine Cis,
cisplatin Gem, gemcitabine Carb, carboplatin
AUC, area under the curve Pac, paclitaxel
ORRoverall response rate ECOG, Eastern
Cooperative Oncology Group
Scagliotti et al. J Clin Oncol 2002204285-91.
12
Survival Meta-Analysis in NSCLCGem Platinum
vs. Other Platinum Doublets
?
Gemcitabine platinum, N1861 Non-gemcitabine
platinum, N2695
HR 0.90 (0.840.96)plt0.001
4556 patients from 13 randomized trials
95 confidence interval HR, hazard ratio
Le Chevalier et al. Lung Cancer 200547(1)69-80.
13
Pemetrexed Mechanism of Action
  • Compared with other antifolates, pemetrexed has a
    unique pyrrolopyrimidine nucleus and inhibits
    multiple folate-dependent enzymes1
  • Pemetrexed has a high affinity for binding to
    folate receptor-?,2 and once in the cell, it has
    very rapid conversion to active polyglutamate
    derivatives3
  • Polyglutamation prolongs its intracellular
    retention and enhances pemetrexeds interaction
    with thymidylate synthase (TS) and other
    folate-dependent target enzymes1,3-5
  • These multiple mechanisms of action may explain
    how pemetrexed, compared with other
    antimetabolites such as 5-fluorouracil (5-FU),
    methotrexate, or raltitrexed, has shown greater
    potency and a broader spectrum of antitumor
    activity1,6

1Shih et al. Adv Enzyme Regul 199838135-52.
2Zhao et al. Clin Cancer Res 20006(9)3687-95. 3
Chattopadhyay et al. Mol Cancer Ther
20076(2)404-17. 4Mendelsohn et al. Semin Oncol
199926(2 suppl 6)42-7. 5Taylor et al. J Med
Chem 199235(23)4450-4. 6Chen et al. Br J Cancer
199878(Suppl 3)27-34.
14
Pemetrexed Key Intracellular Folate Enzyme
Targets
Pemetrexed
TS
5-FU, raltitrexed
dUMP
dTMP
DNA
5,10-CH2-THF
10-CHO-THF
DHF
NADPH
GARFT
DHFR
PRPP
Methotrexate
THF
NADP
GAR
fGAR
AMP, GMP
DNA, RNA
TS, thymidylate synthase 5-FU, 5-fluorouracil
GARFT, glycinamide ribonucleotide formyl
transferase DHFR, dihydrofolate reductase DNA,
deoxyribonucleic acid RNA, ribonucleic acid
Data from Kindler HL. Cancer 200295928-32.
15
Cis/Pem vs. Cis/Gem in First-Line NSCLC Rationale
  • Cis/Pem is the standard of care for the
    management of MPM and is shown to be a safe
    efficacious combination1
  • Pemetrexed is one of the standards of care for
    second-line treatment of NSCLC with a favorable
    safety profile and a convenient 10-minute
    administration2
  • Phase II studies of pemetrexedplatinum compounds
    have shown activity in advanced NSCLC and a
    favorable safety profile3-6
  • Cis/Gem, in a 3-week schedule, is an effective,
    widely used regimen for first-line treatment of
    NSCLC7,8

Cis/Pem, cisplatin/pemetrexed MPM, malignant
pleural mesothelialoma Cis/Gem,
cisplatin/gemcitabine
1Vogelzang et al. J Clin Oncol 200321(14)2636-44
. 2Hanna et al. J Clin Oncol 200422(9)1589-97.
3Manegold et al. Ann Oncol 200011(4)435-40.
4Shepherd et al. Cancer 200192(3)595-600.
5Scagliotti et al. Clin Cancer Res 200511(2 Pt
1)690-6. 6Zinner et al. Cancer
2005104(11)2449-56. 7Le Chevalier et al. Lung
Cancer 200547(1)69-80. 8Scagliotti et al. J
Clin Oncol 2002204285-91.
16
Cis/Pem vs. Cis/Gem in First-Line NSCLC Study
Design
  • Randomization Factors
  • Stage
  • Performance status
  • (0 vs. 1)
  • Gender
  • Histologic vs. cytologic diagnosis
  • History of brain metastases

Cisplatin 75 mg/m2 day 1 Gemcitabine 1250
mg/m2 days 1 8
Vitamin B12, folate, and dexamethasone given in
both arms
Cis/Pem, cisplatin/pemetrexed Cis/Gem,
cisplatin/gemcitabine
Scagliotti et al. J Clin Oncol
doi10.1200/JCO.2007.15.0375
17
Cis/Pem vs. Cis/Gem in First-Line NSCLC Study
Statistics
  • Noninferiority study design 15 fixed margin1
  • 80 power to reject null hypothesis (H0). H0 is
    that Cis/Gem would provide a ?15 reduction in
    the risk of death over Cis/Pem. HA is alternative
    hypothesis1
  • H0HR (upper 95 CI) ? 1.17647 vs. HA lt1.176472
  • Assuming true HR1.0, 1190 deaths needed
  • Randomize 850 patients per arm, 30 censored
  • Pre- specified analyses randomization factors
    age, ethnicity, smoking status, and histology1

Ho, null hypothesis Cis/Gem, cisplatin/gemcitabin
e Cis/Pem, cisplatin/pemetrexed HA, alterntive
hypothesis HR, hazard ratio CI, confidence
interval
1Scagliotti et al. J Clin Oncol
doi10.1200/JCO.2007.15.0375 2Scagliotti GV et
al, 12th World Conference on Lung Cancer Sept 5,
2007 Seoul, Korea
18
Cis/Pem vs. Cis/Gem in First-Line NSCLC Main
Patient Characteristics (N1725)
Cis/Pem N862 Cis/Gem N863
Median age (range) 61.1 (2983) 61.0 (2679)
Age lt65 years 541 (62.8) 577 (66.9)
Males 605 (70.2) 605 (70.1)
ECOG PS 1 556 (64.5) 554 (64.2)
Never-smokers 128 (14.8) 122 (14.1)
Caucasians 669 (77.6) 680 (78.8)
Cis/Pem, cisplatin/pemetrexed Cis/Gem,
cisplatin/gemcitabine ECOG, Eastern Cooperative
Oncology Group PS, performance status
1Scagliotti et al. J Clin Oncol
doi10.1200/JCO.2007.15.0375 2Scagliotti GV et
al, 12th World Conference on Lung Cancer Sept 5,
2007 Seoul, Korea
19
Cis/Pem vs. Cis/Gem in First-Line NSCLC Main
Disease Characteristics
Cis/Pem N862 Cis/Gem N863
Adenocarcinoma1 Large cell1 Other1 Squamous cell1 436 (50.6) 76 (8.8) 106 (12.3) 244 (28.3) 411 (47.6) 77 (8.9) 146 (16.9) 229 (26.5)
Stage IV1 Stage IIIB1 657 (76.2) 205 (23.8) 653 (75.7) 210 (24.3)
Brain metastases2 17 (2.0) 17 (2.0)
Patients whose histologic diagnosis did not
clearly qualify as adenocarcinoma, large cell, or
squamous cell carcinoma Cis/Pem,
cisplatin/pemetrexed Cis/Gem, cisplatin/gemcitabi
ne
1 Scagliotti et al. J Clin Oncol
doi10.1200/JCO.2007.15.0375 2Scagliotti GV et
al, 12th World Conference on Lung Cancer Sept 5,
2007 Seoul, Korea
20
Cis/Pem vs. Cis/Gem in First-Line NSCLC Drug
Administration
Cis/Pem N839 Cis/Gem N830
Median no. cycles 5.0 5.0
Cycles delayed 315 (8.6) 408 (11.3 )
Doses reduced Cis 64 (1.8) Pem 54 (1.5) Cis 154 (4.2) Gem 362 (10.0)
Gem day-8 omission Not applicable 339 (9.3)
Relative dose intensity Cis 95.0 Pem 94.8 Cis 93.5 Gem 85.8
of total cycles administered Cis/Pem,
cisplatin/pemetrexed Cis/Gem, cisplatin/gemcitabi
ne Cis, cisplatin Pem, pemetrexed Gem,
gemcitabine
Scagliotti et al. J Clin Oncol
doi10.1200/JCO.2007.15.0375
21
Cis/Pem vs. Cis/Gem in First-Line NSCLC Overall
Survival (OS) All Patients
Overall Survival Probability
Overall Survival Time (months) in All Patients
Cis/Pem, cisplatin/pemetrexed Cis/Gem,
cisplatin/gemcitabine CI, confidence interval
HR, hazard ratio mos, months
Scagliotti et al. J Clin Oncol
doi10.1200/JCO.2007.15.0375
22
Cis/Pem vs. Cis/Gem in First-Line NSCLC
Progression-Free Survival (PFS) All Patients
0
6
12
18
24
30
PFS Time (months) in All Patients
PFS, progression-free survival Cis/Pem,
cisplatin/pemetrexed Cis/Gem, cisplatin/gemcitabi
ne CI, confidence interval HR, hazard ratio
mos, months
Scagliotti et al. J Clin Oncol
doi10.1200/JCO.2007.15.0375
23
Cis/Pem vs. Cis/Gem in First-Line NSCLC Response
Rates
Cis/PemN762 Cis/GemN755 Superiority p-value
CR 2 (0.3) 3 (0.4) 0.647
PR 231 (30.3) 210 (27.8) 0.284
SD 314 (41.2) 346 (45.8) 0.070
PD 174 (22.8) 155 (20.5) 0.276
ORR(95 CI) 233 (30.6)(27.3, 33.9) 213 (28.2)(25.0, 31.4) 0.312
Median duration of response (95 CI) 4.5 months (4.27, 5.32) 5.1 months (4.57, 5.52) 0.198
N reflects the tumor-qualified
population Cis/Pem, cisplatin/pemetrexed
Cis/Gem, cisplatin/gemcitabine CR, complete
response PR, partial response SD, stable
disease PD, progressive disease ORR, objective
response rate CI, confidence interval
Scagliotti GV et al, 12th World Conference on
Lung Cancer Sept 5, 2007 Seoul, Korea.
24
Cis/Pem vs. Cis/Gem in First-Line NSCLC
Toxicities and Supportive Care
Cis/Pem N839 Cis/Gem N830 p-value
Hematologic Grade 3/4 Toxicities Hematologic Grade 3/4 Toxicities Hematologic Grade 3/4 Toxicities
Neutropenia 15.1 26.7 lt0.001
Thrombocytopenia 4.1 12.7 lt0.001
Anemia 5.6 9.9 0.001
Leukopenia 4.8 7.6 0.019
Supportive Care Use N862 N863 p-value
Any transfusion 16.4 28.9 lt0.001
Red blood cell transfusion 16.1 27.3 lt0.001
Platelet transfusion 1.8 4.5 0.002
Erythropoietin / darbepoetin use 10.4 18.1 lt0.001
G-CSF/GM-CSF use 3.1 6.1 0.004
Drug-related Grade 3/4 toxicities reported in
at least 3 of patients in at least 1 arm are
listed Supportive Care Use Analyses were
based on an intent-to-treat population (ITT) and
the Ns reflect the ITT groups. G-CSF
granulocyte colony-stimulating factor GM-CSF,
granulocyte macrophage colony stimulating factor
Scagliotti et al. J Clin Oncol
doi10.1200/JCO.2007.15.0375
25
Cis/Pem vs. Cis/Gem in First-Line NSCLC
Nonhematologic Toxicities
CTC Grade 3/4Drug-Related Toxicities Cis/Pem N839 Cis/Gem N830 p-value
Nonhematologic Toxicities Nonhematologic Toxicities Nonhematologic Toxicities Nonhematologic Toxicities
Febrile neutropenia 1.3 3.7 0.002
Grade 3/4 fatigue 6.7 4.9 0.143
Grade 3/4 nausea 7.2 3.9 0.004
Grade 3/4 vomiting 6.1 6.1 1.000
Dehydration (any grade) 3.6 2.0 0.075
Alopecia (any grade) 11.9 21.4 lt0.001
Drug-related grade 3/4 toxicities reported in
at least 3 of patients in at least 1 arm are
listed
  • Deaths attributed to study drug toxicity were low
    and were similar between arms
  • 9 patients (1.0) for Cis/Pem, 6 patients
    (0.7) for Cis/Gem

Cis/Pem, cisplatin/pemetrexed Cis/Gem,
cisplatin/gemcitabine CTC, Common Toxicity
criteria
Scagliotti et al. J Clin Oncol
doi10.1200/JCO.2007.15.0375
26
Cis/Pem vs. Cis/Gem in First-Line NSCLC Overall
Efficacy and Safety Results
  • In the overall study population, the primary
    endpoint of overall survival was successfully
    met
  • Cis/Pem is noninferior to Cis/Gem (HR0.94)
  • All secondary efficacy endpoints comparable
    between regimens
  • Both regimens generally well-tolerated key
    hematologic and nonhematologic toxicities
    significantly lower for Cis/Pem
  • In the Cis/Pem arm, patients required
    significantly less treatment with red blood cell
    and platelet transfusions, erythropoiesis-stimulat
    ing agents, and colony stimulating factors
  • Clinically relevant and significant survival
    differences were observed according to NSCLC
    histology

Cis/Pem, cisplatin/pemetrexed Cis/Gem,
cisplatin/gemcitabine HR, hazard ratio
Scagliotti et al. J Clin Oncol
doi10.1200/JCO.2007.15.0375
27
Cis/Pem vs. Cis/Gem in First-Line NSCLC
Rationale for Pre-specified Histology Analyses
  • Preclinical data indicate that high expression of
    TS correlates with reduced sensitivity to
    pemetrexed1,2
  • In specimens from chemonaive patients with NSCLC,
    TS expression was significantly higher in
    squamous cell carcinoma when compared with
    adenocarcinoma3
  • Retrospective analyses of the large phase III
    study of pemetrexed vs. docetaxel in advanced
    NSCLC showed treatment-by-histology interactions
    for OS and PFS were highly statistically
    significant4
  • These interactions seemed to result from
    differences in the efficacy of pemetrexed between
    nonsquamous and squamous histologic groups4
  • Since efficacy of pemetrexed may differ by
    histologic type, analyses were pre-specified for
    histology and efficacy in the first-line Cis/Pem
    versus Cis/Gem study5

Cis/Pem, cisplatin/pemetrexed Cis/Gem,
cisplatin/gemcitabine TS, thymidylate synthase
OS, overall survival PFS, progression free
survival
1Sigmond et al. Biochem Pharmacol
200366(3)431-8. 2Giovannetti et al. Mol
Pharmacol 200568(1)110-8. 3Ceppi et al. Cancer
2006107(7)1589-96. 4Peterson et al. 12th World
Conference on Lung Cancer. 2007 Seoul, Korea.
5Scagliotti et al. J Clin Oncol
doi10.1200/JCO.2007.15.0375
28
Cis/Pem vs. Cis/Gem in First-Line NSCLCOverall
Survival in Adenocarcinoma or Large Cell
1.0
OS Median (95 CI)
0.9
Cis/Pem (N512) 11.8 mos (10.4, 13.2)
0.8
Cis/Gem (N488) 10.4 mos (9.6, 11.2)
0.7
OS Adjusted HR (95 CI)
0.6
Cis/Pem vs. Cis/Gem 0.81(0.70-0.94)
Cis/Pem statistically superior OS vs. Cis/Gem
0.5
Overall Survival Probability
0.4
0.3
0.2
0.1
0.0
0
6
12
18
24
30
Overall Survival Time (months) in Non-Squamous
Patients
non-squamous patients with adenocarcinoma or
large cell carcinoma
Cis/Pem, cisplatin/pemetrexed Cis/Gem,
cisplatin/gemcitabine CI, confidence interval
HR, hazard ratio mos, months
Scagliotti et al. J Clin Oncol
doi10.1200/JCO.2007.15.0375
29
Cis/Pem vs. Cis/Gem in First-Line NSCLC PFS in
Adenocarcinoma or Large Cell
1.0
PFS Median (95 CI)
0.9
Cis/Pem (N512) 5.3 mos (4.8, 5.7)
0.8
Cis/Gem (N488) 4.7 mos (4.4, 5.4)
0.7
PFS Adjusted HR (95 CI)
0.6
Cis/Pem vs. Cis/Gem 0.90 (0.79-1.02)
0.5
PFS Probability
Cis/Pem statistically noninferior PFS vs. Cis/Gem
0.4
0.3
0.2
0.1
0.0
0
6
12
18
24
30
PFS (months) in Non-Squamous Patients
non-squamous patients with adenocarcinoma or
large cell carcinoma
PFS, progression-free survival Cis/Pem,
cisplatin/pemetrexed Cis/Gem, cisplatin/gemcitabi
ne CI, confidence interval HR, hazard ratio
mos,months
Scagliotti et al. J Clin Oncol
doi10.1200/JCO.2007.15.0375
30
Cis/Pem vs. Cis/Gem in First-line NSCLC Overall
Survival in Squamous Cell Carcinoma
1.0
OS Median (95 CI)
0.9
Cis/Pem (N244) 9.4 mos (8.4, 10.2)
0.8
Cis/Gem (N229) 10.8 mos (9.5, 12.1)
0.7
OS Adjusted HR (95 CI)
0.6
Cis/Pem vs. Cis/Gem 1.23 (1.00-1.51)
0.5
Overall Survival Probability
OS effect with Cis/Pem less than with Cis/Gem
0.4
0.3
0.2
0.1
0.0
0
6
12
18
24
30
Overall Survival Time (months) in Squamous
Patients
Cis/Pem, cisplatin/pemetrexed Cis/Gem,
cisplatin/gemcitabine CI, confidence interval
CP, patients treated with cisplatinpemetrexed
CG, patients treated with cisplatingemcitabine
HR, hazard ratio mos, months
Scagliotti et al. J Clin Oncol
doi10.1200/JCO.2007.15.0375
31
Cis/Pem vs. Cis/Gem in First-Line NSCLC PFS in
Squamous Cell Carcinoma
1.0
PFS (months) in Squamous Patients
PFS, progression free survival Cis/Pem,
cisplatin/pemetrexed Cis/Gem, cisplatin/gemcitabi
ne CI, confidence interval HR, hazard ratio
mos, months
Scagliotti et al. J Clin Oncol
doi10.1200/JCO.2007.15.0375
32
Cis/Pem vs. Cis/Gem in First-Line NSCLC Efficacy
by Histology
Median OS, months Median OS, months Median OS, months Median PFS, months Median PFS, months Median PFS, months RR, RR, RR,
Cis/Pem Cis/Gem Adj. p-value HR (95CI) Cis/Pem Cis/Gem Adj. p-value HR (95CI) Cis/Pem Cis/Gem Adj. p-value

Adenocarcinoma n847 12.6 10.9 p0.0330.84 (0.71, 0.99) 5.5 5.0 p0.1250.90 (0.78, 1.03) 31.9 24.5 p0.024
Large Cell n153 10.4 6.7 p0.0270.67 (0.48, 0.96) 4.5 4.2 p0.4990.89 (0.65, 1.24) 31.3 30.9 p0.954
Other n252 8.6 9.2 p0.5861.08 (0.81, 1.45) 4.5 5.6 p0.0641.28 (0.99, 1.67) 33.0 24.2 p0.156
Squamous n473 9.4 10.8 p0.0501.23 (1.00, 1.51) 4.4 5.5 p0.0021.36 (1.12, 1.65) 26.9 36.7 p0.033
Patients whose histologic diagnosis did not
clearly qualify as adenocarcinoma, large or
squamous cell carcinoma Cis/Pem,
cisplatin/pemetrexed Cis/Gem, cisplatin/gemcitabi
ne OS, overall survival PFS, progression free
survival RR, response rate
Manegold et al. 14th European Congress of
Clinical Oncology Sept 27, 2007 Barcelona,
Spain.
33
Cis/Pem vs. Cis/Gem in First-Line NSCLC Systemic
Post-Discontinuation Therapy
Drug name Cis/PemN862 Cis/GemN863 p-value
Any post-study therapy 453 (52.6) 484 (56.1) 0.147
Gemcitabine 144 (16.7) 74 (8.6) lt0.001
Pemetrexed 30 (3.5) 116 (13.4) lt.0001
Cisplatin 53 (6.1) 34 (3.9) 0.037
Carboplatin 73 (8.5) 84 (9.7) 0.403
Docetaxel 219 (25.4) 238 (27.6) 0.326
Paclitaxel 42 (4.9) 37 (4.3) 0.567
Vinorelbine 63 (7.3) 64 (7.4) 1.000
Bevacizumab 9 (1.0) 6 (0.7) 0.452
Cetuximab 1 (0.1) 2 (0.2) 1.000
TKI (Erlotinib or Gefitinib) 215 (24.9) 194 (22.5) 0.235
Patients could receive multiple
post-discontinuation therapies. Cis/Pem,
cisplatin/pemetrexed Cis/Gem, cisplatin/gemcitabi
ne
Scagliotti et al. 12th World Conference on Lung
Cancer Sept 5, 2007 Seoul, Korea.
34
Cis/Pem vs. Cis/Gem in First-Line NSCLC Impact
of Baseline Characteristics on Overall Survival
Favors Cis/Pem
Favors Cis/Gem
0.94
All Patients (N1722)
Age lt 65 (n1116)
Age ?65 (n606)
Female (n514)
Male (n1208)
Caucasian (n1346)
East/Southeast Asian (n220)
Other Origin (n156)
Ever-smoker (n1265)
Never-smoker (n250)
ECOG Perf Status 0 (n612)
ECOG Perf Status 1 (n1110)
Histologic Diagnosis (n1145)
Cytologic Diagnosis (n577)
Stage IIIB (n414)
Stage IV (n1308)
Adenocarcinoma (n846)
Large Cell Carcinoma (n153)
Squamous Cell Carcinoma (n473)
Other Histologic Diagnosis (n250)
0.97
0.88
0.84
0.98
0.93
0.88
1.34
0.93
1.00
Hazard Ratio
0.91
0.95
0.92
0.99
0.89
0.95
0.84
0.67
1.23
1.08
0.4
0.6
0.8
1.0
1.2
1.4
1.6
1.8
2.0
2.2
Overall Survival Hazard Ratio with 95 CI
Scagliotti et al. J Clin Oncol
doi10.1200/JCO.2007.15.0375
35
Cis/Pem vs. Cis/Gem in First-Line NSCLC Smoking
Status Analysis
Median Survival, months Median Survival, months
Smoking Status Cis/Pem Cis/Gem
Never-smokers 15.9 15.3
Former/Current Smokers 10.0 10.3
  • On both treatment arms, never-smokers had longer
    median survival than former/current smokers
  • Regardless of treatment, former/current smokers
    had significantly higher risk of death than
    never-smokers
  • Cox adjusted analysis (HR1.74, superiority
    plt0.001)

Cis/Pem, cisplatin/pemetrexed Cis/Gem,
cisplatin/gemcitabine HR, hazard ratio
Scagliotti et al. J Clin Oncol
doi10.1200/JCO.2007.15.0375
36
Cis/Pem vs. Cis/Gem in First-Line NSCLC
Conclusions (1 of 2)
  • Overall Survival with Cis/Pem was noninferior to
    Cis/Gem (HR0.94)
  • All secondary efficacy endpoints comparable
    between regimens, in the overall study
    population
  • Both regimens were generally well-tolerated
  • Key hematologic and nonhematologic toxicities
    significantly lower for Cis/Pem
  • Cis/Pem patients required significantly fewer
    red blood cell and platelet transfusions, less
    use of erythropoietin/darbepoetin and granulocyte
    colony-stimulating factors

Cis/Pem, cisplatin/pemetrexed Cis/Gem,
cisplatin/gemcitabine
Scagliotti et al. J Clin Oncol
doi10.1200/JCO.2007.15.0375
37
Cis/Pem vs. Cis/Gem in First-Line NSCLC
Conclusions (2 of 2)
  • Pre-specified histology analyses
  • Adenocarcinoma carcinoma Cis/Pem had
    statistically superior OS time vs. Cis/Gem
    (p0.03)
  • Large Cell carcinoma Cis/Pem had statistically
    superior OS time vs. Cis/Gem (p0.03)
  • Squamous carcinoma OS time with Cis/Pem less
    than with Cis/Gem (p0.05)
  • Overall Survival for patients with nonsquamous
    histology significantly improved with Cis/Pem
  • Treatment-by-histology interaction analysis
    (p0.0011)
  • These prospective histology analyses confirm
    retrospective findings in prior pemetrexed vs.
    docetaxel second-line NSCLC study
  • This treatment-by-histology interaction for
    pemetrexed may be related to a differential
    expression of TS across NSCLC histologic groups

Nonsquamousadenocarcinoma or large cell
Cis/Pem, cisplatin/pemetrexed Cis/Gem,
cisplatin/gemcitabine TS, thymidylate synthase
Scagliotti et al. J Clin Oncol
doi10.1200/JCO.2007.15.0375
38
Cis/Pem Therapy in First-line Advanced or
Metastatic NSCLC
  • Cis/Pem compared with Cis/Gem
  • Largest randomized phase III trial in first-line
    advanced or metastatic NSCLC, to date
  • Overall survival and other efficacy endpoints
    similar between arms
  • Cis/Pem had statistically and clinically
    significant safety advantages particularly for
    grade 3/4 hematologic toxicities
  • Patients treated with Cis/Pem had fewer
    transfusions and less use of growth factors
  • Patients with adenocarcinoma and large cell
    carcinoma had superior survival with Cis/Pem,
    while survival time for those with squamous cell
    carcinoma was less with Cis/Pem than with Cis/Gem
  • First phase III study in NSCLC to prospectively
    report survival differences between platinum
    doublets according to histology
  • Cis/Pem represents a preferred regimen in the
    treatment of first-line advanced or metastatic
    NSCLC1

Cis/Pem, cisplatin/pemetrexed Cis/Gem,
cisplatin/gemcitabine
1Einhorn. In Scagliotti. 12th World Conference
on Lung Cancer Sept 5, 2007 Seoul, Korea.
39
Indications
  • Malignant Pleural Mesothelioma
  • ALIMTA in combination with cisplatin is indicated
    for the treatment of patients with malignant
    pleural mesothelioma whose disease is
    unresectable or who are otherwise not candidates
    for curative surgery.
  • Non-small cell lung cancer
  • ALIMTA in combination with cisplatin is indicated
    for the first line treatment of patients with
    locally advanced or metastatic non-small cell
    lung cancer other than predominantly squamous
    cell histology.
  • ALIMTA is indicated as monotherapy for the second
    line treatment of patients with locally advanced
    or metastatic non-small cell lung cancer other
    than predominantly squamous cell histology.
  • Vials 500mg. pemetrexed, 100mg pemetrexed
  • ???? ??? ????, ????
  • ??? ????? ??? ???? ????? ??"? ?.?. 2160 ??????
    ????? 46120
  • ????? ??? ?? ???? ????? ????? ??? ????? ?"? ????
    ???????
About PowerShow.com