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Lung Update

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

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Lung Update

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  1. Lung Update

  2. 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

  3. 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.

  4. INTEREST study:study design Douillard JY et al. WCLC 2007; Abstract PRS-2.

  5. Gefinitib 2.2 9.1 (n = 659) Docetaxel 2.7 7.6 (n = 657) INTEREST study:study conduct Mean time on treatment (months) Objective tumour response* *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.

  6. INTEREST study:demography Douillard JY et al. WCLC 2007; Abstract PRS-2.

  7. INTEREST study:overall survival Douillard JY et al. WCLC 2007; Abstract PRS-2.

  8. INTEREST study:progression-free survival Douillard JY et al. WCLC 2007; Abstract PRS-2.

  9. INTEREST study:overall survival – high EGFR Douillard JY et al. WCLC 2007; Abstract PRS-2.

  10. INTEREST study:overall survival by biomarkers Douillard JY et al. WCLC 2007; Abstract PRS-2.

  11. INTEREST study:post-study treatment Post-study treatments (ITT population) Douillard JY et al. WCLC 2007; Abstract PRS-2.

  12. INTEREST study:QoL results Douillard JY et al. WCLC 2007; Abstract PRS-2.

  13. INTEREST study:adverse events Douillard JY et al. WCLC 2007; Abstract PRS-2.

  14. INTEREST study:adverse events Douillard JY et al. WCLC 2007; Abstract PRS-2.

  15. INTEREST study:adverse events Douillard JY et al. WCLC 2007; Abstract PRS-2.

  16. INTEREST study:conclusions • The study met the primary objective of demonstrating non-inferiority of gefitinib relative to docetaxel in terms of overall survival • High gene copy number has not predicted a greater response or survival benefit from gefitinib over docetaxel in the INTEREST study group • PFS, ORR, and disease-related symptom improvements were similar for gefitinib and docetaxel • 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.

  17. Discussant for INTEREST trial: issue to be addressedShould 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.

  18. 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 • Approved in 9 countries for second and third line • Approved in 25 countries only for third line Shepherd F et al. WCLC 2007; Abstract PRS-2 Discussant.

  19. Supporting data for INTEREST trial:V-15-32 Shepherd F et al. WCLC 2007; Abstract PRS-2 Discussant.

  20. Supporting data for INTEREST trial:overall survival Shepherd F et al. WCLC 2007; Abstract PRS-2 Discussant.

  21. Supporting data for INTEREST trial:QoL Shepherd F et al. WCLC 2007; Abstract PRS-2 Discussant.

  22. Supporting data for INTEREST trial:post-study treatment Shepherd F et al. WCLC 2007; Abstract PRS-2 Discussant.

  23. Supporting data for INTEREST trial:paradigm shift to maintenance treatment? • 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.

  24. 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.

  25. 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.

  26. 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.

  27. TRUST study:results AE = adverse effect SAE = serious adverse effect Gottfried M et al. WCLC 2007; Abstract B3-06.

  28. TRUST study:results – compared to BR.21 †TRUST – patient numbers are different between parameters Given the differences between the study designs and patient populations, the studies are not exactly comparable 1. Shepherd FA et al. N Engl J Med 2005;353:123–132. 2. Gottfried M et al. WCLC 2007; Abstract B3-06.

  29. 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.

  30. 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.

  31. 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.

  32. 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.

  33. BR.21 study:results ICER = incremental cost-effectiveness ratio Bradbury P et al. WCLC 2007; Abstract P#-086.

  34. 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.

  35. 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.

  36. 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.

  37. 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 CR = complete response; PD = progressive disease; PR = partial response; SD = stable disease Tan EH et al. WCLC 2007; Abstract D2-04.

  38. MERIT study:tumour response & clinical benefit CR = complete response; PD = progressive disease; PR = partial response; SD = stable disease Tan EH et al. WCLC 2007; Abstract D2-04.

  39. MERIT study:results Tan EH et al. WCLC 2007; Abstract D2-04.

  40. 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: identify molecular determinants of response • 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.

  41. 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.

  42. 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-naïve patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) Scagliotti G et al. WCLC 2007; Abstract C6-02.

  43. Cisplatin 75 mg/m2, day 1 + pemetrexed 500 mg/m2, day 1 n = 862 RANDOM I ZE • Randomization • factors • Stage • PS • Gender • Histo vs. cyto dx • Brain mets hx Each cycle repeated Q3W up to 6 cycles Cisplatin 75 mg/m2, day 1 + gemcitabine 1250 mg/m2, days 1 & 8 n = 863 Biomarker expression:study design • 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.

  44. 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.

  45. 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.

  46. 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.

  47. KRAS genotype:results RR = response rate; TTP = time to progression Jackman D et al. WCLC 2007; Abstract D2-06.

  48. EGFR genotype:outcomes by EGFR TKI Jackman D et al. WCLC 2007; Abstract D2-06.

  49. EGFR genotype:clinical correlation Jackman D et al. WCLC 2007; Abstract D2-06.

  50. 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. .

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