Treatment of advanced NSCLC in 2013: Algorithm, failures, and perspectives

Transcription

1 Treatment of advanced NSCLC in 2013: Algorithm, failures, and perspectives Prof. Christian Manegold Medical Faculty Mannheim University of Heidelberg

2 Disclosures Consultancy: Hoffmann-La Roche, Pfizer, Eli Lilly, Merck-Serono, Novartis, Amgen, Boehringer Ingelheim, AstraZeneca Speaking: Hoffmann-La Roche, Eli Lilly, Merck- Serono, AstraZeneca Grant support: Merck-Serono, Sanofi-Aventis, Eli Lilly Travel Support: Hoffmann-La Roche, Merck-Serono, Eli Lilly, AstraZeneca

3 Advanced NSCLC: Treatment strategies in 2013 Individualized therapy Treatment by molecular biology Treatment by histology

4 NSCLC: Incidence of single driver mutations No mutation detected KRAS 22% AKT1 NRAS MEK1 MET AMP HER2 PIK3CA EML4-ALK 7% EGFR 17% BRAF Double mutants 3% Mutation found in 54% (280/516) of tumours completely tested (CI 50-59%) Kris et al. J Clin Oncol 29: 2011 (suppl; abstr 7506)

5 Advanced NSCLC: Treatment algorithm in 2013 Mutant tumors Non-Squamous Squamous 1st-line EGFR-TKI Platinum-Doublets (Pem!) plus Bev Platinum-Doublets (No Pem, no Bev) Maintenance 2nd-line Treatment until progression Oligo progression: Cont. TKI + Local therapy Diffuse progression Cont. TKI + Chemo Chemo TKI re-expo 2 nd generation TKI Switch: Pemetrexed Erlotinib Continuous: Pemetrexed Single agent Non-cross resistant ALK-Inhibitor Switch: Erlotinib Single agent Non-cross resistant

6 Advanced NSCLC : Gefitinib 1 st - line (IPASS) PFS according to EGFR-Mutations Status EGFR-mutation positive EGFR-mutation negative Mok et al. N Engl J Med, 361, , 2009

7 PFS probability Advanced NSCLC: Erlotinib 1 st -line (OPTIMAL) PFS in mutated tumors Erlotinib (n=82) Gem/carbo (n=72) HR=0.16 ( ) Log-rank p< Time (months) Zhou et al. Lancet Oncol 12: , 2011

8 Advanced NSCLC: Erlotinib vs standard CT in EGFR-mutant NSCLC (EURTAC) Rosell et al Lancet Oncol 13; ;2012

9 Advanced NSCLC: EMA recommendation for 1st-line Gefitinib and Erlotinib Patients with locally advanced or metastatic NSCLC whose tumors show EGFR - Mutations EMA 2009/2011

10 EGFR-Mutation /ALK Testing: General Considerations Which patient All / some Which mutation Exon 19 / 21 or more Overal testing process Flow chart / time frame Analysis method DNA sequencing Sample source Histology / cytology CAP/IASLC/AMP Guideline on Molecular Testing for Lung Cancer, J Thorarc Oncol 2013 Pirker et al. Consensus for EGFR Mutation Testing in Non-small Cell Lung Cancer, J Thorarc Oncol 5, , 2010

11 Advanced NSCLC: Treatment algorithm in 2013 Mutant tumors Non-Squamous Squamous 1st-line EGFR-TKI Platinum-Doublets (Pem!) plus Bev Platinum-Doublets (No Pem, no Bev) Maintenance 2nd-line Treatment until progression Oligo progression: Cont. TKI + Local therapy Diffuse progression Cont. TKI + Chemo Chemo TKI re-expo 2 nd generation TKI Switch: Pemetrexed Erlotinib Continuous: Pemetrexed Single agent Non-cross resistant ALK-Inhibitor Switch: Erlotinib Single agent Non-cross resistant

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

13 NSCLC: Pemetrexed registration Second-line therapy First-line therapy (combined with cisplatin) Maintenance: as single agent following platinum based therapy (predominantly other than squamous cell histology; non-progression after four cycles of chemotherapy) EMA/ CHMP/ / 2009

14 Advanced NSCLC: Bevacizumab plus Standard CT Results by primary endpoints ECOG 4599: Carbo/Taxol AVAiL: Cis/Gem 10.3 m 12.3 m 6.1 m 6.7 m 6.1 m 6.5 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 Time Months

15 Advanced NSCLC: Bevacizumab safety & efficacy confirmed in clinical practice (>4,000 patients) SAiL 1 (Phase IV study: Safety of Avastin in Lung) International First-line, advanced non-squamous NSCLC (n=2,212) Bevacizumab + standard of care chemotherapy Bev to progression PD ARIES 2 (Avastin Registry: Investigation of Effectiveness and Safety) USA First-line, advanced non-squamous NSCLC (n 2,000) Bevacizumab + chemotherapy Bev continued at clinician s discretion Crinò, et al. Lancet Oncol 2010; Wozniak, et al. ASCO 2010

16 NSCLC: Bevacizumab - Efficacy improves RR improves duration of response prolongs PFS increases OS 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 NSCLC: Bevacizumab - Registration EMA:..at a dose of 7.5mg/kg or 15mg/kg, in combination with platinum-based chemotherapy, for the first-line treatment of patients with unresectable advanced, metastatic or recurrent NSCLC other than predominantly squamous cell histology.. FDA:.. 15mg/kg, in combination with carboplatin and paclitaxel, for first-line treatment of patients with unresectable, locally advanced, recurrent or metastatic nonsquamous, NSCLC.. EMA (2008):..removal of bevacizumab contradiction in patients with untreated CNS metastases..

18 NSCLC: Bevacizumab - Eligibility Inclusion criteria non-squamous NSCLC chemo-naïve ECOG PS of 0 1 Exclusion criteria 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

19 NSCLC: Bevacizumab - Elderly Outcome Pac-Carbo Elderly >70 y Pac- Carbo- Bev CR + PR 17% 29% SD 50% 39% PFS 4.9 mos 5.9 mos p= yr-S 50% 46% Gr 3/4 toxicity (%) >70 y <70 y p Neutropenia (Gr 4) Melena/GI bleed Proteinuria Muscle weakness Motor neuropathy Dizziness Worst grade <0.001 TRDs MS 12.1 mos 11.3 mos p=0.4 Ramalingam et al., J ClinOncol 26, 60-65, 2008 Soria et al Ann Oncol 24,20-30,2013 Vokes et al Ann Oncol 24, 6-9,2013

20 Advanced NSCLC: Treatment algorithm in 2013 Mutant tumors Non-Squamous Squamous 1st-line EGFR-TKI Platinum-Doublets (Pem!) plus Bev Platinum-Doublets (No Pem, no Bev) Maintenance 2nd-line Treatment until progression Oligo progression: Cont. TKI + Local therapy Diffuse progression Cont. TKI + Chemo Chemo TKI re-expo 2 nd generation TKI Switch: Pemetrexed Erlotinib Continuous: Pemetrexed Single agent Non-cross resistant ALK-Inhibitor Switch: Erlotinib Single agent Non-cross resistant

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

22 NSCLC: Erlotinib Switch-Maintenance (SATURN) Survival for SD in wild-type tumours Coudert et al. Ann Oncol 23, , 2012 Cappuzzo et al. Lancet Oncol 11, ; 2010

23 Overall Survival NSCLC - Pemetrexed Switch Maintenance (JMEN) Overall survival by histology Non-squamous HR=0.70 (95% CI: ) p=0.002 Squamous HR=1.07 (95% CI: ) p=0.678 Pemetrexed: 15.5 mos Placebo: 10.8 mos Placebo: 10.3 mos Pemetrexed: 9.9 mos Time (months) Time (months) Ciuleanu T. et al. Lancet 374, ; 2009

24 Progression free Survival NSCLC Pemetrexed cont. Maintenance (Paramount) Progression free survival Paz-Ares Lancet Oncol 13, , 2012

25 NSCLC Pemetrexed cont. Maintenance (Paramount) Overall survival Paz-Ares et al. J Clin Oncol 30 (suppl 15) 481 (abstr LBA) 7507, 2012

26 NSCLC Pemetrexed cont. Maintenance (Paramount) Overall survival by response Objective regression Disease stabilization Survival Probability CR/PR HR = Time from Randomization (Months) Survival Probability SD HR = Time from Randomization (Months) Paz-Ares et al. J Clin Oncol 30 (suppl 15) 481 (abstr LBA) 7507, 2012

27 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

28 NSCLC - Pemetrexed registration: Switch and continuation maintenance therapy...as single agent following platinum based therapy - predominantly other than squamous cell histology; non-progression after four cycles of chemotherapy EMA: 2009 / 2011

29 NSCLC Bevacizumab until progression / continuation maintenance ECOG Bev until progression AVAiL.. Bev until progression SAiL Bev until progression ARIES. Bev until progression Pointbreak Sandler* vs Carbo/Pem/Bev Bev/PEM PRONOUNCE.. Sandler* vs Carbo/Pem PEM AVAPERL. Cis/Pem/Bev Bev or Bev/Pem *) Carbo / Pac / Bev as in ECOG 4599

30 NSCLC Bevacizumab cont maintenance (AVAPERL) Key efficacy data: PFS and OS Bev Bev+Pem HR (95% CI) p value PFS (months) From the time of randomisation From the start of induction therapy with PBC ( ) 0.58 ( ) < < OS (months) From the time of randomisation From the start of induction therapy with PBC ( ) 0.88 ( ) Rittmeyer et al. J Clin Oncol 31 (suppl 15; abstr 8014), 2013

31 ECOG 5508: NSCLC-Maintenance Bevacizumab and/or Pemetrexed Primary Endpoint: OS 4 cycles Bevacizumab Chemo-naive Nonsquamous-NSCLC stage IIIB / IV (n=1,282) 15 mg/kg q3w + Carboplatin + Paclitaxel R 1:1:1 Bevacizumab 15 mg/kg, q3w Pemetrexed 500 mg/m 2, q3w Bevacizumab 15 mg/kg, q3w + Pemetrexed 500 mg/m2, q3w Until PD Until PD Until PD PI: S Ramalingam

32 Advanced NSCLC: Treatment algorithm in 2013 Mutant tumors Non-Squamous Squamous 1st-line EGFR-TKI Platinum-Doublets (Pem!) plus Bev Platinum-Doublets (No Pem, no Bev) Maintenance 2nd-line Treatment until progression Oligo progression: Cont. TKI + Local therapy Diffuse progression Cont. TKI + Chemo Chemo TKI re-expo 2nd generation TKI Switch: Pemetrexed Erlotinib Continuous: Pemetrexed Single agent Non-cross resistant ALK-Inhibitor Switch: Erlotinib Single agent Non-cross resistant

33 Advanced NSCLC: Crizotinib for ALK-positive disease Phase III (PROFILE 1007) 2 nd line Primary Endpoint: PFS 347 patients, Advanced NSCLC, Prior platinumbased CT, all histologies, EML4-ALK Translocation Randomization Crizotinib 250 mg bid Pemetrexed or Docetaxel PD Crizotinib 250 mg bid Shaw et al. N Engl J Med 368, , 2013

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

35 Advanced NSCLC: Crizotinib - registration for the treatment of adults with previously treated (ALK)-positive advanced non-small cell lung cancer (NSCLC) EMA/CHMP/453868/2012

36 Failures

37 Advanced NSCLC: Negative Phase III - trials Compound Mechanism N Endpoint Gefitinib EGFR-TKI 5975 OS Erlotinib EGFR-TKI 3661 OS Afatinib HER1-4 TKI 585 OS Cetuximab EGFR-AB 676 PFS Prinomastat Matrix metalloprotease inhib OS Rebimastat Matrix metalloprotease inhib. 774 OS PF-676 TLR OS Aprinocarsen protein kinase C-α antisense o.n OS Bexarotene Retinoid X receptor act OS Lonafarnib Farnesyl-transferase inhib. 675 OS Figitumumab ICF-1R AB 681 OS Celecoxib Cox2 inhibitor 561 OS IL-2 Cytokine 241 OS Thalidomide Anti-angiogenic 1267 OS Cediranib VEGF-TKI 296 OS Vandetanib Multikinase TKI 2698 PFS/OS AE-941 Anti-angiogenic 379 OS Sorafenib Multikinase TKI 1830 OS Sunitinib Multikinase TKI 960 OS Aflibercept VEGF/PIGF 913 OS TOTAL

38 Advanced NSCLC: Toll-like receptor 9 analogue immunomodulation (PF ) N=74 Phase II N=37 Phase III Manegold et al. J Clin Oncol 26: , 2008 Manegold et al. Ann Oncol 23: 72-77, 2012

39 Advanced NSCLC: Oral recombinant human talactoferrin FORTIS-M, A Randomized, Double-blind, Placebocontrolled Phase 3 Study of Oral Talactoferrin alfa with Best Supportive Care in Patients with Advanced Non- Small Cell Lung Cancer following Two or More Prior Regimens- by The FORTIS-M Study Group Ramalingam et al. ESMO 2012 Median overall survival in the talactoferrin arm was 7.5 months compared to 7.7 months for placebo (hazard ratio 1.04, p-value 0.66).

40 Advanced NSCLC: Second line Erlotinib plus cmet-inhibition by TKI-Tivantinib - phase III (MARQUEE) Arqule and Daiichi Sankyo announce discontinuation of Phase III Marquee clinical trial in NSCLC (Oct. 2012)

41 Advanced NSCLC: VEGFR1-3, PDGFR, RET, KIT inhibition by oral motesanib plus carboplatin/paclitaxel in nonsquamous tumors (Phase III; MONET1) Scagliotti J Clin Oncol 30: , 2012

42 Advanced NSCLC: Carboplatin/paclitaxel plus vascular disrupting agent (ASA404) - Phase III Arm ASA404 + PC Placebo + PC Median survival (95% CI) 13.4 months (11.4, 16.6) 12.7 months (11.3, 14.4) Lara et al. J Clin Oncol 29, , 2011 McKeage et al. Brit J Cancer 99, , 2008 McKeage et al. Lung Cancer 65, , 2009

43 Advanced NSCLC: Cetuximab First-Line (FLEX - Phase III trial) Pirker et al. Lancet 373, , 2009

44 Advanced NSCLC: Cetuximab First-Line (FLEX - Phase III trial) Erbitux works in advanced NSCLC Erbitux works in all NSCLC histo types Erbitux improves survival when combined with standard platinum-based chemotherapy Erbitux s toxicity is well defined and managable An Erbitux efficacy predictor has been identified (EGFR Immunohistochemistry score) Pirker et al. Lancet, 373, , 2009 O Byrne et al. Lancet Oncol 12, , 2011 Pirker et al. Lancet Oncol 13: 33 42, 2012 Gatzemeier et al. Lancet Oncol 12, 30-37; 2011

45 Perspectives

46 NSCLC: molecular treatment targets EGFR VEGF, PDGFR ALK BCL-2 BCR-ABL/ -STAT BRAF HSP90, HDAC Proteosome FGFR Hedgehog Hormone therapy Hypoxia activated prodrug HIF-1 Immunmodulat. -CTLA-4 - PD1/PDL1 - Fusion prot. IGF-1R mtor cmet/hgfr MEK Mitosisinhibitor -Aurorakinase -ChK -Kinesin protein -Polo-like kinase Notch PI-3K/AKT PARP Survivin Vascular disrupting Vaccines Anti-sense Oligon. Others -TLR9 -Endostatin -Serine threonine

47 NSCLC: Molecular features of squamous tumors KRASmut DDR2mut PIK3CAmut PTENloss unknown PTENmut FGFR1amp Paik et al. J Clin Oncol 29, (suppl) abstr 7505, 2012 Hammerman et al. Nature 489, , 2012

48 Molecular profiling and targeted therapy

49 Trametinib

50 Ganetespib

51 Nintedanib Results: significant improvement of PFS regardless of histology significant improvement of OS in adeno-carcinoma BIBF: TKI to VEGFR1-3, FGFR1+3, PDGFR α,β

52 Afatinib Results: Afatinib significantly prolongs PFS

53 PD-L1 antibody

54

55 Advanced NSCLC: Talactoferrinimmunomodulation Oral recombinant human lactoferrin dendritic cell recruitment and activation in gut-associated lymphoid tissue anti-infective and anti-tumor activity Parikh et al, J Clin Oncol. 29: , 2011 Digumarti et al, J Thorac Oncol 6: , 2011