TERAPIA DI MANTENIMENTO NEL NSCLC. Dr Giuseppe L. Banna Oncologia Medica A.O. Cannizzaro Catania

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1 TERAPIA DI MANTENIMENTO NEL NSCLC Dr Giuseppe L. Banna Oncologia Medica A.O. Cannizzaro Catania

2 Conflitti di interesse Ai sensi dell art. 3.3 del Regolamento applicativo dell Accordo Stato- Regioni , dichiaro che negli ultimi due anni ho avuto i seguenti rapporti anche di finanziamento con i seguenti soggetti portatori di interessi commerciali in campo sanitario: Italfarmaco Lilly Roche In fede, Giuseppe Luigi Banna

3 Obiettivi formativi Applicazione nella pratica quotidiana dei principi e delle procedure dell evidence based practice (EBM; EBN; EBP) relativamente alla terapia di mantenimento nel NSCLC con particolare riguardo a: definizione e strategie di mantenimento risultati di outcome degli studi clinici indicatori predittivi di outcome per le diverse strategie beneficio assoluto, tossicità, preferenza e qualità di vita per il paziente linee guida

4 Historical & new approach to NSCLC Traditional approach First-line treatment Platinum doublet chemotherapy (4 6 cycles) Watch and wait Second and further lines of treatment Diagnosis CR/PR/SD PD PD Pfister DG, et al. J Clin Oncol 2004 Courtesy of Silvia Novello

5 Historical & new approach to NSCLC Traditional approach First-line treatment Platinum doublet chemotherapy (4 6 cycles) Watch and wait Second and further lines of treatment Diagnosis CR/PR/SD PD PD PD Maintenance approach Maintenance therapy Increased time to PD & OS Diagnosis CR/PR/SD PD PD Pfister DG, et al. J Clin Oncol 2004 Courtesy of Silvia Novello

6 Historical & new approach to NSCLC Traditional approach First-line treatment Platinum doublet chemotherapy (4 6 cycles) Watch and wait Second and further lines of treatment Diagnosis CR/PR/SD PD PD PD Second-line Platinumbased Maintenance doublet chemotherapy approach Non-PD (CR/PR/SD) Monitor Maintenance Maintenance therapy therapy PD Increased time to PD & OS Docetaxel, erlotinib, pemetrexed, (or gemcitabine) Diagnosis CR/PR/SD PD PD Pfister DG, et al. J Clin Oncol 2004 Courtesy of Silvia Novello

7 Historical & new approach to NSCLC Traditional approach First-line treatment Platinum doublet chemotherapy (4 6 cycles) Watch and wait Second and further lines of treatment Diagnosis CR/PR/SD PD PD Second-line Platinumbased doublet chemotherapy Non-PD (CR/PR/SD) Monitor Maintenance therapy PD Docetaxel, erlotinib, pemetrexed, (or gemcitabine) Pfister DG, et al. J Clin Oncol 2004 Courtesy of Silvia Novello

8 Historical & new approach to NSCLC Traditional approach First-line treatment Platinum doublet chemotherapy (4 6 cycles) Watch and wait Second and further lines of treatment Diagnosis CR/PR/SD PD PD Pfister DG, et al. J Clin Oncol 2004 Courtesy of Silvia Novello

9 Historical & new approach to NSCLC Traditional approach First-line treatment Platinum doublet chemotherapy (4 6 cycles) Watch and wait Second and further lines of treatment Diagnosis CR/PR/SD PD PD Maintenance Second-line Platinumbased doublet chemotherapy Non-PD (CR/PR/SD) Docetaxel, Maintenance erlotinib, therapy gefitinib pemetrexed or gemcitabine PD Based on prior therapy Pfister DG, et al. J Clin Oncol 2004 Courtesy of Silvia Novello

10 2 nd line following PD to 1 st line (% pts) Socinski et al Belani et al Brodowicz et al von Plessen et al Barata et al Park et al Ciuleanu et al Pirker et al Scagliotti et al Fidias et al Gridelli et al Patients receiving 2nd line therapy (%)

11 Maintenance treatment Continuation of treatment in patients not progressed after first-line platinum-based chemotherapy (not early second line) The goal is the to increase the duration of disease control and improve survival Feasible option due to better tolerated drugs Implication in terms of costs, quality of life, potential toxicity, patient preference

12 The ideal maintenance agent Efficacious (PFS & Survival) Well tolerated No cumulative toxicity Ability to administer easily in the outpatient setting Affordable

13 Types of Maintenance Continuation therapy: Prolonged platinum doublet chemotherapy Continuation Maintenance: Continuation of the non-platinum cytotoxic (and possibly targeted) agent used in doublet chemotherapy e.g. gemcitabine, pemetrexed (+bevacizumab) Switch Maintenance: Introduction of a new cytotoxic or targeted agent e.g. docetaxel, pemetrexed, erlotinib, gefitinib, bevacizumab

14 Types of Maintenance Continuation therapy: Prolonged platinum doublet chemotherapy Continuation Maintenance: Continuation of non-platinum cytotoxic (and possibly targeted) agent used in doublet chemotherapy e.g. gemcitabine, pemetrexed (+bevacizumab) Switch Maintenance: Introduction of a new cytotoxic or targeted agent e.g. docetaxel, pemetrexed, erlotinib, gefitinib, bevacizumab

15 Carboplatin-Paclitaxel: continuation Grade 2-4 neuropathy Socinski, M. A. et al. J Clin Oncol; 20:

16 Types of Maintenance Continuation therapy: Prolonged platinum doublet chemotherapy Continuation Maintenance: Continuation of non-platinum cytotoxic (and possibly targeted) agent used in doublet chemotherapy e.g. gemcitabine, pemetrexed (+bevacizumab) Switch Maintenance: Introduction of a new cytotoxic or targeted agent e.g. docetaxel, pemetrexed, erlotinib, gefitinib, bevacizumab

17 Types of Maintenance Continuation therapy: Prolonged platinum doublet chemotherapy Continuation Maintenance: Continuation of non-platinum cytotoxic (and possibly targeted) agent used in doublet chemotherapy e.g. gemcitabine, pemetrexed (+bevacizumab) Switch Maintenance: Introduction of a new cytotoxic or targeted agent e.g. docetaxel, pemetrexed, erlotinib, gefitinib, bevacizumab

18 Maintenance: cytotoxic agents Docetaxel (switch) Pemetrexed (switch & continuation) Gemcitabine (continuation)

19 Docetaxel: switch Carboplatin + Gemcitabine x 4 CR, PR SD R A N D O M I Z E Immediate Docetaxel Delayed Docetaxel at time of PD Primary end-point: OS Fidias JCO 2009

20 Docetaxel: switch Immediate (n=153) Delayed (n=154) LR p-value PFS Median PFS months (95% CI) 12-month PFS, % (95% CI) 6.5 (4.4, 7.2) 20% (13, 26) 2.8 (2.6, 3.4) 9% (5, 14) < = pts OS Median OS, months (95% CI) 12-mo survival (95% CI) Immediate (n=153) 11.9 (10.0, 13.7) 48.5% (39.9, 57.1) Delayed (n=154) 9.1 (8.0, 11.2) 38.3% (30.0, 46.5) LR p-value =+2.8 Fidias et al, J Clin Oncol 2009

21 Pemetrexed: switch & continuation Switch maintenance: JMEN (Lancet 2009) Pemetrexed 500 mg/m 2 + BSC Stage IIIB/IV NSCLC ECOG PS prior cycles of gem, doc, or tax + cis or carb, with CR\PR\SD 2:1 R N=663 Primary end-point: PFS Placebo + BSC Continuation maintenance: PARAMOUNT (ASCO ) Pemetrexed 500 mg/m 2 + BSC Non-squamous NSCLC ECOG PS prior cycles of CDDP 75 + Pemetrexed 500 with CR\PR\SD 2:1 R N=539 Primary end-point: PFS Placebo + BSC

22 Pemetrexed: PFS Switch maintenance: JMEN Continuation maintenance: PARAMOUNT =+2.0 =+1.3

23 Pemetrexed: OS Continuation maintenance: PARAMOUNT Switch maintenance: JMEN =2.9 =+2.8 Paz Ares ASCO 2012

24 Gemcitabine: continuation 1 European trial 2 American trial 3 French trial Positive =+1.6 Negative Positive =+1.9 Brodowicz Lung Cancer 2006 Belani ASCO 2010 Perol JCO 2012

25 Maintenance: targeted agents Erlotinib (switch) Gefitinib (switch) Bevacizumab (continuation) Bevacizumab+pemetrexed (continuation)

26 Erlotinib & Gefitinib: switch Erlotinib maintenance: SATURN (Lancet Oncol 2010) Chemonaïve advanced NSCLC n=1,949 Stratification factors: 4 cycles of 1st-line platinumbased doublet* Non-PD n=889 Erlotinib 150mg/day 1:1 EGFR IHC (positive vs negative vs indeterminate) Stage (IIIB vs IV) ECOG PS (0 vs 1) Placebo Mandatory tumor sampling CT regimen (cis/gem vs carbo/doc vs others) Smoking history (current vs former vs never) Region Primary end-point: PFS Gefitinib maintenance: INFORM (Lancet Oncol 2012) 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 Non-PD n=296 Gefitinib (250 mg/day) 1:1 randomization Placebo Primary end-point: PFS

27 PFS: ITT population Erlotinib maintenance: SATURN Gefitinib maintenance: INFORM HR=0.71 ( ) p< HR=0.42 ( ) p< =+0.3 =+2.2

28 OS: ITT population Erlotinib maintenance: SATURN HR=0.81 ( ) p= Gefitinib maintenance: INFORM HR = 0.83 ( ) p=0.2109

29 Gemcitabine cont. or Erlotinib switch Stage IIIB/IV NSCLC ECOG PS prior cycles CDDP 80 + GEM 1250 N = 464 Endpoint: PFS Prespecified second-line therapy: pemetrexed R Continuation Gemcitabine 1250 mg\m2 g1,8 Switch Erlotinib Observation Gemcitabine =+1.9 Erlotinib =+1.0 Perol et al. JCO 2012

30 Bevacizumab: continuation Positive results in first line therapy in combination with platinum-based chemotherapy (ECOG, AVAIL trial) No randomized data regarding the absolute role of bevacizumab maintenance

31 Beva+Pem: continuation =+3.6 The contribution of bevacizumab to the positive result cannot be evaluated First comparison of doublet continuation strategy versus single one Bevacizumab can be given as continuation maintenance after platinum-based first line therapy containing bevacizumab Barlesi ESMO 2011

32 POINT BREAK Beva+Pem: continuation Primary endpoint Overall Survival Median OS: 12.6 (Pem-C-Beva) vs (PTX-C-Beva) (HR 1.0; P= 0.949) Median PFS: 6.0 (Pem-C-Beva) vs. 5.6 (PTX-C-Beva) (HR 0.83; P=0.012) Different toxicity profile Patel J, et al Clin Lung Cancer 2009 Chicago Thoracic Symposium 2012

33 Quesito n.1 Quale indicatore di outcome è più importante per la terapia di mantenimento? a.il tasso di risposte b.la progression-free survival c.la overall survival d.la percentuale di pazienti trattati con una seconda linea

34 Historical & new approach to NSCLC Traditional approach First-line treatment Platinum doublet chemotherapy (4 6 cycles) Watch and wait Second and further lines of treatment Diagnosis CR/PR/SD PD PD Pfister DG, et al. J Clin Oncol 2004 Courtesy of Silvia Novello

35 Historical & new approach to NSCLC Traditional approach First-line treatment Platinum doublet chemotherapy (4 6 cycles) Watch and wait Second and further lines of treatment Diagnosis CR/PR/SD PD PD PD Maintenance approach Maintenance therapy Increased time to PD & OS Diagnosis CR/PR/SD PD PD Pfister DG, et al. J Clin Oncol 2004 Courtesy of Silvia Novello

36 Historical & new approach to NSCLC Traditional approach First-line treatment Platinum doublet chemotherapy (4 6 cycles) Watch and wait Second and further lines of treatment Diagnosis CR/PR/SD PD PD Pfister DG, et al. J Clin Oncol 2004 Courtesy of Silvia Novello

37 Predictors for maintenance Performance Status Radiological Response EGFR status

38 Predictors for maintenance Performance Status Radiological Response EGFR status

39 Performance Status PS is a variable associated with worsened survival Brodowicz T et al, Lung Cancer 2006; 52: Belani CP et al, JCO 2010; 28: abstr 7506

40 Gemcitabine cont. or Erlotinib switch Gemcitabine Erlotinib Perol et al. JCO 2012 Perol et al. JCO 2012

41 Predictors for maintenance Performance Status Radiological Response EGFR status

42 Radiological Response: switch CT DOCETAXEL PEMETREXED (JMEN) p = CR/PR* HR 0.81 CR\PR SD* 0.61 SD Favours pemetrexed *Non-squamous group HR Favours placebo Ciuleanu Lancet 2009 Fidias JCO 2009

43 Radiological Response: switch TKI ERLOTINIB (SATURN) 1.0 SD 1.0 CR/PR 0.8 HR=0.72 ( ) 0.8 HR=0.94 ( ) OS probability Log-rank p= Erlotinib (n=252) Placebo (n=235) Log-rank p= Erlotinib (n=184) Placebo (n=210) Time (months) Time (months) *OS is measured from time of randomisation into the maintenance phase

44 Radiological Response: switch TKI ERLOTINIB (IFCT-GFPC 0502) Erlotinib Perol et al. JCO 2012 Perol et al. JCO 2012

45 Radiological Response: cont. CT HR PEMETREXED (PARAMOUNT) CR/PR 0.81 SD 0.76 GEMCITABINE (IFCT-GFPC 0502) Favours pemetrexed HR 1.2 Favours placebo Paz Ares et al. ASCO 2012 Gemcitabine

46 Radiological Response: cont. CT PEMETREXED-BEVACIZUMAB

47 Challenges in RR & PFS evaluation Response Criteria Instrument/Technique Operator Timing of exhamination

48 Predictors for maintenance Performance Status Radiological Response EGFR status

49 TKIs: PFS in mutated patients Erlotinib maintenance: SATURN Gefitinib maintenance: INFORM HR=0.10 ( ) P< HR=0.17 ( ) 100 Erlotinib (n=22) 100 Gefitinib (n=15) 80 Placebo (n=27) 80 Placebo (n=15) PFS (%) PFS (%) Time (weeks) Time (weeks)

50 The ideal patient Not progressed after 4 cycles of first-line platinum-based chemotherapy Performance status 0-1 No residual toxicity from chemotherapy Informed and motivated

51 The strategy Continuation maintenance: - pemetrexed, gemcitabine Switch maintenance: - pemetrexed, erlotinib, gefitinib, docetaxel - erlotinib (gefitinib) in EGFR-mutated pts

52 Quesito n.2 Quale paziente può beneficiare maggiormente di una terapia di mantenimento dopo la chemioterapia di induzione? a.paziente con PS 0-1 b.paziente con risposta completa o parziale c.paziente con malattia stabile d.a+b+c

53 Adverse Events, QoL, Pt s Preference Three meta-analyses reported an increased adverse event rate in the maintenance arm No clear data about QoL with maintenance therapy vs. observation - some have shown no deterioration in QoL No data about patient s preference with maintenance therapy vs. observation

54 Adverse Events: meta-analysis EJC Zhang et al. Chest 140 July, 2011

55 Adverse Events: meta-analysis EJC Zhang et al. Chest 140 July, 2011

56 QoL Author Year Instrument Overall Specific Findings Fidias 2008 LCSS Ciuleanu 2009 LCSS Cappuzzo 2009 FACT-L Better (not sign 0.76) No difference TTD No difference TTD - Delayed in worsening of 2/6 symptoms (pain, hemoptysis) Delayed time to pain & analgesic use (HR 0.96) No diff in time to cough and dyspnea Miller Perol nr nr Paz Ares 2011 EQ5D No difference - Zhang 2011 FACT-L Better TTD time to deterioration in QoL Delayed median time to worsening in lung cancer symptoms

57 AB, NNT, HR (+RCTs on 12m-OS) RCTs #Pts OS AB HR (95% CI) p NNT JMEN % 0.79 ( ).012 1:8 PARAMOUNT % 0.78 ( ) :8 SATURN % 0.81 ( ) :20 FIDIAS % NA.071 1:10 Le misure assolute sono più comprensibili dai pazienti rispetto ad HR: da studi di comunicazione in BC, se si utilizza HR è più probabile che i pazienti preferiscano la chemioterapia ma meno probabile che ne abbiano compreso il reale beneficio Chao C et al, J Clin Oncol 2003

58 AB, NNT, HR (+RCTs on 12m-OS) Absolute mo.= 5-13% NNT= 1:8/20 RR= dal 19 al 21%

59 Toward a personalized medicine Risk (prognostic profile) Predictivity (predictive profile) Compliance S Mayor, BMJ 2007

60 Biomarkers ERCC1 (IHC) (BioALT) vantaggio in OS ristretto a tumori ERCC1 negativi in IALT (prognostico negativo, predittivo positivo) (HR=0.76; 95% CI ) 1 Ras wild-type trend a favore di maggiore beneficio per cancerspecific survival da CT adiuvante in JBR.10 (non prognostico) 2 RRM1 and p53 mutations sono state testate in trials recenti 3 ALK fusion oncogenes (4%) e inibitori di ALK 4 Bio-LACE in corso 5 ; TUBB3 prognostic but not predictive 6 BRCA1 mrna levels: low-level correlato con OS dopo CDDPbased CT 7 ; high-level correlato con OS dopo taxane-based CT 8 TS maggiormente espresso in SCC 9 1. Olaussen KA et al, New Engl J Med Arriagada R et al, J Clin Oncol Chhatwani L et al, Proc Am Thorac Surg Bang Y et al, Proc. ASCO Douillard JY et al, J Clin Oncol Reiman T, Ann Oncol Taron M, Hum Mol Genet Quinn JE Clin Cancer Res Ceppi P, Cancer 2006

61 PIII-RCTs ongoing with biomarkers Tailoring CT: ITACA (ERCC1, TS); SCAT (BRCA); TASTE (ERCC1) TASTE Intergroup Francophone de Cancerologie Thoracique Targeted therapies: RADIANT, ECOG E1505 MAGRIT (MAGE-A3)

62 Guidelines

63 Quesito n.3 Una pausa terapeutica e un follow-up stretto dopo chemioterapia di induzione rimangono ad oggi una strategia accettabile? a. nei pazienti con PS >1 b. in caso di tossicità residua rilevante c. in base alla preferenza del paziente d. a+b+c

64 Conclusions As in other setting, for maintenance, is essential the selection of the right patient population (PS, response [?], target ). It s unlikely that all patienst will benefit from it (biomarkers) QoL, toxicities and patient preference are very important in a disease in which the primary goal is palliative and OS remains modest Treatment-free interval after first line remains an option

65 Silvia Novello Federico Cappuzzo Linda De Maio Aknowledgements Board scientifico di:

66 La migliore cura del NSCLC GRAZIE PER L ATTENZIONE!