Therapie des Lungenkarzinom ASCO2015. Tumorzentrum Berlin Buch

Transcription

1 Therapie des Lungenkarzinom ASCO2015 Tumorzentrum Berlin Buch

2 Lungenkarzinom Highlights Liquid Biopsy bei NSCLC und TKI Einsatz Zweitlinientherapie orale Therapieformen Zweitlinie Immuntherapie

3 Lung Cancer - Non-Small Cell Metastatic Lung Cancer - Non-Small Cell Metastatic Efficacy of Rociletinib (CO-1686) in Plasma-genotyped T790M positive NSCLC patients Abstract No.: 8001 Citation: J Clin Oncol 33, 2015 (suppl; abstr 8001) Presenter: Lecia V. Sequist Presenter: Lecia V. Sequist

4 Lung Cancer - Non-Small Cell Metastatic Presenter: Lecia V. Sequist

7 Non-Small Cell Metastatic Non-Small Cell Metastatic Influence of dose adjustment on afatinib safety and efficacy in patients (pts) with advanced EGFRmutation-positive (EGFRm+) non-small cell lung cancer (NSCLC) Abstract No.: 8073 Citation: J Clin Oncol 33, 2015 (suppl; abstr 8073) Presenter: James Chih-Hsin Yang Presenter: James Chih-Hsin Yang

8 Presenter: James Chih-Hsin Yang

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17 Lung Cancer Immunotherapy NSCLC Somatic mutation frequency (/ Mb) Somatic mutation frequencies in different tumors1 High rates of somatic mutations in lung cancer may contribute to increased immunogenicity2 Therapies targeting the PD-L1/PD-1 pathway will alter the treatment of NSCLC 1Lawrence 17 MS, et al. Nature. 2013; 2Chen DS, et al. CCR Mod. Spira AI et al. ASCO 2015, Clinical Science Symposium Immunotherapy in Lung Cancer: A Paradigm Shift, Abstract No. 8010

18 Regulation der T-Zell Aktivierung: Aktivierende und inhibierende Checkpoint-Moleküle Immun-Checkpoints Limitieren eine dauerhafte Immunantwort Verhindern die Zerstörung von gesundem Gewebe Negative Costimulation, (Coinhibition) hilft Immunantworten runterzuregeln Beispiele für co-inhibitorische Checkpoint-Moleküle: PD-1, CTLA-4, and LAG-3 Die Amplitude und Qualität der T-Zellantwort wird durch eine Balance zwischen aktivierenden und inhibitorischen Signalen reguliert. T-Zelle APC/ Tumor B7-2 (CD86) CD28 B7-1 (CD80) CTLA-4 Aktivierung Inhibition PD-L1 PD-1 Inhibition PD-L2 B7-1 (CD80) LAG-3 MHC CD40 CD137L OX-40L Inhibition Inhibition TCR CD40L Aktivierung Aktivierung OX-40 Aktivierung CD137 APC = antigen-presenting cell; MHC = major histocompatibility complex; TCR = T cell receptor Pardoll DM, Nat Rev Cancer 2012; 12:

19 CheckMate 017 (NCT ) - Study Design Stage IIIb/IV SQ NSCLC Nivolumab 3 mg/kg IV Q2W until PD or unacceptable toxicity n=135 1 prior platinum doublet-based chemotherapy ECOG PS 0-1 Pre-treatment (archival or fresh) tumor samples required for PDL1 analysis n=272 R 1:1 Docetaxel 75 mg/m2 IV Q3W until PD or unacceptable toxicity n=137 Patients stratified by region and prior Paclitaxel use One pre-planned interim analysis for OS At time of DBL (December 15, 2014), 199 deaths were reported (86% of deaths required for final analysis) The boundary for declaring superiority for OS at the pre-planned interim analysis was p< Primary Endpoint: OS Additional Endpoints: Investigator-assessed ORR lnvestigator-assessed PFS Correlation between PDL1 expression and efficacy Safety Quality of life (LCSS) LCSS=Lung cancer symptom scale Mod. Spigel DR et al. ASCO 2015, Clinical Science Symposium Immunotherapy in Lung Cancer: A Paradigm Shift, Abstract No. 8009

20 OS (%) Overall Survival Nivolumab Docetaxel n=135 n=137 mos mo, (95% CI) (7.3, 13.3) (5.1, 7.3) # events HR= , 0.79), p= yr (95% OS CI: rate=42% Nivolumab Docetaxel 1-yr OS rate=24% Number of Patients at Risk Nivolumab Time (months) Docetaxel Symbols represent censored observations 20 Mod. Spigel DR et al. ASCO 2015, Clinical Science Symposium Immunotherapy in Lung Cancer: A Paradigm Shift, Abstract No. 8009

21 OS by PD-L1 Expression 1% PD-L1 Expression level 5% PD-L1 Expression level mos (mo) 10% PD-L1 Expression level mos (mo) mos (mo) Docetaxel PD-L1 1% PD-L1 <1% Nivolumab Docetaxel PD-L1 5% PD-L1 <5% Nivolumab Docetaxel PD-L1 10% PD-L1 <10% OS (%) Nivolumab Time (months) Time (months) Nivolumab PD-L1+ Nivolumab PD-L1 21 Time (months) Docetaxel PD-L1+ Docetaxel PD-L1 Mod. Spigel DR et al. ASCO 2015, Clinical Science Symposium Immunotherapy in Lung Cancer: A Paradigm Shift, Abstract No. 8009

22 Summary Nivolumab is the first PD-1 inhibitor to demonstrate a survival benefit versus standard-of-care Docetaxel in previously-treated patient with advanced SQ NSCLC 41% reduction in risk of death (HR 0.59; p= ) 1-yr OS: 42% vs 24% mos: 9.2 vs 6.0 mo Nivolumab demonstrated superiority over Docetaxel across all secondary efficacy endpoints ORR: 20% vs 9% (p=0.0083) 1-yr PFS: 21% vs 6.4%; mpfs: 3.5 vs 2.8 mo (HR 0.62; p=0.0004) Nivolumab benefit was independent of PD-L1 expression The safety profile of Nivolumab was favorable versus Docetaxel and consistent with prior studies Nivolumab received FDA approval in the US on March 4, 2015 for metastatic SQ-NSCLC with progression on or after Platinum-based chemotherapy 22 Mod. Spigel DR et al. ASCO 2015, Clinical Science Symposium Immunotherapy in Lung Cancer: A Paradigm Shift, Abstract No. 8009

23 CheckMate 057 (NCT ) Study Design Stage IIIB/IV non-sq NSCLC Pre-treatment (archival or recent) tumor samples required for PD-L1 ECOG PS 0-1 Failed 1 prior platinum doublet Prior maintenance therapy alloweda Prior TKI therapy allowed for known ALK translocation or EGFR mutation n=582 Nivolumab 3mg/kg IV Q2W until PD or unacceptable toxicity n=292 R 1:1 Docetaxel 75mg/m2 IV Q3W until PD or unacceptable toxicity n=290 Patients stratified by prior maintenance therapy and line of therapy (second- vs. third-line) Primary Endpoint OS Additional Endpoints ORRb PFSb Safety Efficacy by tumor PD-L1 expression Quality of life (LCSS) PD-L 1 expression measured using the Dako/BMS automated IHC assay14,15 Fully validated with analytical performance having met all pre-determined acceptance criteria for sensitivity, specificity, precision, and robustness amaintenance therapy included Pemetrexed, Bevacizumab, or Erlotinib (not 14. Rizvi et al. Lancet Oncol 2015;16: considered a separate line of therapy). bper RECIST v1.1 criteria as determined by the doi: /S (15) Epub 2015 Feb 20. investigator. 15. Brahmer et al. N Engl Med 2015 (in press). 23 Mod. Paz-Ares L et al. ASCO 2015, Clinical Science Symposium Immunotherapy for Every Patient: Check Your Enthusiasm, Abstract No. LBA109

24 Overall Survival mos, mo Nivolumab Docetaxel (n=292) (n=290) OS (%) HR=0.73 (96% Cl: 0.59, 0.89); p= yr OS rate=51% Nivolumab 1-yr OS rate=39% Docetaxel Number of Patient at Risk Time (months) Nivolumab Docetaxel Symbols represent censored observations. 24 Mod. Paz-Ares L et al. ASCO 2015, Clinical Science Symposium Immunotherapy for Every Patient: Check Your Enthusiasm, Abstract No. LBA109

25 Treatment Effect on OS in Predefined Subgroups n Unstratified HR (95% Cl) (0.62, 0.91) < (0.62, 1.04) 65 and < (0.45, 0.89) (0.43, 1.87) Male (0.56, 0.96) Female (0.58, 1.04) (0.44, 0.93) (0.63, 1.00) Current/Former Smoker (0.56, 0.86) Never Smoked (0.64, 1.61) Positive (0.69, 2.00) Not Detected (0.51, 0.86) Overall Age Categorization (yrs) Gender Baseline ECOG PS Smoking Status EGFR Mutation Status Not Reported patients (Nivolumab, n=292; 160 (0.51, 1.06) All randomized Docetaxel,0.74 n=290) Nivolumab Docetaxel 4.0 Mod. Paz-Ares L et al. ASCO 2015, Clinical Science Symposium Immunotherapy for Every Patient: Check Your Enthusiasm, Abstract No. LBA109

26 Summary Nivolumab is the first PD-1 inhibitor to significantly improve OS vs Docetaxel in previously treated patients with advanced non-sq NSCLC 27% reduction in risk of death (HR=0.73; p=0.0015) Nivolumab significantly improved ORR vs Docetaxel (p=0.0246) PD-L1 expression is predictive of benefit with Nivolumab, starting at the lowest expression level (1%) Median OS nearly doubled with Nivolumab vs Docetaxel across PD-L1 expression continuum No difference in OS seen when PD-L1 was not expressed in the tumor ORR nearly tripled in PD-L1 expressors Safety profile of Nivolumab was favorable vs Docetaxel and consistent with prior studies CheckMate 057 is the second phase III trial to demonstrate superior survival of Nivolumab over Docetaxel in advanced NSCLC 26 Mod. Paz-Ares L et al. ASCO 2015, Clinical Science Symposium Immunotherapy for Every Patient: Check Your Enthusiasm, Abstract No. LBA109

27 Regulation der T-Zell Aktivierung: Aktivierende und inhibierende Checkpoint-Moleküle Immun-Checkpoints Limitieren eine dauerhafte Immunantwort Verhindern die Zerstörung von gesundem Gewebe Negative Costimulation, (Coinhibition) hilft Immunantworten runterzuregeln Beispiele für co-inhibitorische Checkpoint-Moleküle: PD-1, CTLA-4, and LAG-3 Die Amplitude und Qualität der T-Zellantwort wird durch eine Balance zwischen aktivierenden und inhibitorischen Signalen reguliert. T-Zelle APC/ Tumor B7-2 (CD86) CD28 B7-1 (CD80) CTLA-4 Aktivierung Inhibition PD-L1 PD-1 Inhibition PD-L2 B7-1 (CD80) LAG-3 MHC CD40 CD137L OX-40L Inhibition Inhibition TCR CD40L Aktivierung Aktivierung OX-40 Aktivierung CD137 APC = antigen-presenting cell; MHC = major histocompatibility complex; TCR = T cell receptor Pardoll DM, Nat Rev Cancer 2012; 12:

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29 Efficacy, safety and predictive biomarker results from a randomized phase II study comparing Atezolizumab (MPDL3280A) vs Docetaxel in 2L/3L NSCLC (POPLAR) Alexander I. Spira,1 Keunchil Park,2 Julien Mazieres,3 Johan Vansteenkiste,4 Achim Rittmeyer,5 Marcus Ballinger,6 Daniel Waterkamp,6 Marcin Kowanetz,6 Pei He,6 Louis Fehrenbacher7 1Virginia Cancer Specialists Research Institute, Fairfax, VA; US Oncology Research, The Woodlands, TX; 2Samsung Medical Centre; Division of Hematology/Oncology, Seoul, South Korea; 3Toulouse University Hospital, Toulouse, France; 4University Hospitals KU Leuven, Leuven, Belgium; 5Lungenfachklinik Immenhausen, Immenhausen, Germany; 6Genentech, Inc., South San Francisco, CA; 7Kaiser Permanente Medical Center, Vallejo, CA Spira A I et al. Clinical Science Symposium Immunotherapy in Lung Cancer: A Paradigm Shift Abstract No. 8010

30 POPLAR: A Randomized All-comer Phase II Study Metastatic or locally advanced NSCLC (2L/3L) Disease progression on a prior Platinum therapy n=287 Atezolizumab 1200 mg IV q3w until loss of clinical benefit Stratification Factors PD-L1 IC expression (0 vs 1 vs 2 vs 3)a Histology (squamous vs non-squamous) Prior chemotherapy regimens (1 vs 2) Docetaxel 75 mg/m2 IV q3w until disease progression 1:1 Primary study objective: R Estimate OS in PD-L1 selected and ITT populations Secondary study objectives: Evaluate PFS, ORR and DOR in PD-L1 selected and ITT populations Evaluate safety Interim analysis is based on 153 events with a minimum follow-up 10 months 30 aarchival or fresh tissue required for pre-dose testing. Mod. Spira AI et al. ASCO 2015, Clinical Science Symposium Immunotherapy in Lung Cancer: A Paradigm Shift, Abstract No. 8010

31 TC2/3 POPLAR: PD-L1 Expression Subgroups TC2/3 or IC2/3 interim OS (n=105) IC2/3 Overall Survival Minimum follow-up = 10 months Median 13.0 mo (8.4, NE) Atezolizumab Docetaxel Censored HRa=0.56 (0.33, 0.94) Median 7.4 mo (6.0, 12.5) p value=0.026 Time (mo) No. of Patients at Risk Atezolizumab Docetaxel aunstratified 31 2 HR. Data cut-off Jan 30, Mod. Spira AI et al. ASCO 2015, Clinical Science Symposium Immunotherapy in Lung Cancer: A Paradigm Shift, Abstract No. 8010

32 Summary The POPLAR Phase II randomized study demonstrated a pattern of improved survival that correlated with increasing PD-L1 expression OS HR=0.46 in TC3 or IC3 patients (highest PD-L1 expression) OS HR=1.12 in TC0 and IC0 patients (less than 1% expression); may not derive benefit relative to Docetaxel OS HR=0.77 in ITT patients Interim data with a minimum of 10 months of follow up The highly sensitive and specific IHC SP142 assay measures PD-L1 on both TC and IC and is a predictive diagnostic biomarker for Atezolizumab in NSCLC Atezolizumab was well tolerated with a safety profile consistent with previous studies, distinct from chemotherapy 32 Mod. Spira AI et al. ASCO 2015, Clinical Science Symposium Immunotherapy in Lung Cancer: A Paradigm Shift, Abstract No. 8010

33 Ausgewählte Biomarker-Ansätze für Immunonkologische Therapien 1. Expression von Markern bezogen auf das Ziel-Molekül oder den Ziel-Signalweg z. B. PD-L1 für PD-1-Signalweg gerichete Therapien1 2. Therapiebedingte Veränderungen des Immunsystems oder der Tumorumgebung ( Microenvironment ) z. B. absolute Lymphozytenzahl (ALC)2, Antikörperantwort auf Tumorantigene3 oder Veränderung der Tumor-infiltrierenden Lymphozyten (TIL)4 3. Genexpressionsprofil des Patienten oder des Tumors z. B. differenzielle Expression des Tumors von immunologischen Genen5 1. Callahan et al, J Clin Oncol 2013; 31(15 Suppl): abstract 3003; 2. Ku et al, Cancer 2010; 116: 1767; 3. Postow et al, N Engl J Med 2012; 366(10): 925; 4. Hamid et al, J Transl Med 2011; 9: 204; 5. Ulloa-Montoya et al, J Clin Oncol 2013; 31:

34 Identifizierung von Biomarkern dringend geboten Tumor ImmunEscape: Netzwerk von dynamischen Signalwegen BiomarkerIdentifizierung stellt eine große Herausforderung dar Alternative BiomarkerAnsätze notwendig? Ziel: Selektion der Patienten erhöhen, welche von einer I-O Therapie profitieren 34

35 Vielen Dank /12