XVIII Congresso Nazionale CIPOMO Lazise 15-17/05/14 La valorizzazione dei benefici per il paziente con l’introduzione dei nuovi farmaci nel carcinoma polmonare AO-PR/AA’14 Andrea Ardizzoni, U.O. Oncologia Medica Azienda Ospedaliera Universitaria di Parma Nuovi farmaci nel NSCLC • Presente – EGFR-TKIs di 1a e 2a generazione – ALK/ROS1-TKI • Futuro prossimo – – – – – AO-PR/AA’14 BRAF-TKI EGFR-TKIs di 3a generazione ALK/ROS1-TKIs di 2a generazione Antiangiogenetics: ramucirumab, nindetanib Immune checkpoint inhibitors Registered targeted agents for oncogene-adicted NSCLC Pz candidate for targeted therapies: <15% AO-PR/AA’14 Valorizzazione dei benefici della terapia medica nel A-NSCLC: il benchmark della CT Terapia Guadagno in SM Guadagno in 1YS HR/OR CT 1st line vs BSC + 1.5 mesi + 9% 0.77 Doppietta vs Mono NR + 5% 0.80 Platino vs no-platino NR + 5% 1.21 Cis-Gem vs altri + 3.9% 0.90 Cis-Pem vs Cis-Gem + 1.4 mesi NR 0.81 Pem mant. Cont. + 13% 0.78 AO-PR/AA’14 + 0.8 + 2.9 mesi Somatic EGFR gene mutations AO-PR/AA’14 Lynch NEJM 2004; Paez Science 2004; Pao PNAS 2004; Sequist JCO 2007 Randomized studies of EGFR TKI vs CT in first line therapy AO-PR/AA’14 Author Study N (EGFR m +) RR (TKI vs CT) PFS (HR, 95%CI) Mok IPASS CT vs Gefitinib 261 71.2% vs 47.3% 9.5 vs 6.3 months HR 0.48 (0.36-0.64) Lee First-SIGNAL PG vs Gefitinib 42 84.6% vs 37.5% 8.4 vs 6.7 months HR 0.61 (0.31-1.22) Mitsudomi WJTOG 3405 PD vs Gefitinib 198 62.1% vs 32.2% 9.2 vs 6.3 months HR 0.49 (0.34-0.71) Kobayashi NEJGSG002 CT vs Gefitinib 177 74.5% vs 29% 10.4 vs 5.5 months HR 0.36 (0.25-0.51) Zhou OPTIMAL 154 CG vs Erlotinib 83% vs 36% 13.1 vs 4.6 months HR 0.16 (0.10-0.26) Rosell EURTAC P-X vs Erlotini 174 58.1% vs 14.9% 9.7 vs 5.2 months HR 0.37 (0.25-0.54) Yang LUX-LUNG 3 PA vs Afatinib 345 56.1% vs 22.6 % 11.1 vs 6.9 months HR 0.58 Overall Survival according to erlotinib treatment line Median overall survival for patients receiving first line therapy was 28.0 months and for those receiving second-line therapy, it was 27.0 AO-PR/AA’14 Rosell R, NEJM 2009 Tossicità EGFR-TKIs vs CT AO-PR/AA’14 Acquired Resistance to EGFR TKIs AO-PR/AA’14 Sequist, Sci Transl Med 2011 3rd generation EGFR-TKIs in EGFR-TKI-resistant NSCLC # Pts (T790M+) % RR (T790M+) AZD9291 27 (9) 50 (58) CO-1886 22 (22) 64 (64) AO-PR/AA’14 ELCC’13 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 EGFRTKIs AO-PR/AA’14 Solomon et al, JTO 2009, Shaw et al, JCO 2010 Tumor responses to Crizotinib for patients with ALK-positive NSCLC Maximum change in tumor size (%) 60 Progressive disease Stable disease 40 Confirmed partial response Confirmed complete response 20 0 –20 –30% –40 –60 –80 –100 AO-PR/AA’14 No. prior regimens* 0 1 2 ≥3 ORR % (n/N) 80 (4/5) 52 (14/27) 67 (10/15) 56 (19/34) Objective response rate (ORR): 57% (95% CI: 46, 68%) * Bang Y et al, NEJM 2010 AO-PR/AA’14 PF1007: Crizotinib vs docetaxel/pemetrexed in 2nd-line AO-PR/AA’14 Shaw AT et al; NEJM, 2013 Pfizer Reports Positive Phase 3 Study Outcome Of XALKORI® (crizotinib) Compared To Chemotherapy In Previously Untreated Pts With ALK+ Advanced NSCLC Tuesday, March 25, 2014 - 8:30am EDT Pfizer Inc. announced today that PROFILE 1014, a Phase 3 study of anaplastic lymphoma kinase (ALK) inhibitor XALKORI®(crizotinib), met its primary objective of significantly prolonging progression-free survival (PFS) in previously untreated patients with ALK-positive advanced non-squamous non-small cell lung cancer (NSCLC) when compared to standard platinum-based chemotherapy regimens. PROFILE 1014 is the second positive global Phase 3 study that evaluated XALKORI against chemotherapy, a standard of care for patients with advanced NSCLC. AO-PR/AA’14 Acquired Resistance in ALK+ NSCLC u ALK-rearranged (ALK+) NSCLC is sensitive to crizotinib1–3 – ORR 60% – Median PFS 8–10 months u Most patients develop resistance to crizotinib4,5 – Usually within 1–2 years – CNS relapses are common6 u Unknown ALK amp ALK+ No ALK amp or mut Mechanisms of resistance are diverse4,5 – ALK resistance mutations – Alternative signaling pathways amp, amplification; CNS, central nervous system; mut, mutation; ORR, objective response rate; PFS, progression-free survival. 1. Camidge DR, et al. Lancet Oncol 2012;13:1011–1019; 2. Kim D-W, et al. ESMO 2012 (Abstr 1230PD); 3. Shaw AT, et al. ESMO 2012 (Abstr LBA1_PR); 4. Katayama R, et al. Sci Transl Med 2012;4:120ra17; 5. Doebele RC, et al. Clin Cancer Res 2012;18:1472–1482; 6. Takeda M, et al. J Thorac Oncol 2013;8:654–657. AO-PR/AA’14 Bypass tracks ALK mut AO-PR/AA’14 AO-PR/AA’14 Stage IV adenocarcinomas AO-PR/AA’14 Li et al, J Clin Oncol 2013 Maximum Percent Reduction at Time of Best Disease Assessment Dabrafenib in BRAF V600E NSCLC: Best Confirmed Response for the First 20 Ptsa 50 40 *** 30 *** 20 10 *** 0 −10 * −20 ** −30 ** ** −40 ** −50 −60 Best Confirmed Response −70 Partial response −80 Stable disease −90 Progressive disease Smoking History Nonsmoker * Smoker, ≤ 40 pack years ** *** Smoker, > 40 pack years * ** * ** * ** ** * −100 a3 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. AO-PR/AA’14 Planchard D. et al Proc. ASCO 2013 VEGF inhibitors PlGF VEGF-B VEGF-A VEGF-C, VEGF-D Bevacizumab Ramucirumab Aflibercept (VEGF Trap) Sunitinib Sorafenib Vandetanib Nintedanib AO-PR/AA’14 VEGF-R1 (Flt-1) Migration Invasion Survival VEGF-R2 (KDR/Flk-1) Proliferation Survival Permeability VEGF-R3 (Flt-4) Lymphangiogenesis LUME Lung 1: OS curves in adenocarcinoma AO-PR/AA’14 Reck M, Lancet Oncology 2014 Revel: Docetaxel and Ramucirumab versus Docetaxel and placebo AO-PR/AA’14 Immune Checkpoints Pathways AO-PR/AA’14 Fumito, Chang : Surgical Oncology Clinics of North America Volume 22, Issue 4 2013 765 - 783 PD-1 and PD-L1 Antibodies in Clinical Development Anti-PD-1 Nivolumab Bristol-Myers Squibb IgG4 (fully human) Phase 3 MK-3475 Merck & Co IgG4 (humanized) Phase 3 Anti-PD-L1 MPDL3280A Genentech/Roche IgG1 (engineered human) Phase 3 BMS -936559 Bristol-Myers Squibb IgG4 (fully human) Phase 1 MEDI-4736 AstraZeneca IgG1 (engineered human) Phase 1 AO-PR/AA’14 Anti-PD1/PDL-1 Phase I-II results # Pts RR% PFS OS Nivolumab 129 17 2.3 mos 9.9 mos MK-3475 33 21 9.7 wks 51 wks MPDL328-0A 53 23 45% 2Y NA AO-PR/AA’14 WLCC ‘13 • Diapo 13 AO-PR/AA’14 Taxotere come benchmark per la terapia di seconda linea RR=5.8% MST= 7.5 m MST= 4.6 m F Shepherd et al, J Clin Oncol 2000 Valorizzazione dei benefici dei nuovi farmaci nel A-NSCLC: Conclusioni • Terapia a target molecolare superiore alla CT standard (raddoppio RR e riduzione 50% rischio PD) con minore tossicità e somministrazione orale vs i.v. in una piccola % di tumori “oncogene addicted” (EGFR/ALK) • Probabile ruolo terapie anti-angiogenetiche in seconda linea in associazione a CT (ma rapporto rischio/beneficio e costo/beneficio incerti) • Probabile ruolo degli inibitori di PD1/PDL1 in seconda linea in alternativa a CT (minore tossicità, maggiore attività, rapporto costo/beneficio??) AO-PR/AA’14
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