Lung Update

WCLC 2007:

Overview of advances in lung cancer care

INTEREST – interim analysis

Gefitinib versus docetaxel in patients with locally advanced or metastatic non-small-cell lung cancer pre-treated with platinum based chemotherapy: a randomized, open-label Phase III Study

TRUST – interim safety results

Interim safety results from TRUST, a global open-label study of erlotinib in patients with advanced non-small-cell lung cancer

BR.21

– economic analysis

An economic analysis of the National Cancer Institute of Canada Clinical Trials Group BR.21, a randomized trial of erlotinib versus best supportive care after cisplatin-based chemotherapy in advanced non-small cell lung cancer

MERIT – biomarker relations

A prospective study of putative relationships between tumour biomarkers and clinical benefit from erlotinib in advanced non-small cell lung cancer (NSCLC)

Biomarker Expression

Correlations of biomarker expression and clinical outcome in a large phase III trial of pemetrexed plus cisplatin or gemcitabine plus cisplatin in chemo-naive patients with locally advanced or metastatic non-small cell lung cancer (NSCLC)

EGFR & KRAS genotypes

The impact of EGFR and KRAS genotype in chemotherapy naïve patients with advanced non-small cell lung cancer treated with erlotinib

Elderly

Erlotinib as single agent in elderly patients with advanced or metastatic NSCLC

TargetT Study – single agent



Poor performance status

Erlotinib as monotherapy for patients with advanced or metastatic non-small cell lung cancer and poor performance 

Good performance status

Erlotinib as a single agent in the treatment of patients with advanced or metastatic non-small-cell lung cancer and good performance status

INTEREST Study:

interim results*

Gefitinib versus docetaxel in patients with locally advanced or metastatic non-small-cell lung cancer pre-treated with platinum-based chemotherapy: a randomized, open-label Phase III Study *Results are final for primary endpoint of OS Douillard F et al. WCLC 2007; Abstract PRS-2.

INTEREST study:

study design

Douillard JY et al. WCLC 2007; Abstract PRS-2.

INTEREST study:

study conduct

Mean time on treatment (months)

Gefinitib 2.2

Objective tumour response*

9.1 (n = 659) Docetaxel 2.7

7.6 (n = 657) *RECIST -EFR population *OR (95% CI) = 1.22 (0.82, 1.84) p = 0.3257

*OR >1 implies a greater chance of response on gefinitib; OR and p-value from logistic regression with covariates OR = odds ratio; RECIST = response evaluation criteria in solid tumours; Douillard JY et al. WCLC 2007; Abstract PRS-2.

INTEREST study:

demography

Douillard JY et al. WCLC 2007; Abstract PRS-2.

INTEREST study:

overall survival

Douillard JY et al. WCLC 2007; Abstract PRS-2.

INTEREST study:

progression-free survival

 Douillard JY et al. WCLC 2007; Abstract PRS-2.

INTEREST study:

overall survival – high EGFR

Douillard JY et al. WCLC 2007; Abstract PRS-2.

INTEREST study:

overall survival by biomarkers

Douillard JY et al. WCLC 2007; Abstract PRS-2.

INTEREST study:

post-study treatment

Post-study treatments (ITT population)

Douillard JY et al. WCLC 2007; Abstract PRS-2.

INTEREST study:

QoL results

Douillard JY et al. WCLC 2007; Abstract PRS-2.

INTEREST study:

adverse events

Douillard JY et al. WCLC 2007; Abstract PRS-2.

INTEREST study:

adverse events

Douillard JY et al. WCLC 2007; Abstract PRS-2.

INTEREST study:

adverse events

Douillard JY et al. WCLC 2007; Abstract PRS-2.

INTEREST study:

conclusions

 The study met the primary objective of demonstrating non-inferiority of gefitinib relative to docetaxel in terms of overall survival   PFS, ORR, and disease-related symptom improvements were similar for gefitinib and docetaxel  High gene copy number has not predicted a greater response or survival benefit from gefitinib over docetaxel in the INTEREST study group Gefitinib had a more favourable tolerability profile than docetaxel  Significantly more gefitinib-treated patients experienced a clinically more important improvement in QoL versus docetaxel Douillard JY et al. WCLC 2007; Abstract PRS-2.

Discussant for INTEREST trial:

issue to be addressed

Should EGFR TKIs be used in preference to standard chemo for the second-line treatment of NSCLC?

Shepherd F et al. WCLC 2007; Abstract PRS-2.

Background:

NSCLC second-line chemo

 According to ASCO 1997 guidelines there was no current evidence to confirm or refute that second-line chemotherapy improved survival in patients with advanced NSCLC  Approved agents for second-line treatment of NSCLC • Docetaxel • Pemetrexed • Erlotinib • Gefitinib w Approved in 9 countries for second and third line w Approved in 25 countries only for third line Shepherd F et al. WCLC 2007; Abstract PRS-2 Discussant.

Supporting data for INTEREST trial:

V-15-32

Shepherd F et al. WCLC 2007; Abstract PRS-2 Discussant.

Supporting data for INTEREST trial:

overall survival

Shepherd F et al. WCLC 2007; Abstract PRS-2 Discussant.

Supporting data for INTEREST trial:

QoL

Shepherd F et al. WCLC 2007; Abstract PRS-2 Discussant.

Supporting data for INTEREST trial:

treatment post-study

Shepherd F et al. WCLC 2007; Abstract PRS-2 Discussant.

Supporting data for INTEREST trial:

to maintenance treatment?

paradigm shift

 SATURN study: compares maintenance erlotinib to placebo in patients who are stable and responding  EORTC 08021: compares gefitinib to placebo in patients who are stable and responding, and are EGFR IHC positive  BeTa Lung Trial: compares maintenance bevacizumab with or without erlotinib in stable and responding patients with first-line chemotherapy plus bevacizumab Shepherd F et al. WCLC 2007; Abstract PRS-2 Discussant.

INTEREST trial:

discussant conclusions

 EGFR TKI therapy is a reasonable option for the second-line treatment of NSCLC in unselected patients  Symptom improvement favours EGFR TKIs  Toxicity profile favours EGFR TKIs  Results of trials comparing erlotinib and pemetrexed are awaited  Results of trials of erlotinib and bevacizumab are also awaited Shepherd F et al. WCLC 2007; Abstract PRS-2 Discussant.

TRUST Study:

interim safety results

Interim safety results from TRUST, a global open label study of erlotinib in patients with advanced non-small cell lung cancer Gottfried M et al. WCLC 2007; Abstract B3-06.

TRUST study:

study design

   

Primary objective:

to provide access to erlotinib for suitable patients in countries where the drug was not yet licensed • In 52 countries 7,040 patients recruited

Secondary endpoints:

safety, best response (RECIST), progression-free survival (PFS), overall survival  Phase IV, open-label, non-randomized multicentre trial Recruitment continued until erlotinib licence granted in country Erlotinib 150 mg PO daily until disease progression, death, or unacceptable toxicity; dose interruption or reduction in the event of treatment-related side effects Gottfried M et al. WCLC 2007; Abstract B3-06.

TRUST study:

results

Gottfried M et al. WCLC 2007; Abstract B3-06.

AE = adverse effect SAE = serious adverse effect

TRUST study:

results – compared to BR.21

TRUST n >5000 † (%) BR.21

1 n = 485 (%) Complete response <1 1 Partial response 11 8 Stable disease 56 35 Disease control rate (DCR) Dose reductions due to erlotinib related event Withdrawals due to erlotinib-related event Erlotinib-related rash 14 6 70 19 5 76 Interstitial lung disease <1 † TRUST – patient numbers are different between parameters Given the differences between the study designs and patient populations, the studies are not exactly comparable <1 1. Shepherd FA et al.

N Engl J Med

2005;353:123 –132.

2. Gottfried M et al. WCLC 2007; Abstract B3-06.

68 44

TRUST study:

conclusions

 These interim safety data confirm the favourable safety profile of erlotinib observed in the phase III BR.21 study  These interim efficacy data appear to be consistent with previous findings with erlotinib • Estimates of DCR and median PFS are in line with those from the BR.21 study Gottfried M et al. WCLC 2007; Abstract B3-06.

BR.21 Study:

economic analysis

An economic analysis of the National Cancer Institute of Canada Clinical Trials Group BR.21, a randomized trial of erlotinib versus best supportive care after cisplatin-based chemotherapy in advanced non-small cell lung cancer Bradbury P et al. WCLC 2007; Abstract P3-086.

BR.21 study:

economic objectives

 To investigate the cost-effectiveness of erlotinib in patients with advanced NSCLC after chemotherapy failure, from the perspective of the Canadian healthcare system  To investigate the cost-effectiveness of erlotinib in subgroups of patients predicted to have greater benefit based on clinical and molecular predictors of response and/or survival  To investigate the cost effectiveness of erlotinib when used as second- versus third-line therapy Bradbury P et al. WCLC 2007; Abstract P#-086.

BR.21 study:

ICER methods

 ICER (incremental cost-effectiveness ratio) compares the new drug with the previous way of treating the patient group for whom the new drug is being proposed  Calculated by dividing the cost difference between the new and old treatments by the difference in effects, to yield the additional cost per unit outcome (e.g., $50,000 per quality-adjusted life year [QALY]) Gafni A et al.

CMAJ

2003.

BR.21 study:

results

Bradbury P et al. WCLC 2007; Abstract P#-086.

ICER = incremental cost-effectiveness ratio

BR.21 study:

conclusions

 ICER numbers for subgroups differed as follows: • Men $96,601 and women $120,671 • One prior regimen $67,844 • Never smokers $39,487 • Adenocarcinoma $75,059 • Asians $83,181 Bradbury P et al. WCLC 2007; Abstract P#-086.

BR.21 study:

conclusions

 The overall ICER for erlotinib is consistent with use of other targeted anticancer agents  The mean ICER for erlotinib therapy in advanced NSCLC patients after chemotherapy is $95,686 in 2007 Canadian dollars  Smoking status had a significant impact on ICER in sub-group analysis Bradbury P et al. WCLC 2007; Abstract P#-086.

MERIT Study:

biomarker relations

A prospective study of putative relationships between tumour biomarkers and clinical benefit from erlotinib in advanced non-small cell lung cancer (NSCLC) Tan EH et al. WCLC 2007; Abstract D2-04.

MERIT study:

study design and objectives

Primary objective:

differentially expressed genes that predict clinical benefit (CR, PR, SD ≥12 weeks) with erlotinib

Secondary objectives:

EGFR mutations; correlation with clinical benefit. Exploratory assessment of EGFR and downstream targets *Or refused/were unsuitable for chemotherapy Tan EH et al. WCLC 2007; Abstract D2-04.

CR = complete response; PD = progressive disease; PR = partial response; SD = stable disease

MERIT study:

tumour response & clinical benefit

PR SD  6 weeks SD  12 weeks PD Not available Clinical benefit OR (RECIST) or SD  12 weeks Disease control CR+PR+SD Enrolled n = 264 n (%) 36 (14) Analyzed n = 102 n (%) 6 (6) 80 (30) 47 (18) 116 (44) 32 (12) 83 (32) 116 (44) 31 (30) 15 (15) 49 (48) 16 (16) 21 (21) 37 (36) CR = complete response; PD = progressive disease; PR = partial response; SD = stable disease Tan EH et al. WCLC 2007; Abstract D2-04.

MERIT study:

results

Tan EH et al. WCLC 2007; Abstract D2-04.

MERIT study:

analysis of differential gene expression (DGE)



Primary objective:

identify ‘binary’ marker of clinical benefit • Powered to detect five genes with eight-fold change in gene expression for clinical benefit versus no clinical benefit 

Exploratory analysis:

response identify molecular determinants of 

Approach:

statistical remodelling of gene expression profiles • • Multivariate linear model fitted independently to each probe set Significance criterion based on False Discovery Rate (FDR) to adjust for multiple testing Tan EH et al. WCLC 2007; Abstract D2-04.

MERIT study:

conclusions

 MERIT is the largest prospective genomic profiling study ever conducted in advanced NSCLC  The findings support the use of erlotinib in patients with advanced NSCLC who have failed a chemotherapy regimen  There are no binary markers for clinical benefit identified at the RNA expression level in baseline tumour biopsy samples  In exploratory analyses, three markers for response were identified on chromosome 7: EGFR, PSPH, RAPGEF5 Tan EH et al. WCLC 2007; Abstract D2-04.

Biomarker expression:

cis/pem vs. cis/gem biomarker analysis

Correlations of biomarker expression and clinical outcome in a large phase III trial of pemetrexed plus cisplatin or gemcitabine plus cisplatin in chemo-na ïve patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) Scagliotti G et al. WCLC 2007; Abstract C6-02.

Biomarker expression:

study design

Randomization factors

• • • • •

Stage PS Gender Histo vs. cyto dx Brain mets hx R A N D O M I Z E Cisplatin 75 mg/m 2 , day 1 + pemetrexed 500 mg/m 2 , day 1 n = 862

Each cycle repeated Q3W up to 6 cycles

Cisplatin 75 mg/m 2 , day 1 + gemcitabine 1250 mg/m 2 , days 1 & 8 n = 863

  Non-inferiority study design – Fixed Margin Method Vitamin B12, folate, and dexamethasone given in both arms PS = performance status Scagliotti G et al. WCLC 2007; Abstract C6-02.

Biomarker expression:

results

 Overall survival: cis/pem non-inferior to cis/gem • 10.3 vs. 10.3 mo [HR 0.94, 95% CI: 0.84

–1.05] • • Progression-free survival (PFS) & overall response rate (ORR): Cis/pem non-inferior to cis/gem PFS: 4.8 vs. 5.1 mo [HR 1.04, 95% CI: 0.94

–1.15] ORR: 31% [95% CI: 27 –34] vs. 28% [95% CI: 25–31] Cis/pem appears to have better efficacy vs. cis/gem in adenocarcinoma and large cell carcinoma  Cis/pem showed a significantly better safety profile vs. cis/gem • neutropenia, thrombocytopenia, febrile neutropenia, other toxicities  Low thymidylate synthase (TS) levels were associated with better outcomes for cis/pem CI = confidence interval; HR = hazard ratio Scagliotti G et al. WCLC 2007; Abstract C6-02.

Biomarker expression:

conclusions

 In this multicentre study, tissue procurement was not mandatory. Samples obtained in <15% of enrolled patients  IHC analyses feasible in majority of samples collected, but determination of mRNA by TaqMan feasible in only 30%. Notably, associations between expression and clinical outcomes were stronger for mRNA than for IHC  Elevated EGFR expression appears to be “prognostic” for better outcomes (TtTP, ORR)  ERCC1 and FPGS expression showed significant association with clinical outcomes (TtTP for both; PFS and TtTF for ERCC1) Scagliotti G et al. WCLC 2007; Abstract C6-02.

EGFR & KRAS genotype:

impact

The impact of

EGFR

and

KRAS

genotype in chemotherapy naïve patients with advanced non-small cell lung cancer treated with erlotinib Jackman D et al. WCLC 2007; Abstract D2-06.

KRAS genotype:

results

Jackman D et al. WCLC 2007; Abstract D2-06.

RR = response rate; TTP = time to progression

EGFR genotype:

outcomes by EGFR TKI

Jackman D et al. WCLC 2007; Abstract D2-06.

EGFR genotype:

clinical correlation

Jackman D et al. WCLC 2007; Abstract D2-06.

EGFR & KRAS genotype:

conclusions

 Supports the impact of

EGFR

genotype on outcome to treatment with an EGFR TKI  Additional evidence that patients with

KRAS

mutations, exon 20 insertions, and

T790M

should be considered for other treatments   Within the subset of patients with known sensitizing

EGFR

mutations, no correlation between outcomes and • • • Smoking Gender EGFR TKI used Research is continuing; the total samples in database are only 94 previously untreated patients .

Jackman D et al. WCLC 2007; Abstract D2-06.

Elderly patients:

erlotinib as single agent

Erlotinib as single agent in elderly patients with advanced or metastatic non-small cell lung cancer Alberola V et al. WCLC 2007; Abstract P3-061.

Single agent:

objectives



Primary endpoint:

Evaluate time to progression (TTP) in the intent to treat population 

Secondary endpoint:

• Determine the efficacy of erlotinib in terms of disease control rate • • Determine overall survival (OS) in this patient population Define safety profile of erlotinib as determined by NCI CTCAE v3.0

Alberola V et al. WCLC 2007; Abstract P3-061.

Single agent:

results

Alberola V et al. WCLC 2007; Abstract P3-061.

HR = hazard ratio; TTP = time to progression

Single agent:

results

0.0011

Alberola V et al. WCLC 2007; Abstract P3-061.

TTP = time to progression

Single agent:

conclusions

 Confirms erlotinib as an active and well-tolerated agent in elderly patients (age 70 or older) with advanced or metastatic NSCLC   Gender, smoking status, and line of treatment are predictive factors for tumour response  Response rates and overall survival are similar to those found previously for standard chemotherapy in this patient population Time to progression and overall survival were significantly different depending on smoking history Alberola V et al. WCLC 2007; Abstract P3-061.

Poor performance status :

erlotinib monotherapy

Erlotinib as monotherapy for patients with advanced or metastatic non-small cell lung cancer and poor performance Garcia R et al. WCLC 2007; Abstract P3-081.

Poor performance status:

study design

• TargetT trial: Open-label, multicentre, non-randomized, phase II trial.

Stage IIIB or IV NSCLC 1,796 patients ECOG PS 0-2 1 or 2 CT regimens



18 years Erlotinib

150 mg/day PO

Poor PS ECOG PS 2 ECOG 2 n= 386 n = 386 Good PS ECOG 0-1 n = 1,153

PD or withdrawal PD or withdrawal •

Poor Performance status:

Sub-group analysis of 386 patients with ECOG PS 2 •

Primary endpoint:

Time to progression (TTP) •

Secondary endpoints:

Disease control rate [CR+PR+SD], overall survival (OS), and safety Garcia R et al. WCLC 2007; Abstract P3-081.

CR = complete response; PD = progressive disease; PR = partial response; PS = performance status; SD = stable disease

Poor performance status:

results

Garcia R et al. WCLC 2007; Abstract P3-081.

HR = hazard ratio; TTP = time to progression

Poor performance status:

results

Garcia R et al. WCLC 2007; Abstract P3-081.

TTP = time to progression

Poor performance status:

conclusions

  Treatment with single-agent erlotinib achieved a disease control rate of 54.73% and 16.22%  Real-life setting confirmed effectiveness of single-agent erlotinib in patients with bad performance status, leading to a median overall survival of 2.5 months Gender, smoking status, histology, and line of treatment are predictive factors for tumour response  Absence of smoking history associated with longer time to progression and survival. Subgroup of non-smokers reached a median overall survival of 3.9 months  Erlotinib is an effective and well-tolerated option for patients with bad performance status. Candidates to receive best supported care treatment Garcia R et al. WCLC 2007; Abstract P3-081.

Good performance status :

erlotinib monotherapy

Erlotinib as a single agent in the treatment of patients with advanced or metastatic non-small cell lung cancer and good performance status Garrido P et al. WCLC 2007; Abstract P3-083.

Good performance status:

study design

• TargetT trial: Open-label, multicentre, non-randomized, phase II trial

Stage IIIB or IV NSCLC 1,796 patients ECOG PS 0-2 1 or 2 CT regimens



18 years Erlotinib

150 mg/day PO

Poor PS ECOG PS 2 ECOG 2 n= 386 n = 386 Good PS ECOG 0-1 n = 1,153

PD or withdrawal PD or withdrawal •

Good performance status:

Sub-group analysis of 1,153 patients with ECOG PS 0-1 •

Primary endpoint:

Time to progression (TTP) •

Secondary endpoints:

Disease control rate [CR+PR+SD], overall survival (OS), and safety CR = complete response; PD = progressive disease; PR = partial response; PS = performance status; SD = stable disease Garrido P et al. WCLC 2007; Abstract P3-083.

Good performance status:

results

Garrido P et al. WCLC 2007; Abstract P3-083.

Good performance status:

results

Garrido P et al. WCLC 2007; Abstract P3-083.

HR = hazard ratio; TTP = time to progression

Good performance status:

conclusions

     Real-life setting confirmed the effectiveness of single-agent erlotinib in patients with good performance status, leading to a median overall survival of 7.2 months Treatment with single-agent erlotinib achieved a disease control rate of 58.4% and a response of 19.3% Gender, smoking status, histology, and line of treatment are predictive factors for tumour response Absence of smoking and line of treatment associated with longer time to progression and survival. Subgroup of non-smokers reached a median overall survival of 13.4 months Erlotinib is an effective and well-tolerated option for patients with good performance status. Candidates to receive standard chemotherapy Garrido P et al. WCLC 2007; Abstract P3-083.