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BALKAN MCO 2011 - V. Gregorc - Individualized systemic therapy in NSCLC
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  • Attualmente, per una miglior ottimizzazione delle terapia di I linea,è indispensabile, non solo distinguere tra le forme a piccole cellule e quelle non a piccole cellule, ma arrivare a definire, in queste ultime, anche il sottotipo istologico distinguendo tra l’stotipo squamoso e istotipo non squamoso.
  • Studi randomizzati con diverse doppiette di terza generazione con cisplatino + un secondo farmaco potenzialmente attivo non hanno evidenziato sostanziali differenze in termini di efficacia come evidenziato nello studio di Shiller che confrontava quattro diverse doppiette: cisplatino + paclitaxel, cisplatino + gemcitabina, cisplatino + docetaxel e carboplatino + paclitaxel. Un unico studio (TAX 326) ha evidenziato un vantaggio in termini di efficacia a favore dell’associazione cisplatino + docetaxel, nei confronti dello schema cisplatino + vinorelbina. Questo risultato potrebbe trovare una giustificazione nel fatto che analisi retrospettive hanno dimostrato che docetaxel in II linea ha avuto uguale attività sia nelle forme squamose, sia in quelle NON squamose.
  • Va da sé che, in assenza di sostanziali differenze in termini di efficacia, la scelta terapeutica è stata determinata per molti anni dal diverso profilo di tossicità delle singole doppiette (vedi diapositive)
  • Solo una piccola % di pazienti sono potenzialmente candidati a trattamento con bevacizumab. L’utilizzo di beva richiede l’utilizzo di nuovi fattori di selezione dei pazienti. Questi sono ad esempio i criteri di inclusione ed esclusione per l’arruolamento dei pazienti nello studio AVAiL. E’ necessario escludere i pazienti con potenziali controindicazioni al Beva come la presenza di emottisi, di ipertensione non controllata, la presenza di disordini trombotici o emorragici, i pazienti in trattamento con anticoagulanti, i pazienti in età avanzata, …… Le metastasi cerebrali sono state recentemente tolte dalle controindicazioni al trattamento con beva.
  • Il secondo farmaco che ha dimostrato un’attività histotype-oriented è il pemetrexed. Lo studio registrativo in prima linea confrontava questo farmaco in associazione a cisplatino rispetto al regime europeo standard cisplatino + gemcitabina
  • Lo studio ha evidenziato una sostanziale equivalenza in termini di efficacia dei due regimi. L’analisi dei risultati prevedeva una valutazione prospettica in relazione all’istotipo: nel sottotipo non squamoso l’associazione cisplatino + pemetrexed è risultata più efficace dell’associazione cisplatino + gemcitabina con una riduzione del rischio di morte di circa il 20%. Al contrario nell’istotipo squamoso la doppietta cisplatino + pemetrexed è risultata meno efficace rispetto a quella con gemcitabina.
  • Da questa tabella si può notare come in tutti i principali studi pubblicati in pazienti con neoplasia polmonare EGFR mutata + il trattamento con gefitinib porti ad una percentuale di risposte variabile tra il 62 e l’84% e a una riduzione del rischio di progressione di malattia tra il 64 e il 39% circa rispetto al trattamento chemioterapico.

BALKAN MCO 2011 - V. Gregorc - Individualized systemic therapy in NSCLC BALKAN MCO 2011 - V. Gregorc - Individualized systemic therapy in NSCLC Presentation Transcript

  • I NDIVIDUALIZED SYSTEMIC THERAPY IN NSCLC Vanesa Gregorc MD Scientific Institute San Raffaele University Hospital Department of Oncology Division of Molecular Oncology Clinical research leader Thoracic Oncology Unit
  • Customizing chemo therapy in advanced NSCLC I
  • 1990 -> 2000 To treat or not to treat ? Spesso solo Terapia di supporto (BSC) NSCLC = SCLC <1980 Today 1. Meta-analysis .BMJ. 1995 Oct 7;311(7010):899-909. 2. Loehrer PJ Sr, Semin Oncol. 1988 Jun;15(3 Suppl 3):2-8. Review. 3. L. Einhorn, JCO 2008;26:3485-3486 4. FR Hirsch JTO 2008;3:1468-1481 . SCLC Platinum Etoposide 2 NSCLC Platinum doublets 1 SCLC Platinum Etoposide 2 NSCLC Platinum doublets 1 Squamos 3,4 Non Squamos 3,4 The Evolving Role of Systemic Treatment in Advanced NSCLC
  • J Schiller et al, NEJM 2002 Study arm OS (mo) 1 year (%) PC 7.8 31 GC 8.1 36 DC 7.4 31 PCb 8.1 34
  • 1. J Clin Oncol 20:4285-4291. 2002 by American Society of Clinical Oncology Worst G 3-4 Tox % GemCis N=197 PacCb N=197 VinCis N=198 Neutropenia 38.1 49.9 64.6 Thrombo 36.6 7.7 0.5 Anemia 17.7 6.1 19.2 N/V 6.6 0.5 12.6 P Neuropathy 0 7 3 Constipation 0.5 0 3 Renal 0.5 0 5 Alopecia G 1-2 10.4 52.3 11.1
  •  
  • CBDCA + Paclitaxel (6 cycles) CBDCA + Paclitaxel + Bevacizumab (6 cycles) Bevacizumab 15 mg/kg Primary end point: OS CDDP + GEM + Placebo (6 cycles) CDDP + GEM + Bevacizumab (15 mg/kg) Bevacizumab CDDP + GEM + Bevacizumab (7.5 mg/kg) CDDP + GEM + Placebo (6 cycles) Bevacizumab Primary end point: PFS Placebo Placebo ECOG 4549 AVAiL Reck M; 2009; JCO Sandler A; 2006; NEJM 878 IIIB/IV PS 0-1 NSCLC Bevacizumab in patients with adenocarcinoma 1043 IIIB/IV PS 0-1 NSCLC
  • ECOG 4549 AVAiL
  • Bevacizumab Reck M, JCO 2009 Inclusion criteria Exclusion criteria NSCLC non-sq Hemopthysis grade 2 Chemo-naïve Brain metastasis Stage IIIB inoperable, stage IV Uncontrolled hypertension ECOG PS 0–1 History of thrombosis or hemorrhage Anticoagulants 10 days before starting Bevacizumab Central lesions that invade main vessels
  • CDDP + VNR + Cetuximab (6 cycles) Cetuximab CDDP + VNR (6 cycles) Primary end point: OS Pirker R; 2009; The Lancet More patients in the chemotherapy group were censored and started a new treatment without progression 1125 IIIB/IV EGFR IHC+ NSCLC Median OS: 11.3 months vs 10.1 months HR=0.871, p=0.044 Median PFS: 4.8 months for both arms HR=0.943, p=0.39 Cetuximab in patients with adenocarcinoma
  • Scagliotti G, JCO 2008 R A N D O M I S E
    • Randomization factors:
    • Stage
    • PS
    • Gender
    • Hysto vs cyto dx
    • Brain mets
    • Vitamin B 12 folate and dexamethasone given in both ar
    Cisplatin 75 mg/m 2 Pemetrexed 500 mg/m 2 d1 q 3 weeks up to 6 cycles Cisplatin 75 mg/m 2 Gemcitabine 1250 mg/m 2 D1,8 q 3 weeks up to 6 cycles Pemetrexed in patients with adenocarcinoma
  • JMDB: OS Scagliotti G, JCO 2008
  • 1994 Dabhalkar J Clin Invest. ERCC1 in ovarian cancer 2001 Shirota J Clin Oncol. ERCC1 and TS in colorectal cancer 2002 Lord Clin Cancer Res ERCC1 in NSCLC 2003 Rosell Oncogene beta-tubulin III, stathmin, RRM1, COX-2 and GSTP1 in NSCLC 2004 Rosell Clin Cancer Res RRM1 in NSCLC 2004 Taron Hum Mol Genet BRCA1 in NSCLC 2007 Cobo J Clin Oncol ERCC1 in NSCLC prospectively evaluated 2008 Scagliotti J Clin Oncol Adenocarcinoma (TS) prospectively evaluated 2009 ITACA (adjuvant) ongoing 2009 Rosell PLOS One BRCA1 Evolution for application of customized chemotherapy
  • Gazdar A; 2007; NEJM ERCC1 - XPF RRM1 Damage recognition Assembly of the nucleotide excision repair complex Dual incision Damage excision Adduct formation Repair synthesis DNA ligation Repaired DNA RRM1 ERCC1-XPF XPG ERCC1-XPF TFIIH XPG ERCC1
    • The IALT study demonstrated an absolute benefit of 4.1% in 5 year overall survival among 1867 patients who were treated with adjuvant cisplatin based chemotherapy
    • In the IALT Bio study ERCC1 expression in 761 out of 1045 patients enrolled in the IALT study was analyzed through IHC
    Ken A Olaussen et al; NEJM; 2006 International Adjuvant Lung cancer Trial Bio study
    • ERCC1 negative tumours :
    • OS was longer in the chemotherapy group than in the control group (14 months longer) (HR= 0.65; 95% CI, 0.50 to 0.86; p=0.002)
    • DFS was longer in the chemotherapy group (HR = 0.65; 95% CI, 0.50 to 0.85; p= 0.001)
    • ERCC1 positive tumours :
    • No significant difference in survival between the chemotherapy and the control groups (HR= 1.14; 95% CI, 0.84 to 1.55; p=0.40)
    ERCC1 as a predictor and prognostic molecular marker
    • RR: 39.3% vs 51.2% for control and genotypic arm
    • OS: 9.82 m vs 9.8 m for control and genotypic arm
    • PFS: 5.2 m vs 6.1 m for control and genotypic arm
    • 366 patients enrolled
    • Primary end point : overall response rate
    • Secondary end points : PFS and OS
    Cobo M. et al. J Clin Oncol; 2007 Control arm Docetaxel / Cisplatin Experimental arm ERCC1 mRNA R A N D O M I Z E Low ERCC1 mRNA Docetaxel & Cisplatin 1:2 High ERCC1 mRNA Docetaxel & Gemcitabine A S S I G N M E N T Customizing chemotherapy by ERCC1 mRNA profiling in advanced NSCLC
  • It is implicated in transcription coupled nucleotide excision repair It is involved in homologous recombination repair and non homologous end joining It is a regulator of the mitotic spindle assembly: it mediates G2/M arrest in response to agents that disrupt the mitotic spindle It is linked to apoptosis through the c-Jun N-terminal kinase pathway, which is activated in CDDP induced DNA damage The absence of BRCA1 results in high sensitivity to CDDP, its presence increases sensitivity to antimicrotubule agents. BRCA1
  • Rosell R et al; PLOS one; 2009 Customizing chemotherapy by BRCA1 mRNA profiling in advanced NSCLC 123 patients 12 positive for EGFR mutations 111 screened for BRCA1 levels LOW BRCA1 CDDP+Gem (38) INTERMEDIATE BRCA1 CDDP+TXT (40) HIGH BRCA1 TXT (33)
  • Median survival with TXT = Median survival with CDDP + TXT (11 months) Median survival and 2 years survival rate with CDDP + Gem > Median survival and 2 years survival rate with CDDP + Gem in unselected population (10.3 m vs 11 m and 41.2% vs 22%) Rosell R et al; PLOS one; 2009 BRCA1 mRNA and survival LIMITS: no control arm EGFR BRCA1 Low BRCA1 Intermediate BRCA1 High ORR 90% 25% 45.7% 41.9% TTP 13 months 5 months 5 months 8 months
  • Pemetrexed inhibits TS: high levels of TS are responsible for Pemetrexed resistance
  • TS mRNA expression levels in NSCLC subtypes and SCLC Monica V et al. Clin Cancer Res 2009;15:7547-7552
  • Scagliotti GV, JCO 2008 CDDP + Alimta 1.6 1.0 0.5 CDDP + GEM 0.81 [0.70;0.94] 0.68 [0.48;0.97] 1.3 [1.0, 1.50] ADENOCARCINOMA (847 pts) LARGE CELLS (153 pts) SQUAMOUS (473 pts) NSCLC (252 pts) 0.94 [0.84;1.05] OVERALL (1725 pts) Hazard ratio OS according to different histotypes
  • Control: Investigator’s choice (CDDP + VNR; CDDP+GEM; CDDP+DOC) Primary objective : OS Secondary objective : RFS PI: Giorgio Scagliotti ITACA Adjuvant Trial (ongoing)
    • AGENDA:
    • EGFR- TKIs
    • ALK- TKIs
    • MET-Ab
    Customizing therapy in advanced NSCLC II
  • The Evolving Role of Systemic Treatment in Advanced NSCLC 1980 2009 2000 One fits all 2004 2006 2007 2009 EGFR mutation discovered Antivascular agent Phase III study Role of histotype Phase III study EML4/ALK Pharmacogenetics and pharmacogenomics
  • Gefitinib : approved for patients carrying EGFR activating mutations in any line of treatment. Erlotinib : approved for unselected patients after 1 st line therapy. EGFR TKIs
  • Survival in NSCLC: Supportive care and chemotherapy 1991–2010 4.96 7.22 8.66 8.6 BSC 1995-2001 P alone PE Old Cis + no PE New Cis + 3 rd Carbo +3rd +45.5% +11% +17.9% +10.2% -11.4% Carbo+P+ Beva Gefitinib in mEGFR +43% 12.3 13.6 +10% 21.9 +61% CDDP+GEM+Beva 7.77 9.17
  • LREA 19 deletions and 21 L858R represent 85% to 90% of EGFR mutations EGFR mutations are found in 10% of cases in North America and Western Europe EGFR activating mutations and EGFR TKIs
  • Mutated EGFR represents the genetic lesion to which the tumor is addicted . The acute withdrawal of these signals by EGFR-TKIs triggers oncogenic shock and tumor cell apoptosis. Sharma et al. Nature Reviews Cancer; 2007 Engelman et al. Cl Can Res, 2008 T790M MET amplification in 60-70% tumors
  • WJTOG3405 IPASS Mok TS, NEJM 2009 Mitsudomi T, Lancet Oncol 2010 ORR : 71.2% in patients treated with Gefitinib vs 47.3% in patients treated with CT (p<0.001) Gefitinib standard of care in first line EGFR mut NSCLC patients: Phase III Asiatic studies
  • Gefitinib first line NSCLC Author Study N (EGFR mut +) RR (TKI vs CT) PFS (HR, 95%CI) Mok T NEJM 2009 IPASS 261 71.2% vs 47.3% 0.48 (0.36, 0.64) Lee JS WCLC 2009 First-SIGNAL 42 84.6% vs 37.5% 0.61 (0.31, 1.22) Mitsudomi T Lancet Oncol 2009 WJTOG 3405 198 62.1% vs 32.2% 0.49 (0.34, 0.71) Maemondo M NEJM 2010 NEJGSG002 177 74.5% vs 29% 0.36 (0.25, 0.51)
    • Primary endpoint: PFS
    • Secondary endpoints: ORR, OS, QoL and safety
    • Phase III study initiated by Tongji University, Shanghai, China
    • Recruitment in China
    Zhou et al: LBA 4799 Erlotinib 150mg/day until PD
    • Chemonaïve advanced NSCLC
    • EGFR mutation-positive (exon 19 or 21)
    • ECOG PS 0–2
    • n~150
    Gemcitabine (1,000 mg/m 2 , IV, d1 and d8) plus carboplatin (AUC=5, IV d1) repeated every 3 weeks up to 4 cycles R OPTIMAL: erlotinib versus gem/carb in EGFR mutation+ NSCLC
  • PFS probability 1.0 0.8 0.6 0.4 0.2 0 Erlotinib (n=82) Gem/carbo (n=72) HR=0.16 (0.10–0.26) Log-rank p<0.0001 Time (months) 0 5 10 15 20 25 Patients at risk Erlotinib 82 70 51 20 2 0 GC 72 26 4 0 0 0 13.1 4.6 OPTIMAL: erlotinib versus gem/carb in EGFR mutation+ NSCLC
  • K-RAS mutations are not a selective biomarker due to the absence of clinical benefit with EGFR-TKIs therapy in EGFR wild type. INTEREST BR.21 Should we use K-RAS mutation as biomarkers to exclude NSCLC patients with ANTI-EGFR agents in EGFR wild type patients? 19% (275/1433) patients had available tissue; 18% of samples were positive for K-RAS mutations 28% (206/731) patients had available tissue; 15% of samples were positive for K-RAS mutations (8 pts on placebo, 22 on erlotinib)
  • FISH Predicts Benefit of EGFR-TKIs (?) BR.21 INTEREST EGFR gene copy number is not a predictive biomarker for clinical benefit with EGFR-TKIs therapy in comparison with chemotherapy, but it is a prognostic marker of poorer survival 26% (374/1433) patients had available tissue; 47% of samples were positive for EGFR gene amplification 21% (206/731) patients had available tissue; 38% of samples were positive for EGFR gene amplification
  • EGFR-TKI Acquired Resistance Baseline After 4 months After 25 months
    • EGFR T790M esone 20
    • MET amplification
    • BRCA1
    EGFR MUTANT
    • IGF-1R
    • PTEN loss
    EGFR WILD TYPE
  • Rosell R; Clin Cancer Res; 2011 T790M is present in 35% of patients at baseline
  • AFATINIB: LUX-Lung 1 - Trial design 33
    • Radiographic assessments at 4, 8, 12 wks and every 8 wks thereafter
    • Exploratory biomarkers:
    • Archival tissue testing for EGFR mutations (optional; central lab)
    • Serum EGFR mutational analysis (all patients)
    • Patients with:
    • Adenocarcinoma of the lung
    • Stage IIIB/IV
    • Progressed after one or two lines of chemotherapy (incl. one platinum-based regimen) and ≥12 weeks of treatment with erlotinib or gefitinib
    • ECOG 0–2
    • N=585
    Randomization 2:1 (Double Blind) Oral afatinib 50 mg once daily plus BSC Oral placebo once daily plus BSC Primary endpoint: Overall survival (OS) Secondary: PFS, RECIST response, QoL (LC13 & C30), safety
  • PFS OS AFATINIB: LUX-Lung 1
  • Did not receive subsequent systemic treatment Received subsequent systemic treatment AFATINIB: LUX-Lung 1
  • Rosell R; Clin Cancer Res; 2011 Novel EGFR TKIs resistance mechanisms: BRCA1
  • Rosell R; Clin Cancer Res; 2011 PFS in 81 NSCLC patients with EGFR mut, according to BRCA1 mRNA levels
  • Janjigian; JTO; 2011 Retrospective analysis of EGFR TKIs in adjuvant
  • Primary end point: DFS at 2 years Janjigian; JTO; 2011 Schema for a clinical trial of adjuvant EGFR-TKIs
  • “ GOOD” “POOR” TTP: 84 days TTP: 61 days HR: 0.56; 95% CI 0.28-0.89; p=0.002 OS: 207 days OS: 92 days HR: 0.50; 95% CI 0.24-0.78; p=0.0054 Clinical Benefit TTP > 6 m No Clinical Benefit TTP < 1 m Good Profile Poor Profile PROTEOMICS: VeriStrat algorithm
  • Carbone, European Lung Cancer Conference, 2010 ____ indicates median OS unselected patients BR21 with 95% Conf. Int. Median OS = 6.7 months (CI: 5.5 -7.8 ) N = 61 N = 98 N =34 N =170 N =30 N =176 N =266 N =170 ∞ Comparison between different biomarkers
  • VeriStrat Good 2 nd line Adv. NSCLC 275 pts. Erlotinib Chemotherapy VeriStrat Testing PROSE : Randomized VeriStrat Stratified Phase III Study of Second Line Erlotinib versus Chemotherapy in Patients with advanced Non-Small Cell Lung Cancer VeriStrat Poor VeriStrat Poor Stratified Randomization Objectives Protocol Current status To evaluate the efficacy of treatment stratification using the VeriStrat test on the effect of erlotinib vs. chemotherapy in 2 nd line therapy in patients with advanced stage NSCLC.
    • Initiated March 2008
    • Primary endpoint: OS
    • Secondary endpoint: PFS, ORR
    • Italian multi-institutional study, PI Dr. Vanesa Gregorc
    • Enrollment to date: 214/275
    • 15 Institutions
    • Presentation of the results expected in 2012
    • AGENDA:
    • EGFR- TKIs
    • ALK- TKIs
    • MET-Ab
    Customizing therapy in advanced NSCLC II
  •  
    • The EML4-ALK translocation defines a new molecular subset of NSCLC with distinct clinical and pathologic features.
    • Compared with the EGFR mutant and WT/WT cohorts, patients with EML4-ALK mutant tumors were:
      • younger
      • never/light smokers
      • adenocarcinomas, predominantly the signet ring cell subtype
    • EML4-ALK positivity was associated with resistance to EGFR tyrosine kinase inhibitors ALK gene.
    • Rearrangements in about 3% to 7% of patients.
    Shaw AT, JCO 2009 EML4-ALK CLINICAL CHARACTERISTICS
  • Responses to Crizotinib Kwak EL, NEJM 2010 RESPONSES TO CRIZOTINIB
    • Crizotinib is active in patients with anaplastic lymphoma kinase (ALK)–positive non-small-cell lung cancer (NSCLC)
    • ORR: 57% (80% with no previous treatment)
    • 6-month PFS rate: 72% (median PFS not yet reached)
    • Response or SD (disease control) in majority (87%) of patients
    • Few serious adverse events reported
    • Most toxicity related to mild or moderate gastrointestinal events or visual disturbances
    Kwak EL, NEJM 2010 CRIZOTINIB IN ADVANCED NSCLC
    • High response to crizotinib in a population of largely pretreated NSCLC patients suggests crizotinib may become a potential new standard of care for ALK-positive patients
    • Phase III study initiated to compare crizotinib with standard-of-care chemotherapy (pemetrexed or docetaxel) in ALK-positive NSCLC
    Kwak EL, NEJM 2010 CRIZOTINIB IN ADVANCED NSCLC
  • Choi YL, NEJM 2010 Secondary mutations within EML4-ALK
    • AGENDA:
    • EGFR- TKIs
    • ALK- TKIs
    • MET-Ab
    Customizing therapy in advanced NSCLC II
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  • + +Bevacizumab (selected patients) or Cet u ximab (not yet!)