Treatment Paradigm in NSCLC Treatment

Transcription

1 Treatment Paradigm in NSCLC Treatment Era of Targeted Therapy Aumkhae Sookprasert, MD Medicine Department, KKU

2 Which factors taken to be account in NSCLC treatment? 1. Staging 2. ECOG performance status 3. Histology

3 Early stage Potentially resectable disease Locally advanced : unresectable disease Metastatic disease

4 Early stage Surgery then Adjuvant CT in stage IIa,IIb Potentially resectable disease IA IB Locally advanced : unresectable disease IIA IIB Metastatic disease IIA

5 Early stage (resectable disease) Adjuvant Chemotherapy begin at stage IIA (IB +/- ; Category 2B)

6 Adjuvant Trials Scorecard Trials Stage IA Stage IB Stage II Stage IIIA 2004 Japan Negative Positive Not tested Not tested 2003ALPI Negative Negative Negative Negative 2004 IALT Negative Negative Negative Positive 2004CALGB Not tested Negative Not tested Not tested 2005JBR10 Not tested Negative Positive Not tested 2005ANITA Not tested Negative Positive Positive

7 Adjuvant Chemo in NSCLC; with what? Patient Regimen 1st Agent 2nd Agent Fit,young - best NP q 3 x 4 Vinorelbine D1,8 Cis D1 Fit,young - alternative EP q 3-4 x 4 Etoposide 100 D1-3 Cis 100 D1 Acceptable regimen GC q 3 x 4 Gem 1250 D1,8 Cis 75 D1 Pt with comorbid, not tolerate cis TCar q 3 x 4 Taxol 200 D1 Carbo AUC 6 D1

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9 Stage I,II,III (except IA)

10 Early stage Potentially resectable disease Locally advanced : unresectable disease Metastatic disease

11 Confirm pathologic N2 (if possible)

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14 Early stage Potentially resectable disease Locally advanced : unresectable disease Metastatic disease

15 Which factors taken to be account in NSCLC treatment? 1. Staging 2. ECOG performance status 3. Histology

16 American Society of Clinical Oncology Clinical Practice Guideline on CT for stage IV NSCLC Azzoli C, Baker S, Temin S, et al. JCO 2009

17 First line treatment in NSCLC ASCO Detail R A1 CT indicate in ECOG 0,1 possibly 2 R A2 PS 0,1 = 2 drugs Platinum preferred R A3 Single CT in PS 2 R A4 R A5 R A6 R A7 R A8 Not use age alone in decide Either Cis or Carbo are acceptable 1 line should be stop at PD, or after 4 in NR 1 line Gefitinib may be for pt EGFR mutation Bev + tax/carboplatin recommend except SCC R A9 Cet + V/C may consider in EGFR +

18 V 2012

19 Which factors taken to be account in NSCLC treatment? 1. Staging 2. ECOG performance status 3. Histology

20 Histological type of NSCLC / / / /

21 Which factors taken to be account in NSCLC treatment? 1. Staging 2. ECOG performance status 3. Histology Squamous cell carcinoma Non-squamous cell carcinoma - Adenocarcinoma - Large cell carcinoma

22 Squamous histology Clinical Male,smoker Clinical Central,cavitation Small cell Squamous cell CA Molecul ar Ras and EGFR mutation rare High TS and EGFR over expression common

23 Smoker adeno histology Non smoker - adeno histology Clinical Clinical Molecul ar Male,smoker Peripheral,pleural disease High ras mutation, EGFR over expression, low EGFR mutation, low TS Clinical Clinical Molecular Female, non smoker, asian Peripheral, multifocal,ground glass appearance Frequent EGFR mutation, EGFR over expression Ras mutation rare, low TS

24 From pathology to molecular biology 1. EGFR mutation + : EGFR-TKIs 2. EGFR over expression : EGFR-Mob (cetuximab) 3. EML4-ALK translocation : Crizotinib

25 Systemic Treatment Options in NSCLC 1. Standard doublet chemotherapy 2. Targeted therapy with EGFR-TKIs - Gefitinib, Erlotinib 3. Targeted therapy plus standard chemotherapy - Bevacizumab plus GC or TCar - Cetuximab plus VC

26 Limitation of 1 st line doublet CT in NSCLC Survival: ECOG st line 3 rd generation chemotherapy in NSCLC RR = 19 % TTP = 3.6 months MST = 7.9 months 1 yr survival = 33% 2 yr survival = 11% Schiller et al. NEJM 2002.

27 Does histology matter... For the selection of CT in NSCLC

28 Squamous histology Clinical Male,smoker Clinical Central,cavitation Small cell Squamous cell CA Molecul ar Ras and EGFR mutation rare High TS and EGFR over expression common

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30 Smoker adeno histology Non smoker - adeno histology Clinical Clinical Molecul ar Male,smoker Peripheral,pleural disease High ras mutation, EGFR over expression, low EGFR mutation, low TS Clinical Clinical Molecular Female, non smoker, asian Peripheral, multifocal,ground glass appearance Frequent EGFR mutation, EGFR over expression Ras mutation rare, low TS Pemetrexed

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32 CONSORT: Phase III Gemcitabine or Pemetrexed + Cisplatin as First-line Therapy Advanced-stage, previously untreated NSCLC patients (N = 1725) Stratified by: ECOG PS (0 vs 1) Disease stage (IIIB vs IV) Brain metastases (yes vs no) Sex (male vs female) Pathologic diagnosis (histologic vs cytologic) Treatment center Cisplatin 75 mg/m 2 on Day 1 Gemcitabine 1250 mg/m 2 on Days 1 and 8 Six 3-wk cycles Cisplatin 75 mg/m 2 on Day 1 Pemetrexed 500 mg/m 2 on Day 1 Six 3-wk cycles Scagliotti GV, et al. J Clin Oncol. 2008;26:

33 CONSORT: Efficacy Survival Median OS, mos Pemetrexed + Cisplatin (n = 862) Gemcitabine + Cisplatin (n = 863) HR (95% CI) 0.94 ( ) P Value Noninfe rior Adenocarcinoma (N = 847) Large-cell carcinoma (N = 153) Squamous cell carcinoma (N = 473) ( ) ( ) ( ).05 Scagliotti GV, et al. J Clin Oncol. 2008;26:

34 Targeted Therapy in NSCLC 1. Target at tumor cells - over expression of EGFR : cetuximab - EGFR mutation : TKIs 2. Target at vascular endothelial cells - Inc VEGF : anti-vegf (bevacizumab )

35 EGFR expression in NSCLC x x x x

36 Proposed MoA of Bevacizumab : A dynamic effect throughout treatment EARLY EFFECTS CONTINUED EFFECTS 1 Regression 2 Normalization 3 Inhibition Decreases tumour size Improves delivery of CTx Suppresses new vessel growth Suppresses regrowth via vessel scaffolds

37 Bevacizumab plus TCarb in non-squamous NSCLC E4599: OS OS estimate Overall population CP Bevacizumab 15mg/kg + CP Months Median OS (months) CP: 10.3 Bevacizumab 15mg/kg + CP: 12.3 HR=0.79; p=0.003 OS estimate Adenocarcinoma* CP 0.8 Bevacizumab 15mg/kg + CP Months Median OS (months) CP: 10.3 Bevacizumab 15mg/kg + CP: 14.2 HR= Sandler, et al. NEJM Sandler, et al. JTO 2010 (in press)

38 Only PFS benefit in AVAiL (Bevacizumab+GC in non-squamous NSCLC) PFS estimate E Bev 15mg/kg + CP CP Time (months) AVAiL 2 Bev 7.5mg/kg + CG Bev 15mg/kg + CG Placebo + CG Time (months) Bevacizumab 15mg/kg Bevacizumab 7.5mg/kg Bevacizumab 15mg/kg Median PFS 6.2 vs 4.5 months HR=0.66; p< vs 6.1 months HR=0.75; p= vs 6.1 months HR=0.82; p=0.03 Pre-planned analysis applying the same censoring rules to both trials 3 HR=0.68; p< HR=0.74; p= Sandler, et al. NEJM 2006; 2. Reck, et al. JCO Sandler, et al. ECCO 2007

39 EGFR expression in NSCLC EGFR TKIs x x x x

40 Role of EGFR-TKIs in NSCLC Clinical selection - Female - Non smoker - Asian ethnicity - Adenocarcinoma histo

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45 Role of EGFR-TKIs in NSCLC Clinical selection Molecular selection - Female - Non smoker - EGFR mutation - EGFR amplification - Asian ethnicity - Adenocarcinoma histo

46 NSCLC patients with somatic mutation of EGFR have been shown to be hyperresponsive to the EGFR TKIs The most common NSCLC-associated EGFR mutations are In-frame deletion in exon 19 (E746-A750del) Point mutation in exon 21 (L858R) 46% 39%

47 Mutations in EGFR TK in Unselected Patients With NSCLC Subgroup Tumors Screened, n Mutations Mean % (Range) United States (2-14) Europe (NR) Australia (NR) Eastern Asia (26-40) Adenocarcinoma (9-55) Other histology (0-3) Men (6-32) Women (20-59) Smokers (5-22) Nonsmokers (12-69) Haber DA, et al. AACR 2005.

48 IPASS biomarkers study

49 At least 2 positive clinical factors (1 = Asean ethnicity)

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54 Overall survival (ITT population) Gefitinib CBDCA/TXL (n=98) Logrank (n=100) test Median survival m HR (95%CI) ( ) p value* Overall survival (%) *Log-rank test 2-year survival rate Gefitinib 61% CBDCA/TXL 45% Inoue et al. ECCO-ESMO 2009; Abstract 9LBA

55 Summary Overall population HRQoL endpoints were consistent with efficacy outcomes in IPASS EGFR M+ population Improvement rates in HRQoL and symptoms significantly favored gefitinib over C/P Times to worsening of HRQoL and symptoms were substantially longer for gefitinib than C/P Median time to improvement in HRQoL and symptoms were as rapid as 8 days with gefitinib in patients who improved EGFR M- population Improvement rates in HRQoL and symptoms significantly favored C/P over gefitinib Times to worsening for HRQoL and symptoms were longer for C/P than gefitinib Thongprasert et al. ELCC 2010; Abstract 205O

56 EURTAC : First-line Erlotinib vs Chemo in European Patients With EGFR Mutations 174 patients Trial run in Europe (lead by Spanish group) Outcome CT Erlotinib HR P Value Response rate, % NR Median PFS, mos <.0001 Median OS, mos NR NR Most common toxicities, % ALT elevation: 72 Anemia: 46 Neutropenia: 36 ALT elevation: 80 Rash: 80 Diarrhea: 57 Rosell R, et al. ASCO Abstract 7503.

57 Evidence based management decision for 1st line NSCLC good ECOG EGFR mutation + EGFR unknown Squamous CA Non-squamous EGFR TKIs Traditional 3rd gen doublet CT (non-pemetrexed) Bev + doublet CT Or Pem doublet CT Or Traditional CT

58 ASCO : Recommendations ECOG 0-1 :1 st -line platinum doublet (4 6 cycles) ECOG 2 : single agent CT Wait and Watch policy 2nd-line treatment Diagnosis CR,PR or SD PD PD When should 1 st line be stopped 1. PD while on treatment 2. After 4 cycles in patient whose disease is not responding to Px (SD) 3. 2 drug combinations should be administered for no more than 6 cycles American Society of Clinical Oncology CPG update on chemotherapy for stage IV NSCLC. JCO 2009.

59 Second line treatment in Advanced NSCLC BSC Docetaxel Pemetrexed Erlotinib

60 2004: pemetrexed versus docetaxel efficacy and tolerability 1.00 D (n=276) P (n=265) Median OS (mos) Variable Pemetrexed Docetaxel p-value Overall response (%) NS Progression-free survival, median (mos) NS Time to progression, median (mos) NS yr survival (%) Duration of response, median (mos) NS OS probability Pemetrexed Docetaxel HR=0.99 ( ) Survival time, median (mos) NS 1-year survival rate (%) NS Neutropenia grade 3 4 (%) <0.001 Febrile neutropenia (%) <0.001 >1 hospitalisation for febrile neutropenia (%) <0.001 G-CSF (%) <0.001 >1 hospitalisation for any drugrelated AE (%) Time (months) Pemetrexed had similar efficacy to docetaxel with reduced haematological toxicity Hanna, et al. JCO 2004

61 2005: erlotinib showed OS advantage in pre-treated NSCLC (BR.21) 1.00 Erlotinib (n=488) Placebo (n=243) 0.75 Median OS (months) OS probability HR=0.73 ( ), p=0.001* Time (months) Shepherd, et al. NEJM 2005

62 Second line treatment in Advanced NSCLC Gefitinib? BSC Docetaxel Pemetrexed Erlotinib

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64 Maintenance Therapy Emerging Approach in NSCLC Historical approach First-line treatment Platinum doublet chemotherapy (4 6 cycles) Watch and wait Second and further lines of treatment Diagnosis CR/PR/SD PD PD Increased time to PD New approach Maintenance therapy Diagnosis CR/PR/SD PD PD

65 Summary of available clinical evidences of Maintenance therapy 1. Maintenance therapy with same drug : Continuation 1.1 Gem after GC x Gem or Erlotinib after GC x 4 2. Maintenance therapy with different drug : Switching 2.2 Doc after GC x Pem after GC x 4 (JMEN) 2.2 Erlotinib after GC x 4 (SATURN) 3. Maintenance therapy with Both 3.1 Bev + Erlotinib after Bev + CT (ATLAS)

66 JMEN (maintenance pemetrexed): PFS and OS in ITT population Patients with stage IIIB/IV NSCLC and PS 0 1 who had received 4 previous cycles of gemcitabine, docetaxel, or paclitaxel + platinum with CR, PR, or SD (n=663) R A N D O M I S E 2:1 Pemetrexed 500mg/m 2 on d1 q21d + BSC (n=441) Placebo on d1 q21d + BSC (n=222) PFS probability Pemetrexed Placebo HR=0.60 (95% CI ); p< OS probability Pemetrexed Placebo HR=0.79 (95% CI ); p= ITT=intent-to-treat Time (months) Time (months) Ciuleanu, et al. Lancet 2009

67 Maintenance Pemetrexed : DFS Benefit of non-squamous histology Ciuleanu et al. Lancet 2009.

68 Evidence base systemic treatment in NSCLC stage IV

69 1st Line

70 1st Line 2nd Line Doublet Chemotherapy TCarb PemCis (Adenocarcinoma) GC 3rd Line Pemetrexed Docetaxel 4th Line AYC AYC

71 1st Line 2nd Line Docetaxel Docetaxel

72 1st Line 2nd Line Docetaxel 3rd Line EGFR-TKIs Docetaxel EGFR-TKIs