Options for secondline treatment of advanced NSCLC: what should the standard of care be

1
Options for second-line treatment of advanced
NSCLC what should the standard of care be?

• Johan Vansteenkiste
• University Hospital Gasthuisberg, Leuven, Belgium

2
Goals for second-line therapy
Efficacy
Tolerability
Increased overall survival Increased disease
control rate Symptom improvement Increased time
to progression
Reduced toxicity Improved QoL
3
Approved second-line therapies

• Chemotherapy
• docetaxel
• pemetrexed
• EGFR tyrosine-kinase inhibitors
• Tarceva
• gefitinib

Approved in more than 60 countries worldwide,
including the USA, Canada and the EURestricted
availability mainly in Asian countries
4
Phase III studies of docetaxel (?second line)

• TAX317

Due to toxicity
Docetaxel 75mg/m2i.v. q3 wks(n55)
Docetaxel 100mg/m2i.v. q3 wks(n49)
BSC(n100)
PS 02 ( 25 PS 2)
5
TAX317 overall survival
1.0 0.8 0.6 0.4 0.2 0
Overall survival
Docetaxel
Cumulative probability
Overall survival significantly greater in
docetaxel group versus BSC (p0.01)
BSC
0 3 6 9 12 15 18 21
Survival time (months)
75mg/m2 control group
Shepherd FA, et al. J Clin Oncol 2000182095103
6
TAX317 toxicity

• Three deaths due to febrile neutropenia in
  100mg/m2 arm led to protocol amendment, with
  subsequent recruitment at 75mg/m2

Shepherd FA, et al. J Clin Oncol 2000182095103
7
TAX317 QoL outcomes

• Lung Cancer Symptom Scale (LCSS)
• Trends in observer-rated fatigue, pain and
  overall LCSS score favouring docetaxel overall
• No significant improvements in QoL for 75mg/m2
  dose

NS not significant
Dancey J, et al. Lung Cancer 20044318394
8
TAX320 overall survival
1-year survival
1.0 0.8 0.6 0.4 0.2 0
Docetaxel100mg/m2
21
p0.58
Docetaxel75mg/m2
32
p0.13 (c2 test p0.025)
Vinorelbine/ ifosfamide
19
Cumulative probability
0 3 6 9 12 15 18 21
Survival time (months)
Fossella FV, et al. J Clin Oncol 200018235462
Log-rank test
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TAX320 overall survival
1.0 0.8 0.6 0.4 0.2 0
Docetaxel100mg/m2
Docetaxel75mg/m2
Vinorelbine/ ifosfamide
Cumulative probability
0 3 6 9 12 15 18 21
Survival time (months)
Fossella FV, et al. J Clin Oncol 200018235462
10
Precautions for use of docetaxel

• Increased treatment-related mortality in
• patients with abnormal liver function
• patients receiving higher doses
• Increased risk of grade 4 AEs in patients with
  decreasedliver function
• Not to be given to patients with low neutrophil
  count
• frequent monitoring required
• Severe hypersensitivity reactions and severe
  fluid retention noted in some patients
• dexamethasone co-medication required (8mg b.i.d.)

Taxotere prescribing information, Sanofi-Aventis,
2006
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Phase III JMEI study of pemetrexed (second line)

• Primary endpoint superiority in overall
  survival versus docetaxel
• non-inferiority if superiority not proven

Pemetrexed500mg/m2i.v. q3 wks(n283)
Docetaxel 75mg/m2i.v. q3 wks(n288)
PS 02 (12 PS 2)
Dexamethasone4mg p.o. b.i.d.prepost
chemotherapy
Dexamethasone8mg p.o. b.i.d.prepost
chemotherapy
Folic acid3501,000µg p.o. daily
Vitamin B-121mg i.m.q9 wks
i.m. intramuscular
Hanna N, et al. J Clin Oncol 200422158997
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JMEI overall survival
1.00 0.75 0.50 0.25 0
HR0.99 (95 CI 0.81.2)
Survival distribution function
Pemetrexed Docetaxel
0 2.5 5.0 7.5 10.0 12.5 15.0 17.5 20.0 22.5
Months
Hanna N, et al. J Clin Oncol 200422158997
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JMEI selected AEs
Hanna N, et al. J Clin Oncol 200422158997
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JMEI QoL outcomes

• Rate of change in average symptom burden index of
  LCSS

• No significant difference between treatments
  across all categories (p0.1447 Mantel-Haenszel
  c2 test)

Hanna N, et al. J Clin Oncol 200422158997
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Goals for second-line therapy how does
chemotherapy measure up?
Efficacy
Tolerability
Reduced toxicity Improved QoL
Increased overall survival Increased disease
control rate Symptom improvement Increased time
to progression
16
Goals for second-line therapy how does
chemotherapy measure up?
Increased overall survival Increased disease
control rate Symptom improvement Increased time
to progression
Reduced toxicity Improved QoL
17
Gefitinib in relapsed advanced NSCLC

• Phase III Iressa Survival Evaluation in Lung
  Cancer (ISEL) study
• second- or third-line treatment

Gefitinib250mg/day(n1,129)
Placebo(n563)
21randomisation
Thatcher N, et al. Lancet 2005366152737
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Phase III BR.21 study of Tarceva ( second line)

• Randomised, double-blind study
• patients who had received one or two prior
  chemotherapy regimens and who were not suitable
  for further chemotherapy
• performed by National Cancer Institute of Canada
  Clinical Trials Group
• primary endpoint overall survival

Tarceva150mg/day(n488)
Placebo(n243)
PS 03
21randomisation
25 PS 29 PS 3
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Potentially important differences between Tarceva
and gefitinib approaches

• Tarceva is a more potent EGFR inhibitor than
  gefitinib
• Ki 0.4nM vs 3nM1
• Tarceva is usually administered at a dose of
  150mg/day
• using this dose (the MTD), maximises exposure to
  the drug and increases clinical benefit
• Gefitinib is usually administered at a dose of
  250mg/day
• this is the optimal biological dose around a
  third of the MTD (7001,000mg/day)

1Wood ER, et al. Cancer Res 200464665259
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BR.21 overall survival
1.00 0.75 0.50 0.25 0
Survival distribution function
HR0.73, plt0.001
0 5 10 15 20 25 30
Months
HR and p (log-rank test) adjusted for
stratification factors at randomisation and EGFR
status
Shepherd F, et al. N Engl J Med 200535312332
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BR.21 time to symptom deterioration (months)
Log-rank test, adjusted
Bezjak A, et al. J Clin Oncol 20062438317 Sheph
erd F, et al. N Engl J Med 200535312332
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BR.21 change in QoL domains (EORTC QLQ-C30)
³10 point change from baseline at any time
(clinically significant) p0.01
Bezjak A, et al. J Clin Oncol 20062438317
23
BR.21 adverse events ()
Tarceva does not produce haematological toxicity
Shepherd FA, et al. N Engl J Med 200535312332
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Approved second-line therapies

• Chemotherapy
• docetaxel
• pemetrexed
• EGFR tyrosine-kinase inhibitors
• Tarceva
• gefitinib

Which patients should receive which therapy?
Approved in more than 60 countries worldwide,
including the USA, Canada and the EURestricted
availability mainly in Asian countries
25
Can we select patients based on clinical or
molecular characteristics?
Gefitinib
Tarceva
Pemetrexed
Docetaxel
Clinicalcriteria?
Good PS
Good PS
XBenefit in all subgroups including good PS
?Benefit in some subgroups only
But should all good PS receive chemotherapy?
Molecularcriteria?
X
X
XStudies ongoing to determine which patients
benefit most
?Suggestion that EGFR FISH benefit more
No reliable molecular markers identified to date
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Efficacy of second-line therapies
Pemetrexed3
Docetaxel13
Tarceva4,5
1Shepherd F, et al. J Clin Oncol
20001820951032Fossella F, et al. J Clin Oncol
2000182354623Hanna N, et al. J Clin Oncol
200422158997 4Shepherd F, et al. N Engl J Med
2005353123325OSI and Roche data on file
Results cannot be compared directlybecause of
different patient populations
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Tolerability of second-line therapies
Tarceva
Pemetrexed
Docetaxel
Associatedwith serious,life-threatening AEs
Clinically relevant grade 3/4 toxicities lt10
(mainly rash and diarrhoea, easily managed)
Clinically relevant grade 3/4 toxicities lt10
(mainly haematological)

• Should patients be exposed to the toxicities of
  chemotherapy without a clear indication that they
  are likely to benefit?

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QoL benefits of second-line therapies
Tarceva
Pemetrexed
Docetaxel
Only shown for 100mg/m2 dose
Equivalent to docetaxel 75mg/m2
Significant symptom and QoL benefits compared
with BSC alone
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Convenience of second-line therapies
Tarceva
Pemetrexed
Docetaxel
i.v. infusion Co-medication with steroids Routine
monitoring required
i.v. infusion Co-medication with steroids and
vitamins
Once daily oral pill No routine monitoring
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Cost-effectiveness of second-line therapies
Tarceva
Pemetrexed
Docetaxel
Cost-effective versus BSC1
Cost-effective or cost-saving versus
chemotherapyand BSC27
Not reported
1Holmes J, et al. Pharmacoeconomics
20042258194 2Côté I, et al. Value Health
20069A2793Gabriel A, et al. Value Health
20069A278 4Rubio Terres C, et al. Value Health
20069A28345Orlewska E, et al. Value Health
20069A279 6Lewis G, et al. Value Health
20069A20347Pompen M, et al. Value Health
200620069A203
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Second-line options summary
Tarceva
Pemetrexed
Docetaxel










?
?
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Summary

• Selection of second-line therapy involves a
  balance between a numberof factors
• particularly efficacy versus tolerability and QoL
• Based on present data, Tarceva is a good option
  for treatment of patients in the second-line
  setting
• equivalent efficacy to chemotherapy
• improved tolerability profile versus chemotherapy
• no life-threatening haematological toxicity
• symptom and QoL benefits
• convenient once-daily oral dosing
• cost-effective versus chemotherapy
• Studies are ongoing to define which patients
  benefit most from treatment with Tarceva