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Maintenance therapy for NSCLC

Maintenance therapy for NSCLC. Istituto Toscano Tumori-Livorno-Italy. Federico Cappuzzo Istituto Toscano Tumori Ospedale Civile Livorno-Italy. The maintenance therapy paradigm. No progression after 4 cycles of platinum-based CT, PS=0-1.

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Maintenance therapy for NSCLC

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  1. Maintenance therapy for NSCLC Istituto Toscano Tumori-Livorno-Italy Federico Cappuzzo Istituto Toscano Tumori Ospedale Civile Livorno-Italy

  2. The maintenance therapy paradigm No progression after 4 cycles of platinum-based CT, PS=0-1 Stratification for EGFR, ALK, histology, response to CT EGFR WT/ALK-: Response to CT /Histology Istituto Toscano Tumori-Livorno-Italy CR/PR SD Continuation maintenance SCC: Switch maintenance Non-SCC: cont/switch maintenance SCC Gemcitabine Non-SCC Pemetrexed or beva Erlotinib or Docetaxel Pem or beva Erlot or Docetax

  3. Immediate vs. delayed docetaxelas 2nd line NSCLC treatment R A N D O MI Z E Immediate Docetaxel CR, PR SD Carboplatin Plus Gemcitabine X 4 Istituto Toscano Tumori-Livorno-Italy Delayed Docetaxel at time of PD

  4. Docetaxel study results PFS Istituto Toscano Tumori-Livorno-Italy OS

  5. TFINE study: multicenter, randomized phase III studyof continuation docetaxel Docetaxel 75 mg/m2 IV Cisplatin 75 mg/m2 IV q Docetaxel 60 mg/m2 IV q 3wk Up to six cycles IIIB/IV Chemo-Naïve NSCLC N=382 CR PR SD R1 R2 Istituto Toscano Tumori-Livorno-Italy Docetaxel 60 mg/m2 IV Cisplatin 75 mg/m2 IV BSC Zhang et al. ASCO 2013, Abstract # 8015

  6. TFINE study, C-TONG 0904PFS results Istituto Toscano Tumori-Livorno-Italy

  7. Maintenance trials with pemetrexed Switch maintenance: JMEN • Stage IIIB/IV NSCLC • ECOG 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 • non-platinum drug • brain mets 2:1 Randomization Pemetrexed 500 mg/m2 (d1,q21d) + BSC (N=441)* Istituto Toscano Tumori-Livorno-Italy Continuation maintenance: PARAMOUNT • Nonsquamous NSCLC • No prior systemic treatment for lung cancer • ECOG PS 0-1 500 mg/m2 Pemetrexed + BSC, d1, q21d CR, CP, SD 2:1 randomization Placebo (d1, q21d) + BSC (N=222)* Placebo + BSC, d1, q21d 500 mg/m2 Pemetrexed + 75 mg/m2 Cisplatin, d1, q21d • Stratified for: • PS (0 vs 1) • Disease stage (IIIb vs IV) prior to induction • Response to induction (CR/PR vs SD) PD

  8. Progression-free Survival Continuation maintenance: PARAMOUNT Switch maintenance: JMEN Istituto Toscano Tumori-Livorno-Italy

  9. Overall Survival: pemetrexed maintenance data Continuation maintenance: PARAMOUNT Switch maintenance: JMEN Istituto Toscano Tumori-Livorno-Italy

  10. JMEN & PARAMOUNT: OS according to response to first-line chemotherapy HR Induction response CR/PR* 0.81 0.61 Induction response SD* Istituto Toscano Tumori-Livorno-Italy Induction response CR/PR 0.81 0.76 Induction response SD 0.6 0.8 1.0 1.2 0.4 HR Favours pemetrexed Favours placebo *Non-squamous group Ciuleanu et al. Lancet 2009; Paz Ares et al. ASCO 2012

  11. Maintenance trials with EGFR-TKIs Erlotinib maintenance: SATURN Erlotinib 150mg/day PD Chemonaïve advanced NSCLC n=1,949 4 cycles of 1st-line platinum-based doublet* Non-PD n=889 1:1 Placebo • Stratification factors: • EGFR IHC (positive vs negative vs indeterminate) • Stage (IIIB vs IV) • ECOG PS (0 vs 1) • CT regimen (cis/gem vscarbo/doc vs others) • Smoking history (current vs former vs never) • Region PD Mandatory tumor sampling Istituto Toscano Tumori-Livorno-Italy Gefitinib maintenance: INFORM • Patients • Age ≥18 years • Completed 4 cycles of first-line platinum-based chemotherapy without PD or unacceptable toxicity • Life expectancy≥12 weeks • WHO PS 0-2 • Measurable Stage IIIB/IV disease Gefitinib(250 mg/day) 1:1 randomization Placebo(once daily)

  12. Progression-free Survival in ITT population Erlotinib maintenance: SATURN Gefitinib maintenance: INFORM HR=0.71 (0.62–0.82) p<0.0001 HR=0.42 (0.32–0.54) Istituto Toscano Tumori-Livorno-Italy

  13. Overall Survival in ITT population Erlotinib maintenance: SATURN Gefitinib maintenance: INFORM HR=0.81 (0.70–0.95) p=0.0088 HR = 0.83 (0.61, 1.12) p=0.2109 Istituto Toscano Tumori-Livorno-Italy

  14. Effect of erlotinib and gefitinib in EGFR wild-type patients: PFS and OS data PFS and OS in SATURN PFS in INFORM Istituto Toscano Tumori-Livorno-Italy

  15. OS according to response to first-line chemotherapy* SD 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) Istituto Toscano Tumori-Livorno-Italy Log-rank p=0.0019 Log-rank p=0.6181 OS probability 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) *OS is measured from time of randomisation into the maintenance phase

  16. IFCT-GFPC 0502 study design PD: off Maintenance treatment Progression: 2nd line A Observation PD Pemetrexed N=155 Cisplatin gemcitabine x 4 cycles N=834 Objective response or stable disease B R*N=464 Gemcitabine PD Pemetrexed N=154 Istituto Toscano Tumori-Livorno-Italy C Erlotinib PD Pemetrexed NSCLC Stage IIIB wet – IV PS 0-1, 18-70 years Asymptomatic brain mets allowed Tumor tissue EGFR IHC EGFR mutation N=155 Primary endpoint: PFS *Stratification factors: • gender • histology: adenocarcinoma vs other histology • smoking status: non-smokers vs current/former smokers • center • response vs stabilization to induction chemotherapy Induction chemo: cisplatin 80mg/m2 d1 + gemcitabine 1,250mg/m2 d1, d8 Arm B: gemcitabine 1,250mg/m2 d1, d8 /3 wks Arm C: erlotinib 150mg daily EGFR = epidermal growth factor receptor IHC = immunohistochemistry; PD = progressive disease

  17. PFS and OS results with continuation gemcitabine Istituto Toscano Tumori-Livorno-Italy Perol et al. JCO 2012

  18. PFS and OS results with switch erlotinib Istituto Toscano Tumori-Livorno-Italy Perol et al. JCO 2012

  19. Is continuation maintenance with pemetrexed plus bevacizumab better than beva or pem alone? AVAPERL First-line induction4 cycles, q3w Continuation maintenance q3w until PD Istituto Toscano Tumori-Livorno-Italy Avastinn=125 CR/PR/SD per RECIST§ 1 Previously untreated stage IIIB-IV NSCLC N=376 Avastin‡ + pemetrexed‡ + cisplatin‡ n=253 R 67% Avastin + pemetrexedn=128 1 PD • Stratification factors • Gender • Smoking status • Response at randomisation Follow-up

  20. AVAPERL: PFS from randomisation 1.0 0.8 0.6 0.4 0.2 0 Avastin + Pem 7.4m Avastin 3.7m HR: 0.48; p<0.001 PFS estimate Istituto Toscano Tumori-Livorno-Italy 0 3 6 9 12 15 Time (months) OS for Pem/Bev was better than for Bev (17.1 vs 13.2 months), p=0.29, HR 0.87 (CI 0.63-1.21) EMCC 2011, ASCO 2013

  21. PointBreak: Study Design Istituto Toscano Tumori-Livorno-Italy Pemetrexed + Carboplatin + Bevacizumab Pemetrexed + Bevacizumab Paclitaxel + Carboplatin + Bevacizumab Bevacizumab Patel et al., 2012 Chicago Multidisciplinary symposium in Thoracic Oncology

  22. PointBreak: KM Plot for OS (Intent-to-treat) HR=1.0 (95% CI: 0.86–1.16) Log-rank P=0.949 Pem Arm Median OS = 12.55 mo (95% CI: 11.30–14.03) Pac Arm Median OS = 13.4 mo (95% CI: 11.86–14.91) 100 80 60 Istituto Toscano Tumori-Livorno-Italy 40 20 0 0 3 6 9 12 15 18 21 24 27 30 33 36 39

  23. PRONOUNCE: Study Design • Randomized, open-label, phase III superiority study conducted in US • Pemetrexed 500 mg/m2, Carboplatin AUC 6 (Pem+Cb) • Paclitaxel 200 mg/m2, Carboplatin AUC 6, Bevacizumab 15 mg/kg (Pac+Cb+Bev) Induction Phaseq21d, 4 cycles Maintenance Phase q21d until PD • Bev-Eligible Population • Inclusion: • - Chemo-naïve patients • - PS 0/1 • - Stage IV, nonsquam • - Stable treated CNS mets • Exclusion: • - Uncontrolled effusions Pemetrexed (folic acid & vitamin B12) + Carboplatin Pemetrexed (folic acid & vitamin B12) Istituto Toscano Tumori-Livorno-Italy 180 patients each R1:1 Bevacizumab Paclitaxel + Carboplatin + Bevacizumab Stratified for: PS (0 vs 1); gender (M vs F); disease stage (M1a vs M1b) Zinner ASCO 2013

  24. Primary Endpoint: G4PFS (ITT) 100 Pem+Cb: median G4PFS = 3.9 (mo) -------- Pac+Cb+Bev: median G4PFS = 2.9 (mo) Log-rank p-value = 0.176 HR (90% CI) = 0.85 (0.70, 1.04) 80 60 Istituto Toscano Tumori-Livorno-Italy 40 20 0 0 3 6 9 12 15 18 21 24 27 Patients at Risk Zinner ASCO 2013

  25. Secondary end-points Istituto Toscano Tumori-Livorno-Italy Zinner ASCO 2013

  26. There is any patient unsuitable for maintenance therapy? • Randomization factors: • PS status • Stage • Best tumour repsonse • Primary Endpoint OS ~60% of PS2 Patients R A N D O MI Z E Istituto Toscano Tumori-Livorno-Italy Gemcitabine q 21 days + BSC N= 128 CR, PR SD Gemcitabine + Carboplatin X 4 cycles BSC N= 127 PD Off study Belani et al, ASCO 2010

  27. No benefit with maintenance therapy in PS2 patients 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 HR=0.97 (95% CI:0.72, 1.30) P =0.838 Istituto Toscano Tumori-Livorno-Italy BSC 9.3 mos. Survival Probability Gemcitabine 8.0 mos. 0 6 12 18 24 30 36 42 48 54 60 Overall Survival (months)

  28. The maintenance therapy paradigm No progression after 4 cycles of platinum-based CT, PS irrelevant EGFR mutated Istituto Toscano Tumori-Livorno-Italy EGFR-TKI

  29. Progression-free Survival in mutated patients Erlotinib maintenance: SATURN Gefitinib maintenance: INFORM HR=0.10 (0.04–0.25) P<0.0001 HR=0.17 (0.07–0.42) 100 100 Istituto Toscano Tumori-Livorno-Italy 80 80 60 60 PFS (%) PFS (%) 40 40 20 20 0 8 16 24 32 40 48 56 64 72 80 88 96 0 8 16 24 32 40 48 56 64 72 80 88 96 104 112 Time (weeks) Time (weeks)

  30. The maintenance therapy paradigm No progression after 4 cycles of platinum-based CT, PS irrelevant ? ALK+ Istituto Toscano Tumori-Livorno-Italy Pemetrexed Crizotinib

  31. ALK Fusion not Associated with Sensitivity to Platinum-based Chemotherapy and EGFR –TKIs • ALK-positive patients display similar sensitivity to platinum-based chemotherapy compared with ALK-negative patients • Patients with the ALK fusion gene may not benefit from EGFR TKIs TTP on platinum-based chemotherapy TTP on EGFR-TKI monotherapy Istituto Toscano Tumori-Livorno-Italy 100 100 80 80 ALK-positive EGFR mut-positive WT/WT ALK-positive EGFR mut-positive WT/WT 60 60 Progression-free (%) Progression-free (%) p=0.004 (ALK vs EGFR) 40 40 20 20 0 12 24 36 48 0 12 24 36 48 60 Months Months Shaw AT, et al. J Clin Oncol 2009;27:4247‒53

  32. ALK fusion predictive for pemetrexed sensitivity Istituto Toscano Tumori-Livorno-Italy Low TS levels in ALK+ Takeda M, Clin Lung Cancer 2012; Camidge JTO 2011

  33. Profile 1007: PFS by Independent Radiologic Review (in overall population and according to chemotherapy) Istituto Toscano Tumori-Livorno-Italy Shaw AT., Lancet Oncol 2013

  34. Overall Survival Istituto Toscano Tumori-Livorno-Italy * 112 patients crossed over to crizotinib Shaw AT., Lancet Oncol 2013

  35. Conclusions • Maintenance therapy is a relevant option to discuss with patients • Treatment choice should be based on EGFR, ALK, histology, response to front-line therapy and patient preferences • In EGFR/ALK wild-type maintenance is not recommended for patients with low performance status • In EGFR mutated patients EGFR-TKIs are the best option • In ALK+ any effort should be done for reducing the risk to preclude crizotinib therapy Istituto Toscano Tumori-Livorno-Italy

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