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Advanced NSCLC: Treatment algorithms 2014 Prof. Christian Manegold Medical Faculty Mannheim University of Heidelberg.

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1 Advanced NSCLC: Treatment algorithms 2014 Prof. Christian Manegold Medical Faculty Mannheim University of Heidelberg

2 NSCLC: Incidence of single driver mutations Mutation found in 54% (280/516) of tumours completely tested (CI 50-59%) Kris et al. J Clin Oncol 29 (suppl 15) 477 (abstr 7506); 2011

3 1st-line Platinum-Doublets (Pem!) plus Bev Non-Squamous Advanced NSCLC: Current Treatment algorithm EGFR-TKI Platinum-Doublets (No Pem, no Bev) Maintenance Switch: Pemetrexed Erlotinib Continuous: Pemetrexed Switch: Erlotinib 2nd-line ALK-Inhibitor Single agent Non-cross resistant Single agent Non-cross resistant Squamous Mutant tumors Oligo progression: Cont. TKI + Local therapy Diffuse progression Cont. TKI + Chemo Chemo  TKI re-expo 2 nd generation TKI Treatment until progression Wild type tumors

4 Advanced NSCLC: Treatment for non-mutant tumors First-line – (induction) – therapy -Selection by histo-type Maintenance therapy -Switch / continuation Second-line / subsequent-line therapy

5 NSCLC: International treatment recommendations for advanced disease Chemotherapy prolongs survival and is most appropriate for individuals with good performance status (PS 0 or 1, and possibly 2). Chemotherapy should be a platinum-based two-drug combination regimen. Non-platinum containing regimens may be used as alternatives to platinum-based regimens. For elderly patients, or patients with PS 2, available data support the use of single-agent chemotherapy. Chemotherapy should be stopped at 4 cycles in patients who are not responding to treatment, and should be administered for no more than six cycles. If chemotherapy is to be given it should be initiated while the patient still has good PS. Azzoli et al. J Clin Oncol 29, , 2011 Peters et al. Ann Oncol 23 (Suppl 7), 56-64, 2012

6 Advanced NSCLC: Medical management – practical aspects Feasibility / tolerability: Cis-platin vs carbo-platin -Hotta et al. J Clin Oncol 22, , 2004, Rudd et al. J Clin Oncol 23, , Artizoni et al. J Natl Cancer Inst 99, , 2007 Co-morbidity / regimen: Platin based / free -D‘Addario et al. J Clin Oncol 23, , Laack et al. J Clin Oncol 22, , 2004, Age ≥ 70 years: Single agent / combination -Gridelli et al. J Clin Oncol 23, , 2005; Gridelli et al. J Natl Cancer Inst 95, , Gridelli et al. J Natl Cancer Inst 91, 66-72, 1999; Sederholm et al. J Clin Oncol 23, , 2005 Performance status ≥ 2 : Single agent / combination - Gridelli et al. Ann Oncol 15, , 2004, Patient’s expectations: Active therapy / BSC -Gridelli et al. J Clin Oncol 23, , 2005

7 Selection by histo-type according to efficacy (non-squamous vs squamous)

8 Pemetrexed+Cisplatin Median OS: 11.0 mos Gemcitabine+Cisplatin Median OS: 10.1 mos HR=0.844 (95% CI: 0.74 – 0.96) p=0.011 Pemetrexed+Cisplatin Median OS: 9.4 mos Gemcitabine+Cisplatin Median OS: 10.8 mos HR=1.229 (95% CI: 1.00 – 1.51) p=0.051 Nonsquamous* (n=1252) Squamous (n=473) Survival Time (months) Survival Probability Advanced NSCLC: Treatment by histology Cisplatin plus Pemetrexed or Gemcitabine Scagliotti et al J Clin Oncol, 26, , 2008

9 Efficacy by Histology in Pemetrexed Studies NSCLC Histologic Group Second-line Pem vs. Docetaxel First-line Pem/Cis vs. Gem/Cis Maintenance Pem vs. Placebo PemDocCis/PemCis/GemPemPlacebo Non-squamousn=205n=194n=618n=634n=325n=156 Median OS, months Adjusted HR (95% CI) P value 0.78 (0.61–1.00) (0.74–0.96) (0.56–0.88) Squamousn=78n=94n=244n=229n=116n=66 Median OS, months Adjusted HR (95% CI) P value 1.56 (1.08–2.26) (1.00–1.51) (0.77–1.50) Non-squamous = adenocarcinoma, large cell carcinoma, and other/indeterminate NSCLC histology Scagliotti et al. J Thorac Oncol 6, 64-70, 2011

10 Ifosfamide in NSCLC: MIC Regimen Mitomycin C6 mg/m²i.v. Bolus day 1 Ifosfamide3.000 mg/m²i.v./3 h day 1 Cisplatin50 mg/m²i.v./1 h day 1 Cycle repeated q3w Cullen et al, Br J Cancer 58, , 1988 MESNA-Uroprotection 20 % (IFO) i.v. fractionated(0 hours) 4 h + 8 h 100 % (IFO) i.v. continuous(0 hours) during IFO + for additional 12 q 24 h

11 MIC `s Efficacy is not inferior to other Platinum Doublets nRRTTPMST1-y-sRef. NVB / CIS20630 %n.r.9.5 mo*37 %Le Chevalier VDS / CIS20019 %n.r.7.6 mo28 %(1994) PAC 135 / CISTotal27 %*4.5 mo*9.6 mo*37 %Bonomi PAC 250 / CIS56032 %*5.3 mo*10 mo*39 %(1996) ETO / CIS12 %3.0 mo7.7 mo32 % GEM / CIS15440 %4.8 mo8.6 mo33 %Crino MIC15228 %5.0 mo9.5 mo34 %(1998) GEM / CIS6941 %*6.9 mo*8,7 mo32 %Cardenal ETO / CIS6622 %4.3 mo7.2 mo26 %(1999) PAC / CARBO19023 %*4.0 mo7.7 mo32 %Belani ETO / CIS17914 %3.3 mo8.2 mo37 %(1998) *p<.05

12 Phase II Stage IIIb/IV PAC 250 mg/m² (3h), d 1 IFO 1600 mg/m², d 1-3 q3w x 6 NAV 30 mg/m², d 1-3 IFO 1600 mg/m², d 1-3 q3w x 6 Perry et al, Lung Cancer 48,63-68, 2000 RR MS 1yS A: 38% 9mo 35% B: 31% 8mo 38% Arm A n=48 Arm B n=45 Platinum-free, Ifosfamide based doublets have been developed

13 Phase III Stage IIIb/IV PS 0-2 Cis 100 mg/m², d 1 x 6 (n=166) Gem 1250 mg/m², d 1, 8 Cis 100 mg/m², d 1 x 6 (n=176) Gem 1000 mg/m², d 1, 8 Vin 25 mg/m², d 1, 8 Gem 1000 mg/m², d 1, 8 x 3 (n=175) Vin 30 mg/m², d 1, 8 Ifo 3000 mg/m², d 1 x 3 Vin 30 mg/m², d 1, 8 Alberola et al, J Clin Oncol, 21: , 2003 RR: 41% 40% 24% MS: 10m 8m 11m Ntp3/4: 26% 30% 18% Tbp3/4: 18% 23% 7%0 Platinum-free, Ifosfamide based doublets have been developed

14 Selection by toxicity profile (non-squamous vs squamous)

15 Advanced NSCLC: Bevacizumab plus Standard CT Results by primary endpoints 12.3 m Time Months 10.3 m 6.7 m 6.1 m 6.5 m 6.1 m Sandler et al N Engl J Med 355, , 2006 Reck et al, Ann Oncol 21, , 2010 Reck et al, J Clin Oncol 27, , 2009 ECOG 4599: Carbo/Taxol AVAiL: Cis/Gem

16 NSCLC: Bevacizumab - Eligibility Inclusion criteriaExclusion criteria  non-squamous NSCLC  chemo-naïve  ECOG PS of 0–1  grade  2haemoptysis  radiological evidence of tumour invasion of major blood vessels  spinal cord compression  uncontrolled hypertension  history of thrombotic or haemorrhagic disorders  therapeutic anticoagulation within 10 days of first dose Sandler et al N Engl J Med 355, , 2006 Crino et al, LancetOncol 11, , 2010 Reck et al, J ClinOncol 27, , 2009 Reck et al, Ann Oncol 21, ,2010 Sandler et al J Thorac Oncol 5, ,2010 Soria et al Ann Oncol 24,20-30,2013

17 Advanced NSCLC: Basics of medical management First-line – (induction) – therapy -Selection by histo-type Maintenance therapy -Switch / continuation Second-line / subsequent-line therapy

18 Advanced NSCLC: Medical Treatment in wild type tumors Combination or single agent CT defined number of cycles (4-6) Combination or single agent CT defined number of cycles (4-6) single agent, Non-cross-resistant until progression single agent, Non-cross-resistant until progression Tumor progression 1st-line 2nd-/subsequent line Traditional (standard) approach  one of the first line agents until progression (continuation)  „new“ non-cross-resistant agent until progression (switch)  one of the first line agents until progression (continuation)  „new“ non-cross-resistant agent until progression (switch) 1st-line Maintenance New (maintenance) approach Combination or single agent CT defined number of cycles (4-6) Combination or single agent CT defined number of cycles (4-6) Non- progression 2nd-/ subsequent line

19 Advanced NSCLC: Switch/continuation maintenance Cappuzzo et al. Lancet Oncol 11, ; 2010 Ciuleanu T. et al. Lancet 374, ; 2009 Paz-Ares Lancet Oncol 13, , 2012 Zhang et al. Lancet Oncol 13, ,2012 Fidias et al J Clin Oncol 27, , 2008 Perol et al J Clin Oncol 30, , 2012 Paz-Ares et al J Clin Oncol 31, , 2013

20 Advanced NSCLC: Maintenance Switch type („early second line“) Docetaxel Fidias et al J Clin Oncol 27, , 2009

21 Stage IIIb/IV ECOG PS = 0–2 CNS Mets allowed Stage IIIb/IV ECOG PS = 0–2 CNS Mets allowed Gem, 1000 mg/m 2, d1, 8 Carbo AUC 5, d1, q3w x 4 Gem, 1000 mg/m 2, d1, 8 Carbo AUC 5, d1, q3w x 4 RANDOMIZERANDOMIZE Immediate Docetaxel 75 mg/m 2 d1, q3w x 6 Delayed Docetaxel 75 mg/m 2 d1, q3w x 6 Delayed Docetaxel 75 mg/m 2 d1, q3w x 6 CR, PR SD Fidias et al., J Clin Oncol 27, , 2009 Immediate vs delayed (2 nd -line) Docetaxel Advanced NSCLC - Maintenance: Docetaxel following Standard Doublet Chemotherapy n=552 n=142/153 n=91/154 n=307 Off study: n=245 Primary endpoint: overall survival

22 Immediate Doc (n=153) Delayed Doc (n=154) p-value PFS, mos (95% CI) 6.5 (4.4–7.2) 2.8 (2.6–3.4) < yr-PFS, % (95% CI) 20% (13–26) 9% (5–14) Overall survival time (months) Immediate Doc (n=153) Delayed Doc (n=154) p-value MS, mos (95% CI) 11.9 (10.0–13.7) 9.1 (8.0–11.2) yr-S % (95% CI) 48.5% (39.9–57.1) 38.3 (30.0–46.5) Advanced NSCLC - Maintenance: Extension by Docetaxel following Standard Doublet Chemotherapy Immediate vs delayed (2 nd -line) Docetaxel Fidias et al., J Clin Oncol 27, , 2009

23 Advanced NSCLC: Maintenance Switch type („early second line“) Erlotinib Cappuzzo et al, Lancet Oncol 11, , 2010

24 Advanced NSCLC: Erlotinib switch maintenance (Saturn) 1:1 Chemonaïve advanced NSCLC n=1,949 Chemonaïve advanced NSCLC n=1,949 Non-PD n=889 Non-PD n=889 4 cycles of first-line platinum doublet chemotherapy * Placebo PD Erlotinib 150mg/day Erlotinib 150mg/day PD Mandatory tumour sampling Stratification factors: EGFR IHC (positive vs negative vs indeterminate) Stage (IIIB vs IV) ECOG PS (0 vs 1) CT regimen (cis/gem vs carbo/doc vs others) Smoking history (current vs former vs never) Region Co-primary endpoints: PFS in all patients PFS in patients with EGFR IHC+ tumours Secondary endpoints: OS in all patients and those with EGFR IHC+ tumours, OS and PFS in EGFR IHC– tumours; biomarker analyses; safety; time to symptom progression; QoL *Cisplatin/paclitaxel; cisplatin/gemcitabine; cisplatin/docetaxel cisplatin/vinorelbine; carboplatin/gemcitabine; carboplatin/docetaxel carboplatin/paclitaxel

25 Advanced NSCLC: Erlotinib switch maintenance Progression free survival Cappuzzo et al. Lancet Oncol 11, ; 2010 Progression free Survival

26 Cappuzzo et al. Lancet Oncol 11, ; 2010 Advanced NSCLC: Erlotinib switch maintenance Overall survival Overall Survival

27 Time (months) Time (months) Log-rank p= HR=0.72 (0.59–0.89) Erlotinib (n=252) Placebo (n=235) Log-rank p= HR=0.94 (0.74–1.20) Erlotinib (n=184) Placebo (n=210) Stable disease CR/PR Measured from time of randomisation into the maintenance phase Advanced NSCLC: Erlotinib switch-maintenance Overall survival by response Coudert et al. Ann Oncol 23, , 2012 Cappuzzo et al. Lancet Oncol 11, ; 2010

28 Advanced NSCLC: Maintenance Switch type („early second line“) Pemetrexed Ciuleanu et al Lancet 374, , 2009

29 Advanced NSCLC: Pemetrexed switch maintenance Stage IIIB/IV NSCLC PS prior cycles of gem, doc, or tax + cis or carb, with CR, PR, or SD Randomization factors: gender PS stage best tumor response to induction non-platinum induction drug brain mets Pemetrexed 500 mg/m2 (d1,q21d) + BSC (N=441)* Primary Endpoint = PFS Placebo (d1, q21d) + BSC (N=222)* *B 12, FOLATE, AND DEXAMETHASONE GIVEN IN BOTH ARMS 2:1 Randomization Ciuleanu T. et al. Lancet 374, ; 2009

30 Advanced NSCLC: Pemetrexed switch maintenance Progression free survival by histology Time (months) Progression-free Probability Time (months) Non-squamous Squamous Placebo: 1.8 mos Pemetrexed: 4.4 mos Placebo: 2.5 mos Pemetrexed: 2.4 mos HR=0.47 (95% CI: ) p < HR=1.03 (95% CI: ) p=0.896 Ciuleanu T. et al. Lancet 374, ; 2009

31 Placebo: 10.3 mos Pemetrexed: 15.5 mos HR=0.70 (95% CI: ) p=0.002 Placebo: 10.8 mos Pemetrexed: 9.9 mos HR=1.07 (95% CI: ) p=0.678 Ciuleanu T. et al. Lancet 374, ; 2009 Advanced NSCLC: Pemetrexed switch maintenance Overall survival by histology

32 Advanced NSCLC: switch maintenance ASCO recommendations 2011 For patients with SD or response after 4 cycles, immediate treatment with an alternative, single-agent chemotherapy such as pemetrexed in patients with non-squamous histology, docetaxel in unselected patients, or erlotinib in unselected patients may be considered (alternative to second-line therapy!) Azzoli et al. J Clin Oncol 29, , 2011 Fidias et al. J Clin Oncol 27, , 2009 Coudert et al. Ann Oncol 23, , 2012 Cappuzzo et al. Lancet Oncol 11, ; 2010 Paz-Ares Lancet Oncol 13, , 2012

33 Advanced NSCLC: Maintenance Continuation type („true maintenance“) Pemetrexed

34 Advanced NSCLC: Pemetrexed continuation maintenance (PARAMOUNT) Stadium IV Non- squamous SD nach 4-6x Induktions-CT Cisplatin/Pem etrexed Stadium IV Non- squamous SD nach 4-6x Induktions-CT Cisplatin/Pem etrexed Randomisation 2:1 Pemetrexed 3qw bis PD Pemetrexed 3qw bis PD Placebo 3qw bis PD Placebo 3qw bis PD Non PD Paz-Ares et al Lancet Oncol 13, , 2012 Paz-Ares et al J Clin Oncol 31, , 2013

35 Advanced NSCLC: Pemetrexed continuation maintenance (PARAMOUNT) – Overall survival by response Paz-Ares et al. J Clin Oncol 31, , 2013

36 Advanced NSCLC: Pemetrexed registration Continuation maintenance therapy......as single agent following platinum based therapy - predominantly other than squamous cell histology; non-progression after four cycles of chemotherapy…… EMA: 2011

37 Advanced NSCLC - Maintenance Comparison switch vs continuation Erlotinib (switch) Gemcitabine (continuation) Perol et al J Clin Oncol 30, , 2012

38 Patients stratified by sex, histology, smoking status, treatment center, and response/stabilization following first-line therapy Primary endpoint: PFS Other endpoints: OS, safety, symptom control, effect of EGFR status Gemcitabine (n = 154) Observation (n = 155) Erlotinib (n = 155) Chemotherapy- naive patients with stage IIIB/IV NSCLC (N = 834) Cisplatin/Gemcitabine for 4 cycles Patients without disease progression randomized 1:1:1 Perol M et al, J Clin Oncol 30, , 2012 Pem 74 % Pem 84% Pem 75% Advanced NSCLC: Erlotinib (switch) vs Gemcitabine (continuation) maintenance (IFCT-GFPC 0502)

39 Perol M et al, J Clin Oncol 30, , 2012 Advanced NSCLC: Erlotinib (switch) vs Gemcitabine (continuation) maintenance (IFCT-GFPC 0502)

40 Advanced NSCLC: Basics of medical management First-line – (induction) – therapy -Selection by histo-type Maintenance therapy -Switch / continuation Second-line / subsequent-line therapy

41 Current ASCO Guidelines for NSCLC Docetaxel, EGFR-TKI’s, and Pemetrexed are acceptable as second-line therapy for patients with advanced NSCLC with adequate performance status when the disease has progressed during or after first- line platinum-based therapy Azzoli et al. J Clin Oncol 29, , 2011 Shepherd et al. N Engl J Med 353, , 2005 Thatcher et al. Lancet 366, , 2005 Hanna et al. J Clin Oncol 22, , 2004

42 Advanced NSCLC: EGFR-TKIs as second-line therapy Kim et al. Cancer 116, , 2010 Karampazis et al. Cancer 119, , 2013 Garassino et al. Lancet Oncol 14, , 2013 Ciuleanu et al. Lancet Oncol 13, , 2012 Shepherd et al. N Engl J Med 353, , 2005 Kim et al. Lancet 372, , 2008 Thatcher et al. Lancet 366, , 2005

43 Lee et al. JAMA 311, , 2014 Meta-analysis in wild-type NSCLC favors CT over EGFR-TKI therapy: First- / second-line

44 Advanced NSCLC: Systemic therapy in the absence of driver mutations – Summary (1) Chemotherapy remains standard for the majority of patients - (first-line; platinum doublets; 4 – 6 cycles) The selection of the platinum-partner should depend on tumor histo-type - (non-squamous vs squamous; pemetrexed vs gemcitabine etc.) Modification of the first-line standard is clinically advisable according to co-morbidity, performance status, and patient’s age - (single agent; platinum-free; BSC only) Treatment until progression by the anti-angiogenic bevacizumab as recommended in selected patients - (eligibility criteria; group toxicity)

45 Advanced NSCLC: Systemic therapy in the absence of driver mutations – Summary (2) Prolongation of induction chemotherapy beyond 4 – 6 cycles for maintaining “response” until progression has been established as a new strategy - (switch/continuation maintenance) Second/subsequent – line chemotherapy is recommended in patients with acceptable performance status - (single agent; docetaxel; pemetrexed) EGFR-TKI’s have also been licensed for wild-type tumors - (maintenance; second/third-line therapy) A tight cooperation between the pathologist and the clinician is critical - (histology – subtyping; molecular testing; result reporting)

46 1st-line Platinum-Doublets (Pem!) plus Bev Non-Squamous Advanced NSCLC: Current Treatment algorithm EGFR-TKI Platinum-Doublets (No Pem, no Bev) Maintenance Switch: Pemetrexed Erlotinib Continuous: Pemetrexed Switch: Erlotinib 2nd-line ALK-Inhibitor Single agent Non-cross resistant Single agent Non-cross resistant Squamous Mutant tumors Oligo progression: Cont. TKI + Local therapy Diffuse progression Cont. TKI + Chemo Chemo  TKI re-expo 2 nd generation TKI Treatment until progression Wild type tumors

47 Advanced NSCLC: EGFR-TKIs as first line therapy Mok et al. N Engl J Med, 361, , 2009 Rosell et al Lancet Oncol 13; ;2012 Lee et al Lancet Oncol 13, , 2012 Zhou et al. Lancet Oncol 12, , 2011 Mitsudomi et al Lancet Oncol 11, , 2010 Sequist et al. J Clin Oncol 31, , 2013 Gridelli et al J Clin Oncol 30, , 2012

48 First-line trials of EGFR tyrosine kinase inhibitors vs. chemotherapy in pts with EGFR mutations EGFR TKI ComparatorN (Total) EGFR mut- positive Response rate (%) Progression-free survival (months) Overall survival (months) IPASS 1,2 GefitinibCarboplatin/ paclitaxel vs 47 p= vs 6.3 HR 0.48 (0.36 ‒ 0.64) 21.6 vs 21.9 HR 1.0 (0.76–1.33) First- SIGNAL 3 GefitinibGemcitabine/ cisplatin vs 38 p= vs 6.3 HR 0.54 (0.27–1.10) 27.2 vs 25.6 HR 1.04 (0.50–2.18) NEJ002 4 GefitinibCarboplatin/ paclitaxel vs 31 p< vs 5.4 HR 0.30 (0.22–0.41) 30.5 vs 23.6 WJTOG GefitinibCisplatin/ docetaxel vs 32 p< vs 6.3 HR 0.5 (0.34–0.71) 30.9 vs NR HR 1.64 (0.75–3.6) OPTIMAL 6 ErlotinibGemcitabine/ carboplatin vs 36 p< vs 4.6 HR 0.16 (0.10–0.26) Not mature EURTAC 7 ErlotinibChemotherapy vs vs 5.2 HR 0.37 (0.25–0.54) 19.3 vs 19.5 HR 1.04 (0.65–1.68) LUX-LUNG 3 8 AfatinibPemetrexed/ cisplatin vs 23 p< vs 6.9 HR 0.58 (0.43–0.78) Not mature LUX-LUNG 6 9 AfatinibGemcitabine/ cisplatin vs 23 p< vs 5.6 HR 0.28 (0.20–0.39) Not mature 1. Mok T et al., N Engl J Med 2009;361:947–957; 2. Fukuoka M et al., J Clin Oncol 2011; 29:2866 ‒ 2874; 3. Han J-Y et al., J Clin Oncol 2012; 30:1122 ‒ 128; 4. Maemondo M et al., N Engl J Med 2010;362:2380–2388; 5. Mitsudomi T et al., Lancet Oncol 2010;:121–128; 6. Zhou C et al., Lancet Oncol 2011;12:735 ‒ 742; 7. Rosell R et al., Lancet Oncol 2012;13:239–246; 8. Yang JC et al., J Clin Oncol 2012;30 (Suppl. 16):LBA 7500, Wu Y et al., Lancet 2014; 15:213. NR = not reported

49 … EGFR-TKI therapy should be prescribed for patients with tumors bearing activated EGFR-mutations … … Patients with PS 3-4 may also be offered EGFR-TKI treatment … Advanced NSCLC: First-line EGFR-TKI therapy ASCO / ESMO-recommendation Azzoli et al. J Clin Oncol 29, , 2011 Peters et al. Ann Oncol 23 (Suppl 7), 56-64, 2012

50 EGFR mutations: whom to test? (1) EGFR molecular testing should be used to select patients for EGFR-targeted TKI therapy, and patients with lung adenocarcinoma should not be excluded from testing on the basis of clinical characteristics Lindeman et al., J Thorac Oncol, , 2013

51 EGFR mutations: whom to test ? (2) In the setting of more limited lung cancer specimens (biopsies, cytology) where an adenocarcinoma component cannot be completely excluded, EGFR testing may be performed in cases showing squamous or small cell histology but clinical criteria (eg, young age, lack of smoking history) may be useful in selecting a subset of these samples for testing. Lindeman et al., J Thorac Oncol, , 2013

52 Laboratories should follow similar quality control and quality assurance policies and procedures for EGFR testing in lung cancers as for other clinical laboratory assays. In particular, laboratories performing EGFR testing for TKI therapy should enroll in proficiency testing, if available. EGFR mutations: laboratory issues Lindeman et al., J Thorac Oncol, , 2013

53 Second-line therapy in case of progression in first-line EGFR-TKI therapy Oligo progression: – Continuous TKI + Local therapy Diffuse progression – Continuous TKI + Chemotherapy – Chemotherapy  TKI re-exposition – 2 nd generation TKI

54 Advanced NSCLC: EMA registration for Erlotinib Second / third line: In patients after failure of at least one prior chemotherapy Maintenance: In patients with stable disease after 4 cycles of platinum based first-line chemotherapy CHMP, 18 March 2010

55 Shaw et al. N Engl J Med 368, , 2013 Advanced NSCLC: Crizotinib for ALK-positive disease Phase III (PROFILE 1007) – 2 nd line

56 347 patients, Advanced NSCLC, Prior platinumbased CT, all histologies, EML4-ALK Translocation Primary Endpoint: PFS Randomization Shaw et al. N Engl J Med 368, , 2013 Crizotinib 250 mg bid Pemetrexed or Docetaxel Crizotinib 250 mg bid PD

57

58 Advanced NSCLC: Systemic therapy in existence of driver mutations- Role of TKI’s Has changed significantly the treatment algorithm – (treatment by genotype) Is specifically relevant for mutant tumors – (First-line therapy) Has been licensed and recommended in wild type tumors and tumors with unknown EGFR-status – (Maintenance, second/third-line therapy) Has underlined the importance of the pathologist’s and its tight cooperation with the clinicians – (molecular testing)

59 4th International Thoracic Oncology Congress Dresden September 12 th – 14 th 2014 Maritim Hotel and International Congress Center Dresden, Germany Organizers: Christian Manegold - Mannheim Giorgio V. Scagliotti - Torino Nico van Zandwijk - Sydney Advances through Molecular Biology in Thoracic Cancer More Information: Save the date!


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