Nuevos fármacos anti ALK. Javier de Castro
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1 Nuevos fármacos anti ALK Javier de Castro
2 Cáncer de Pulmón ALK + Incidencia 2-7% 5-6ª dec, No fumador De Castro J, Clin and Trasl 2013
3 Fusión de NPM-ALK descubierta LACG* Fusión de EML4- ALK descubierta en CPCNP Crizotinib aprobado por la FDA (Agosto 2011) Identificación de Crizotinib PROFILE 1001: Primer paciente Respuestas Parciales: ALK+ CPCNP, IMT Garantía de prioridad de revisión por FDA (Mayo 2011)
4 Crizotinib (PF )
5 Resistencia Inicial Progresión 11 meses Camidge, Lancet Oncol 2012 Solomon BJ, N Engl J Med 2014 Progresión SNC Costa DB, J Clin Oncol 2015
6 Major modes of crizotinib resistance in ALK+ NSCLC Brain metastasis (new/progression of existing metastasis) Gatekeeper L1196M Crizotinib Acquired resistance in ALK Non solvent-front; non-gatekeeper F1174L/V/C Loss of ALK/activation of secondary signalling pathway Solvent-front G1202R R-spine I1171T/N/S
7 About One-Third of Resistant Tumors Harbor ALK Resistance Mutations Unknown ALK amp ALK+ ALK mut Bypass tracks No ALK amp or mut EGFR CKIT SRC IGF1R
8 Crizotinib resistance mutations in ALK+ NSCLC * Number of patients * F1174V Modified from Lovly and Pao. Sci Transl Med 2012
9 Friboulet et al. Cancer Discov 2014
10 NCT ASCEND-1 Global pivotal phase 1 trial including 20 centers across 11 countries 1 Expansion Phase Evaluate 750 mg RD N=255 patients with ALK+ tumors* N=246 patients with ALK+ NSCLC tumors Recruitment closed July October 2013 data cut-off used for current analysis Study ongoing *9 ALK+ patients had cancers other than NSCLC ALK inhibitor treated** N=163 ALK inhibitor naïve N=83 **All received crizotinib and 5 also received alectinib Key Objectives: to determine anti-tumor efficacy and safety of ceritinib Dose escalation phase (n=59) closed May 2012 with RD of 750 mg/day 1 Shaw A et al. NEJM 2014;370(13): ALKi: ALK inhibitor; RD: recommended dose Shaw, et al. N Engl J Med 2014
11 NCT ASCEND-1: Overall Response Rate in ALK+ NSCLC Patients Treated with Ceritinib (750 mg daily) Efficacy Parameter (RECIST 1.0) ALK inhibitor treated (N=163) ALK inhibitor naïve (N=83) All (N=246) Complete Response (CR), n (%) 2 (1.2) 1 (1.2) 3 (1.2) Partial response (PR), n (%) 87 (53.4) 54 (65.1) 141 (57.3) Stable Disease (SD), n (%) 32 (19.6) 19 (22.9) 51 (20.7) Progressive Disease (PD), n (%) 16 (9.8) 0 16 (6.5) Unknown*, n (%) 26 (16.0) 9 (10.8) 35 (14.2) Overall Response Rate (ORR), n (%) [95% CI] 89 (54.6) [46.6, 62.4] 55 (66.3) [55.1, 76.3] 144 (58.5) [52.1, 64.8] *No post-baseline assessment done, or the post-baseline assessment had overall response that was not CR, PR, SD or PD Presented by: Dong-Wan Kim ASCO 2014
12 NCT ASCEND-1 Progression-Free Survival in Patients Presented by: E. Felip ESMO 2014
13 NCT ASCEND-1 Adverse Events & Laboratory Abnormalities Regardless of Study Drug Relationship All patients treated with 750 mg (N=255; includes 9 non-nsclc patients) Most common adverse events (AE) All grades* (%) Grade 3/4* (%) Diarrhea 86 6 Nausea 80 4 Vomiting 60 4 Abdominal pain 54 2 Constipation 29 0 Fatigue 52 5 Decreased appetite 34 1 Interstitial lung disease (ILD)/pneumonitis 4 3 Key Laboratory abnormalities All grades* (%) Grade 3/4* (%) Hemoglobin decreased 84 5 Alanine transaminase (ALT) increased Aspartate transaminase (AST) increased Creatinine increased 58 2 Glucose increased Phosphate decreased 36 7 Lipase increased *All grades (>20%); Grade 3/4 ( 2%). QTc prolongation >60ms occurred in 3% of pts. 1 pt at 700mg had QTc >500 ms. Presented by: Dong-Wan Kim ASCO 2014
14 Ceritinib Trials in Progress Ongoing Phase III trials Ceritinib (LDK378) versus chemotherapy in patients who have received prior chemotherapy and crizotinib (NCT ) Ceritinib (LDK378) versus chemotherapy in patients who are both chemotherapy-naïve and crizotinibnaïve (NCT ) Two phase II trials have completed enrolment Ceritinib (LDK378) in adult patients previously treated with chemotherapy and crizotinib (NCT ) Ceritinib (LDK378) in crizotinib-naïve adult patients (NCT )
15 Crystal structure of AF802 in complex with ALK AF802 Sakamoto H,, Cancer Cell 2011
16 Alectinib: overview of clinical development Study ID Phase Study design Location Data availability AF001JP Phase I / II 2L crizotinib-naïve (single-arm) Japan Published 1,2 AF002JG / NP28761 Phase I / II 2L crizotinib-failure (single-arm) USA Published 3,4 NP28673 Phase I / II 2L crizotinib-naïve (single-arm) Global Study ongoing JO28928 (J-ALEX) Phase III 1L / 2L crizotinib-naïve H2H vs crizotinib Japan Study ongoing BO28984 (ALEX) Phase III 1L H2H vs crizotinib Global Study ongoing 1. Seto, et al. Lancet Oncol 2013; 2. Inoue, et al. WCLC 2013; 3. Ou, et al. ESMO 2013; 4. Gadgeel, et al. WCLC 2013
17 Change from baseline (%) AF-001JP: alectinib in ALK inhibitor-naïve patients with ALK+ disease (ITT population; by IRC) 0 Percentage change in tumour size from baseline CR PR SD NE * ORR = 93.5% n=46 * * *Lymph nodes are identified as target lesion for RECIST evaluation CR = complete response; NE = not evaluated; PR = partial response; SD = stable disease 31 Jan 2014 cut-off Alectinib is not approved in Malaysia for the treatment of patients with ALK+ NSCLC 1. Seto, et al. Lancet Oncol 2013; 2. Inoue, et al. WCLC 2013 Tamura, et al. CMSTO 2014
18 Best change from baseline (%) AF-002JG (phase 1/2 alectinib trial): response in patients previously treated with crizotinib mg 460mg 600mg 760mg 900mg ORR = 55% Alectinib is not approved in Malaysia for the treatment of patients with ALK+ NSCLC Gadgeel, et al. Lancet Oncol 2014
19 PFS probability AF-001JP: PFS with alectinib (ITT population; by IRC) Median PFS: 27.7 months (95% CI: 26.9 NR) No. at risk Time (months) Median treatment duration was 23 months (range 1 33) NR = not reached 31 Jan 2014 cut-off Tamura, et al. CMSTO 2014
20 Phase III studies of 1L alectinib vs ALEX (BO28984) 1,2 Stage IIIB/IV NSCLC ALK+ disease according to IHC test* Treatment-naïve ECOG PS 0 2 J-ALEX 3 (n=286) crizotinib R 1:1 Alectinib 600mg BID Crizotinib 250mg BID Primary endpoint PFS (investigator assessed) Innovative features Regularly scheduled brain MRI to assess time to CNS progression QoL measured post-progression Stage IIIB/IV NSCLC ALK+ disease according to IHC, FISH or RT-PCR Treatment-naïve or received 1L chemo R 1:1 Alectinib 300mg BID Primary endpoint PFS (independent review) ECOG PS 0 2 (n=200) Crizotinib 250mg BID *IHC test is being developed by Ventana as a CDx to alectinib. Sufficient tumour tissue is required to test for ALK+ disease via IHC and FISH 1. NCT Peters, et al. ESMO 2014; 3. JapicCTI
21
22 NCT ASCEND-1 Efficacy of Ceritinib in Patients with Brain Metastases Of 246 ALK+ NSCLC patients enrolled in the ASCEND-1 trial and treated with ceritinib 750 mg/day, 124 had brain metastases at study entry, as per investigator assessment. Among the 124 patients with brain metastases at study entry, 26 were ALK inhibitor naïve while 98 had previously been treated with an ALK inhibitor Most patients had adenocarcinoma histology, were aged <65 years and had good performance status $ Caucasian and Asian represented the predominant races and accounted for 98% of the patient cohort $ Eastern Cooperative Oncology Group Performance Status 1; *Remaining patients either had CT scans or scans that were not available. ALK, anaplastic lymphoma kinase gene; CT, computerised tomography; MRI, magnetic resonance imaging; NSCLC, non-small cell lung cancer Presented by: A. Shaw ESMO 2014
23 NCT ASCEND-1 Overall Intracranial Response Rate for Patients with Measurable Brain Metastases at Baseline Best Overall Response n (%) ALK inhibitor treated N=10 ALK inhibitor naïve N=4 All patients N=14 Complete response Partial response Stable disease Progressive disease Unknown OIRR [95% CI] 4 (40.0) [12.2, 73.8] CI, confidence interval; OIRR, overall intracranial response rate 3 (75.0) [19.4, 99.4] 7 (50.0) [23.0, 77.0] Presented by: Dong-Wan Kim ASCO 2014
24 Probability (%) Intracranial PFS* with Ceritinib in Patients with ALK+ NSCLC with Baseline Brain Metastases Evaluable by MRI/CT NSCLC with prior ALKi (N = 75) NSCLC ALKi naïve (N = 19) Median: non-estimable (95% CI 7.4, non-estimable) Intracranial* PFS rate at 12 months: 54.9% (95% CI 21.8, 79.0) Median: 6.0 months (95% CI 4.2, 9.4) Intracranial* PFS rate at 12 months: 24.5% (95% CI 13.6, 37.2) Number of patients still at risk Time (Months) Time (Months) NSCLC with prior ALKi NSCLC ALKi naïve *Intracranial PFS calculated as time to progression in brain + deaths due to any cause. Analyses include patients evaluated by MRI (n=74) and CT (n=20) ALK, anaplastic lymphoma kinase; CI, confidence interval; NE, not estimable; NSCLC, non-small cell lung cancer; PFS, progression-free survival 21 Mehra et al Miami SNO 14 Nov. 2014
25 Change from baseline (%) AF-002JG: alectinib activity against brain metastases Patients with measurable brain metastases at baseline (n=9) 460mg 600mg 760mg 900mg Best intracranial response, % OIRR 52 CR 29 PR 24 SD 38 PD Patients with brain metastases at baseline (n=21) 0.8 OIRR = overall intracranial response rate Alectinib is not approved in Malaysia for the treatment of patients with ALK+ NSCLC Gadgeel, et al. Lancet Oncol 2014
26 Concentration of alectinib in CSF (nmol/l) Plasma/CSF levels of alectinib may explain clinical activity seen against 15 CNS metastases r 2 = Extrapolated C trough in CSF = 2.69nmol/L Unbound systemic C trough = 3.12nmol/L In-vitro IC 50 for ALK inhibition in cell-free assays = 1.9nmol/L (n=5) Unbound alectinib in plasma (nmol/l) Alectinib is not approved in Malaysia for the treatment of patients with ALK+ NSCLC Gadgeel, et al. Lancet Oncol 2014
27 CNS penetration and the P-gp transporter crizotinib Lipid soluble Lipid-soluble solutes that can freely diffuse through the capillary endothelial membrane may passively cross the BBB BBB is reinforced by a high concentration of P-gp, a drug-efflux-transporter protein BBB = blood-brain barrier; P-gp = protein P-glycoprotein Misra, et al. J Pharm Pharm Sci 2003
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29 Crizotinib Ceritinib Alectinib May 2012 Nov 2012 Oct 2014
30 Treat with ceritinib Modeling the Evolution of Resistance WT G1269A I1322M 1151 T-ins G1202R Culture in absence of drug Culture with crizotinib I1322M G1269A I1322M WT G1269A I1322M 1151 T-ins G1202R Ceritinib is not approved in the EU Culture in absence of drug Culture with ceritinib Ryohei Katayama and Tahsin Khan. Unpublished data G1202R
31 About Two-Thirds of Resistant Tumors do not Harbor ALK Resistance Mutations Unknown ALK amp ALK+ ALK mut Bypass tracks No ALK amp or mut EGFR CKIT SRC IGF1R
32 Heterogeneidad de los mecanismos de resistencia Friboulet, et al. Cancer Discov 2014
33 EGFR and CKIT May Mediate Crizotinib Resistance Pre-crizotinib Resistant (BAC) Resistant (solid) IHC (KIT) IHC (SCF) pegfr Ki67 Katayama, et al. Sci Transl Med 2012
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35 Current and Emerging Combinations Mechanism EGFR activation Strategy ALK + EGFR inhibitors MET amplification ALK + C-MET inhibitors Multiple mechanisms (or unknown) ALK + hsp90 inhibitors ALK + chemotherapy ALK + anti-angiogenesis ALK + immunotherapy ALK + CDK4/6 inhibitor
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37 CRIZOTINIB QUIMIOTERAPIA QUIMIOTERAPIA CRIZOTINIB CERITINIB ALECTINIB CERITINIB/ALECTINIB NUEVOS AGENTES QUIMIOTERAPIA
38 Inmunoterapia? D Incecco et al, B J Cancer 2015 *Up-regulation of PD-L1 by EGFR Activation Mediates the Immune Escape in EGFR-driven NSCLC: Implication for Optional Immune Targeted Therapy for NSCLC Patients with EGFR Mutation. Chen et al. J Thorac Oncol 2015
39 Next generation ALK inhibitors ALK TKI Ceritinib (LDK378) Alectinib (CH ) Sponsor ROS1 Activity Status Novartis Yes FDA approved ( ) Roche No Investigational (Breakthrough Therapy Designation) Approved in Japan Ongoing Studies Reference Phase 3 Shaw, et al. NEJM 2014; Kim, et al. ASCO 2014 Phase 3 Seto, et al. Lancet Onc 2013; Gadgeel, et al. Lancet Onc 2014 AP26113 Ariad Yes Investigational Phase 2 Gettinger, et al. ASCO 2014 X-396 Xcovery Yes Investigational Phase 1 Horn, et al. ASCO 2014 TSR-011 Tesaro Unk Investigational Phase 1/2 Weiss, et al. WCLC 2013 NMS-E628 Ignyta Yes Investigational Phase 1/2a De Braud, et al. ASCO 2014 CEP Teva Unk Investigational Phase 1 NCT PF Pfizer Yes Investigational Phase 1/2 Zou, et al. EORTC-AACR- NCI 2013 Ceritinib and alectinib are not approved in the EU All other agents on this slide are: experimental use, not authorised
40 Cáncer de Pulmón ALK + una entidad clínica diferente Crizotinib altamente eficaz Progresión 11 m/ SNC Nuevos inhibidores de ALK Ceritinib Alectinib Nuevas Opciones Nuevas secuencias Kris MG, JAMA 2014
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