Ελλάδα Ελευθεριάδου Ειδικός Πνευμονολόγος Επιστημονική συνεργάτης της Πνευμονολογικής Κλινικής ΑΠΘ Νοσοκομείου Παπανικολάου και υποψήφια διδάκτορας

Transcription

1 Ελλάδα Ελευθεριάδου Ειδικός Πνευμονολόγος Επιστημονική συνεργάτης της Πνευμονολογικής Κλινικής ΑΠΘ Νοσοκομείου Παπανικολάου και υποψήφια διδάκτορας ΑΠΘ

2 Μετεγχειριτική αντιμετώπιση του ΜΜΚΠ

3 Significant milestones in lung cancer therapy 5-year survival rate (%) Study Treatment Active Control p IALT Cisplatin-based CT <0.03 JBR-10 Vinorelbine/cisplatin ANITA Vinorelbine/cisplatin s Increasing evidence for adjuvant chemotherapy in early-stage NSCLC CALGB 9633 Carboplatin/ paclitaxel Arriagada R, et al. N Engl J Med 2004;350: Winton TL, et al. N Engl J Med 2005;352: Rosell R, et al. Lung Cancer 2005;49(Suppl. 2):s3 (Abs. Pr3) Strauss GM, et al. J Clin Oncol 2006;24(Suppl. 18): 365 (Abs. 7007)

4 IALT study:adjuvant chemotherapy Overall survival Chemotherapy Control Patients (%) HR=0.86 ( ); p< Years At risk The IALT Collaborative Group. N Engl J Med 2004;350:351 60

5 Προεγχειρητική αντιμετώπιση του ΜΜΚΠ

6 Προεγχειρητική αντιμετώπιση του ΜΜΚΠ

7 Management of NSCLC according to prognostic and predictive factors

8 Biomarkers for chemotherapy High RRM1 and ERCC1 expression is associated with longer survival after resection of early stage NSCLC (prognostic). High RRM1 and ERCC1 are predictors of lower tumour response rate and shorter survival for treatment with gemcitabine and cisplatin (predictive) Low ERCC1 expression is associated with survival benefit from adjuvant chemotherapy for NSCLC (predictive) These biomarkers have not been prospectively validated

9 Test of interaction between ERCC1 and treatment: p< year survival rate (95% CI), median survival HR (95% CI) Chemotherapy (n=389) Control (n=372) CT vs no CT ERCC1 ve (n=426) 47% (40 55%) 56 months 39% (32 47%) 42 months 0.65 ( ) p=0.002 ERCC1 +ve (n=335) 40% (32 49%) 50 months 46% (37 55%) 55 months For ERCC1 ve tumours 14-month benefit in overall survival for CT vs control 6-month benefit in overall survival for CT vs ERCC1 +ve tumours 1.14 ( ) p=0.40 Olaussen KA, et al. N Engl J Med 2006;355:983 91

10 Prognostic value of RRM1 & ERCC1 expression (AQUA) HR=1.8 p=0.02 NEJM 356: 800, 2007

11 RRM1 mrna expression: prognostic and predictive factor Resected NSCLC RRM1* as a Prognostic marker in Surgically Resected NSCLC high RRM1 low RRM1 p=0.002 Bepler et al. JCO 2004 RRM1 as a Predictive marker for Chemotherapy Survival in NSCLC *regulatory subunit of ribonucleotide reductase; provides deoxyribonucleotides for DNAsynthesis & also for DNA-repair Stage IV NSCLC gem/cis low RRM1 high RRM1 p=0.002 Rosell, Scagliotti et al. Oncogene 2003

12 Genetic Determinants of Pemetrexed (antifolate) Activity In several phase II and III studies superior clinical activity in non squamous histology Baseline expression of the TS gene and protein were significantly higher in squamous cell carcinoma when compared with adenocarcinoma. (Ceppi et al. Cancer 2006) Preclinical data indicate that high expression of TS correlates with reduced sensitivity to Pemetrexed. (Sigmond et al. Biochem. Pharmacol. 2003; Giovannetti et al. Mol. Pharmacol. 2005)

13 Significant milestones in lung cancer therapy Survival distribution function Pemetrexed Docetaxel HR=0.99 (95% CI: 0.8, 1.2) 2003 Phase III study suggests equivalent efficacy for pemetrexed and docetaxel in relapsed advanced NSCLC Hanna N, et al. J Clin Oncol 2004;22: Months EU+US approvals

14 More effective treatment strategies are needed CChemotherapy in advanced NSCLC has reached a plateau TTriplet chemotherapy regimens do not appear to improve survival substantially, and are associated with increased toxicity 1 NNovel chemotherapy combinations are not likely to confer substantial improvements in survival CChemotherapy results in unacceptable levels of toxicity for patients with poor PS (>2), thus outweighing potential improvements in survival 2 QQuality of life and symptom improvement are crucial aspects to consider in lung cancer patient management 1 Delbaldo C, et al. JAMA 2004;292: National Comprehensive Cancer Network (NCCN) clinical practice guidelines in oncology. Non-small cell lung cancer, version Available at:

15 Conclusions An increased understanding of tumour biology has led to the rational development of novel agents that target specific tumorigenic processes In recent years, research effort has focused on agents targeting the VEGF and EGFR pathways The preclinical and clinical results achieved for agents targeting VEGF and EGFR to date have set a precedent for targeting specific molecular targets

16 Τα χαρακτηριστικά του καρκινικού κυττάρου ως θεραπευτικός στόχος Στοχεύοντας τον EGFR Ανεξέλεγκτος κυτταρικός πολλαπλασιασμός Ανθεκτικότητα σε αντιαυξητικά σήματα καρκίνος Μειωμένοι αποπτωτικοί μηχανισμοί Απεριόριστες δυνατότητες αντιγραφής Ανάπτυξη και συντήρηση αγγείωσης (αγγειογένεση) Διήθηση και μετάσταση Hanahan, et al. Cell 2000

17 H αναστολή της φωσφορυλίωσης της τυροσινικής κινάσης έχει πολλαπλές αντικαρκινικές δράσεις πολλαπλασιασμός διήθηση X Tarceva απόπτωση χημειοευαισθησία μετάσταση αγγειογένεση προσκόλληση Etessami, Bourhis. Drugs Future 2000 Moyer, et al. Cancer Res 1997 Harari, Huang. Semin Radiat Oncol 2002

18 Significant milestones in lung cancer therapy Tarceva significantly prolongs survival in relapsed advanced NSCLC Only EGFR inhibitor proven to provide an overall survival benefit in this disease Survival distribution function Tarceva Placebo HR=0.73, p< Shepherd FA, et al. N Engl J Med 2005;353: Survival time (months) EU+US approvals

19 Concurrent administration of erlotinib and CHT did not improve overall survival TALENT Erlotinib + cisplatin/gemcitabine TRIBUTE Erlotinib + carboplatin/paclitaxel Gatzemeier et al. JCO 2007 Herbst et al. JCO 2005

20 TALENT study of concurrent firstline Tarceva and chemotherapy Chemonaïve advanced NSCLC R 6 cycles platinum doublet chemotherapy* + concurrent Tarceva 150mg/day Tarceva 150mg/day PD 6 cycles platinum doublet chemotherapy* + concurrent placebo Concurrent combination phase Placebo Maintenance phase PD * cisplatin/gemcitabine

21 Possible explanation: pharmacodynamic antagonism Erlotinib docetaxel Apoptosis Docetaxel Erlotinib Apoptosis M G 2 Cell cycle M G 2 Cell cycle S G 1 Apoptosis S G 1 Erlotinib induces G 1 arrest, which can block the M-phase activity of docetaxel Docetaxel induces M-phase arrest and apoptosis, enhanced by the anti-cell survival effect of erlotinib Gandara D, et al. Clin Cancer Res 2005;11(Suppl. 13):5057s 62s

22 TALENT: gemcitabine + cisplatin plus continuous Tarceva improved survival in never smokers Survival distribution function Median (months) Tarceva (NS) Tarceva (F/CS) Placebo (NS) Placebo (F/CS) Placebo Erlotinib HR (95% CI) p value Never smoked 11.4 (n=10) NR (n=8) 0.39 (0.08, 2.04) Former/current smoker 14.4 (n=57) 11.1 (n=64) 1.05 (0.62, 1.75) 0.86 Study day NS = never smoked F/CS = former/current smoker NR = not reached 1 Gatzemeier U, et al. J Clin Oncol 2005;23(Suppl. 16S Pt I):627s (Abs.7028)

23 TRIBUTE: carboplatin + paclitaxel plus continuous Tarceva improved survival in never smokers Tarceva Placebo Survival rate Tarceva Median survival (months) 22.5 No. of patients 64 Placebo P value Months on study Miller V, et al. J Clin Oncol 2004;22(Suppl. 14S):628 (Abs. 7061)

24 EGFR mutations in NSCLC EGFR mutations are over-represented in responders to EGFR inhibitors These mutations include: exon 19 small in-frame deletions exon 21 point mutations e.g. EGFR L858R Mutations known to cause resistance to firstgeneration EGFR include: exon 20 in-frame insertions exon 20 point mutations (e.g. T790M) Sharma et al. Nature Rev Cancer 2007;7;169 Ji et al. Proc Natl Acad Sci USA 2006;103;7817 Stephens et al. Nature 2004;431:525 Deletions (viii) ~ 1% Exon TM Extracellular ligand-binding domain Tyrosine kinase domain

25 FLEX Study design NSCLC wet IIIB/IV EGFRexpressing Chemotherapy + Cetuximab Chemotherapy Maintenance Cetuximab until PD or intolerable toxicity Chemotherapy (CT) Cetuximab Cisplatin 80 mg/m 2 day 1 Vinorelbine 25 (30) mg/m 2 days 1, 8 Every 3 weeks, up to 6 cycles initial dose 400 mg/m 2 then 250 mg/m 2 weekly Pirker R et al. J Clin Oncol 2008, 18S (abstract 3)

26

27

28 Lessons from FLEX: Prognostic factors FLEX demonstrated the following prognostic factors Performance status Gender Histology Smoking status Ethnicity? Patient populations have to be considered when comparing different trials

29 What did we learn from FLEX? Cetuximab improves survival when added to first-line chemotherapy in advanced NSCLC EGFR is a clinically relevant target in advanced NSCLC Predictive factors Rash? Others not (yet?) available

30

31

32 Maintenance therapy with cytotoxic agents Prolonged platinum doublet chemotherapy Continuation of non-platinum agent used in doublet chemotherapy e.g. paclitaxel, gemcitabine Introduction of a new cytotoxic agent e.g. docetaxel, pemetrexed Limited benefits outweighed by toxicity disadvantages Stinchcombe, TE et al. J Thoracic Oncol 2009;4:243 50

33

34

35 Pivotal phase III BR.21 study of Tarceva as second/third-line therapy Phase III trial Advanced stage IIIB/IV NSCLC n=731 R A N D O M I S E 2 1 Tarceva 150mg daily (n=488) Placebo (n=243) Primary endpoint = OS Secondary endpoints = PFS, response rate and duration of response, safety, QoL Shepherd FA, et al. N Engl J Med 2005;353:123 32

36 Tarceva is an established second-line treatment with significant survival benefits Overall survival 27% reduction in risk of death with Tarceva Progression-free survival 39% reduction in risk of PD or death with Tarceva Probability of OS Tarceva (n=488) Placebo (n=243) HR = 0.73 ( ) p=0.001* Probability of PFS Tarceva (n=488) Placebo (n=243) HR = 0.61 ( ) p<0.001* Survival time (months) Survival time (months) *HR and p (log-rank test) adjusted for stratification factors at randomisation and EGFR status Shepherd FA, et al. N Engl J Med 2005;353:123 3 Tarceva EU SmPC

37 TALENT: longer duration of response with Tarceva in maintenance phase Tarceva + chemotherapy Placebo + chemotherapy 0.6 Concurrent combination phase Maintenance phase Probability Log-rank p= Time (weeks) Gatzemeier U, et al. J Clin Oncol 2007;25:

38 Phase III ATLAS study of maintenance Tarceva added to Avastin until progression Chemonaïve advanced non-squamous NSCLC n=1,160 Avastin 15mg/kg plus chemotherapy* Non-PD n=768 Avastin 15mg/kg + Tarceva 150mg/day 1:1 Avastin 15mg/kg + placebo PD PD Stratification factors: Gender (male vs female) Smoking history (never vs former/current) ECOG PS (0 vs 1) CT regimen (carbo/pac vs carbo/gem vs carbo/doc vs cis/gem vs other) Primary endpoint: PFS in all patients *carboplatin/paclitaxel; carboplatin/docetaxel; carboplatin/gemcitabine; cisplatin/gemcitabine; cisplatin/vinorelbine; cisplatin/docetaxel

39 Phase III SATURN study of maintenance Tarceva in advanced NSCLC Tarceva 150mg/day PD Chemonaïve advanced NSCLC n=1,949 4 cycles of platinum doublet chemotherapy* Non-PD n=889 1:1 Placebo PD Mandatory tumour sampling 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 Primary endpoints: PFS in all patients PFS in EGFR IHC+ *cisplatin/paclitaxel; cisplatin/gemcitabine; cisplatin/docetaxel; cisplatin/vinorelbine; carboplatin/gemcitabine; carboplatin/docetaxel; carboplatin/paclitaxel

40 PFS*: all patients (ITT) PFS probability HR=0.71 ( ) Log-rank p< Erlotinib Placebo PFS at 12 wks (%) PFS at 24 wks (%) Erlotinib (n=437) Placebo (n=447) Time (weeks) *PFS is measured from time of randomisation into the maintenance phase; assessments were every 6 weeks; ITT = intent-to-treat population

41 PFS*: EGFR IHC+ tumours (co-primary endpoint) PFS probability HR=0.69 ( ) Log-rank p< Erlotinib Placebo PFS at 12 wks (%) PFS at 24 wks (%) Erlotinib (n=307) Placebo (n=311) Time (weeks) *PFS is measured from time of randomisation into the maintenance phase; assessments were every 6 weeks

42 PFS in EGFR mutation+ tumours* PFS probability Erlotinib (n=22) Placebo (n=27) HR=0.10 ( ) Log-rank p< Time (weeks) *60% censored

43 Summary Advanced NSCLC is a rapidly progressing disease, with only a short window of opportunity for therapeutic intervention First-line platinum doublet chemotherapy is stopped after 4 6 cycles because of cumulative toxicity and limited incremental benefit Up to 50% of patients receive no further therapy due to rapid worsening of symptoms and performance status Maintenance therapy offers the possibility of continued active treatment to delay disease progression and symptom deterioration Avastin provides significant survival benefits when administered until disease progression Two major phase III studies (ATLAS and SATURN) evaluated Tarceva as maintenance therapy, either with or without Avastin

44 Ο ρόλος της θεραπείας συντήρησης Σε ασθενείς με εκτεταμένη ή περιορισμένη ΜΚΠ νόσο με μερική ή πλήρη ανταπόκριση δεν συνιστάται θεραπεία συντήρησης εκτός ερευνητικής μελέτης

45 Mo T4 Τ3 Τ2 Τ1 Ν0 Ν1 Ν2 Ν3 M1 (any T any N) Surgery CHT with: Gemcitabine+platinum analogues or Taxanes+ platinum analogues or Pemetrexed+platinum analogues ± Biological agents: ANTI EGFR: Tarceva, Cetuximab or ANTI VEGFR: Avastin, VEGF Trap ± Radiotherapy CHT with: Gemcitabine+platinum analogues or Taxanes+ platinum analogues or Pemetrexed+platinum analogues ± Biological agents: ANTI EGFR: Tarceva, Cetuximab or ANTI VEGFR: Avastin, VEGF Trap ± Radiotherapy Vaccines? Local recurrence Distant metastasis