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Rossana Berardi Clinica di Oncologia Medica Università Politecnica delle Marche Ospedali Riuniti di Ancona TK Inhibitors in NSCLC.

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Presentation on theme: "Rossana Berardi Clinica di Oncologia Medica Università Politecnica delle Marche Ospedali Riuniti di Ancona TK Inhibitors in NSCLC."— Presentation transcript:

1 Rossana Berardi Clinica di Oncologia Medica Università Politecnica delle Marche Ospedali Riuniti di Ancona TK Inhibitors in NSCLC

2 Intracellular mTKI Targets EGFR PDGFR VEGFR Abl JAK Src Raf MAPK MEKERKRas PI3-K AKT Raf MAPK MEKERKRas PI3-K AKT Tumor CellEndothelial Cell Proliferation/Survival Metastasis Angiogenesis Transcription STAT Erlotinib LapatinibGefitinib Vandetanib Sunitinib Sorafenib Dasatinib Nilotinib Imatinib Axitinib Motesanib

3 Obiettivo CURARE IL TUMORE DEL POLMONE CURARE IL TUMORE DEL POLMONE del Sig. Rossi Si va verso una TERAPIA SU MISURA TERAPIA SU MISURA FR Hirsch JTO 2008;3: Ohe Y, Clin Cancer Res Jul 1;14(13):

4 The Epidermal Growth Factor Pathway Ciardiello F, et al. EGFR Antagonists in Cancer Treatment. N Engl J Med. 2008:358:

5 TARCEVA indicato nel trattamento di pazienti adulti con carcinoma polmonare non a piccole cellule (NSCLC) localmente avanzato o metastatico dopo fallimento di uno o più trattamenti chemioterarpici

6 indicazione include la prima linea di trattamento IRESSA è indicato nel trattamento di pazienti adulti con carcinoma polmonare non a piccole cellule (NSCLC) localmente avanzato o metastatico con mutazione attivante lEGFR-TK Approvazione EMEA 24 giugno 2009


8 RAND RRAANNDDOMIOMISSEERRAANNDDOMIOMISSEESE ERLOTINIB* 150 mg daily NSCLC unsuitable to receive CT stratified by: -Centre -Performance status 0/1 vs 2/3 -Response to prior Rx (CR/PR:SD:PD) -Prior regimens (1 vs 2) -Prior platinum (yes vs no) Placebo 150 mg daily * 2:1 randomisation F Shepherd et al, N Eng J Med 2005 BR.21 STUDY DESIGN

9 Erlotinib prolunga significativamente la sopravvivenza nei pazienti con NSCLC avanzato Shepherd FA, et al. N Engl J Med Sopravvivenza (%) TarcevaPlacebo Tempo (mesi) AutoreTerapiaN RR (%) PFS Mediana OS (m) 1-aa OS (%) Shepherd Tarceva Placebo < % 22% SECONDA LINEA

10 TRUST PHASE IV STUDY TaRceva LUng Cancer Survival Treatment

11 Erlotinib (BR.21), n=488 Placebo (BR.21), n=243 Median PFS: erlotinib 2.2 mo vs placebo 1.8 mo (p<0.001) Survival distribution function PFS (months) BR.21 1 Median PFS: 3.2 mo TRUST 2 Erlotinib (TRUST), n=6,580 1 Shepherd FA, et al. N Engl J Med M Reck et al, ESMO 2008 Progression Free Survival in UE Subpopulation TRUST vs BR.21: an indirect comparison

12 Survival distribution function Survival time (months) Erlotinib (BR.21), n=488 Placebo (BR.21), n=243 Median OS: 7.9 months (28% censored) TRUST 2 Erlotinib (TRUST), n=6,580 Overall Survival in UE Subpopulation Median OS: erlotinib 6.7 mo vs placebo 4.7 mo (p<0.001) BR Shepherd FA, et al. N Engl J Med M Reck et al, ESMO 2008 TRUST vs BR.21: an indirect comparison


14 NEW OPTIONS IN A-NSCLC Prolongation of Disease Control RS Herbst et al, ASCO 2003

15 SATURN TRIAL DESIGN F Cappuzzo et al, P ESMO 2009


17 SATURN: OS* (all patients, ITT) Time (months) OS probability Erlotinib (n=438) Placebo (n=451) *OS is measured from time of randomisation into the maintenance phase; ITT = intent-to-treat population HR=0.81 (0.70–0.95) Log-rank p= F Cappuzzo et al, P ESMO 2009

18 Subgroup analysis of PFS All Male Female Caucasian Asian Adenocarcinoma Squamous-cell Never smoker Former smoker Current smoker HR (95% CI)n 0.71 (0.62–0.82) (0.66–0.92) (0.42–0.76) (0.64–0.88) (0.38–0.87) (0.48–0.75) (0.60–0.95) (0.38–0.81) (0.50–0.88) (0.67–0.97) Favours erlotinib Favours placebo HR

19 Log-rank p< HR=0.60 (0.48– 0.75) PFS probability Time (weeks) Erlotinib (n=204) Placebo (n=197) Adenocarcinoma Log-rank p= HR=0.76 (0.60– 0.95) Squamous-cell carcinoma Time (weeks) Erlotinib (n=166) Placebo (n=193) PFS probability SATURN: PFS based on histology

20 Zd1839-Iressa in refractary lung cancer IDEAL 1 (Europe) - GEM/CDDP RR Median OS 250 mg18. 4%7.6 mo R 500 mg19.0%8.1 mo IDEAL 2 (US) - Carbo/Taxol RR Median OS 250 mg11.8%6.1 mo R 500 mg8.8%6.0 mo

21 INTACT Trials GEM/CDDP + Iressa GEM/CDDP + Placebo CarboCDDP/Paclitaxel + Iressa CarboCDDP/Paclitaxel + Placebo 1200 patients No differences (October 2002)


23 Previously untreated NSCLC patients (N = 1217) Up to six 3-wk cycles Gefitinib 250 mg/day PO (n = 609) Paclitaxel 200 mg/m 2 IV on Day 1 + Carboplatin AUC 5-6 mg/mL/min IV on Day 1 (n = 608) Mok TS, et al. N Engl J Med. 2009;361: IPASS Study Design

24 CharacteristicGefitinib (n = 609) Paclitaxel/Carboplatin (n = 608) Female, % Median age, yrs (range)57 (24-84)57 (25-84) Smoking history, % Nonsmoker Former light smoker WHO PS, % Disease stage at entry, % IIIB IV Unknown Mok TS, et al. N Engl J Med. 2009;361: Baseline Characteristics

25 (74.4%) (81.7%) N Events HR (95% CI) = (0.651, 0.845) p< Gefitinib Primary objective exceeded: Gefitinib demonstrated superiority relative to carboplatin / paclitaxel in terms of PFS Carboplatin / paclitaxel Carboplatin / paclitaxel Gefitinib Median PFS (months) 4 months progression-free 6 months progression-free 12 months progression-free % 48% 25% % 48% 7% Months Probability of PFS At risk : Objective response rate 43% vs 32% p= IPASS: PFS e ORR

26 EGFR mutations: the strongest predictor of response

27 85% circa di queste mutazioni delezioni multinucleotidiche in-frame (ESONE 19) mutazioni puntiformi (ESONE 21) MUTAZIONI DI EGFR Mutazioni più frequenti: delezione esone 19 o sostituzione L858R dellesone 21

28 Stratification of NSCLC according to activating mutations PFS: 14 mo with erlotinib in pts with EGFR mutations Sharma, Haber & Settleman. Nat Rev Cancer 2010

29 MS Tsao et al, N Engl J Med 2005 BR.21 study: EGFR mutation status predicts response… …but not survival n Response rate (%) p value EGFR Mutation status 1 Wild-type* Mutant Mutant EGFR protein expression (IHC) 2 Negative804NS Positive10611 EGFR gene copy number (FISH) 2 Negative Positive

30 EGFR Mutation Status, %Gefitinib (n = 609) Paclitaxel/Carboplatin (n = 608) Negative Positive Exon 19 deletion* Exon 21 L858R* Exon 20 T790M* Other* Unknown *11 patients had multiple EGFR mutations and are counted for each mutation present. Mok TS, et al. N Engl J Med. 2009;361: IPASS Baseline Characteristics: EGFR Status

31 IPASS: Main Findings: Significance of EGFR Mutation Status Significant interaction between treatment and EGFR mutation status –In EGFR mutation–positive subgroup, significantly longer PFS with gefitinib (HR: 0.48; 95% CI: ; P <.001) –In EGFR mutation–negative subgroup, significantly shorter PFS with gefitinib (HR: 2.85; 95% CI: ; P <.001) Mok TS, et al. N Engl J Med. 2009;361: Reproduced with permission. Copyright © 2009 Massachusetts Medical Society. All rights reserved. EGFR Mutation Positive HR: 0.48 (95% CI: ; P <.001) Probability of PFS Mos Since Randomization Gefitinib Paclitaxel/ carboplatin EGFR Mutation Negative HR: 2.85 (95% CI: ; P <.001) Probability of PFS Mos Since Randomization Gefitinib Paclitaxel/ carboplatin Events Gefitinib: 97 (73.5%) Pac/carbo: 111 (86.0%) Events Gefitinib: 88 (96.7%) Pac/carbo: 70 (82.4%)

32 IPASS Main Findings: Response Rates Significantly higher ORR with gefitinib than carboplatin- paclitaxel –Driven by EGFR mutation–positive subgroup Significantly higher quality of life improvements with gefitinib than paclitaxel/carboplatin Rates of symptom reduction similar between arms ORR, %GefitinibPaclitaxel/ Carboplatin P Value Overall population <.001 EGFR mutation positive <.001 EGFR wild type Mok TS, et al. N Engl J Med. 2009;361:

33 IPASS: diversa Risposta Tumorale nei pz EGFR M+ ed EGFR M- Gefitinib Carboplatino/ paclitaxel EGFR M+ odds ratio (IC 95%) = 2.75 ( ), p< EGFR M- odds ratio (IC 95%) = 0.04 (0.01 to 0.27), p= Risposta tumorale (%) (n=132)(n=129)(n=91)(n=85) Odds ratio >1 implica una maggior probabilità di risposta con gefitinib 71,2% 47,31% 1,1% 23,5% Mok T NEJM 2009

34 IPASS: Superior quality of life and symptom improvement rates for gefitinib in EGFR mutation positive patients p< p= EFQ, evaluable for quality of life; FACT-L, Functional Assessment of Cancer Therapy-Lung; TOI, Trial Outcome Index; LCS, Lung Cancer Subscale % patients with sustained clinically relevant improvement p-values from logistic regression with covariates. Post-hoc analysis, EFQ population Clinically relevant improvement pre-defined as 6-point improvement for FACT-L and TOI; 2-point improvement for LCS, maintained for at least 21 days.



37 Efficacy results from the randomised phase III OPTIMAL (CTONG 0802) study comparing first-line erlotinib versus carboplatin (CBDCA) plus gemcitabine (GEM), in Chinese advanced non-small-cell lung cancer (NSCLC) patients (pts) with EGFR activating mutations Caicun Zhou, 1 Yi-long Wu, 2 Gongyan Chen, 3 Jifeng Feng, 4 Xiaoqing Liu, 5 Changli Wang, 6 Shucai Zhang, 7 Jie Wang, 8 Songwen Zhou, 1 Shengxiang Ren, 1 on behalf of the OPTIMAL investigators 1 Shanghai Pulmonary Hospital, Tongji University, Shanghai; 2 Guangdong Lung Cancer Institute, Guangdong General Hospital & Guangdong Academy of Medical Sciences, Guangzhou; 3 The Cancer Hospital of Harbin Medical University, Harbin; 4 Jiangsu Province Cancer Hospital, Nanjing; Hospital of the Academy of Military Medical Sciences, Cancer Center, Beijing; 6 Tianjin Cancer Hospital, Tianjin; 7 Beijing Chest Hospital, Beijing; 8 Peking University School of Oncology, Beijing Cancer Hospital, Beijing; China ESMO 2010

38 OPTIMAL study design Erlotinib 150mg/day Chemonaїve Stage IIIB/IV NSCLC EGFR Act Mut+ (exon 19 deletion or exon 21 L858R mutation) ECOG PS 0–2 (n=165) Gemcitabine (1,000 mg/m 2 d1,8) Carboplatin (AUC5 d1) q3w, up to 4 cycles R Act Mut+ = activating mutations; ECOG = Eastern Cooperative Oncology Group; PS = performance status HRQoL = health-related quality of life; FACT-L = Functional Assessment of Cancer Therapy-Lung; LCSS = lung cancer symptom scale 1:1 Primary endpoint Progression-free survival (PFS) Secondary endpoints Overall survival (OS), objective response rate (ORR), time to disease progression, duration of response, safety, HRQoL (FACT-L, LCSS), exploratory biomarker analyses Stratification factors Mutation type Histology Smoking status Efficacy assessment Every 6 weeks

39 OPTIMAL PFS: primary analysis (ITT) PFS probability HR=0.16 (0.10–0.26) Log-rank p< Time (months) Patients at risk Erlotinib Gem/carbo (n=72) Erlotinib (n=82) Gem/carbo

40 OPTIMAL PFS: updated analysis (ITT) HR=0.16 (0.10–0.26) Log-rank p< Time (months) Gem/carbo (n=72) Erlotinib (n=82) PFS probability Patients at risk Erlotinib Gem/carbo

41 Subgroup analysis of PFS Overall Stage IV Stage IIIB Female Male Age 65 Age <65 PS 0–1 PS 2 Never smoker Current/former smoker Adenocarcinoma Non-adenocarcinoma (0.10–0.26) (0.11–0.28) (0.06–1.16) (0.07–0.24) (0.14–0.50) (0.07–0.43) (0.11–0.31) (0.10–0.26) (0.04–1.28) (0.08–0.25) (0.09–0.49) (0.11–0.28) (0.06–0.73)20 HR (95% Cl)n HR Favours erlotinibFavours gem/carbo

42 Best tumour response* Erlotinib [n=82] n (%) Gem/carbo [n=72] n (%) CR2 (2)0 (0) PR66 (81)26 (36) ORR68 (83)26 (36)p< SD11 (13)33 (46) DCR79 (96)59 (82)p=0.002 PD3 (4)12 (17) *in evaluable patients; CR = complete response; PR = partial response; SD = stable disease; DCR = disease control rate (CR + PR + SD)

43 K-RAS mutations?

44 Mutazioni k-RAS: fattore prognostico negativo e fattore predittivo di resistenza primaria ai TKI

45 Resistance to EGFR TK inhibitors

46 Acquired resistance to EGFR TK inhibitors MET amplification: Proto-oncogene detected in 4 of 18 pts with initial response to gefitinib or erlotinib, who then had progressive disease Found to cause resistance by ErbB3 (HER3)- dependent activation of PI3K Inhibition of MET signaling in these cells restored sensitivity to gefitinib Engelman et al, Science 2007; 316: Amplificazione MET responsabile del 10-20% delle resistenze ai TKI per attivazione attraverso HER3 di PI3K e AKT (indipendente da EGFR)

47 ARQ-197=oral c-met inhibitor Dual EGFR-MET inhibition for overcoming MET- mediated resistance to EGFRinhibitors



50 ALK Pathway 1. Inamura K et al. J Thorac Oncol 2008;3:13–17 2. Soda M et al. Proc Natl Acad Sci U S A 2008;105:19893–19897 Figure based on: Chiarle R et al. Nat Rev Cancer 2008;8(1):11–23; Mossé YP et al. Clin Cancer Res 2009;15(18):5609–5614; and Data on file. Pfizer Inc. * Subcellular localization of the ALK fusion gene, while likely to occur in the cytoplasm, is not confirmed. 1,2 Translocation Or ALK ALK fusion protein* Tumor cell proliferation Inversion Cell survival PI3K BAD AKT STAT3/5 mTOR S6K RAS MEK ErK PLC- Y PIP 2 IP 3


52 Clinical Activity of the Oral ALK Inhibitor, Crizotinib (PF ), in Patients with ALK-positive Non-Small Cell Lung Cancer Bang Y, 1 Kwak EL, 2 Shaw A, 2 Camidge DR, 3 Iafrate AJ, 2 Maki RG, 4 Solomon B, 5 Ou SI, 6 Salgia R, 7 Clark J 2 1 Seoul National University, Seoul, Korea; 2 Massachusetts General Hospital, Boston, MA, USA; 3 University of Colorado Cancer Center, Aurora, CO, USA; 4 Memorial Sloan-Kettering Cancer Center, New York, NY, USA; 5 Peter MacCallum Cancer Centre, East Melbourne, Australia; 6 University of California at Irvine, Irvine, CA, USA; 7 University of Chicago Cancer Center, Chicago, IL, USA Abstract 3 ASCO Annual Meeting 2010

53 1 Shaw AT et al. J Clin Oncol 2009;27:4247–4253 Platinum-based chemotherapyEGFR TKI Patients with ALK-positive NSCLC Do not Appear to Respond to EGFR TKIs TTP for EGFR TKI 1 TTP for chemotherapy 1 Months EML4–ALK EGFR WT/WT % Months % EML4–ALK EGFR WT/WT *WT/WT = wild type: no ALK fusion or EGFR mutation

54 Selectivity findings Crizotinib – ALK and c-MET inhibition at clinically relevant dose levels Crizotinib – low probability of pharmacologically relevant inhibition of any other kinase at clinically relevant dose levels Cellular selectivity on 10 of 13 relevant hits Upstate 102 kinase 13 kinase hits <100X selective for c-MET * The cellular kinase activities were measured using ELISA capture method Kinase IC 50 (nM) mean* Selectivity ratio c-MET8– ALK202X RON 29834X 18922X Axl 29434X 32237X Tie X Trk A58067X Trk B39946X Abl1,159166X IRK2,887334X Lck2,741283X Sky>10,000>1,000X VEGFR2>10,000>1,000X PDGFR >10,000>1,000X Crizotinib (PF ) Crizotinib Selectivity Profile Crizotinib: inhibits ALK and c-met

55 Clinical and Demographic Features of Patients with ALK-positive NSCLC N=82 Mean (range) age, years51 (25–78) Gender, male/female 43/39 Performance status,* n (%) 0 24 (29) 1 44 (54) 213 (16) 31 (1) Race, n (%)Caucasian46 (56) Asian29 (35) Smoking history, n (%) Never smoker 62 (76) Former smoker19 (23) Current smoker1 (1) Histology, n (%)Adenocarcinoma79 (96) Squamous 1 (1) Other 2 (2) Prior treatment regimens, n (%) 05 (6) 127 (33) 215 (18) 3 34 (41) Not reported 1 (1) *Performance status = Eastern Cooperative Oncology Group

56 –20 –40 –60 –80 –100 Progressive disease Stable disease Confirmed partial response Confirmed complete response Maximum change in tumor size (%) – 30% Tumor Responses to Crizotinib for Patients with ALK-positive NSCLC * Partial response patients with 100% change have non-target disease present *

57 Treatment with crizotinib resulted in impressive clinical activity in patients with ALK-positive advanced NSCLC –ORR: 57% –DCR at 8 weeks: 87% –PFS probability at 6 months: 72%

58 Median PFS has Not been Reached 70% of Patients in Follow-up for PFS Progression-free survival probability Progression-free survival (months) PFS probability at 6 months: 72% (95% CI: 61, 83%) Median follow-up for PFS: 6.4 months (25–75% percentile: 3.5–10 months) 95% Hall–Wellner confidence bands

59 Treatment-related Grade 3/4 Adverse Events in ALK-positive NSCLC Adverse event Grade 3 n (%) Grade 4 n (%) Any adverse event10 (12)1 (1) ALT elevation*4 (5)1 (1) AST elevation5 (6)0 Lymphopenia2 (2)0 Hypophosphatemia1 (1)0 Neutropenia1 (1) 0 Hypoxia1 (1)0 Dyspnea1 (1) 0 Pulmonary embolism1 (1)0 *Based on laboratory data (n=71), ALT increase to grade 1, 52%; to grade 2, 4% (In preclinical toxicology studies, no histologic changes in the liver were observed) 1 patient discontinued for ALT elevation


61 Options A-NSCLC Clinical Practice 1 st -Line Options in 2010 SQUAMOUS & NOS PTS NON SQUAMOUS LC PTS P-based CT (**)+ Bevacizumab in selected patients (**) Cb+Pac > Cis+Gem P-based Doublets: Cis+Gemcitabine Cis+Docetaxel better than Cis+Vin or Cb+Pac EGFR Mut+ PTS P-based Doublets: Cis+Pemetrexed better than Cis+ Gemcitabine P-based CT+Cetuximab (*) (*) According to registration for EGFR status and CT Gefitinib P-based CT+Cetuximab (*) Courtesy Dr De Marinis

62 Progressi nel 2010?

63 We will need strategies…

64 GREAT (Group REsearch And Trials) MD Oncologists: Azzurra OnofriData Managers:Alessandra Lucarelli Chiara PierantoniMichela Burattini Research Nurse:Fabiana Marcucci Chest Surgeons: Armando Sabbatini Pathologist:Alfredo Santinelli Alessandro Brunelli Pharmacists: Celestino BufariniRadiologist:Gianluca Valeri Andrea Marinozzi

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