Thorakale Onkologie. ASCO 2013 Aktuelle Studien TZ Berlin Buch

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1 Triple negativ

2 Thorakale Onkologie ASCO 2013 Aktuelle Studien TZ Berlin Buch

3 Driver Oncogene Mutations in non sq-nsclc Genome Res November; 22(11):

4 8021: Detection of EGFR-activating mutations from plasma DNA as a potent predictor of survival outcomes in FASTACT 2: A randomized phase III study on intercalated combination of erlotinib (E) and chemotherapy (C) Mok T et al Retrospective plasma and tumour analysis of randomised, double-blind, placebo-controlled phase III study Objective: To investigate the sensitivity of using plasma samples to test for EGFR mutation compared with tumour samples as predictor of survival in patients with advanced NSCLC Induction phase q4w, 6 cycles Maintenance phase until PD Key patient inclusion criteria Previously untreated stage IIIB/IV NSCLC PS 0-1 (n=451) R 1:1 GC-erlotinib Gem 1,250 mg/m 2 + carboplatin AUC5 or cisplatin 75 mg/m 2 + erlotinib 150 mg/day (n=472) GC-placebo Gem 1,250 mg/m 2 + carboplatin AUC5 or cisplatin 75 mg/m 2 + placebo (n=472) Plasma and tumour samples collected for sample analysis Tested for 41 unique mutations of exons of the EGFR gene Erlotinib 150 mg/kg Placebo Mok et al. J Clin Oncol 31, 2013 (suppl; abstr 8021)

5 8016: LUX-Lung 6: A randomized, open-label, phase III study of afatinib versus gemcitabine/cisplatin as first-line treatment for Asian patients with EGFR mutation-positive advanced adenocarcinoma of the lung Wu YL et al Randomised, open-label, Phase III study Objective: To compare the efficacy and safety of first-line treatment with afatinib versus gemcitabine+cisplatin in Asian patients with EGFR mutation-positive (EGFR M+) stage IIIB/IV lung adenocarcinoma Key patient inclusion criteria No prior treatment for advanced disease Stage IIIB/IV lung adenocarcinoma EGFR mutation positive Asian ECOG PS 0-1 (n=364) Primary endpoint PFS R 2:1 Afatinib 40 mg/day (n=242) Gemcitabine 1,000 mg/m 2 days 1/8 + cisplatin 75 mg/m 2 day 1 q3w (n=122) Up to 6 cycles Secondary endpoints ORR, DCR, OS, PROs PD PD Safety Wu et al. J Clin Oncol 31, 2013 (suppl; abstr 8016)

6 Triple negativ

7 8013: 65plus: A randomized, phase III trial of pemetrexed and bevacizumab vs pemetrexed, bevacizumab and carboplatin as first-line treatment for elderly patients with advanced non-squamous, non-small cell lung cancer (NSCLC) Schuette W et al Randomised, open-label, multicentre Phase III study First-line treatment q3w, 4-6 cycles Objective: To investigate efficacy of pemetrexed (P) + bevacizumab (B) versus P + B + carboplatin (C) in elderly patients ( 65 years) with advanced q3w nonsquamous until PD NSCLC Key patient inclusion criteria Stage IIIB/IV nonsquamous NSCLC Previously untreated ECOG PS 0-2 Aged 65 years (n=271) Primary endpoint PFS R 1:1 *Plus Pem at the discretion of the investigator Pem 500 mg/m 2 + Bev 7.5 mg/kg (n=133) Pem 500 mg/m 2 + Bev 7.5 mg/kg + Carboplatin AUC5 (n=134) Secondary endpoints Maintenance phase Bevacizumab* Bevacizumab* RR, OS, quality of life, activities of daily living Safety Schuette et al. J Clin Oncol 31, 2013 (suppl; abstr 8013)

8 Pan-negative NSCLC Ist die Immunohistochemie prädiktiv für die Therapieplanung? Wie behandelt man die early progressors des NSCLC? Immunotherapie als 3. Standbein?

9 Key results: OS by thyroid transcription factor-1 IHC expression for positive vs. negative H score Overall By treatment arm TTF-1+ Pem Arm (n=73), 17.6 mo TTF-1+ Pac Arm (n=66), 12.8 mo TTF-1- Pem Arm (n=36), 7.6 mo TTF-1- Pac Arm (n=30), 9.1 mo Compared with TTF-1 - patients, TTF-1 + patients had longer OS (and PFS and a higher RR, data not shown) OS was longer among TTF-1 + patients treated on the pemetrexed arm (17.6 months) than the paclitaxel arm (12.8 months) although this did not reach significance (p=0.08) TTF-1, thyroid transcription factor-1 Garon et al. J Clin Oncol 31, 2013 (suppl; abstr 8086)

10 8001: Molecular analysis-directed, international, phase III trial in patients with advanced non-small-cell lung cancer Bepler G et al Randomised, open-label trial Objective: To investigate feasibility of using ERCC1 and RRM1 as predictive markers for response to platinum agents and gemcitabine in patients with advanced NSCLC Primary endpoint PFS Stratification PS, sex, prior (neo)adjuvant therapy Key patient inclusion criteria Stage IV or wet IIIB NSCLC ECOG PS 0-1 (n=275) R 2:1 RRM1 and ERCC1 determination by AQUA ERCC1 low 66.0 ERCC1 high RRM1 low 40.5 RRM1 high Gemcitabin e + carboplatin Gemcitabin e + docetaxel Docetaxel + carboplatin Docetaxel + vinorelbine NB. 6 cycles, no maintenance therapy, no bevacizumab RRM1 low 40.5 RRM1 high ERCC1 low 66.0 Gemcitabine + ERCC1 carboplatin high Bepler et al. J Clin Oncol 31, 2013 (suppl; abstr 8001)

11 LBA8002: Interim analysis of the Spanish Lung Cancer Group (SLCG) BRCA1- RAP80 Expression Customization (BREC) randomized phase III trial of customized therapy in advanced non-small cell lung cancer (NSCLC) patients (p) (NCT /GECP-BREC) Moran T et al Randomised, prospective Phase III study Objective: To evaluate customised therapy based on RAP80 and BRCA1 expression with non-customised cisplatin+docetaxel in patients with advanced NSCLC Key patient inclusion criteria Advanced NSCLC EGFR wt (n=382) R 1:1 Stratification Non-customised arm Cisplatin+docetaxel (n=190) ECOG PS 0/1; squamous vs. non-squamous; RAP80 tertiles; BRCA1 tertiles Gem/Cis for T1 RAP80 (T1-T3 BRCA1) (n=81) Doc/Cis for T2-T3 RAP80 (T1-T2 BRCA1) (n=62) Doc for T2-T3 RAP80 (T3 BRCA1) (n=49) Customised arm Primary endpoint PFS Secondary endpoints OS Tumour response rate Moran et al. J Clin Oncol 31, 2013 (suppl; abstr LBA8002)

12 LBA8005: Randomized proteomic stratified phase III study of second-line erlotinib versus chemotherapy in patients with inoperable non-small cell lung cancer (PROSE) Lazzari C et al Randomised, Phase III biomarker validation trial Objective: To prospectively evaluate the predictive utility of VeriStrat classification on the survival outcome of second-line erlotinib or chemotherapy in patients with NSCLC Key patient inclusion criteria Cytological or histological diagnosis of NSCLC Erlotinib 150 mg/day (n=134) PD Advanced stage IIIB/IV One previous line platinumbased therapy non EGFR- TKIs ECOG PS 0-2 (n=285) R 1:1 Stratification ECOG PS, smoking VeriStrat classification Pemetrexed 500 mg/m 2 or Docetaxel 75 mg/m 2 (n=129) PD Primary endpoint OS Secondary endpoints PFS, ORR Crossover permitted at progression VeriStrat is a serum protein test (VSG, good; VSP, poor) Lazzari et al. J Clin Oncol 31, 2013 (suppl; abstr LBA8005)

13 Fazit IHC IHC ist für die Randomisierung nur sehr bedingt geeignet Proteonomics als Biomarker möglich

14 Multikinase Inhibition

15 Characteristics of Nintedanib* Oral angiokinase inhibitor targeting VEGFR 1 3, FGFR 1 3, and PDGFR α/β as well as RET 1,2 No drug drug interaction liability via CYP450 3 Manageable safety profile in combination with Docetaxel 3 Pemetrexed 4 Paclitaxel/carboplatin 5 Gemcitabine/cisplatin 6 Afatinib 7 Single-agent nintedanib was active in a phase II trial in recurrent NSCLC 8 1. Hilberg F, et al. Cancer Res 2008;68:4774 8; 2. Data on File; 3. Stopfer P, et al. Xenobiotica 2011;41: ; 4. Bousquet G, et al. Br J Cancer 2011;105:1640 5; 5. Ellis PM, et al. Clin Cancer Res 2010;16:2881 9; 6. Doebele RC, et al. Ann Oncol 2012;23: ; Data on File (clinicaltrials.gov NCT ); 7. Soria J-C, et al. Ann Oncol 2012;23(Suppl.9): abs 979; 8.Reck M, et al. Ann Oncol 2011;22: *Nintedanib is an investigational compound and is not yet approved.

16 LUME-Lung 1 Study Design Stage IIIB/IV or recurrent NSCLC patients after 1 st line chemotherapy (all histologies) R A N D O M IZ E 1:1 Nintedanib 200mg BID p.o., D2 21, + Docetaxel 75mg/m 2 IV, D1, 21-day cycles (n=655) Placebo BID p.o., D2 21, + Docetaxel 75mg/m 2 IV, D1, 21-day cycles (n=659) PD PD N=1314 Number of docetaxel cycles not restricted Monotherapy allowed after 4 cycles of combination therapy Stratification: ECOG PS (0 vs 1) Prior bevacizumab (yes vs no) Histology (squamous vs non-squamous) Brain metastases (yes vs no) Regions: Europe / Asia / South Africa Accrual: Dec 23, 2008 to Feb 9,

17 Probability of survival (%) No. at risk Nintedanib Placebo Overall Survival Patients with Adenocarcinoma Histology % Nintedanib + docetaxel Placebo + docetaxel Median, mo HR (95% CI) 0.83 (0.70 to 0.99) p-value % 25.7% 19.1% Time (months)

18 Overall Survival Patients with Adenocarcinoma Histology Characteristic Hazard ratio (95% CI) Int. p-value Overall 0.83 (0.70, 0.99) Sex Female 0.84 (0.63, 1.12) Male 0.84 (0.68, 1.05) Age class <65 years 0.83 (0.68, 1.02) 65 years 0.82 (0.58, 1.15) Ethnic origin Asian 0.89 (0.61, 1.31) Non-Asian 0.81 (0.67, 0.98) Smoking status Current smoker/ex-smoker 0.86 (0.69, 1.06) Never smoker 0.81 (0.60, 1.09) ECOG PS (0.57, 1.08) (0.70, 1.04) Brain metastases No 0.80 (0.67, 0.96) Yes 1.27 (0.67, 2.38) Prior bevacizumab No 0.85 (0.71, 1.01) Yes 0.61 (0.31, 1.20) Time since start of 1 st line <9 months 0.75 (0.60, 0.92) 9 months 0.89 (0.66, 1.19) Best response to 1 st line CR/PR/SD 0.90 (0.73, 1.10) PD 0.62 (0.41, 0.94) Favors nintedanib Favors placebo 18

19 PD1 Signalweg N Engl J Med Jun 28;366(26): Curr Opin Immunol April; 24(2):

20 8008: Clinical activity, safety, and biomarkers of MPDL3280A, an engineered PD-L1 antibody in patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) Spigel DR et al Open-label, Phase Ia dose expansion trial Objective: To determine recommended Phase II dose of the human monoclonal antibody, MPDL3208A in patients with various tumours including squamous or non-squamous NSCLC Key patient inclusion criteria Squamous or non-squamous NSCLC Incurable or metastatic solid tumour Measurable disease per RECIST v1.1 ECOG PS 0-1 (n=52) MPDL3280A 1-20 mg/kg q3w 16 cycles (standard 3+3 at doses 0.3 mg/kg) PD Primary endpoints Safety ORR (RECIST v1.1) Spigel et al. J Clin Oncol 31, 2013 (suppl; abstr 8008)

21 ASCO 2013 Thorakale Onkologie NSCLC IV IHC Studienstratifizierung ad acta Multikinase Inhibition NSQ-NSCLC 2.line eine mögliche Therapieoption Immunotherapie als Add On in der Prüfung Kleine Kohorten aufgrund der Genetik (Biomathematische Erfassung?)