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LUNG CANCER TRANSLATION INTO THE ITALIAN CLINICAL PRACTICE: OPPORTUNITY AND LIMITS Lucio Crinò

LUNG CANCER TRANSLATION INTO THE ITALIAN CLINICAL PRACTICE: OPPORTUNITY AND LIMITS Lucio Crinò S.C. Oncologia Medica Azienda Ospedaliera di Perugia. LUNG CANCER ASCO HIGHLIGHTS. DIAGNOSIS AND STAGING TREATMENT OF EARLY STAGES MOLECULAR MARKERS TARGETED THERAPIES ADVANCED DISEASE.

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LUNG CANCER TRANSLATION INTO THE ITALIAN CLINICAL PRACTICE: OPPORTUNITY AND LIMITS Lucio Crinò

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  1. LUNG CANCER TRANSLATION INTO THE ITALIAN CLINICAL PRACTICE: OPPORTUNITY AND LIMITS LucioCrinò S.C. OncologiaMedica AziendaOspedalieradi Perugia

  2. LUNG CANCER ASCO HIGHLIGHTS DIAGNOSIS AND STAGING TREATMENT OF EARLY STAGES MOLECULAR MARKERS TARGETED THERAPIES ADVANCED DISEASE

  3. ENDOSONOGRAPHY AND SURGICAL STAGING VS SURGICAL MEDIASTINAL STAGING ALONE IN NSCLC – An European randomised study The Aster study abstr. 7000 • Primary end point N2-N3 detection • Secondary end point Rate of futile thoracothomy and complication 241 pts with PET ES + SS (EUSFNA and EBUS TBNA) or CT scan stage III NSCLC SS alone (mediastinoscopy mediastinotomy, VATS) R A N D O M

  4. ENDOSONOGRAPHY AND SURGICAL STAGING VS SURGICAL MEDIASTINAL STAGING ALONE IN NSCLC – An European randomised study

  5. ITALIAN EXPERIENCE • Limited experience with mediastinum surgical staging • At the moment most of the diagnostic approach to mediastinum staging is based on endoscopy (TBNA) and CT scan ± PET • A very limited number of thoracic-oncology departments have the opportunity and the skills for systematic use of endosonography

  6. EGFR TKIs GEFITINIB AS ADJUVANT TREATMENT IN COMPLETELY RESECTED STAGE IB-IIIANSCLC – A NCIC randomised trial Gefitinib 250 mg daily x 2 years Sept 2002- Apr 2005 R 503 pts fully resected Placebo Results Gefitinib Control M. follow-up 4.7 yrs MDFS 4.2 yrs HR 1.22 Not reached MDOS 5.1 yrs NYR EGFR mutations or amplification KRAS mutation are not predictive neither prognostic

  7. BR.19 – Disease Free Survival

  8. EGFR TKIs GEFITINIB AS ADJUVANT TREATMENT IN COMPLETELY RESECTED STAGE IB-IIIA NSCLC – A NCIC randomised trialCOMMENTS • No evidence of benefit for TKIs in adjuvant setting • Mutational status of EGFR or KRAS has no prognostic value • In adjuvant setting potential detrimental effect in absence of overt disease • Radiant trial with erlotinib in IHC selected population has completed the accrual in adjuvant setting

  9. MOLECULAR EPIDEMIOLOGY OF KRAS AND EGFR MUTATIONS IN NSCLC. RESULTS OF TWO PROSPECTIVE STUDIES INOVER 1600 RESECTED EARLY STAGE NSCLC (SWOG and MSKCC) • KRAS mutation was present in 19.3%, more frequent in smokers 20% vs 9% and in adenocarcinoma • EGFR mutation was observed in 12.8%, significantly more common in never smoker 45% vs 9% and in adenocarcinoma • EGFR and KRAS mutations are exclusive and smoking history and histology but not gender were independent variable • EGFR mutation shows a trend for better survival compared to wild type • KRAS mutation has a less clear detrimental impact on survival

  10. MOLECULAR EPIDEMIOLOGY OF KRAS AND EGFR MUTATIONS IN NSCLC. RESULTS OF TWO PROSPECTIVE STUDIES IN RESECTED EARLY STAGE NSCLCCOMMENTS • KRAS and EGFR mutations represents molecular signature of different diseases in adenocarcinoma in NSCLC • Future prospective studies will definitively assess their prognostic value • In our country all the early stages resected patients should be evaluated for the presence of EGFR and KRAS mutation prospectively

  11. MOLECULAR TARGETED THERAPIES • Trials designed to define the spectrum of activity of EGFR TKIs • Trials designed to overcome TKIs resistance • Trials designed on new molecular targets (IGFR1-ELM4-ALK)

  12. MOLECULAR TARGETED THERAPIESCOMMENTS (I) • Clear indications in two randomised trial for selective use of TKIs. A positive CALGB study in 188 never or light smokers adenocarcinomas of erlotinib alone vs ECP: validation of IPASS results, with equivalent activity better outcome in EGFR mutated pts. A negative Italian trial of erlotinib vs CDDP Gem in unselected patients • Negative prospective trial in pts unfit for chemotherapy of erlotinib vs BSC. Better outcome in female adenocarcinoma subgroups.

  13. Clinical Activity of the Oral ALK Inhibitor, Crizotinib (PF-02341066), in Patients with ALK-positive Non-small Cell Lung Cancer 1Seoul National University, Seoul, Korea; 2Massachusetts General Hospital, Boston, MA, USA; 3University of Colorado Cancer Center, Aurora, CO, USA; 4Memorial Sloan-Kettering Cancer Center, New York, NY, USA;5Peter MacCallum Cancer Centre, East Melbourne, Australia; 6University of California at Irvine, Irvine, CA, USA; 7University of Chicago Cancer Center, Chicago, IL, USA Bang Y,1 Kwak EL,2 Shaw A,2 Camidge DR,3 Iafrate AJ,2 Maki RG,4Solomon B,5 Ou SI,6 Salgia R,7 Clark J2 Abstract 3 ASCO Annual Meeting 2010

  14. Potential Oncogenic “Drivers” in Non-small Cell Lung Cancer (NSCLC) Adenocarcinoma Other ALK (~5%) ALK = anaplastic lymphoma kinase; EGFR = epidermal growth factor receptor; Her2 = human epidermal growth factor receptor 2; PIK3CA = phosphoinositide-3-kinase, catalytic, alpha polypeptide Massachusetts General Hospital, data on file. [AT Shaw, personal communication]

  15. FISH Assay for ALK Rearrangement* p25.2 p25.2 ALK 29.3 p24.3 p24.3 p24.1 p24.1 Centromere Telomere 2p23 region p23.2 p23.2 p22.3 p22.3 p22.1 p22.1 t(2;5) ALK gene breakpoint region EML4 42.3 p16.3 p16.3 p16.1 p16.1 p14 p14 3’ 5’ p13.2 p13.2 p12 p12 ~250 kb ~300 kb q12.1 q12.1 q12.3 q12.3 q14.1 q14.1 Break-apart FISH assay for ALK-fusion genes1 q14.3 q14.3 q21.2 q21.2 q22.1 q22.1 q22.2 q22.2 q23.2 q23.2 q24.1 q24.1 q24.3 q24.3 q31.3 q31.3 q32.1 q32.3 q33.2 q32.1 q32.3 q33.2 Split signal Non-split signal q34 q34 q36.1 q36.3q37.2 q36.1 q36.3q37.2 ALK break-apart FISH assay[Courtesy John Iafrate, Massachusetts General Hospital] *Assay is positive if rearrangements can be detected in ≥15% of cellsFISH = fluorescence in situ hybridization 1Shaw AT et al.J ClinOncol2009;27:4247–4253

  16. Clinical and Demographic Features of Patients with ALK-positive NSCLC *Performance status = Eastern Cooperative Oncology Group

  17. Tumor Responses to Crizotinib forPatients with ALK-positive NSCLC 60 40 20 0 –20 –40 –60 –80 –100 Progressive disease Stable disease Confirmed partial response Confirmed complete response Maximum change in tumor size (%) –30% * *Partial response patients with 100% change have non-target disease present

  18. 77% of Patients with ALK-positive NSCLC Remain on Crizotinib Treatment • Duration of treatment (median: 5.7 months) 0–3 mo 13 pts >3–6 mo 29 pts >6–9 mo 24 pts >9–12 mo 9 pts >12–18 mo  4 pts >18 mo 3 pts Individual patients • Reasons for discontinuation • Related AEs 1 • Non-related AEs 1 • Unrelated death 2 • Other 2 • Progression 13 0 3 69 12 15 18 21 Treatment duration (months) N=82; red bars represent discontinued patients

  19. Summary • 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% • Crizotinib was well tolerated • The most frequent adverse events were mild and moderate gastrointestinal events and mild visual disturbances

  20. MOLECULAR TARGETED THERAPIESCOMMENTS (II) • C-Met inhibitors seem to be very active in combination with erlotinib vs erlotinib alone. Potential interest in EGFR wild type and KRAS mutation • Identification of a new activating mutation in adenocarcinoma, EML4-ALK translocation present in 4% of pts. High activity of a specific TKIs at the moment evaluated in selected pts in Europe and USA in phase II-III trials • Anti IGFR1 monoclonal antibody failed in combination with chemotherapy in phase III trial • In a whole, constant better results for small molecules TKIs versus monoclonal antibody in NSCLC

  21. RANDOMISED PHASE III STUDY IN ELDERLY PATIENT (75-89 YEARS) OF SINGLE AGENT STANDARDS CHEMOTHERAPY VERSUS PLATINUM DOUBLET • Benefit in OS for doublet 10, 5 months vs 6.2 months • Benefit in PFS for doublet 6.3 months vs 3.2 months • Flu hematological toxicity worse in doublet arm (Grade 3-4 54% vs 17.9) COMMENTS • Large age interval 75-89 years • Large proportion >30% of PS 2 patients • Unacceptable mortality rate 23.7%, 16.6% in both arm respectively • Data to evaluate in the contest of SER USA results showing a significant benefit with platinum containing chemotherapy in elderly JCO 2010

  22. Chemotherapy and survival benefit in elderly patients with advanced NSCLCEdelman DM et al, JCO 2010 • Any chemotherapy was associated with HR reduction (0.558, CI 0.547-0.569) and with increase of 1 year survival from 11,6% to 27% • Platinum doublet increases one year survival over single agent regimens from 19,4% to 30,1%

  23. CONCLUSIONS • Most elderly patient with advanced NSCLC do not receive chemotherapy, yet there are clear survival benefits, even with controls for age, comorbidity and PS • The benefit of chemotherapy is greater for platinum-based doublet regimens, than for single agent chemotherapy

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