Transcript Erlotinib Update - ASCO 2007

Erlotinib Update
ASCO 2007: an overview of highlighted Tarceva trials in NSCLC
Phase III and IV
TRUST
Interim safety analysis – Abstract 7645
Biomarker analysis – Abstract 7674
Association between different predictive markers – Abstract 7651
BR.21 Update
Updated molecular analyses of exons 19 and 21 of the EGFR gene; and codons 12 and
13 of the KRAS gene in patients with non–small cell lung cancer (NSCLC) treated with
erlotinib in National Cancer Institute of Canada Clinical Trials Group BR.21
TRIBUTE
Fluorescence in situ hybridization (FISH) subgroup analysis of TRIBUTE: a phase III trial
of erlotinib plus carboplatin and paclitaxel in NSCLC
EGFR = epidermal growth factor receptor
ASCO 2007: an overview of highlighted Tarceva trials in NSCLC
Phase II
• Erlotinib as initial therapy in patients with advanced non–small cell lung cancer (NSCLC) and a
performance status of 2: a SWOG phase II trial (S0341)
• Erlotinib for first-line treatment in unselected patients (p) with advanced or metastatic non–small cell
lung cancer (NSCLC)
• Skin rash as surrogate marker of efficacy in patients with non–small cell lung cancer treated with
erlotinib
• Final results of ECOG 3503: a pilot study to determine if downstream markers of EGFR-linked
signalling pathways predict response to erlotinib (OSI-774) in the first-line treatment of patients with
advanced non–small cell lung cancer (NSCLC)
• Phase II study of erlotinib in chemo-naïve women with advanced pulmonary adenocarcinoma
• Correlation of the EGFR gene mutation, gene amplification and protein expression in non–small cell
lung cancer with clinical outcomes of erlotinib monotherapy: an exploratory analysis of biomarkers by
the Korean Cancer Study Group
• Cost-effectiveness of erlotinib vs. docetaxel or pemetrexed in the treatment of refractory non–small
cell lung cancer (NSCLC)
ECOG = Eastern Cooperative Oncology Group
EGFR = epidermal growth factor receptor
TRUST Study: Safety Analysis
Erlotinib in non–small cell lung cancer (NSCLC):
interim safety analysis of the TRUST study
Gatzemeier U, et al. ASCO 2007: Abstract 7645.
TRUST study: study design
•
Primary endpoint: provide erlotinib access to patients with
advanced Stage IIIB or IV NSCLC who have previously failed
or are unsuitable for standard chemo or radiotherapy
•
Secondary endpoint: efficacy; safety; biomarker relationship and
clinical benefit
•
Design: Phase IV, open-label, non-randomized, multicentre trial
•
Treatment: Erlotinib 150 mg PO daily until disease progression,
death, or unacceptable toxicity; dose interruption or reduction in the
event of treatment-related side effects
Gatzemeier U, et al. ASCO 2007: Abstract 7645.
NSCLC = non–small cell lung cancer
TRUST study: safety results
*Overall safety data were available for 5,378 patients, of whom 53% experienced at least one AE
Gatzemeier U, et al. ASCO 2007: Abstract 7645.
AE = adverse effect
TRUST study: efficacy results
•Disease control rate (DCR=CR+PR+SD) at time of analysis was:
•73% first-line
•67% second-line
•66% third-line
Gatzemeier U, et al. ASCO 2007: Abstract 7645.
CR = complete response
DCR = disease control rate
PR = partial response
SD = stable disease
TRUST study: conclusions
•
Erlotinib was well tolerated by patients
•
AEs were generally mild to moderate and in most cases could be
managed without dose reduction or treatment withdrawal
•
Efficacy data shows promise: DCR = 66% to 73% across all
treatment lines
•
This phase IV trial confirms a favourable safety profile of erlotinib in
patients who have previously failed or are unsuitable for standard
chemotherapy
Gatzemeier U, et al. ASCO 2007: Abstract 7645.
AE = adverse event
DCR = disease control rate
TRUST Study: Biomarker Analysis
A trial of erlotinib in non–small cell lung cancer
(NSCLC)
Schneider C, et al. ASCO 2007: Abstract 7674.
TRUST study: study design
•
Primary endpoint: explore potential predictive biomarkers and
assess any correlation with benefit from erlotinib treatment
•
Treatment: oral erlotinib 150 mg/day until progression or
unacceptable toxicity
•
Biomarker analysis: EGFR protein expression analysis of 284
samples by immunohistochemistry (IHC); pMAPK and pAKT were
assessed using immunohistochemistry (IHC); EGFR gene copy
number assessed by fluorescence in situ hybridization (FISH);
mutation analyses of EGFR exons 19 and 21, and KRAS exons 2
and 3
Schneider C, et al. ASCO 2007: Abstract 7674.
EGFR = epidermal growth factor receptor
TRUST study: survival results (1)
EGFR IHC+ n = 229
EGFR IHC – n = 55
EGFR IHC+ n = 250
EGFR IHC – n = 30
Schneider C, et al. ASCO 2007: Abstract 7674.
TRUST study: survival results (2)
pMAPK+ n = 29
pMAPK – n = 79
EGFR FISH+ n = 49
EGFR FISH – n = 156
Schneider C, et al. ASCO 2007: Abstract 7674.
EGFR = epidermal growth factor receptor; FISH = fluorescence in situ hybridization
IHC = immunohistochemistry; HR = hazard ratio
TRUST study: survival results (3)
EGFR mutation n = 6
Wild-type
n = 79
Indeterminate
n = 95
KRAS mutation n = 17
Wild-type
n = 90
Indeterminate n = 73
Schneider C, et al. ASCO 2007: Abstract 7674.
EGFR = epidermal growth factor receptor; HR = hazard ratio
TRUST study: conclusions
•
Patients with tumours showing EGFR protein expression or high
gene copy may have longer survival rates with erlotinib than
patients with EGFR-negative tumours (by IHC or FISH)
•
No conclusions can be drawn on the predictive value of pMAPK
•
Patients with EGFR mutations may survive longer during treatment
with erlotinib than those with EGFR wild-type or indeterminate
EGFR mutations status
•
Patients with KRAS mutations may derive less benefit from erlotinib
therapy than those with wild-type KRAS
TRUST is a single arm, non-randomized study; therefore, firm conclusions
cannot be drawn regarding the predictive or prognostic value of the potential
biomarkers analyzed.
Schneider C, et al. ASCO 2007: Abstract 7674.
EGFR = epidermal growth factor receptor
FISH = fluorescence in situ hybridization
IHC = immunohistochemistry
TRUST Study: Predictive Markers
Association between different potential predictive
markers from TRUST: a trial of erlotinib in
non–small–cell lung cancer (NSCLC)
Laack E, et al. ASCO 2007: Abstract 7651.
TRUST study: study design
•
Objective: explore interrelationships between tumour and patient
characteristics for patients treated within the TRUST study in
German centers
•
Treatment: oral erlotinib 150 mg/day until progression or
unacceptable toxicity
•
Biomarker analysis: EGFR protein expression analysis by
immunohistochemistry (IHC); EGFR gene copy number assessed
by fluorescence in situ hybridization (FISH); EGFR (exons 19 and
21) and KRAS (exons 2 and 3) mutations were assessed by direct
DNA sequencing
Laack E, et al. ASCO 2007: Abstract 7651.
EGFR = epidermal growth factor receptor
TRUST study: results
Laack E, et al. ASCO 2007: Abstract 7651.
EGFR = epidermal growth factor receptor; FISH = fluorescence in situ hybridization
IHC = immunohistochemistry
TRUST study: conclusions
•
Correlation analyses suggest that
 Smokers have a higher occurrence of squamous-cell carcinoma and
obtain less clinical benefit
 EGFR FISH-positive status is related to clinical benefit; EGFR protein
expression increases with increasing FISH stratum
•
Most EGFR FISH-positive or pAKT-positive tumours were also EGFR IHCpositive
•
Adenocarcinoma more common in female than male patients, possibly
related to higher number of male smokers
•
Trends that require further investigation:
 KRAS mutations occur primarily in patients with adenocarcinoma,
smokers, and EGFR FISH-negative tumours
 EGFR mutations occur in patients with adenocarcinoma and EGFR-
positive tumours
Laack E, et al. ASCO 2007: Abstract 7651.
EGFR = epidermal growth factor receptor
FISH = fluorescence in situ hybridization
IHC = immunohistochemistry
BR.21: Updated
Updated molecular analyses of exons 19 and 21 of
the EGFR gene and codons 12 and 13 of the KRAS
gene in non–small cell lung cancer (NSCLC) patients
treated with erlotinib in National Cancer Institute of
Canada Clinical Trials Group BR.21
Shepherd FA, et al. ASCO 2007: Abstract 7571.
EGFR = epidermal growth factor receptor
BR.21 update: study design
•
Primary endpoint: overall survival
•
Secondary endpoint: response
•
Design: phase III, placebo-controlled, randomized trial
•
Treatment: patients were randomly assigned in a 2:1 ratio to
receive erlotinib 150 mg/day or a placebo
•
Biomarker analyses: KRAS exon 2 mutations were assessed by
DNA sequencing; EGFR (exons 19 and 21) mutations were
assessed by fragment length analysis, surveyor-WAVE HS
analysis, and SCORPION Amplified Refractory Mutation System
(ARMS)
Shepherd FA, et al. ASCO 2007: Abstract 7571.
EGFR = epidermal growth factor receptor
BR.21 update: results (1)
EGFR = epidermal growth factor receptor
Shepherd FA, et al. ASCO 2007: Abstract 7571.
HR = hazard ratio
BR.21update: results (2)
Shepherd FA, et al. ASCO 2007: Abstract 7571.
HR = hazard ratio
BR.21update: conclusions
•
Re-analysis of BR.21 samples for EGFR exon 19 deletions and an
exon 21 L858R mutation using more sensitive assays revealed 10
additional patients with mutations
•
Survival benefit is slightly but not significantly greater in patients
with mutations compared to those without
•
Increased gene copy number, as assessed by FISH, shows a
greater differential benefit than mutation status
Shepherd FA, et al. ASCO 2007: Abstract 7571.
EGFR = epidermal growth factor receptor
FISH = fluorescence in situ hybridization
TRIBUTE: FISH Subgroup Analysis
Fluorescence in situ hybridization (FISH) subgroup
analysis of TRIBUTE: a phase III trial of erlotinib plus
carboplatin and paclitaxel in NSCLC
Hirsch FR, et al. ASCO 2007: Abstract 7570.
NSCLC = non–small cell lung cancer
TRIBUTE subgroup analysis: study design
Hirsch FR, et al. ASCO 2007: Abstract 7570.
NSCLC = non–small cell lung cancer
TRIBUTE subgroup analysis: results by FISH (1)
Hirsch FR, et al. ASCO 2007: Abstract 7570.
FISH = fluorescence in situ hybridization
TRIBUTE subgroup analysis: results by FISH (2)
Hirsch FR, et al. ASCO 2007: Abstract 7570.
FISH = fluorescence in situ hybridization
TRIBUTE subgroup analysis: conclusions
•
EGFR gene copy number by FISH did not predict survival benefit
•
In FISH-positive patients, there was a longer time to progression,
but lower response rate was observed
•
Non-concurrent combination approach warrants further
investigation in patients selected by EGFR FISH
Hirsch FR, et al. ASCO 2007: Abstract 7570.
EGFR = epidermal growth factor receptor
FISH = fluorescence in situ hybridization
SWOG Trial S0341
Erlotinib as initial therapy in patients with advanced
non–small cell lung cancer (NSCLC) and a
performance status (PS) of 2: A SWOG phase II trial
(S0341)
Hesketh PJ, et al. ASCO 2007: Abstract 7536.
Not an official event of the ASCO Meeting. Not sponsored or endorsed by ASCO or The ASCO Foundation
SWOG trial S0341: study design
• Primary endpoint: survival in patients with a Zubrod PS of 2 treated with
erlotinib
• Secondary endpoints: objective response; correlation of EGFR
expression/polymorphisms with response/survival; correlations of
activated signal pathways with survival
• Erlotinib 150 mg orally daily
• Treatment cycle = 21 days
• Response assessment every other cycle
• Treatment duration: until progressive disease or unacceptable toxicity
Hesketh PJ, et al. ASCO 2007: Abstract 7536.
EGFR = epidermal growth factor receptor
PS = performance status
SWOG trial S0341: response
Response
Number of patients (%)
Complete (CR)
0 (0)
Partial (PR)
5 (7)
Stable (SD)
26 (36)
DCR (CR+PR+SD)
31 (43)
Progression/symptomatic deterioration
30 (42)
Unevaluable
10 (14)
Early death
1 (1)
Hesketh PJ, et al. ASCO 2007: Abstract 7536.
DCR = disease control rate
SWOG trial S0341: overall survival
Hesketh PJ, et al. ASCO 2007: Abstract 7536.
SWOG trial S0341: conclusions
•
Single agent erlotinib is a well-tolerated treatment for
chemotherapy-naïve patients with advanced NSCLC and a PS of 2
•
This treatment achieved an overall disease control rate (DCR) of
43% with a median survival of 5 months
•
Survival is comparable to the outcome noted in SWOG trial S0027
in PS 2 patients with sequential vinorelbine and docetaxel with less
toxicity
•
Outcome remains disappointing in this population. Authors
hypothesize that patient selection by an EGFR biomarker strategy
will improve results with erlotinib, and that erlotinib will be superior
to chemotherapy in this selected population. This trial design is
under development within SWOG
EGFR = epidermal growth factor receptor
NSCLC = non–small cell lung cancer
Hesketh PJ, et al. ASCO 2007: Abstract 7536.
PS = performance status
First-line Metastatic: Unselected
Erlotinib for first line treatment in unselected
patients (p) with advanced or metastatic
non–small cell lung cancer (NSCLC)
Jimenez U, et al. ASCO 2007: Abstract 7639.
First-line metastatic: study design
•
Primary endpoint: TTP in the ITT population with erlotinib
administered as first, second, and third, or successive lines of
treatment
•
Secondary endpoint: efficacy clinical benefit; overall survival;
safety
•
Treatment: erlotinib 150 mg/day until disease progression or
withdrawal
•
Efficacy assessment: physical examination; radiological
assessment
•
Safety assessment: determined by NCI CTCAE v3.0
CTCAE = common terminology criteria for adverse events
ITT = intention to treat
NCI = National Cancer Institute
Jimenez U, et al. ASCO 2007: Abstract 7639.
TTP = time to progression
First-line metastatic: results
CI = confidence interval
HR = hazard ratio
Jimenez U, et al. ASCO 2007: Abstract 7639.
TTP = time to progression
First-line metastatic: conclusions
•
Confirmation of erlotinib as an active and well-tolerated treatment in
unselected NSCLC patients who had not received prior
chemotherapy for advanced disease; TTP 6.6 months
•
Erlotinib in first-line treatment of NSCLC has been able to control
the disease in 71% of patients; median survival 7.0 months
•
Effect on disease control rate does not seem to be dependent on
histology; history and gender are predictive factors for tumour
response
•
Absence of smoking history and a good performance status are
associated with a longer survival
NSCLC = non–small cell lung cancer
Jimenez U, et al. ASCO 2007: Abstract 7639.
TTP = time to progression
Surrogate Marker: Skin Rash
Skin rash as surrogate marker of efficacy in patients
with non–small cell lung cancer treated with erlotinib
Cobo M, et al. ASCO 2007: Abstract 7602.
Surrogate marker: study design
•
Primary endpoint: time to progression (TTP)
•
Secondary endpoint: disease control rate (CR + PR + SD); overall
survival; safety profile
•
Design: open-label, multicentre, non-randomized, phase II trial
•
Treatment: erlotinib 150 mg/day until disease progression or
withdrawal
•
Efficacy assessment: physical examination; radiological
assessment
•
Safety assessment: determined by NCI CTCAE v3.0
CR = complete response
CTCAE = common terminology criteria for adverse events
NCI = National Cancer Institute
PR = partial response
Cobo M, et al. ASCO 2007: Abstract 7602.
SD = stable disease
Surrogate marker: efficacy results (1)
* Kaplan-Meier curves for overall survival (OS) by the development of skin rash
revealed the same trend
CI = confidence interval
Cobo M, et al. ASCO 2007: Abstract 7602.
TTP = time to progression
Surrogate marker: efficacy results (2)
* Kaplan-Meier curves for overall survival (OS) by severity of skin rash revealed
the same trend
CI = confidence interval
Cobo M, et al. ASCO 2007: Abstract 7602.
TTP = time to progression
Surrogate marker: conclusions
•
This retrospective analysis suggests a correlation between skin
rash development and severity with treatment outcome
•
Skin rash seems to be a surrogate of efficacy, although
improvement in terms of TTP and OS were also observed in
patients without rash
•
There are ongoing investigations looking at the association of skin
rash and efficacy of erlotinib treatment that will help clarify
OS = overall survival
Cobo M, et al. ASCO 2007: Abstract 7602.
TTP = time to progression
ECOG 5305: Final Results
Final results of ECOG 3503: A pilot study to
determine if downstream markers of EGFR-linked
signalling pathways predict response to erlotinib
(OSI-774) in the first-line treatment of patients with
advanced non–small cell lung cancer (NSCLC)
Kolesar J, et al. ASCO 2007: Abstract 7588.
ECOG = Eastern Cooperative Oncology Group
EGFR = epidermal growth factor receptor
ECOG 3505: study design
•
Primary objective: prospectively identify downstream markers of EGFRlinked signalling pathways that are predictive of response to erlotinib
•
Secondary objective: antitumour objective response, DCR (CR+PR+SD),
TTP, OS, grade 2 rash predictor of response, safety, smoking status link
•
Treatment: 150 mg erlotinib daily; 1 cycle = 28 days; dose escalation
25mg/day every 14 days will continue to 250 mg unless development of a
grade 2 rash or dose-limiting toxicity
CR = complete response
DCR = disease control rate
ECOG = Eastern Cooperative Oncology Group
EGFR = epidermal growth factor receptor
OS = overall survival
PR = partial response
SD = stable disease
Kolesar J, et al. ASCO 2007: Abstract 7588.
TTP = time to progression
ECOG 3505: results
Disease Control Rate (DCR) = 46%
Kolesar J, et al. ASCO 2007: Abstract 7588.
ECOG 3505: conclusions
•
Erlotinib is a CYP3A4 substrate
 CYP3A41B wild-type polymorphism may predict response
•
Erlotinib well tolerated with modest activity in first-line treatment of
advanced NSCLC
 CR 0.88%
 PR 6%
 SD 39%
 DCR 46%
•
pMAPK overexpression is a poor prognostic factor
•
Grade ≥ 2 rash trended toward better survival
CR = complete response
DCR = disease control rate
ECOG = Eastern Cooperative Oncology Group
NSCLC = non–small cell lung cancer
PR = partial response
Kolesar J, et al. ASCO 2007: Abstract 7588.
SD = stable disease
Women with Adeno-NSCLC
Phase II study of erlotinib in chemo-naïve women
with advanced pulmonary adenocarcinoma
Jackman D, et al. ASCO 2007: Abstract 7591.
Women with adeno-NSCLC: study design
•
Primary endpoint: objective response rate
•
Secondary endpoint: median 1- and 2-year survival; safety;
frequency of HER1/EGFR and KRAS mutations
•
Erlotinib 150 mg PO daily until disease progression or unacceptable
toxicity
•
28 days = I cycle
•
Dose interruption or dose reduction (to 100 mg, then to 50 mg) was
permitted for drug-related adverse events
Jackman D, et al. ASCO 2007: Abstract 7591.
EGFR = epidermal growth factor receptor
Women with adeno-NSCLC: results
Jackman D, et al. ASCO 2007: Abstract 7591.
EGFR = epidermal growth factor receptor OS = overall survival PFS = progression-free survival
Women with adeno-NSCLC: conclusions
•
Preliminary results suggest that erlotinib may be a useful treatment
choice for non-smoking chemo-naïve women with adenocarcinoma
•
Furthermore, EGFR mutation status was strongly associated with
improved response, progression-free survival, and overall survival
•
23 patients developed toxicity of grade 3 or greater (most common
were rash and diarrhea)
•
5 patients discontinued for toxicity
•
No response in the KRAS mutant group
Jackman D, et al. ASCO 2007: Abstract 7591.
EGFR = epidermal growth factor receptor
Biomarker Analysis
Correlation of the EGFR gene mutation, gene
amplification and protein expression in non–small
cell lung cancer with clinical outcomes of erlotinib
monotherapy: An exploratory analysis of biomarkers
by the Korean Cancer Study Group
Ahn M, et al. ASCO 2007: Abstract 7608.
Biomarker analysis: study design
•
Primary objective: establish predictors of response rate, time to
progression, and overall survival
•
Eligibility: histologically or cytologically confirmed stage IIIB or IV
NSCLC, including recurrent cancer
•
Treatment: oral erlotinib 150 mg daily until disease progression or
unacceptable toxicity
•
Biomarker analyses: EGFR gene mutation analysis by DNA
sequencing; EGFR gene amplification analysis by real-time PCR;
EGFR protein expression by immunohistochemistry
EGFR = epidermal growth factor receptor
NSCLC = non–small cell lung cancer
Ahn M, et al. ASCO 2007: Abstract 7608.
PCR = polymerase chain reaction
Biomarker analysis: results
CI = confidence interval EGFR = epidermal growth factor receptor F/U = follow up
Ahn M, et al. ASCO 2007: Abstract 7608.
IHC = immunohistochemistry TTP = time to progression
Biomarker analysis: conclusions
•
Predictive factors for prolongation of TTP and OS by univariate
analysis were
 EGFR mutation
 EGFR high gene copy number
 Female gender
 Non-smoker
 Adenocarcinoma
•
By multivariate analysis, independent predictors for prolongation of
TTP were EGFR mutation, high gene copy number, and female
gender.
EGFR = epidermal growth factor receptor
OS = overall survival
Ahn M, et al. ASCO 2007: Abstract 7608.
TTP = time to progression
Cost–effectiveness Trial
Cost-effectiveness of erlotinib vs. docetaxel or
pemetrexed in the treatment of refractory
non–small cell lung cancer (NSCLC)
Carlson J, et al. ASCO 2007: Abstract 7664.
Cost effectiveness trial: study design
•
Objective: to evaluate the incremental cost-effectiveness of
erlotinib compared to docetaxel and pemetrexed in the treatment of
advanced NSCLC (IIIB/IV) in the United States
•
Frame work: a health state transition model with 3 health states
(progression-free, disease progression, and death); US healthcare
system payer
•
Treatments considered: erlotinib, docetaxel, and pemetrexed
•
Costs obtained from published sources, including the Centers for
Medicare and Medicaid Services; and First Data Bank, were
adjusted to 2006 values using the medical component of the
Consumer Price Index
•
Side-effect costs based upon adverse event rates reported in
clinical trials, product package inserts, and guideline-based
treatment assumptions
•
Time horizon: two years with costs and QALYs discounted at 3%
•
Sensitivity analyses performed to evaluate effects of uncertainty in
the model parameters on results
Carlson J, et al. ASCO 2007: Abstract 7664.
NSCLC = non–small cell lung cancer QALY = quality-adjusted life year
Cost effectiveness trial: results
ICER = incremental cost-effectiveness ratio PFS = progression-free survival
Carlson J, et al. ASCO 2007: Abstract 7664.
QALY = quality-adjusted life year
Cost effectiveness trial: conclusions
•
The results suggest erlotinib in the treatment of refractory NSCLC
in the United States is less costly compared with alternative
treatments, with a slight improvement in patient quality of life
•
These findings were driven by drug acquisition, administration, and
side-effect costs
•
Comparative clinical trials will be useful for further evaluation of
potential survival benefits
Carlson J, et al. ASCO 2007: Abstract 7664.
NSCLC = non–small cell lung cancer