XVII CONGRESSO NAZIONALE CIPOMO Roma 27-29/06/13 La terapia personalizzata del NSCLC Andrea Ardizzoni, U.O. Oncologia Medica Azienda Ospedaliera Universitaria di Parma
Fattori di personalizzazione del trattamento del NSCLC avanzato Clinici Ps, comorbidità, età.. Patologici Istotipo (SCC vs non-scc) MolecolariActionable genomic alterations: EGFR, ALK, ROS1 CT molecular predictors
Algoritmo clinico per la terapia medica del NSCLC avanzato NSCLC IIIB-IV FIT PS 0-1/Età < 70/no comorbidità UNFIT PS 2/Età > 70/comorbidità 1 a Linea Doppietta di ultima generazione a base di platino 1 a Linea Mono-CT: GEM, VNR Doppietta con P basse dosi o carboplatino 2 a Linea Mono-CT: Pemetrexed, Docetaxel, Erlotinib
Fattori di personalizzazione del trattamento del NSCLC avanzato Clinici Ps, comorbidità, età.. Patologici Istotipo (SCC vs non-scc) Molecolari Actionable genomic alterations: EGFR, ALK, ROS1 CT molecular predictors
NSCLC: Squamous vs Non-Squamous
Phase III PC vs GC trial: Overall Survival by histology subtype GV Scagliotti et al, JCO 2008
Survival Probability Overall Survival by Histology Non-squamous (n=481) Squamous (n=182) 1.0 HR=0.70 (95% CI: 0.56-0.88) P =0.002 1.0 HR=1.07 (95% CI: 0.49 0.73) P =0.678 0.9 0.8 0.7 0.9 0.8 0.7 0.6 0.6 0.5 Pemetrexed 15.5 mos 0.5 Pemetrexed 9.9 mos 0.4 0.4 0.3 0.2 0.1 Placebo 10.3 mos 0.3 0.2 0.1 Placebo 10.8 mos 0.0 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 0.0 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 Time (months) Time (months) Ciuleanu T, Lancet 2009
Survival by histotype in pemetrexed vs docetaxel 2nd-line trial Scagliotti GV, The Oncologist 2009
VEGF as therapeutic target: Bevacizumab The VEGF family and its receptors VEGF-A VEGF-B PlGF VEGF receptor-1 VEGF-A VEGF receptor-2 VEGF-C VEGF-D VEGF receptor-3 P P P P P P P P P P P P Migration, permeability, DNA synthesis, survival Angiogenesis Lymphangiogenesis Adapted from Ferrara N. Nat Med 2003;9:669 76
Incidence (%) Risk of pulmonary haemorrhage 10 8 9,1 AVF0757g Avastin 7.5 or 15 mg/kg + CP* E4599 Avastin 15 mg/kg + CP AVAiL Avastin 7.5 mg/kg + CG AVAiL Avastin 15 mg/kg + CG 6 4 Restricting eligibility to patients with non-squamous histology and minimal baseline haemoptysis Additional exclusion of tumours abutting or invading major blood vessels 2 1,9 1,5 0,9 0 Grade 3 pulmonary haemorrhage *Phase II trial including patients with squamous cell histology CP = carboplatin/paclitaxel; CG = cisplatin/gemcitabine Johnson D, et al. JCO 2004 Sandler A, et al. NEJM 2006 Manegold C, et al. ASCO 2007
Algoritmo per la terapia personalizzata del NSCLC NSCLC IIIB-IV PS 0-1/no comorbidità/ Età < 70 PS 2/comorbidità/ Età > 70 Non-SCC SCC Non contro a Beva Contro a Beva CT/PG+Beva Platino-Pem Platino-Gem/TXT Platino-Pem Platino-Gem/TXT Platino-Gem/TXT Gem/VNR +/- Platino
Fattori di personalizzazione del trattamento del NSCLC avanzato Clinici Ps, comorbidità, età.. Patologici Istotipo (SCC vs non-scc) Molecolari Actionable genomic alterations: EGFR, ALK, ROS1 CT molecular predictors
Somatic EGFR gene mutations Lynch NEJM 2004; Paez Science 2004; Pao PNAS 2004; Sequist JCO 2007
Randomized studies of EGFR TKIs vs CT in first-line therapy Author Study N (EGFR +) RR, % (TKI vs CT) PFS, months (HR, 95%CI) Mok et al, 2009 Lee et al, 2009 Mitsudomi et al, 2009 Maemondo et al, 2010 Zhou et al, 2011 Rosell et al, 2012 Yang et al, ASCO 2012 IPASS CT vs Gefitinib First-SIGNAL PG vs Gefitinib WJTOG 3405 PD vs Gefitinib NEJGSG002 CT vs Gefitinib OPTIMAL CG vs Erlotinib EURTAC P-bas vs Erlotinib LUX-LUNG 8 PA vs Afatinib 261 71.2 vs 47.3 9.5 vs 6.4 0.48 (0.36-0.64) 42 84.6 vs 37.5 8.4 vs 6.7 0.61 (0.31-1.22) 172 62.1 vs 32.2 9.2 vs 6.3 0.49 (0.34-0.71) 230 74.5 vs 29 10.8 vs 5.4 0.32 (0.24-0.44) 154 83 vs 36 13.7 vs 4.6 0.16 (0.10-0.26) 174 58.1 vs 14.9 9.7 vs 5.2 0.37 (0.25-0.44) 345 56.1 vs 22.6 11.1 vs 6.9 0.58 (0.43-0.78)
EML4 = echinoderm microtubuleassociated protein-like 4 ALK= Anaplastic Lynphoma Kinase Soda M et al. Nature 2007
ALK fusions target a novel subgroup of NSCLC Frequency: 3-13% Caucasian > Asian Male > F Mostly never or light smokers Relatively young age Mutually exclusive with EGFR & KRAS mutations Predominantly adenoca Signet ring subtype Do not respond to EGFR- TKIs Solomon et al, JTO 2009, Shaw et al, JCO 2010
Maximum change in tumor size (%) Tumor responses to Crizotinib for patients with ALK-positive NSCLC 60 40 20 0 Progressive disease Stable disease Confirmed partial response Confirmed complete response 20 30% 40 60 80 100 No. prior ORR regimens* % (n/n) 0 80 (4/5) 1 52 (14/27) 2 67 (10/15) 3 56 (19/34) Objective response rate (ORR): 57% (95% CI: 46, 68%) * Bang Y et al, NEJM 2010
Clinical development of Crizotinib for ALK+ NSCLC Study Phase (planned accrual) Histology Line of therapy Study design Primary endpoint PROFILE 1014 PROFILE 1007 PROFILE 1005 III (334 pts) III (318 pts) II (400 pts) Non-squamous NSCLC *Cisplatin or carboplatin according to investigator s choice Cross-over to crizotinib allowed at PD in the standard arm **Pemetrexed or docetaxel; prior chemo must have been platinum-based chemotherapy May have received Pemetrexed or Docetaxel from previous phase III PROFILE 1007 trial and discontinued treatment due to RECIST-defined progression 1st 2nd Platinum*-Pemetrexed vs Crizotinib 2 nd line chemo** vs Crizotinib PFS PFS NSCLC 3 rd or more Crizotinib monotherapy ORR ORR = overall response rate; PFS = progression-free survival; pts = patients
ESMO
Best % change from baseline LDK378 Response in Molecularly Defined, Crizotinib- Resistant Tumors 100 80 60 Best % change from baseline in target lesions All previously treated with crizotinib All positive for ALK rearrangement 40 20 0 NM NM NM NM NM NM NM NM NM NM NM NM 20 40 60 80 100 PFS event Crizotinib received as last therapy: Yes No Amp, ALK amplification; NM, no ALK mutation or amplification Patients with baseline ALK mutation assessments (n=19) and at least 1 post-baseline assessment of target lesions Shaw A. et al. Abs # 8014, ASCO 13
ROS1 Rearrangements in NSCLC TPM3-ROS1 SDC4-ROS1 SLC34A2-ROS1 CD74-ROS1 EZR-ROS1 Transmembrane TK receptor involved in RAS/MEK/ERK signaling and PI3K and STA3 signaling Present in ~1% of NSCLC cases (also found in some GBMs and cholangiocarcinomas) Enriched in younger never or light smokers with adenocarcinoma histology ROS1 LRIG3-ROS1 No overlap with other oncogenic drivers Bergethon et al., JCO 30(8): 863-70, 2012; Takeuchi et al., Nat Med 18(3): 378-81, 2012
BRF113928: Study Design Single arm, phase 2, open label NSCLC BRAF V600E mutation 1 line prior tx N = 20 Stage 1 N = 20 Stage 2 dabrafenib 150 mg twice daily Primary objective: Investigator-assessed ORR Secondary objectives: PFS, duration of response, overall survival (OS), safety, tolerability, and population pharmacokinetics Green-Dahlberg 2-stage: H(0) ORR 10% versus H(1) ORR 30% (primary cohort) Planchard D. et al Proc. ASCO 2013
Maximum Percent Reduction at Time of Best Disease Assessment Maximum Reduction of Sum of Lesion Diameters by Best Confirmed Response for the First 20 Patients a 50 40 *** 30 20 10 0 *** *** 10 20 30 40 50 60 70 80 90 Best Confirmed Response Partial response Stable disease Progressive disease * ** ** ** ** Smoking History * ** *** Nonsmoker Smoker, 40 pack years Smoker, > 40 pack years * ** * ** * ** ** * 100 a 3 patients are not in the plot: 1 patient had PD on day 6 due to new lesion, target lesions were not assessed postbaseline; and 2 patients discontinued study treatment due to serious adverse events (SAEs) prior to postbaseline disease assessment. Planchard D. et al Proc. ASCO 2013
ERCC1 come fattore predittivo di risposta nella malattia avanzata 56 pazienti stadio IIIB-IV trattati con PG Estrazione mrna da paraffinato RR = 44.7% RR Low vs. High express. ERCC1 = 52 vs. 36.4% (p = 0.38) Lord RVN et al, CCR 2000
Potential treatment algorithm for A-NSCLC (good PS): 2012 Gandara, Clin Lung Cancer 09
Randomized study of ERCC1/RRM1 Customized Chemotherapy Bepler et al, Abstr 8001, ASCO 13
ERCC1/RRM1 Customized Rx Progression-Free and Overall Survival Median PFS: (E) 6.1 m (C) 6.9 m Median OS: (E) 11.0 m (C) 11.3 m Bepler G. et al. Abstract # 08001, ASCO 13
Algoritmo per la terapia personalizzata del NSCLC NSCLC IIIB-IV PS 0-1/no comorbidità/ Età < 70 PS 2/comorbidità/ Età > 70 Non-SCC SCC EGFR+, ALK+ ROS1+, BRAF+ Non contro a Beva Contro a Beva CT/PG+Beva Platino-Pem Platino-Gem/TXT Platino-Pem Platino-Gem/TXT Platino-Gem/TXT TKIs Gem/VNR +/- Platino