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Advanced NSCLC: Treatment algorithms 2014

Advanced NSCLC: Treatment algorithms 2014. Prof. Christian Manegold Medical Faculty Mannheim University of Heidelberg. NSCLC: Incidence of single driver mutations. Mutation found in 54% (280/516) of tumours completely tested (CI 50-59%).

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Advanced NSCLC: Treatment algorithms 2014

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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) oftumours completely tested (CI 50-59%) Kris et al. J Clin Oncol 29 (suppl 15) 477 (abstr 7506); 2011

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

  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, 3825-3831, 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, 3852-3859, 2004, Rudd et al. J Clin Oncol 23, 142-153, 2005 • Artizoni et al. J Natl Cancer Inst 99, 847-857, 2007 • Co-morbidity / regimen: Platin based / free • D‘Addario et al. J Clin Oncol 23, 2926-2936, 2005 • Laack et al. J Clin Oncol 22, 2348-2356, 2004, • Age ≥ 70 years: Single agent / combination • Gridelli et al. J Clin Oncol 23, 3125-3137, 2005; Gridelli et al. J Natl Cancer Inst 95, 362-372, 2003 • Gridelli et al. J Natl Cancer Inst 91, 66-72, 1999; Sederholm et al. J Clin Oncol 23, 8380-8388, 2005 • Performance status ≥ 2: Single agent / combination • Gridelli et al. Ann Oncol 15, 419-426, 2004, • Patient’s expectations: Active therapy / BSC • Gridelli et al. J Clin Oncol 23, 3125-3137, 2005

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

  8. Advanced NSCLC: Treatment by histologyCisplatin plus Pemetrexed or Gemcitabine Squamous (n=473) Nonsquamous* (n=1252) HR=1.229 (95% CI: 1.00–1.51) p=0.051 HR=0.844 (95% CI: 0.74–0.96) p=0.011 Gemcitabine+Cisplatin Median OS: 10.8 mos Pemetrexed+Cisplatin Median OS: 11.0 mos Survival Probability Survival Probability 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, 3543-3551, 2008

  9. Efficacy by Histology in Pemetrexed Studies Non-squamous = adenocarcinoma, large cell carcinoma, and other/indeterminate NSCLC histology Scagliotti et al. J ThoracOncol 6, 64-70, 2011

  10. Ifosfamide in NSCLC: MIC Regimen Mitomycin C 6 mg/m² i.v. Bolus day 1 Ifosfamide 3.000 mg/m² i.v./3 h day 1 Cisplatin 50 mg/m² i.v./1 h day 1 Cycle repeated q3w 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 Cullen et al, Br J Cancer 58, 359-361, 1988

  11. MIC `s Efficacy is not inferior to other Platinum Doublets n RR TTP MST 1-y-s Ref. NVB / CIS 206 30 % n.r. 9.5 mo* 37 % Le Chevalier VDS / CIS 200 19 % n.r. 7.6 mo 28 % (1994) PAC 135 / CIS Total 27 %* 4.5 mo* 9.6 mo* 37 % Bonomi PAC 250 / CIS 560 32 %* 5.3 mo* 10 mo* 39 % (1996) ETO / CIS 12 % 3.0 mo 7.7 mo 32 % GEM / CIS 154 40 % 4.8 mo 8.6 mo 33 % Crino MIC 152 28 % 5.0 mo 9.5 mo 34 % (1998) GEM / CIS 69 41 %* 6.9 mo* 8,7 mo 32 % Cardenal ETO / CIS 66 22 % 4.3 mo 7.2 mo 26 % (1999) PAC / CARBO 190 23 %* 4.0 mo 7.7 mo 32 % Belani ETO / CIS 179 14 % 3.3 mo 8.2 mo 37 % (1998) *p<.05

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

  13. Platinum-free, Ifosfamide based doublets have been developed Cis 100 mg/m², d 1 x 6 (n=166) Gem 1250 mg/m² , d 1, 8 Phase III Stage IIIb/IV PS 0-2 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 RR: 41% 40% 24% MS: 10m 8m 11m Ntp3/4: 26% 30% 18% Tbp3/4: 18% 23% 7%0 Alberola et al, J Clin Oncol, 21:3207-3213, 2003

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

  15. Advanced NSCLC: Bevacizumab plus Standard CT Results by primary endpoints ECOG 4599: Carbo/Taxol AVAiL: Cis/Gem 6.7 m 6.1 m 12.3 m 10.3 m 6.5 m 6.1 m Time Months Sandler et al N Engl J Med 355, 2542-2550, 2006 Reck et al, Ann Oncol 21, 1804-1809, 2010 Reck et al, J Clin Oncol 27, 1227-1235, 2009

  16. NSCLC: Bevacizumab - Eligibility Sandler et al N Engl J Med 355, 2542-2550, 2006 Crino et al, LancetOncol 11, 733-740, 2010 Reck et al, J ClinOncol 27, 1227-1235, 2009 Reck et al, Ann Oncol 21, 1227-1234,2010 Sandler et al J Thorac Oncol 5,1416-1423,2010 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 Traditional (standard) approach 1st-line 2nd-/subsequent line Combination orsingleagent CT definednumber of cycles (4-6) single agent , Non-cross-resistant until progression Tumor progression New (maintenance) approach 1st-line Maintenance Combination orsingleagent CT definednumber of cycles (4-6) • oneofthefirstlineagentsuntilprogression (continuation) • „new“ non-cross-resistantagentuntilprogression (switch) Non- progression 2nd-/subsequent line

  19. Advanced NSCLC: Switch/continuation maintenance Cappuzzo et al. Lancet Oncol 11, 521-529; 2010 Ciuleanu T. et al. Lancet 374, 1432-1440; 2009 Paz-Ares Lancet Oncol 13, 247-255, 2012 Zhang et al. Lancet Oncol 13, 466-475,2012 Fidias et al J ClinOncol 27, 591-598, 2008 Perol et al J ClinOncol 30, 3516-3524, 2012 Paz-Ares et al J ClinOncol 31, 2895-2902, 2013

  20. Advanced NSCLC: Maintenance Switch type („early second line“) • Docetaxel Fidias et al J Clin Oncol 27, 591-598, 2009

  21. Advanced NSCLC - Maintenance: Docetaxel following Standard Doublet Chemotherapy Immediate vs delayed (2nd-line) Docetaxel CR, PR SD n=142/153 n=552 Immediate Docetaxel75 mg/m2 d1, q3w x 6 R A N D O MI Z E • Stage IIIb/IV • ECOG PS = 0–2 • CNS Mets allowed Gem, 1000 mg/m2, d1, 8 Carbo AUC 5, d1, q3w x 4 Delayed Docetaxel75 mg/m2 d1, q3w x 6 Off study: n=245 n=91/154 n=307 Primary endpoint: overall survival Fidias et al., J Clin Oncol 27, 591-598, 2009

  22. Advanced NSCLC - Maintenance: Extension by Docetaxel following Standard Doublet Chemotherapy Immediate vs delayed (2nd-line) Docetaxel Overall survival time (months) Fidias et al., J Clin Oncol 27, 591-598, 2009

  23. Advanced NSCLC: Maintenance Switch type („early second line“) • Erlotinib Cappuzzo et al, Lancet Oncol 11, 521-529, 2010

  24. Advanced NSCLC: Erlotinib switch maintenance (Saturn) Erlotinib 150mg/day PD Chemonaïve advanced NSCLC n=1,949 4 cycles of first-line platinum doublet chemotherapy* Non-PD n=889 1:1 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 Placebo PD Mandatory tumour sampling 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 maintenanceProgression free survival Progression free Survival Cappuzzo et al. Lancet Oncol 11, 521-529; 2010

  26. Advanced NSCLC: Erlotinib switch maintenanceOverall survival Overall Survival Cappuzzo et al. Lancet Oncol 11, 521-529; 2010

  27. Advanced NSCLC: Erlotinib switch-maintenance Overall survival by response Stable disease CR/PR 1.0 0.8 0.6 0.4 0.2 0 1.0 0.8 0.6 0.4 0.2 0 HR=0.72 (0.59–0.89) HR=0.94 (0.74–1.20) Log-rank p=0.0019 Log-rank p=0.6181 Overall Survival 9.6 11.9 12.0 12.5 0 3 6 9 12 15 18 21 24 27 30 33 36 0 3 6 9 12 15 18 21 24 27 30 33 36 Time (months) Time (months) Coudert et al. Ann Oncol 23, 388-394, 2012 Cappuzzo et al. Lancet Oncol 11, 521-529; 2010 Measured from time of randomisation into the maintenance phase

  28. Advanced NSCLC: Maintenance Switch type („early second line“) • Pemetrexed Ciuleanu et al Lancet 374, 1432-1440, 2009

  29. AdvancedNSCLC: Pemetrexedswitchmaintenance • Stage IIIB/IV NSCLC • PS 0-1 • 4 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)* 2:1 Randomization Primary Endpoint = PFS Placebo (d1, q21d) + BSC (N=222)* *B12, FOLATE, AND DEXAMETHASONE GIVEN IN BOTH ARMS Ciuleanu T. et al. Lancet 374, 1432-1440; 2009

  30. Advanced NSCLC: Pemetrexed switch maintenanceProgression free survival by histology Squamous Non-squamous HR=1.03 (95% CI: 0.77-1.5) p=0.896 HR=0.47 (95% CI: 0.37-0.6) p <0.00001 Pemetrexed: 4.4 mos Placebo: 2.5 mos Progression-free Probability Placebo: 1.8 mos Pemetrexed: 2.4 mos Time (months) Time (months) Ciuleanu T. et al. Lancet 374, 1432-1440; 2009

  31. Advanced NSCLC: Pemetrexed switch maintenance Overall survival by histology Non-squamous Squamous HR=0.70 (95% CI: 0.56-0.88) p=0.002 HR=1.07 (95% CI: 0.49-0.73) p=0.678 Overall Survival Pemetrexed: 15.5 mos Placebo: 10.8 mos Pemetrexed: 9.9 mos Placebo: 10.3 mos Time (months) Time (months) Ciuleanu T. et al. Lancet 374, 1432-1440; 2009

  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, 3825-3831, 2011 Fidias et al. J Clin Oncol 27, 591-598, 2009 Coudert et al. Ann Oncol 23, 388-394, 2012 Cappuzzo et al. Lancet Oncol 11, 521-529; 2010 Paz-Ares Lancet Oncol 13, 247-255, 2012

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

  34. Advanced NSCLC: Pemetrexed continuation maintenance (PARAMOUNT) Non PD Pemetrexed 3qw bis PD Stadium IV Non-squamous SD nach 4-6x Induktions-CT Cisplatin/Pemetrexed Randomisation 2:1 Placebo 3qw bis PD Paz-Ares et al Lancet Oncol 13, 247-255, 2012 Paz-Ares et al J Clin Oncol 31, 2895-2902, 2013

  35. Advanced NSCLC: Pemetrexed continuation maintenance (PARAMOUNT) – Overall survival by response Paz-Ares et al. J ClinOncol31, 2895-2902, 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, 3516-3524, 2012

  38. Advanced NSCLC: Erlotinib (switch) vs Gemcitabine (continuation) maintenance (IFCT-GFPC 0502) • 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 Patients without disease progression randomized 1:1:1 Gemcitabine (n = 154) Pem 74 % Chemotherapy-naive patients with stage IIIB/IV NSCLC (N = 834) Cisplatin/Gemcitabine for 4 cycles Erlotinib (n = 155) Pem 75% Observation (n = 155) Pem 84% PerolM et al, J Clin Oncol 30, 3516-3524, 2012

  39. Advanced NSCLC: Erlotinib (switch) vs Gemcitabine (continuation) maintenance (IFCT-GFPC 0502) PerolM et al, J Clin Oncol 30, 3516-3524, 2012

  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, 3825-3831, 2011 Shepherd et al. N Engl J Med 353, 123-132, 2005 Thatcher et al. Lancet 366, 1527-1537, 2005 Hanna et al. J Clin Oncol 22, 1589-1597, 2004

  42. Advanced NSCLC: EGFR-TKIs as second-line therapy Kim et al. Cancer 116, 3025-3033, 2010 Karampazis et al. Cancer 119, 2754-2764, 2013 Garassino et al. Lancet Oncol 14, 981-988, 2013 Ciuleanu et al. Lancet Oncol 13, 300-308, 2012 Shepherd et al. N Engl J Med 353, 123-132, 2005 Kim et al. Lancet 372, 1809-1818, 2008 Thatcher et al. Lancet 366, 1527-1537, 2005

  43. Meta-analysis in wild-type NSCLC favors CT over EGFR-TKI therapy: First- / second-line Lee et al. JAMA 311,1430-1437, 2014

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

  47. Advanced NSCLC: EGFR-TKIs as first line therapy Mok et al. N Engl J Med, 361, 947-957, 2009 Rosell et al Lancet Oncol 13;239-246;2012 Lee et al Lancet Oncol 13, 1161-1170, 2012 Zhou et al. Lancet Oncol 12, 735-742, 2011 Mitsudomi et al Lancet Oncol 11, 121-128, 2010 Sequist et al. J ClinOncol 31, 3327-3334, 2013 Gridelli et al J ClinOncol 30, 3002-3011, 2012

  48. First-linetrials of EGFR tyrosinekinaseinhibitors vs. chemotherapy in pts with EGFR mutations 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 Oncol2011;12:735‒742; 7. Rosell R et al., Lancet Oncol 2012;13:239–246; 8. Yang JC et al., J Clin Oncol2012;30 (Suppl. 16):LBA 7500, Wu Y et al., Lancet 2014; 15:213. NR = not reported

  49. Advanced NSCLC: First-line EGFR-TKI therapyASCO / ESMO-recommendation … 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 … Azzoli et al. J Clin Oncol 29, 3825-3831, 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, 823-859, 2013

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