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Vera Hirsh, MD, FRCPC McGill University Health Centre Montreal, QC, CANADA

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  1. Clinical data on EGFR-TKIs and Overcoming Resistance in Metastatic NSCLC2nd Quebec Conference on Therapeutic Resistance in Cancer Vera Hirsh, MD, FRCPC McGill University Health Centre Montreal, QC, CANADA

  2. EGFR expression in human tumours Tumours showinghigh EGFR expression High expressiongenerally associatedwith NSCLC 40-80% Prostate 40-80% Gastric 33-74% Head and neck 90-100% Breast 14-91% Colorectal 25-77% Pancreatic 30-50% Ovarian 35-70% Invasion Metastasis Late-stage disease Poor outcome

  3. EGFR mutation causes conformational change and increased activation Wild Type EGFR Mutant EGFR Ligand Extracellular domain Trans-membrane domain Tyrosine kinase domain ATP Tyrosine phosphorylation Ras-Raf-MAPK Proliferation Pi3K-AKT Survival EGFR internalisation Degradation/recycling EGFR signals for longer at the cell membrane Arteaga 2006, Gadzar et al 2004, Hendricks et al 2006, Sordella et al 2004

  4. The distribution of activating mutations among EGFR mutation positive patients is similar in Asian and non-Asian studies ATP binding cleft Regulatory domain Transmembrane region Extracellular domain C-lobe N-lobe TK domain A-loop Chelix P-loop 21 20 19 18 Some patients had more than one mutation type

  5. BR.21 Study Design Erlotinib* 150 mg daily RANDOM I ZE Stratified by: Centre PS, 0/1 vs 2/3 Response to prior Rx (CR/PR:SD:PD) Prior regimens, (1 vs 2) Prior platinum, (Yes vs no) Placebo “150 mg” daily *2:1 Randomization

  6. BR.21: Overall Survival 1.00 0.75 0.50 0.25 0 HR=0.70 (95% CI, 0.58-0.85); P < 0.001* Survival distribution function 31% 42.5% improvement in median survival Erlotinib Placebo 21% 0 5 10 15 20 25 30 Survival time (months) *HR and P-value adjusted for stratification factors at randomization plus HER1/EGFR status. Shepherd et al. N Engl J Med. 2005;353:123-132.

  7. IPASS: first-line study design Gefitinib(250 mg/day) 1:1 randomisation Carboplatin (AUC 5 or 6)/ paclitaxel (200 mg/m2) 3 weekly† Endpoints • Patients • Chemo-naïve • Age ≥18 years • Adenocarcinoma histology • Never or light ex-smokers* • Life expectancy≥12 weeks • PS 0-2 • Measurable stage IIIB/ IV disease • Primary • PFS (non-inferiority) • Secondary • ORR • OS • QoL • Disease-related symptoms • Safety and tolerability • Exploratory • Biomarkers • EGFR mutation • EGFR-gene-copy number • EGFR protein expression *Never smokers, <100 cigarettes in lifetime; light ex-smokers, stopped 15 years ago and smoked 10 pack years†Maximum of 6 cycles Carboplatin / paclitaxel was offered to gefitinib patients upon progression; AUC, area under curve Mok et al 2009

  8. IPASS: ORR Patients (%) (n=609) (n=608) Odds ratio >1 implies a greater chance of response on gefitinib Odds ratio and p-value from logistic regression with covariates Mok et al 2009

  9. IPASS: pre-planned analysis of ORR by EGFR mutation status Gefitinib Carboplatin / paclitaxel EGFR M+ OR (95% CI) 2.75 (1.65, 4.60), p=0.0001 EGFR M- OR (95% CI ) 0.04 (0.01, 0.27), p=0.0013 ORR (%) 71.2 47.3 23.5 1.1 (n=132) (n=129) (n=91) (n=85) ITT populationOR>1 implies greater chance of response on gefitinibOR and p-value from logistic regression with covariate Mok et al 2009

  10. IPASS: PFS Carboplatin /paclitaxel Gefitinib N Events 609 453 (74.4%) 608 497 (81.7%) HR (95% CI) = 0.741 (0.651, 0.845) p<0.0001 5.874%48%7% Median PFS (months)4 months progression-free6 months progression-free12 months progression-free 5.761%48%25% Probabilityof PFS 1.0 0.8 0.6 0.4 0.2 0.0 0 4 8 12 16 20 24 Months Primary Cox analysis with covariates; ITT population HR <1 implies a lower risk of progression on gefitinibITT, intent-to-treat Mok et al 2009

  11. IPASS: pre-planned analysis of PFSby EGFR mutation status EGFR M- 1.0 N Median (m) Gefitinib 91 1.5 Carboplatin / paclitaxel 85 5.5 0.8 HR (95% CI) = 2.85 (2.05, 3.98) p<0.0001 0.6 Probability of PFS 0.4 0.2 0.0 0 4 8 12 16 20 24 Time from randomisation (months) EGFR M+ 1.0 N Median (m) Gefitinib 132 9.5 Carboplatin / paclitaxel 129 6.3 0.8 HR (95% CI) = 0.48 (0.36, 0.64) p<0.0001 0.6 Probability of PFS 0.4 0.2 0.0 0 4 8 12 16 20 24 Time from randomisation (months) Primary Cox analysis with covariates; intent-to-treat (ITT) population Hazard ratio (HR) <1 implies a lower risk of progression on gefitinib Mok et al 2009

  12. IPASS: EGFR mutation is a strong predictor for differential PFS benefit between gefitinib and doublet chemotherapy Gefitinib EGFR M+ (n=132)Gefitinib EGFR M- (n=91)Carboplatin / paclitaxel EGFR M+ (n=129) Carboplatin / paclitaxel EGFR M- (n=85) Probabilityof PFS 1.0 EGFR M+HR=0.48, 95% CI 0.36, 0.64 p<0.0001 EGFR M- HR=2.85, 95% CI 2.05, 3.98 p<0.0001 0.8 Treatment by subgroup interaction test, p<0.0001 0.6 0.4 0.2 0.0 0 4 8 12 16 20 24 Time from randomisation (months) M+, mutation positive; M-, mutation negative

  13. PFS by EGFR mutation type: IPASS Exon 19 deletion L858R N N Gefitinib 64 Carboplatin / paclitaxel 47 Gefitinib 66 Carboplatin / paclitaxel 74 1.0 1.0 HR (95% CI) = 0.553 (0.352, 0.868) p=0.0101 HR (95% CI) = 0.337 (0.255, 0.560) p<0.0001 0.8 0.8 0.6 0.6 Probability of PFS Probability of PFS 0.4 0.4 0.2 0.2 0.0 0.0 0 4 8 12 16 20 24 0 4 8 12 16 20 24 Time from randomisation (months) Time from randomisation (months) Mok et al 2009 Post hoc Cox analysis with covariates; ITT population

  14. IPASS: QoL and symptom improvement rates for overall population Gefitinib (n=590) Carboplatin/paclitaxel (n=561) p=0.0148 p=0.3037 p<0.0001 % patients with sustained clinically relevant improvementa Evaluable for QoL population ; logistic regression model with covariatesa≥6-point improvement (FACT-L and TOI); ≥2-point improvement (LCS), maintained ≥21 days Mok et al 2009

  15. IPASS: post hoc QoL and symptom improvement rates for EGFR M+ patients Gefitinib (n=131) Carboplatin / paclitaxel (n=128) p<0.0001 p<0.0001 p=0.0003 % patients with sustained clinically relevant improvementa Evaluable for QoL population; logistic regression model with covariatesa6-point improvement (FACT-L and TOI); 2-point improvement (LCS),maintained ≥21 days Mok et al N Engl J Med 2009

  16. IPASS: 2010 updated OS analysis (ITT) Gefitinib (n=609)Carboplatin/ paclitaxel(n=608) HR (95% CI) 0.90(0.79, 1.02); p=0.109 No. events G 484 (80%) C / P 470 (77%)Median OS G 18.8 monthsC / P 17.4 months 1.0 Probabilityof survival 0.8 0.6 0.4 0.2 0.0 48 0 4 8 12 16 20 24 28 32 36 40 44 52 Patients at risk: Gefitinib 609 608 514 525 468 443 400 364 331 301 270 232 227 183 192 151 148 119 97 65 44 28 13 9 3 1 0 0 C / P Primary Cox analysis with covariates A hazard ratio <1 implies a lower risk of death on gefitinibNo formal adjustment made for multiple testing Yang CH et al. ESMO 2010

  17. IPASS: 2010 summary of subsequent systemic therapy (ITT) *% exclude 20 patients in the gefitinib arm with ongoing randomised treatment**Patients may have also received other chemotherapy and / or EGFR TKI during the study. Excludes single platinum based chemotherapy #Categories are not mutually exclusive Radiotherapy, surgery, medical procedures and other treatments excluded Yang CH et al. ESMO 2010

  18. IPASS: 2010OS by EGFR mutation status (ITT) EGFR mutation + 1.0 0.8 0.6 0.4 0.2 0.0 0 4 8 12 16 20 24 28 32 36 40 44 48 52 EGFR mutation - Gefitinib (n=91)Carboplatin /paclitaxel(n=85) HR (95% CI) 1.18(0.86, 1.63); p=0.309No. events G 82 (90%)C / P 74 (87%)Median OS G 11.2 monthsC / P 12.7 months Gefitinib (n=132)Carboplatin /paclitaxel(n=129) HR (95% CI) 1.00(0.76, 1.33); p=0.990No. events G 104 (79%)C / P 95 (74%)Median OS G 21.6 monthsC / P 21.9 months 1.0 0.8 0.6 Probability of survival Probability of survival 0.4 0.2 0.0 0 4 8 12 16 20 24 28 32 36 40 44 48 52 Time from randomisation (months) Time from randomisation (months) Patients at risk: Gefitinib C / P 132 129 126 123 121 112 103 95 88 80 70 68 58 55 46 48 38 40 24 26 11 15 6 7 3 0 69 76 52 57 40 44 29 33 26 25 19 19 16 16 11 11 8 3 5 1 1 1 0 1 0 0 91 85 0 0 Cox analysis with covariates; a hazard ratio <1 implies a lower risk of death on gefitinib No formal adjustment for multiple testing was made, therefore statistical significance at the traditional 5% level cannot be claimed Yang CH et al. ESMO 2010

  19. IPASS: 2010 overall survival: EGFR mutation non-evaluable (ITT) 1.0 Probabilityof survival 0.8 0.6 0.4 0.2 0.0 0 4 8 12 16 20 24 28 32 36 40 44 48 52 Time from randomisation (months) Patients at risk: Gefitinib 386 394 319 326 295 274 257 225 214 188 174 139 150 109 130 87 99 68 65 36 28 12 6 1 0 0 0 0 C / P Gefitinib (n=386)Carboplatin / paclitaxel(n=394) HR (95% CI) 0.82(0.70, 0.96); p=0.015*No. events G 298 (77%)C / P 301 (76%) Median OS G 18.9 monthsC / P 17.2 months Primary Cox analysis with covariates; a hazard ratio <1 implies a lower risk of death on gefitinib*No formal adjustment for multiple testing was made, therefore statistical significance at the traditional 5% level cannot be claimed Yang CH et al. ESMO 2010

  20. IPASS: PFS and OS by known EGFR mutation status OS (2010) 1.0 Gefitinib EGFR M+ Gefitinib EGFR M- C / P EGFR M+ C / P EGFR M- 0.8 Mutation + 0.6 Probability of survival 0.4 0.2 Mutation - 0.0 4 8 12 16 20 24 4 8 12 16 20 24 28 32 36 40 44 48 52 0 Time from randomisation (months) 126 69 123 76 121 52 112 57 103 40 95 44 88 29 80 33 70 26 68 25 58 19 55 19 46 16 48 16 38 11 40 11 24 8 26 3 11 5 15 1 6 1 7 1 3 0 0 1 0 0 0 0 132 91 129 85 108 21 103 58 71 4 37 14 31 2 7 1 11 1 2 0 3 0 1 0 0 0 0 0 PFS (2008) 1.0 0.8 0.6 Probability of progression-free survival 0.4 0.2 0.0 0 Time from randomisation (months) Patients at risk: Gefitinib M+ Gefitinib M- C / P M+ C / P M- 132 91 129 85 Yang CH et al. ESMO 2010 Patients at risk excludes censored patients and those who have experienced an event

  21. IPASS conclusions: updated survival analysis Mature OS (secondary endpoint) was similar for gefitinib and carboplatin / paclitaxel with no statistically significant difference between treatments in the overall population A consistent OS outcome was observed across clinical subgroups with no significant difference in OS There was no significant difference in OS across the EGFR biomarker subgroups The true effect of the initial randomised treatment on OS is likely to have been confounded by the subsequent therapy, in particular the switching of patients to the alternative study therapy Yang CH et al. ESMO 2010

  22. IPASS conclusions: overall summary IPASS has demonstrated that positive EGFR mutation status is predictive of benefit from treatment with gefitinib over chemotherapy in terms of PFS, ORR and HRQoL PFS is an endpoint unlikely to be confounded by subsequent treatments, therefore is a more appropriate endpoint for evaluation of treatment effect in first-line treatment of NSCLC than OS IPASS has demonstrated the importance of biomarker testing in NSCLC, making a significant step towards personalised medicine IPASS has changed clinical practice and treatment guidelines for patients with advanced NSCLC who harbour an EGFR mutation HRQoL, health-related quality of life; NSCLC, non-small-cell lung cancer; ORR, objective response rate Yang CH et al. ESMO 2010

  23. Recently reported Phase III studies of gefitinib as first-line treatment for NSCLC in selected populations First-SIGNAL (Korea) • Endpoints • Primary • OS • Secondary • PFS, ORR, QoL, disease-related symptomssafety and tolerability Gefitinib250 mg/day • Patients • Chemo-naïve • Adenocarcinoma • Never smokers • ECOG† PS 0–2 Gemcitabine (1250 mg/m2) & cisplatin (80 mg/m2) 3-weekly* NEJ002 (Japan) • Endpoints • Primary • PFS (superiority) • Secondary • OS, ORR, QoL, disease-related symptomssafety and tolerability Gefitinib250 mg/day • Patients • Chemo-naïve • EGFR mutation-positive • PS 0–1 Carboplatin AUC 6 & paclitaxel 200 mg/m2 3-weekly †Eastern Cooperative Oncology Group *Maximum 9 cycles • Kobayashi et al 2009; Lee et al2009

  24. PFS and ORR with first-line gefitinib versus doublet chemotherapy in EGFR mutation-positive Asian patients across three Phase III studies Gefitinib (n=132) C / P (n=129) Gefitinib (n=26) G / C (n=16) Gefitinib (n=98) C / P (n=100) HR (95% CI) = 0.613 (0.308, 1.221) p=0.084 HR (95% CI) = 0.48 (0.36, 0.64) p<0.0001 HR (95% CI) = 0.36 (0.25, 0.51) p<0.001 1.0 1.0 1.0 0.8 0.8 0.8 Probability of PFS Probability of PFS Probability of PFS 0.6 0.6 0.6 0.4 0.4 0.4 0.2 0.2 0.2 0.0 0.0 0.0 0 100 200 300 400 500 0 5 10 15 20 25 30 0 4 8 12 16 20 24 months days months First-SIGNAL IPASS NEJ002 p=0.002 p<0.001 p<0.0001 ORR % ORR % ORR % Mok et al 2009; Lee et al 2009; Kobayashi et al 2009

  25. 1st-line treatment for mutation positive patients with NSCLC EURTAC – Spanish Lung Cancer GroupPhase III1: Erlotinib IIIB/IV NSCLC chemotherapy-naïve EGFR mutation Platinum + taxane or gemcitabine

  26. New-generation erbB inhibitors BIBW 2992 – potency and selectivity (IC50): Solca F et al. Proceedings, AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics. 2005;118:A242 Solca F et al. Proceedings, AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics. 2005;118:A244

  27. Resistance mutations Mutations known to cause resistance to 1st-generation EGFRi include: Exon 20 in-frame insertions Exon 20 point-mutations (e.g. T790M) Sharma et al. Nat Rev Cancer. 2007;7:169–181

  28. BIBW 2992 – active against resistance mutation NCI-H1975 cells express L858R/T790M double-mutant EGFR Li et al. Oncogene. 2008;27:4702–4711

  29. LUX-Lung 1: Trial design • Patients with: • Adenocarcinoma of the lung • Stage IIIB/IV • Progressed after one or two lines of chemotherapy (incl. one platinum-based regimen) and ≥12 weeks of treatment with erlotinib or gefitinib • ECOG 0–2 • N=585 Randomization 2:1 (DoubleBlind) Oral afatinib 50 mg once daily plus BSC Oral placebo once daily plus BSC Primary endpoint: Overall survival (OS) Secondary: PFS, RECIST response, QoL (LC13 & C30), safety • Radiographic assessments at 4, 8, 12 wks and every 8 wks thereafter • Exploratory biomarkers: • Archival tissue testing for EGFR mutations (optional; central lab) • Serum EGFR mutational analysis (all patients)

  30. Demographics/prior treatment 31

  31. Disease control rate and objective responses Median duration of confirmed response: 24 weeks * P < 0.01 compared to placebo ** P < 0.0001 compard to placebo

  32. PFS by independent review

  33. Primary analysis: Overall survival

  34. Summary of anticancer therapy after treatment discontinuation

  35. Patient reported outcomes *All scores were estimated from the EORTC QLQ-LC13 except for “Short of Breath” and “Pain” which used EORTC QLQ-C30; improved means that EORTC symptom scores were ≥10 points lower than baseline at any time during the study **EORTC cough, dyspnea and pain endpoints as pre-specified in the trial protocol

  36. LUX-Lung 2: Study design Patients with: Adenocarcinoma of the lung Stage IIIB/IV EGFR mutation Chemo-naïve or progressive disease following first-line chemotherapy ECOG 0–2 N=120 Oral BIBW 2992 once-daily until disease progression or undue toxicity Response assessment at 4, 8, 12 weeks; every 8 weeks thereafter Primary endpoint: objective response rateSecondary endpoints: PFS, clinical benefit; time to OR; duration of OR; OS; safety

  37. Results High degree of efficiency observed: -For all patients: Confirmed ORR: 60% DCR: 86% Median PFS:14 months Median OS:24 months For patients with del19/L858R Confirmed ORR: 64% DCR: 88% Median PFS:15 months • Similar efficacy results in the first and second-line settings and across all subgroups • Similar magnitude of efficacy in patients with L858R as with del19 mutations

  38. LUX-Lung 3: Phase III first-line trial in lung cancer patients with EGFR mutations Patients (n=330) with: Stage IIIB/IV adenocarcinoma of the lung Presence of EGFR mutation in the tumour tissue Chemonaive ECOG 0 or 1 Randomization 2:1 Oral BIBW 2992 40 mg once-daily Cisplatin/pemetrexed Primary endpoint: PFS

  39. Conclusion EGFR-TKIs for EGFR-mutated tumours are becoming standard Rx in first-line metastatic NSCLC BIBW 2992 activity in NSCLC, especially in EGFR-mutated tumours Active against receptors that are resistant to first generation inhibitors (e.g.EGFRL858R/T790M)

  40. THANK YOU!

  41. MC GILL UNIVERSITY