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

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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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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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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

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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