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

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Presentation on theme: "Maintenance therapy for NSCLC Federico Cappuzzo Istituto Toscano Tumori Ospedale Civile Livorno-Italy Istituto Toscano Tumori-Livorno-Italy."— Presentation transcript:

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

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

3 Immediate vs. delayed docetaxel as 2nd line NSCLC treatment Carboplatin Plus Gemcitabine X 4 RANDOMIZERANDOMIZE Immediate Docetaxel Delayed Docetaxel at time of PD CR, PR SD Istituto Toscano Tumori-Livorno-Italy

4 Docetaxel study results Immediate (n=153) Delayed (n=154) LR p-Value Median PFS months (95% CI) 6.5 (4.4, 7.2) 2.8 (2.6, 3.4) <0.0001 12-month PFS, % (95% CI) 20% (13, 26) 9% (5, 14) PFS OS Immediate (n=153) Delayed (n=154) LR p-Value Median OS, months (95% CI) 11.9 (10.0, 13.7) 9.1 (8.0, 11.2) 0.071 12-mo survival (95% CI) 48.5% (39.9, 57.1) 38.3% (30.0, 46.5) Istituto Toscano Tumori-Livorno-Italy

5 TFINE study: multicenter, randomized phase III study of continuation docetaxel Docetaxel 60 mg/m 2 IV Cisplatin 75 mg/m 2 IV Docetaxel 60 mg/m 2 IV q 3wk Up to six cycles Docetaxel 60 mg/m 2 IV q 3wk Up to six cycles BSC IIIB/IV Chemo- Naïve NSCLC N=382 R1R1 CR PR SD R2R2 Docetaxel 75 mg/m 2 IV Cisplatin 75 mg/m 2 IV q Zhang et al. ASCO 2013, Abstract # 8015 Istituto Toscano Tumori-Livorno-Italy

6 TFINE study, C-TONG 0904 PFS results TrialStrategyInduction regimenmPFS (months) Docetaxel dose Fidias et al.SwitchCarbo+Gem5.7 vs 2.7 (early vs. delayed) 75mg/m 2 Zhang et al.ContinuationCis+Doc5.4 vs 2.7 (Doc vs. BSC) 60mg/m 2

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

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

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

10 JMEN & PARAMOUNT: OS according to response to first-line chemotherapy 1.2 Favours pemetrexed Favours placebo HR 1.00.80.6 0.4 *Non-squamous group HR Induction response SD* 0.61 Induction response CR/PR* 0.81 Ciuleanu et al. Lancet 2009; Paz Ares et al. ASCO 2012 Istituto Toscano Tumori-Livorno-Italy Induction response SD 0.76 Induction response CR/PR 0.81

11 Maintenance trials with EGFR-TKIs Erlotinib maintenance: SATURN Gefitinib maintenance: INFORM 1:1 Chemonaïve advanced NSCLC n=1,949 Non-PD n=889 4 cycles of 1st-line platinum- based doublet* Placebo PD Mandatory tumor sampling Erlotinib 150mg/day 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 Gefitinib (250 mg/day) Placebo (once daily) 1:1 randomization 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 Istituto Toscano Tumori-Livorno-Italy

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

13 HR=0.81 (0.70–0.95) p=0.0088 Overall Survival in ITT population Erlotinib maintenance: SATURN HR = 0.83 (0.61, 1.12) p=0.2109 Gefitinib maintenance: INFORM 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* OS probability 1.0 0.8 0.6 0.4 0.2 0 0369121518212427303336 Time (months) 9.611.9 1.0 0.8 0.6 0.4 0.2 0 0369121518212427303336 Time (months) 12.012.5 Log-rank p=0.0019 HR=0.72 (0.59–0.89) Erlotinib (n=252) Placebo (n=235) Log-rank p=0.6181 HR=0.94 (0.74–1.20) Erlotinib (n=184) Placebo (n=210) SDCR/PR *OS is measured from time of randomisation into the maintenance phase Istituto Toscano Tumori-Livorno-Italy

16 Observation IFCT-GFPC 0502 study design Progression: 2 nd line Primary endpoint: PFS A C Maintenance treatment PD *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/m 2 d1 + gemcitabine 1,250mg/m 2 d1, d8 Arm B: gemcitabine 1,250mg/m 2 d1, d8 /3 wks Arm C: erlotinib 150mg daily N=155 N=154 N=155 EGFR = epidermal growth factor receptor IHC = immunohistochemistry; PD = progressive disease PD: off Objective response or stable disease Cisplatin gemcitabine x 4 cycles N=834 NSCLC Stage IIIB wet – IV PS 0-1, 18-70 years Asymptomatic brain mets allowed Tumor tissue EGFR IHC EGFR mutation R* N=464 B Gemcitabine Erlotinib PD Pemetrexed Istituto Toscano Tumori-Livorno-Italy

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? Istituto Toscano Tumori-Livorno-Italy Stratification factors Gender Smoking status Response at randomisation Avastin n=125 Avastin + pemetrexed n=128 Avastin + pemetrexed + cisplatin n=253 CR/PR/SD per RECIST § First-line induction 4 cycles, q3w PD Continuation maintenance q3w until PD Follow-up R 67% 1 1 Previously untreated stage IIIB-IV NSCLC N=376 AVAPERL

20 AVAPERL: PFS from randomisation 03691215 1.0 0.8 0.6 0.4 0.2 0 EMCC 2011, ASCO 2013 PFS estimate Time (months) Avastin + Pem7.4m Avastin3.7m HR: 0.48; p<0.001 Istituto Toscano Tumori-Livorno-Italy 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)

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

22 PointBreak: KM Plot for OS (Intent-to-treat) 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) HR=1.0 (95% CI: 0.86–1.16) Log-rank P=0.949 Istituto Toscano Tumori-Livorno-Italy 20 40 60 80 100 0 0 36912151821242730333639

23 PRONOUNCE: Study Design Stratified for: PS (0 vs 1); gender (M vs F); disease stage (M1a vs M1b) Randomized, open-label, phase III superiority study conducted in US Pemetrexed 500 mg/m 2, Carboplatin AUC 6 (Pem+Cb) Paclitaxel 200 mg/m 2, Carboplatin AUC 6, Bevacizumab 15 mg/kg (Pac+Cb+Bev) Bev-Eligible Population Inclusion: - Chemo-naïve patients - PS 0/1 - Stage IV, nonsquam - Stable treated CNS mets Exclusion: - Uncontrolled effusions Induction Phase q21d, 4 cycles Maintenance Phase q21d until PD Pemetrexed (folic acid & vitamin B 12 ) + Carboplatin Paclitaxel + Carboplatin + Bevacizumab R 1:1 Pemetrexed (folic acid & vitamin B 12 ) Bevacizumab 180 patients each Istituto Toscano Tumori-Livorno-Italy Zinner ASCO 2013

24 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) PC18287442614753 1 0 PC+Bev1797533179300 0 0 Patients at Risk Primary Endpoint: G4PFS (ITT) Istituto Toscano Tumori-Livorno-Italy Zinner ASCO 2013 100 0 0 20 3691215182124 40 27 60 80

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

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

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

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

29 HR=0.10 (0.04–0.25) P<0.0001 Time (weeks) Erlotinib (n=22) Placebo (n=27) 08162432404856647280 88 96 20 40 60 80 100 081624324048566472808896104112 PFS (%) Time (weeks) HR=0.17 (0.07–0.42) 20 40 60 80 100 PFS (%) Gefitinib (n=15) Placebo (n=15) Progression-free Survival in mutated patients Erlotinib maintenance: SATURNGefitinib maintenance: INFORM Istituto Toscano Tumori-Livorno-Italy

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

31 Istituto Toscano Tumori-Livorno-Italy 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 Shaw AT, et al. J Clin Oncol 2009;27:424753 TTP on EGFR-TKI monotherapy Months 012243648 Progression-free (%) p=0.004 (ALK vs EGFR) Months 100 80 60 40 20 01224364860 TTP on platinum-based chemotherapy ALK-positive EGFR mut-positive WT/WT ALK-positive EGFR mut-positive WT/WT 100 80 60 40 20

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

33 Istituto Toscano Tumori-Livorno-Italy Profile 1007: PFS by Independent Radiologic Review (in overall population and according to chemotherapy) TreatmentmPFS (mos)HR/p value Crizotinib7.7 0.49/P<0.001 Chemotherapy3.0 TreatmentmPFS (mos)HR/p value Crizotinib7.7 Pemetrexed4.2 0.59/P<0.001 Docetaxel2.6 0.30/P<0.001 Shaw AT., Lancet Oncol 2013

34 Istituto Toscano Tumori-Livorno-Italy Overall Survival * 112 patients crossed over to crizotinib TreatmentmOS (mos)HR/p value Crizotinib20.3 0.54/P=0.54 Chemotherapy22.8 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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