romàn pérez-soler gutman professor of medicine and chairman of the department of oncology at the...
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Romàn Pérez-SolerGutman Professor of Medicine and Chairman of the Department of
Oncology at the Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, New York, USA
Worked at the MD Anderson Cancer Center (Departments of Clinical Immunology and Thoracic/Head and Neck Medical Oncology) for 16 years
Former Associate Director of Clinical and Translational Research, Kaplan Comprehensive Cancer Center, New YorkUniversity Medical Center
Author of 150 papers, 20 book chapters, and 175 abstracts
Involved in the development of new targeted anticancer therapies, in particular for lung cancer
Montefiore Medical Center
First choice in second line: erlotinib in NSCLC
Romàn Pérez-SolerMontefiore Medical Center
Albert Einstein College of MedicineNew York, USA
Treating second-line NSCLC
Lung cancer is a major cause of morbidity and mortality
– huge impact on global health systems and one of the leading causes of cancer-related death
Many patients diagnosed with advanced disease and unsuitable for surgery
– first-line chemotherapy is usual course of treatment
Limited second-line treatment options available
– patients may have reduced performance status (PS) due to previous treatment or progression
– need to balance efficacy versus tolerability and quality of life (QoL)
NSCLC = non-small-cell lung cancer
Continuing need for more treatment options
Need for new and different therapeutic options– more choice for clinicians and patients
Increasing interest in concept of tailored therapy– new diagnostic methods e.g. biomarkers could be
used to predict which patients benefit most
Current second-line agents include – chemotherapy (docetaxel, pemetrexed) – epidermal growth factor receptor (EGFR) tyrosine-
kinase inhibitors (erlotinib, gefitinib)
The current treatment algorithm for NSCLC
NSCLCEarly (stage I/II/selected IIIA)
Surgery ± chemotherapy
Radiotherapy (if unfit for surgery)
Locally advanced(stage IIIA/IIIB
no PE)
Chemotherapy(platinum doublet)
+ concomitantradiotherapyor sequential
Second/third line
Relapse
Advanced(stage IIIB with PE/IV)
First line Yes No
Platinum-based doublet chemotherapy ±
bevacizumab
Bestsupportive
careSingleagent
PS 4Frail elderly/
PS 3
Chemotherapy– docetaxel– pemetrexed– vinorelbine– gemcitabine
EGFR-targeted therapy– erlotinib– gefitinib
PE = pleural effusion
Fit elderly/ PS 2?
Suitable for standard chemotherapy?• PS• Age• Controlled/uncontrolled brain metastases• Concomitant medical condition
Data overview: the BR.21 and TRUST studies
BR.21: trial design
Phase III trial
Advanced stage IIIB/IV NSCLC
(n=731)
Erlotinib150mg daily
(n=488)
Placebo(n=243)
RANDOM I SE
2
1
Primary endpoint = overall survival (OS) Secondary endpoints = progression-free survival (PFS), response rate (RR)
and duration of response, safety, QoL
BR.21: key eligibility criteria Confirmed NSCLC, stage IIIB or IV Age 18 years PS 0, 1, 2 or 3 Measurable or non-measurable disease One or two prior chemotherapy regimens Adequate organ function EGFR immunohistochemistry (IHC+) status
not required No prior EGFR inhibitors No prior malignancies or uncontrolled central nervous
system (CNS) metastases Written informed consent
BR.21: overall survival
*HR and p (log-rank test) adjusted for stratification factors at randomisation and EGFR statusHR = hazard ratio
HR=0.73, p=0.001*
Shepherd F, et al. N Engl J Med 2005;353:123–32Tarceva Summary of Product Characteristics,
F. Hoffmann-La Roche Ltd
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%)
Time (months)
100
75
50
25
0 0 5 10 15 20 25 30
42.5% increase in median OS
nMedian survival
(months)1-year
survival
Erlotinib 488 6.7 31
Placebo 243 4.7 21
BR.21: progression-free survival
HR=0.61, p<0.001*
25%
10%
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Time (months)
1.00
0.75
0.50
0.25
00 5 10 15 20 25 30
Shepherd F, et al. N Engl J Med 2005;353:123–32
*HR and p (log-rank test) adjusted for stratificationfactors at randomisation and EGFR status
nMedian survival
(weeks)6 months
(%)
Erlotinib 488 9.7 25
Placebo 243 8.0 10
Is there a clinical benefit with erlotinib in men?Answer: Yes
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Months0 5 10 15 20 25
Placebo (n=83)
Erlotinib (n=173)
Women Men
Placebo (n=160)
Erlotinib (n=315)
Survival
HR=0.8 (0.6–0.9), p=0.01HR=0.8 (0.6–1.1), p=0.13
Months0 5 10 15 20 25 30
Shepherd F, et al. N Engl J Med 2005;353:123–32
1.00
0.75
0.50
0.25
0
1.00
0.75
0.50
0.25
0
Is there a clinical benefit with erlotinib in squamous-cell carcinoma?
Answer: Yes
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HR=0.7 (0.6– 0.9), p=0.008
Placebo (n=119)
Erlotinib (n=246)
0 5 10 15 20 25 30
Adenocarcinomas
0 5 10 15 20 25
Placebo (n=78)
Erlotinib (n=144)
HR=0.67 (0.5–0.9), p=0.0007
Squamous-cell carcinoma
Survival
Months Months
Shepherd F, et al. N Engl J Med 2005;353:123–32
1.00
0.75
0.50
0.25
0
1.00
0.75
0.50
0.25
0
Is there a clinical benefit with erlotinib in current/ex-smokers?
Answer: Yes
HR=0.9 (0.7–1.0), p=0.141*
Placebo (n=187)
Erlotinib (n=358)
*Log-rank test
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Months0 5 10 15 20 250 5 10 15 20 25 30
Current/ex-smokers Never smokers
HR=0.42 (0.28–0.64), p<0.001
Placebo (n=42)
Erlotinib (n=104)
Months
Shepherd F, et al. N Engl J Med 2005;353:123–32
1.00
0.75
0.50
0.25
0
1.00
0.75
0.50
0.25
0
Investigating optimal dosing regimen for current/former smokers
Primary endpoint: non-progression at 8 weeks
Follow-up = 6 months; dose escalation up to 300mg in 50mg increments; regular PK sampling during treatment period
Status: 22/44 recruited (pan-Europe)
Abstract submitted to ASCO 2008
Erlotinib PK single
dose Never smokers: Erlotinib 150mg/day
Current/former smokers: Erlotinib
dose escalation
Day –7 to 0 Day 1
Day 3
PI: Dr EF Smit (The Netherlands)
Screening and tissue collection
PK = pharmacokinetic
BR.21: all patient subgroups derived a survival benefit
CR = complete response; PD = progressive disease; PR = partial response; SD = stable disease;HR <1 = improved survival with erlotinib Shepherd F, et al. N Engl J Med 2005;353:123–32
Erlotinib:placebo
PS 0–1 0.73 (0.6–0.9)
PS 2–3 0.77 (0.6–1.0)
Male 0.76 (0.6–0.9)
Female 0.80 (0.6–1.1)
<65 years 0.75 (0.6–0.9)
65 years 0.79 (0.6–1.0)
Adenocarcinoma 0.71 (0.6–0.9)
Squamous-cell carcinoma 0.67 (0.5–0.9)
Other histology 1.04 (0.7–1.5)
HR
Fac
tors
Erlotinib:placebo
Never-smoker 0.42 (0.3–0.6)
Current/ex-smoker 0.87 (0.7–1.1)
1 prior regimen 0.76 (0.6–1.0)
2+ prior regimens 0.75 (0.6–1.0)
Best prior response: CR/PR 0.67 (0.5–0.9)
Best prior response: SD 0.83 (0.6–1.1)
Best prior response: PD 0.85 (0.6–1.2)
Asian 0.61 (0.4–1.0)
Other 0.79 (0.7–0.9)
0 1 2HR
0 1 2
BR.21: adverse events
Erlotinib (n=485) Placebo (n=242)
Any (%) Grade 3/4 (%) Any (%) Grade 3/4 (%)
Rash 75 9 17 0
Diarrhoea 54 6 18 <1
Nausea 33 3 24 2
Vomiting 23 2 19 2
Stomatitis 17 <1 3 0
Fatigue 52 18 45 20
Ocular (all) 27 1 9 <1
Anorexia 52 9 38 5
Infection 24 4 15 2
Erlotinib does not produce haematological toxicityShepherd F, et al. N Engl J Med 2005;353:123–32
BR.21: change in QoL domains (EORTC QLQ-C30)
Improved* (%) Stable (%) Worse (%)
Variable Erlotinib Placebo Erlotinib Placebo Erlotinib Placebo
Global QoL† 35 26 16 28 49 46
Physical function† 31 19 18 24 51 57
Role function 39 32 14 20 47 47Cognitive function 29 26 23 35 47 39
Emotional function† 39 30 24 36 37 35
Social function 39 37 21 19 39 44*³10 point change from baseline at any time (clinically significant)†p0.01
Bezjak A, et al. J Clin Oncol 2006;24:3831–7EORTC = European Organisation for Research and Treatment of Cancer
TRUST study design
Phase IV, open-label, non-randomised, multicentre study in patients with advanced, inoperable (stage IIIB/IV) NSCLC, previously treated with 1–2 courses of chemotherapy or radiotherapy, or considered unsuitable for such treatment
Erlotinib was given orally (150mg/day) until disease progression or unacceptable toxicity
Dose interruption or reduction (to 100mg/day, then to 50mg/day) was permitted for treatment-related Adverse events (AEs)
Data from 6,236 patients available for interim analysis
TRUST: summary of safety data
Patients with available safety data 5,730
Patients with 1 AE (any cause) (%)* 3,063 (53)
Patients with 1 AE (erlotinib-related) (%)* 635 (11)
Patients with 1 erlotinib-related SAE (%) 256 (4)
Patients who withdrew due toerlotinib-related AEs (%) 319 (6)
*Other than the 15 prespecified AEsSAE = serious adverse event
Ardizzoni A, et al. J Thorac Oncol 2007;2(Suppl 4):S342 (Abstract B3–06)
TRUST: incidence of erlotinib-related rash*
Grade 1/2 rash
Grade 3/4 rash
No rash
58%
12%
30%
*Based on data from 6,153 patientsArdizzoni A, et al. J Thorac Oncol
2007;2(Suppl 4):S342 (Abstract B3–06)
Rash may be related to magnitude of benefit from erlotinib in NSCLC
Excludes patients who died within 28 days of entry
Wacker B, et al. Clin Cancer Res 2007;13:3913–21
Correlation was maintained in multivariate analyses
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1.00
0.75
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0.25
0 0 6 12 18 24 30 36Time (months)
Grade 0 (n=86)Median: 3.3 months
Grade 1 (n=135)Median: 7.1 months
Grade 2+ (n=223)Median: 11.1 months
Grade HR 95% CI p value
2+ vs 0 0.29 0.22–0.38 <0.001
1 vs 0 0.41 0.31–0.55 <0.001
2+ vs 1 0.70 0.54–0.90 0.005
CI = confidence interval
Comparison between TRUST and BR.21
1Ardizzoni A, et al. J Thorac Oncol. 2007;2(Suppl. 4):S342 (Abstract B3–06) 2Shepherd FA, et al. N Engl J Med 2005;353:123–32
*Given the differences between study designs and patient populations, the studies are not directly comparable†Patient numbers are different between parameters
TRUST1 BR.212
n>5,000† (%) n=485 (%)
CR <1 1
PR 11 8
SD 56 35
Disease control rate (CR + PR + SD) 68 44
Dose reductions due to erlotinib-related event 14 19
Withdrawals due to erlotinib-related event
6 5
Incidence of erlotinib-related rash 70 76
Incidence of interstitial lung disease <1 <1
BR.21 and TRUST*: improvement in PFS with erlotinib
Erlotinib (BR.21), n=488
Placebo (BR.21), n=243
Median PFS: erlotinib 9.7 weeks; placebo 8 weeks (p<0.001)
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0.75
0.50
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0 0 5 10 15 20 25 30PFS (months)
BR.211
Median PFS: 13 weeksTRUST2
Erlotinib (TRUST), n=6,181†
*Given the differences between study designs and patient populations, the studies are not directly comparable†Patient numbers are different between parameters
1Shepherd FA, et al. N Engl J Med 2005;353:123–322Ardizzoni A, et al. J Thorac Oncol.
2007;2(Suppl. 4):S342 (Abstract B3–06)
TRUST and BR.21: conclusions
TRUST interim safety data– no new safety signals– confirmed favourable safety profile of erlotinib
observed in phase III BR.21 study
TRUST interim efficacy data – appeared consistent with previous data– observed disease control rate and median PFS in
line with those from BR.21 study
Erlotinib in the routine clinical setting
Case study: patient history and initial treatment
67-year-old female, former smoker (10 pack-years)
December 2006: examination found mass in left upper lobe plus a single brain metastasis (T2N2M1)
January 2007: brain metastasis resected followed by brain radiotherapy (XRT); confirmed adenocarcinoma
March 2007: multiple bone metastases observed– 2 cycles of carboplatin + paclitaxel, followed by
concomitant weekly carboplatin + paclitaxel + chest XRT (completed in July 2007)
– partial response in left lung lesion– stable disease in bone lesions
Case study: second-line treatment with erlotinib
September 2007: 15-pound weight loss, ECOG PS of 2– disease progression confirmed in bone and liver
Patient commenced erlotinib 150mg/day– immediate symptomatic improvement– grade 1 skin rash that resolved with administration
of topical moisturiser; no diarrhoea
February 2008: patient continues to receive erlotinib– no further side effects; sustained partial response
ECOG PS = Eastern Cooperative Oncology Group performance status
Predicting clinical benefitwith erlotinib
Biomarkers
A biomarker is a characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes or pharmacological responses to therapeutic intervention1
A useful biomarker
– can be measured reproducibly, using a reliable and widely available assay
– provides information about the disease that is meaningful to the physician and the patient
– is more informative than other measurable factors
1Biomarker Definitions Working Group, Biomarkers and Surrogate Endpoints: Preferred Definitions and Conceptual Framework. Clin Pharmacol & Ther 2001;69:89–95
Prognostic versus predictive markers:an important distinction
www.cancerdiagnosis.nci.nih.gov
Prognostic marker
Indicates the likelihood of outcome (tumour recurrence or patient survival) regardless of the specific treatment the patient receives
Predictive marker
Indicates the likelihood of response to a specific therapy
Markers may have both prognostic and predictive value – this can complicate assessment
Challenges of biomarker testing
Obtaining tissue in sufficient quantities and of high enough quality for analyses
to take place
Variations in testing methods used at different sites –
results cannot be directly compared
Validation of biomarkers and
testing methods is a complex and lengthy process
Assays need to be quick, reliable,
inexpensive and easy to establish
in laboratories
Need to have consensus and
cooperation between industry
and academia
Future biomarkers, e.g. proteomics and
gene chips, may require new
technology and methods
BR.21: EGFR biomarker status does not predict for survival benefit with erlotinib
*p value for subgroup compared with placebo; †p value for interaction‡Includes indeterminate variants; §Exon 19 deletions and L858R
0.47
Tsao M-S, et al. N Engl J Med 2005;353:133–44Tsao M-S, et al. N Engl J Med 2006;354:527–8
0.25
0.12
Shepherd FA, et al. J Clin Oncol 2007;25(Suppl. 18I):402s (Abstract 7571)
n HR CI p* p†
EGFR expression (IHC) IHC+ IHC–
184141
0.680.93
0.49–0.950.63–1.36
0.02 0.70
Gene copy number (FISH) Low High
98 61
0.800.43
0.49–1.290.23–0.78
0.35 0.004
EGFR mutation status Wild-type‡
Mutant§ 170 34
0.740.55
0.52–1.050.25–1.19
0.09 0.12
FISH = fluorescence in-situ hybridisation
Survival according to EGFR IHC* and EGFR FISH status in TRUST study
TRUST is a single-arm study and cannot therefore distinguish between prognostic and predictive value
*Based on staining in 10% tumour cells†Log-rank test
Schneider CP, et al. J Clin Oncol 2007;25(Suppl. 18 Pt I):S427 (Abstract 7674)
EGFR IHC+ (n=229)
EGFR IHC– (n=55)
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OS (days)
0 100 200 300 400 500 600 700 800
HR=0.766p=0.1056† S
urv
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1.00
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OS (days)
0 100 200 300 400 500 600 700 800
EGFR FISH+ (n=49)
EGFR FISH– (n=156)
HR=0.662p=0.0341†
EGFR mutations and clinicaloutcomes with erlotinib
Presence of an EGFR mutation may increase tumour responsiveness to erlotinib
– requires confirmation in larger, prospective analysis
BR.21 failed to show a significant effect of mutation status on survival
– patients with wild-type and mutated EGFR both derive survival benefit from erlotinib
– OS benefit seen in BR.21 cannot be fully explained by presence of patients with mutations
– presence of EGFR mutations may be prognostic
Small patient numbers, difficulties in obtaining samples and retrospective nature limit the analyses
Second RNA blood
sample
Open-label erlotinib
150mg/day
MERIT (MarkER Identification Trial):design and objectives
Patients stage IIIB/IV
NSCLC (failed 1 first-line treatment*)
PD
*Or refused/were unsuitable for chemotherapyRNA = ribonucleic acid
Day 1
Clinical assessment at screening, then every
6 weeks until PD
Follow-up every
12 weeks
Mandatory samples• Tumour biopsy• Tumour block (if available)• RNA blood sample
Week 6Day –28
Screening
Primary endpoint• To identify differentially
expressed genes that predict clinical benefit (CR, PR, SD 12 weeks) with erlotinib
Secondary endpoints• Correlation of EGFR mutations
with clinical benefit• Exploratory assessment of EGFR
and downstream targets
MERIT: summary of results
MERIT is the largest prospective genomic profiling study ever conducted in advanced NSCLC
The study found no binary markers for clinical benefit at the RNA expression level in baseline tumour biopsy samples
In exploratory analyses, three candidate markers for response were identified on chromosome 7
– EGFR, PSPH, RAPGEF5 The findings from MERIT support the use of erlotinib in
patients with advanced NSCLC who have failed 1 chemotherapy regimen
– further validation of these findings is ongoing
Reck M, et al. Eur J Cancer Suppl 2007;5:360 (Abstract 6512)
TITAN (n=650)or off study
PD
SATURN (Sequential Tarceva® in unresectable NSCLC)
Chemotherapy naïve stage
IIIB/IV NSCLCPlanned n=1,700
Non-PD(n=850)
Tumour samples
(mandatory)
Four cycles of first-line standard platinum-
based doublet
1:1 rand
PD
PD
Placebo
Erlotinib150mg/day
Stratify by EGFR protein
expression (IHC) ‘10% cut-off’
Co-primary endpoint = 33% increase in PFS in patients with EGFR
IHC+ tumours
What answers will SATURN provide?
Primary endpoint = 25% increase in PFS (all
patients)
EGFR IHC+
EGFR IHC–
EGFR IHC+
EGFR IHC–
Placebo
Erlotinib150mg/day
What answers will SATURN provide?
Largest prospective biomarker study ever performed for a targeted agent– results expected in late 2008
Many other putative biomarkers will be prospectively evaluated– EGFR FISH– EGFR/KRAS mutations– pMAPK IHC– pAKT IHC– HER2 IHC– EGFR intron 1 polymorphisms
Placebo
Erlotinib150mg/day
Other erlotinib trials performing biomarker analyses
RADIANT Adjuvant trial in selected patients (IHC and/or FISH+) with mandatory sample collection
US phase II first line
Selecting patients based on IHC and/or FISH+ status and also looking at EGFR and KRAS mutations, EMT, pMAPK
TIE Phase II trial of first-line erlotinib in elderly; examining EGFR IHC, EGFR FISH, EGFR and KRAS mutations
FAST-ACT Sequential erlotinib plus chemotherapy in first-line; analysing IHC: EGFR and related markers (e.g. pAKT, pMAPK), EGFR FISH, EGFR and KRAS mutations
TRUST Global open-label study providing patients with access to erlotinib; IHC (EGFR, pAKT and pMAPK), EGFR FISH and mutation analyses (EGFR and KRAS) have been carried out for the German subpopulation; global data to be presented at ASCO 2008
Adding other agents to erlotinib
Erlotinib as a combination partner in first- and second-line NSCLC
Favourable tolerability profile of erlotinib makes it an ideal agent for combination regimens in NSCLC
Erlotinib/bevacizumab combination has shown promising results in clinical trials and further investigations are ongoing
Erlotinib is also being investigated in sequential regimens with chemotherapy
PD
PD Erlotinib
PD Erlotinib
Phase II study of bevacizumab with chemotherapy or erlotinib in advanced NSCLC
Erlotinib + bevacizumab
(n=39)
Chemotherapy(n=41)
Chemotherapy+ bevacizumab
(n=40)
Herbst R, et al. J Clin Oncol 2007;25:4743–50
Randomised, multicentre studyPrimary endpoint: safety and preliminary efficacy (PFS)Secondary endpoints: ORR (plus duration); duration of survival
OSI-2950gBevacizumab 15mg/kg every 3 weeks; erlotinib 150mg/day orally; docetaxel 75mg/m2 and pemetrexed 500mg/m2 every 3 weeksORR = overall response rate
Promising results seen with this novel approach
Median PFS
(months)6-month PFS
rate (%)1-year OS rate (%)
4.4 33.6 57.1
4.8 30.5 53.6
3.0 21.5 34.8
Previously treated
advanced non-squamous NSCLC (n=120)
ATLAS: bevacizumab plus erlotinib as sequential therapy following bevacizumab
plus CT in first line
Bevacizumab+ placebo
Chemotherapy naïve stage IIIb/IV non-squamous
NSCLC
Erlotinib
Non-PD
AVG3671g (phase IIIb)Bevacizumab 15mg/kg every 3 weeks; erlotinib 150mg/day*Either carboplatin/paclitaxel, carboplatin/gemcitabine or carboplatin/docetaxelCT = chemotherapy
Off study
Bevacizumab + erlotinib
PD
Off study
(n≈800)
PD
1:1Bevacizumab + chemotherapy*
PD or significant
toxicity Primary endpoint = PFS (time from
randomisation until disease progression or death)
Status: ongoing– planned n=1,150
BETA LUNG: erlotinib ± bevacizumab in the second-line setting
Double‑blind, randomised study
Primary endpoint = OS (increase by 33%; from 8.0 to 10.67 months)
Secondary endpoints = PFS, RR and duration, safety and PK
Status: ongoing; planned n=650
OSI-3364g (phase III)*No cross over permitted
Previously treated advanced non-
squamous NSCLC
PD*
PDErlotinib 150mg/day
orally + placebo
Erlotinib 150mg/day orally + bevacizumab
15mg/kg every3 weeks
The future treatment algorithm for NSCLC?
Early(stage I/II/selected
IIIA)
Surgery ± chemotherapy
Radiotherapy (if unfit for surgery)
Locally advanced(stage IIIA/IIIB
no PE)
Chemotherapy(platinum doublet)
+ concomitantradiotherapyor sequential
Second/third line
Relapse
Advanced(stage IIIB with PE/IV)
First line Yes No
Platinum-based doublet chemotherapy ±
bevacizumab
Bestsupportive
careSingleagent
PS 4Frail elderly/
PS 3
Chemotherapy– docetaxel– pemetrexed– vinorelbine– gemcitabine
EGFR-targeted therapy– erlotinib– gefitinib
Add bevacizumab to second- and third-line regimens?
Initiate biomarkertesting at
diagnosis stage?
Fit elderly/ PS 2?
Add erlotinib first line in suitable
patients?
Suitable for standard chemotherapy?• PS• Age• Controlled/uncontrolled brain metastases• Concomitant medical condition
NSCLC
Erlotinib in second-line NSCLC: conclusions
Erlotinib is a well-established and effective treatment option for second-line NSCLC
– favourable safety profile
– provides survival benefit in all subgroups
Extensive clinical trial programme underway to establish whether biomarkers can predict clinical benefit with erlotinib
– includes SATURN study (data due in 2008/09)
Addition of VEGF inhibitor bevacizumab also being investigated as possibility for optimisation of therapy