1. Romàn Pérez-Soler Gutman 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 York University 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

2. First choice in second line: erlotinib in NSCLC
Romàn Pérez-Soler
Montefiore Medical Center Albert Einstein College of Medicine New York, USA

3. 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

4. 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)

5. The current treatment algorithm for NSCLC
Early (stage I/II/ selected IIIA)
NSCLC
Advanced (stage IIIB with PE/IV)
Suitable for standard chemotherapy? PS
Age
Controlled/uncontrolled brain metastases
Concomitant medical condition
Surgery ± chemotherapy
First line
Yes No
Radiotherapy (if unfit for surgery)
Fit elderly/
PS 2?
Frail elderly/ PS 3
PS 4
Best supportive care
Locally advanced
(stage IIIA/IIIB no PE)
Platinum-based doublet chemotherapy ± bevacizumab
Single agent
Relapse
Chemotherapy
(platinum doublet)
+ concomitant
radiotherapy
or sequential
Chemotherapy – docetaxel
– pemetrexed
– vinorelbine
– gemcitabine
EGFR-targeted therapy
– erlotinib
– gefitinib
Second/third line
PE = pleural effusion

6. Data overview: the BR.21 and TRUST studies

7. Erlotinib 150mg daily (n=488)
BR.21: trial design
Erlotinib 150mg daily (n=488)
RANDOM I SE
Phase III trial
Advanced stage IIIB/IV NSCLC
(n=731) 2
Placebo (n=243) 1
Primary endpoint = overall survival (OS)
Secondary endpoints = progression-free survival (PFS), response rate (RR) and duration of response, safety, QoL

8. 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

9. BR.21: overall survival 100 75 50 25 n Median survival (months)n
Median survival (months)
1-year survival
Erlotinib
488
6.7 31
Placebo
243
4.7 21
Survival probability (%)
HR=0.73, p=0.001*
 42.5% increase in median OS
*HR and p (log-rank test) adjusted for stratification factors at randomisation and EGFR status HR = hazard ratio
Time (months)
Shepherd F, et al. N Engl J Med 2005;353:123–32 Tarceva Summary of Product Characteristics, F. Hoffmann-La Roche Ltd

10. BR.21: progression-free survival
1.00
0.75
0.50
0.25 n
Median survival (weeks)
6 months (%)
Erlotinib
488
9.7 25
Placebo
243
8.0 10
HR=0.61, p<0.001*
Survival distribution function
25%
10%
Time (months)
*HR and p (log-rank test) adjusted for stratification
factors at randomisation and EGFR status
Shepherd F, et al. N Engl J Med 2005;353:123–32

11. Is there a clinical benefit with erlotinib in men? Answer: Yes
Survival
Women
Men
1.00
0.75
0.50
0.25
1.00
0.75
0.50
0.25
HR=0.8 (0.6–1.1), p=0.13
HR=0.8 (0.6–0.9), p=0.01
Erlotinib (n=173)
Erlotinib (n=315)
Survival distribution function
Placebo (n=83)
Placebo (n=160)
Months
Months
Shepherd F, et al. N Engl J Med 2005;353:123–32

12. Squamous-cell carcinoma Survival distribution function
Is there a clinical benefit with erlotinib in squamous-cell carcinoma? Answer: Yes
Survival
Adenocarcinomas
Squamous-cell carcinoma
1.00
1.00
0.75
0.50
0.25
0.75
HR=0.7 (0.6– 0.9), p=0.008
HR=0.67 (0.5–0.9), p=0.0007
0.50
Survival distribution function
Erlotinib (n=246)
Erlotinib (n=144)
0.25
Placebo (n=119)
Placebo (n=78)
Months
Months
Shepherd F, et al. N Engl J Med 2005;353:123–32

13. Is there a clinical benefit with erlotinib in current/ex-smokers
Is there a clinical benefit with erlotinib in current/ex-smokers? Answer: Yes
Current/ex-smokers
Never smokers
1.00
1.00
HR=0.9 (0.7–1.0), p=0.141*
HR=0.42 (0.28–0.64), p<0.001
0.75
0.75
Erlotinib (n=358)
Erlotinib (n=104)
Survival distribution function
0.50
0.50
0.25
0.25
Placebo (n=187)
Placebo (n=42)
Months
Months
*Log-rank test
Shepherd F, et al. N Engl J Med 2005;353:123–32

14. Investigating optimal dosing regimen for current/former smokers
Erlotinib PK single dose
Never smokers: Erlotinib 150mg/day
Screening and tissue collection
Day 3
Current/former smokers: Erlotinib dose escalation
Day –7 to 0
Day 1
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
PK = pharmacokinetic
PI: Dr EF Smit (The Netherlands)

15. BR.21: all patient subgroups derived a survival benefit
Erlotinib:placebo
PS 0– (0.6–0.9)
PS 2– (0.6–1.0)
Male (0.6–0.9)
Female (0.6–1.1)
<65 years (0.6–0.9)
65 years (0.6–1.0)
Adenocarcinoma (0.6–0.9)
Squamous-cell carcinoma (0.5–0.9)
Other histology (0.7–1.5)
Erlotinib:placebo
Never-smoker (0.3–0.6)
Current/ex-smoker (0.7–1.1)
1 prior regimen (0.6–1.0)
2+ prior regimens (0.6–1.0)
Best prior response: CR/PR (0.5–0.9)
Best prior response: SD (0.6–1.1)
Best prior response: PD (0.6–1.2)
Asian (0.4–1.0)
Other (0.7–0.9)
Factors
0 1 2
0 1 2 HR HR
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

16. Erlotinib does not produce haematological toxicity
BR.21: adverse events
Erlotinib (n=485)
Placebo (n=242)
Any (%)
Grade 3/4 (%)
Rash 75 9 17
Diarrhoea 54 6 18
<1
Nausea 33 3 24 2
Vomiting 23 19
Stomatitis
Fatigue 52 45 20
Ocular (all) 27 1
Anorexia 38 5
Infection 4 15
Erlotinib does not produce haematological toxicity
Shepherd F, et al. N Engl J Med 2005;353:123–32

17. BR.21: change in QoL domains (EORTC QLQ-C30)
Improved* (%)
Stable (%)
Worse (%)
Variable
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
Cognitive function 29 23
Emotional function† 30 36 37
Social function 21 44
*³10 point change from baseline at any time (clinically significant)
†p0.01
EORTC = European Organisation for Research and Treatment of Cancer
Bezjak A, et al. J Clin Oncol 2006;24:3831–7

18. 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

19. 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 to erlotinib-related AEs (%)
 319 (6)
*Other than the 15 prespecified AEs SAE = serious adverse event
Ardizzoni A, et al. J Thorac Oncol 2007;2(Suppl 4):S342 (Abstract B3–06)

20. TRUST: incidence of erlotinib-related rash*
30%
58%
12%
Ardizzoni A, et al. J Thorac Oncol 2007;2(Suppl 4):S342 (Abstract B3–06)
*Based on data from 6,153 patients

21. Rash may be related to magnitude of benefit from erlotinib in NSCLC
Excludes patients who died within 28 days of entry
Grade 0 (n=86) Median: 3.3 months
Grade 1 (n=135) Median: 7.1 months
Grade 2+ (n=223) Median: 11.1 months
1.00
0.75
0.50
0.25
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
2+ vs 1
0.70
0.54–0.90
0.005
Survival probability
Time (months)
Correlation was maintained in multivariate analyses
CI = confidence interval
Wacker B, et al. Clin Cancer Res 2007;13:3913–21

22. Comparison between TRUST and BR.21CR
<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
*Given the differences between study designs and patient populations, the studies are not directly comparable †Patient numbers are different between parameters
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

23. BR.21 and TRUST*: improvement in PFS with erlotinib
1.00
0.75
0.50
0.25
BR.211
Median PFS: erlotinib 9.7 weeks; placebo 8 weeks (p<0.001)
TRUST2
Median PFS: 13 weeks
Erlotinib (TRUST), n=6,181†
Survival distribution function
Erlotinib (BR.21), n=488
Placebo (BR.21), n=243
*Given the differences between study designs and patient populations, the studies are not directly comparable †Patient numbers are different between parameters
PFS (months)
1Shepherd FA, et al. N Engl J Med 2005;353:123–32 2Ardizzoni A, et al. J Thorac Oncol. 2007;2(Suppl. 4):S342 (Abstract B3–06)

24. 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

25. Erlotinib in the routine clinical setting

26. 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

27. 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

31. Predicting clinical benefit with erlotinib

32. 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

33. Prognostic versus predictive markers: an important distinction
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

34. 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

35. BR.21: EGFR biomarker status does not predict for survival benefit with erlotinibHR CI p* p†
EGFR expression (IHC) IHC+ IHC–
0.49– –1.36
Gene copy number (FISH) Low High
0.49– –0.78
EGFR mutation status Wild-type‡ Mutant§
0.52– –1.19
0.25
0.12
0.47
*p value for subgroup compared with placebo; †p value for interaction ‡Includes indeterminate variants; §Exon 19 deletions and L858R
Tsao M-S, et al. N Engl J Med 2005;353:133–44
Tsao M-S, et al. N Engl J Med 2006;354:527–8
Shepherd FA, et al. J Clin Oncol 2007;25(Suppl. 18I):402s (Abstract 7571)
FISH = fluorescence in-situ hybridisation

36. Survival according to EGFR IHC* and EGFR FISH status in TRUST study
1.00
0.75
0.50
0.25
1.00
0.75
0.50
0.25
EGFR IHC+ (n=229)
EGFR IHC– (n=55)
EGFR FISH+ (n=49)
EGFR FISH– (n=156)
Survival distribution function
Survival distribution function
HR=0.766 p=0.1056†
HR=0.662 p=0.0341†
OS (days)
OS (days)
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)

37. EGFR mutations and clinical outcomes 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

38. MERIT (MarkER Identification Trial): design and objectives
Mandatory samples
Tumour biopsy
Tumour block (if available)
RNA blood sample
Primary endpoint
To identify differentially expressed genes that predict clinical benefit (CR, PR, SD 12 weeks) with erlotinib
Patients
stage IIIB/IV NSCLC (failed 1 first-line treatment*)
Open-label
erlotinib
150mg/day PD
Second RNA blood sample
Follow-up
every 12 weeks
Screening
Day –28
Day 1
Week 6
Secondary endpoints
Correlation of EGFR mutations with clinical benefit
Exploratory assessment of EGFR and downstream targets
Clinical assessment at screening, then every 6 weeks until PD
*Or refused/were unsuitable for chemotherapy RNA = ribonucleic acid

39. 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)

40. SATURN (Sequential Tarceva® in unresectable NSCLC)
Chemotherapy naïve stage IIIB/IV NSCLC
Planned n=1,700
Stratify by EGFR protein expression (IHC) ‘10% cut-off’
Tumour samples
(mandatory) PD
Placebo
Erlotinib
150mg/day
Four cycles of first-line standard platinum-based doublet
Non-PD
(n=850)
1:1 rand
TITAN (n=650)
or off study PD

41. What answers will SATURN provide?
EGFR IHC+
Erlotinib
150mg/day
Co-primary endpoint = 33% increase in PFS in patients with EGFR IHC+ tumours
EGFR IHC–
Primary endpoint = 25% increase in PFS (all patients)
EGFR IHC–
Placebo
EGFR IHC+

42. What answers will SATURN provide?
Many other putative biomarkers will be prospectively evaluated
EGFR FISH
EGFR/KRAS mutations
pMAPK IHC
pAKT IHC
HER2 IHC
EGFR intron 1 polymorphisms
Erlotinib
150mg/day
Placebo
Largest prospective biomarker study ever performed for a targeted agent
results expected in late 2008

43. 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

44. Adding other agents to erlotinib

45. 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

46. Phase II study of bevacizumab with chemotherapy or erlotinib in advanced NSCLC
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
Erlotinib + bevacizumab (n=39) PD
Erlotinib
Previously treated advanced non-squamous NSCLC (n=120)
Chemotherapy + bevacizumab (n=40)
Chemotherapy (n=41)
Randomised, multicentre study
Primary endpoint: safety and preliminary efficacy (PFS)
Secondary endpoints: ORR (plus duration); duration of survival
OSI-2950g
Bevacizumab 15mg/kg every 3 weeks; erlotinib 150mg/day orally; docetaxel 75mg/m2 and pemetrexed 500mg/m2 every 3 weeks
Promising results seen with this novel approach
ORR = overall response rate
Herbst R, et al. J Clin Oncol 2007;25:4743–50

47. ATLAS: bevacizumab plus erlotinib as sequential therapy following bevacizumab plus CT in first line
Bevacizumab + erlotinib PD
Off study
Chemotherapy naïve stage IIIb/IV non-squamous NSCLC
Bevacizumab + chemotherapy*
Non-PD
1:1
(n≈800)
Bevacizumab+ placebo
Erlotinib
PD or significant toxicity PD
Primary endpoint = PFS (time from randomisation until disease progression or death)
Status: ongoing
planned n=1,150
Off study
AVG3671g (phase IIIb) Bevacizumab 15mg/kg every 3 weeks; erlotinib 150mg/day *Either carboplatin/paclitaxel, carboplatin/gemcitabine or carboplatin/docetaxel CT = chemotherapy

48. BETA LUNG: erlotinib ± bevacizumab in the second-line setting
Erlotinib 150mg/day orally + bevacizumab 15mg/kg every 3 weeks
PD*
Previously treated advanced non-squamous NSCLC
Erlotinib 150mg/day orally + placebo PD
Double‑blind, randomised study
Primary endpoint = OS (increase by 33%; from 8.0 to months)
Secondary endpoints = PFS, RR and duration, safety and PK
Status: ongoing; planned n=650
OSI-3364g (phase III)
*No cross over permitted

49. The future treatment algorithm for NSCLC?
Early (stage I/II/selected IIIA)
NSCLC
Advanced (stage IIIB with PE/IV)
Suitable for standard chemotherapy? PS
Age
Controlled/uncontrolled brain metastases
Concomitant medical condition
Initiate biomarker testing at diagnosis stage?
Surgery ± chemotherapy
First line
Yes No
Radiotherapy (if unfit for surgery)
Add erlotinib first line in suitable patients?
Fit elderly/
PS 2?
Frail elderly/ PS 3
PS 4
Locally advanced
(stage IIIA/IIIB no PE)
Platinum-based doublet chemotherapy ± bevacizumab
Best supportive care
Single agent
Relapse
Chemotherapy
(platinum doublet)
+ concomitant
radiotherapy
or sequential
Add bevacizumab to second- and third-line regimens?
Chemotherapy – docetaxel
– pemetrexed
– vinorelbine
– gemcitabine
EGFR-targeted therapy
– erlotinib
– gefitinib
Second/third line

50. 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