Teresa Gamucci U.O.C. Oncologia ASL Frosinone

Transcript

1 V Sessione Chemioterapia antiblastica: ritorno al futuro I nuovi chemioterapici: la piattaforma nab Teresa Gamucci U.O.C. Oncologia ASL Frosinone

2 Background ü L efficacia di un farmaco dipende dalla sua concentrazione nella sede d azione; tuttavia la rapida clearance renale e la distribuzione aspecifica dei farmaci ne compromettono la massima azione terapeutica ü La tecnologia è stata utilizzata per superare questi ostacoli: peghilazione: coniugazione del farmaco al peg-etiline-glicole (PEG) nanocarriers: incorporazione del farmaco in nanoparticelle carriers come liposomi, polimeri, dendrimeri, etc Larsen et al. Molecular and Cellular Therapies 2016

3 Nanocarriers Acqua Glucosio AnFcorpo Virus BaQerio Cellula tumorale Punto Pallina da tennis Nanometri Proteine NanodisposiFvi: Nanopori Dendrimeri Nanotubi PunF quanfci Nanogusci NanoparFcelle Globuli rossi Capello umano = nm Albumina = 5 nm Emoglobina = 6,5 nm Tecnologia nab ~130 nm GR = 8000 nm Larsen et al. Molecular and Cellular Therapies 2016

4 La piattaforma nab La piattaforma nab sfrutta le proprietà dell albumina ü L albumina è un carrier naturale del corpo umano dotata di alta solubilità, numerosi siti di legame, affinità recettoriale e una lunga emivita circolatoria ü Queste proprietà hanno promosso l albumina come un ottimo veicolo di trasporto nella somministrazione di farmaci ü Le cellule tumorali hanno un maggiore uptake metabolico per l albumina Larsen et al. Molecular and Cellular Therapies 2016

5 La piattaforma nab Larsen et al. Molecular and Cellular Therapies 2016

6 Nab-paclitaxel La tecnologia nab utilizza l albumina per veicolare il paclitaxel sottoforma di nanoparticelle delle dimensioni di 130 nm nab-paclitaxel Particle Albumin-Bound Paclitaxel Albumin Paclitaxel rispetto al paclitaxel ü cinetica lineare che garantisce un attività anti-tumurale dose dipendente ü maggiore biodisponilità (legame albumina/gp60/calveolina-1) ü selettività tumorale (legame albumina/proteina SPARC) ü migliore tollerabilità, ridotta ipersensibilità e tossicità farmaco correlate Larsen et al. Molecular and Cellular Therapies 2016

7 Nab-paclitaxel: meccanismo d azione Larsen et al. Molecular and Cellular Therapies 2016

8 Nab-paclitaxel: indicazioni terapeutiche ü Nab-paclitaxel in monoterapia è indicato nel trattamento del tumore metastatico della mammella in pazienti che hanno fallito il trattamento di prima linea per la malattia metastatica e per i quali la terapia standard, contenente antraciclina, non è indicata ü Nab-paclitaxel in associazione con gemcitabina è indicato per il trattamento di prima linea di pazienti con adenocarcinoma metastatico del pancreas ü Nab-paclitaxel in associazione con carboplatino è indicato per il trattamento di prima linea del tumore del polmone non a piccole cellule, in pazienti non candidati a chirurgia potenzialmente curativa e/o radioterapia EMA

9 Nab-paclitaxel & BC

10 mbc Yamamoto Y et al. Oncotargets and Therapy 2011

11 Nab-paclitaxel nella malattia avanzata RR% PFS, m Neurotox,% Fase 3 nabp 260 mg vs sbp 175 mg 33 vs 19 *23 vs vs 49 Gradishar 2005 OS: 65 vs 55.7 m Gradishar 2012 Fase 2 nabp 100 mg vs nabp 150 mg vs nabp 300 mg vs D 100 mg 39 vs 49 vs 45 vs vs 13 vs 11 vs 8 58 vs 57 vs 74 vs 61 Gradishar 2009

12 SNAP trial FASE II, studio attivo, arruolamento concluso

13 SNAP trial

14 GeparSepto trial Untch M et al. Lancet Oncology 2016

15 Primary end-point: pcr (ypt0 ypn0) Untch M et al. Lancet Oncology 2016

16 pcr (ypt0 ypn0) subgroups Untch M et al. Lancet Oncology 2016

17 ETNA trial Target Accrual: 695 (Active, not recruiting) Gianni L et al. ASCO Annual Meeting 2016

18 Primary end-point: pcr Gianni L et al. ASCO Annual Meeting 2016

19 Oncotargets and Therapy 2017

20 Nab-paclitaxel & immunoterapia il razionale Adams S, SABCS 2015

21 neotrip-apdl1 Study

22 neotrip-apdl1 study: end-points

23 Nab-paclitaxel nella malattia triple negative metastatica Palumbo F et al. Ther Adv Med Oncol 2016

24 tnacity study Target Accrual: 790 (completed) Yardlei DA et al. ASCO 2014;

25 tnacity study: PFS (primary endpoint)

26 tnacity study: OS (secondary endpoint)

27 tnacity study: RR (secondary endpoint)

28 IMpassion-130 trial Phase III Randomized Trial of Atezolizumab with Nab-Paclitaxel for 1 st -line Metastatic Triple-Negative Breast Cancer (mtnbc) Target Accrual: 900 (Active, recruiting) Eligibility Locally advanced, measurable TNBC or mtnbc No prior systemic therapy for advanced TNBC ECOG PS 0-1 No history of autoimmune disease R Atezolizumab 840 mg q2wk + nab-paclitaxel (100 mg/m 2, 3 wks on/1 off) x 6 Placebo q2wk + nab-paclitaxel (100 mg/m 2, 3 wks on/1 off) x 6 Stratification: - liver metastases - prior taxane - PD-L1 status Primary Endpoints: PFS, OS Emens LA et al. Proc ASCO 2016;Abstract TPS1104

29 Nab-paclitaxel nella paziente anziana Palumbo F et al. Ther Adv Med Oncol 2016

30 Studio EFFECT Age 65 Locally recurrent or metastatic HER2-neg breast cancer or HER2- positive but considered not eligible for anti-her2 therapy No prior CT for advanced breast cancer Measurable or evaluable disease Target Accrual: 156 (Active, not recruiting) N=156 R nab- paclitaxel 125 mg/m2 day 1, 8, 15 q 28 nab- paclitaxel 100mg/m2 day 1, 8, 15 q 28 Stratification factors: - age vs 75 yrs - diabetes yes, no - G3-4 CIRS yes, no - IADL deficient yes, no unkll disease progression or toxicity

31 Studio EFFECT Primary endpoint Event-free survival (EFS) where an event is either disease progression or death or decline in functional status Secondary endpoints Objective response rate (ORR) Clinical benefit rate (CBR) Progression free survival (PFS) Overall survival (OS) Incidence of Adverse events (defined by CTCAE v4.0)

32 Nab-paclitaxel & PC

33 MPACT study

34 MPACT study 8.5 mos 6.7 mos Von Hoff DD, et al. N Engl J Med. 2013

35 MPACT study 5.5 mos 3.7 mos Von Hoff DD, et al. N Engl J Med. 2013

36 MPACT study: update of survival Goldstein D, et al. J Natl Cancer Inst. 2015

37 MPACT study: update of survival Goldstein D, et al. J Natl Cancer Inst. 2015

38 nabp+gem vs Folfirinox vs Gem FFX n = 80 nab- P + G n = 122 G Monotherapy n = 46 Braiteh FS, et al. ASCO 2016 Gastrointestinal Cancers Symposium [abstracts 429 and 433]

39 Time to Treatment Discontinuation 1.0 ProporFon of PaFents on Therapy Time, months nab-p + G (n = 122) Median TTD, mo Unadjusted P Value Comparison with nab-p + G HR (95% CI) Adjusted P Value 3.4 FFX (n = 80) ( ) 0.75 G (n = 46) ( ) < Braiteh FS, et al. ASCO 2016 Gastrointestinal Cancers Symposium [abstracts 429 and 433]

40 Database persistence 1.0 ProporFon of PaFents in Database Time, months nab-p + G (n = 122) Median DP, mo Unadjusted P Value Comparison with nab-p + G HR (95% CI) Adjusted P Value 8.6 FFX (n = 80) ( ) 0.75 G (n = 46) ( ) 0.12 a DP is defined as the time between first dose to end of patient data (time point at which patient no longer appears in EMR database) and is a proxy for survival. Braiteh FS, et al. ASCO 2016 Gastrointestinal Cancers Symposium Braiteh [abstracts FS, et al. 429 ASCO and 433] Gastrointestinal Cancers Symposium [abstracts 429 and 433]

41 Incidence of Adverse Events (in > 5% of patients), % nab-p + G n = 122 FFX n = 80 G n = 46 Hematologic AEs, all-grade a (grade 3/4 b ) Anemia Neutropenia Thrombocytopenia 70 (13) 50 (28) 43 (11) 66 (6) 54 (30) 45 (14) 83 (18) 30 (29) 57 (15) Nonhematologic AEs, all-grade c Nausea and vomiting Nausea alone Dehydration Fatigue Diarrhea Doses per Patient per 100 Days, n nab-p + G n = 122 FFX n = 80 G n = 46 P Value a P Value b Antiemetic < 0.01 ESA < 0.01 < 0.01 G-CSF < 0.01 < 0.01 Steroids < 0.01 < 0.01 Braiteh FS, et al. ASCO 2016 Gastrointestinal Cancers Symposium [abstracts 429 and 433]

42 nab-p & PC: ongoing trials Trial Patient Population Description APACT (ABI-007-PANC-003) (N = 800) NCT ABI-007-PANC-001 (N = 83) NCT ABI-007-ST-001 (N = 138) NCT LAPACT (ABI-007-PANC-007) (N = 110) NCT Patients with histologically confirmed resected ductal pancreatic adenocarcinoma with macroscopic complete resection (R0 and R1); ECOG PS 0-1 Treatment-naive patients with metastatic pancreatic adenocarcinoma; KPS 70 Patients with advanced pancreatic adenocarcinoma; ECOG PS 0-1 Treatment-naïve patients with nonmetastasic, unresectable pancreatic adenocarcinoma; ECOG PS 0-1 A phase III study of nab-paclitaxel plus gemcitabine vs gemcitabine alone as adjuvant therapy in patients with surgically resected pancreatic cancer Phase II study of nab-paclitaxel plus gemcitabine in Chinese patients with metastatic pancreatic adenocarcinoma Study of nivolumab with nabpaclitaxel plus or minus gemcitabine in pancreatic cancer, nab-paclitaxel / carboplatin in stage iiib/iv non-small cell lung cancer or nab-paclitaxel in recurrent metastatic breast cancer An international, open-label, multicenter, phase II study of nab-paclitaxel plus gemcitabine in locally advanced pancreatic cancer Status (Anticipated Completion Date) Enrolling (10/2020) Completed Enrolling (7/2017) Enrolling (6/2018) Region North America, Europe, Asia/ Pacific China US North America, Europe ClinicalTrials.gov

43 nab-p & PC: ongoing trials Studio attivo, arruolamento in corso Sohal D et al. ASCO Annual Meeting 2016

44 Nab-paclitaxel & NSCLC

45

46 CA031 trial: results Socinski MA et al. J Clin Oncol. 2012

47 CA031 trial: results v Nonostante il vantaggio significakvo in termini di ORR nel braccio di tramamento con nab- P, i dak relakvi a PFS e OS non hanno dimostrato nessuna differenza stakskcamente significakva tra nab- P + carboplakno vs carbplakno + taxolo. Vantaggio nell anziano in OS Socinski MA, et al. Ann Oncol. 2013

48 CA031 trial: PFS, OS Socinski MA et al. J Clin Oncol. 2012

49 nab-p & NSCLC: ongoing trials Enrolling Trial Trial Description Endpoints ABI-007-NSCL-003 First-line squamous maintenance study of 4-6 cycles of nab-paclitaxel followed by either nab-paclitaxel or BSC (Ph III, 540 pts) Primary: PFS Secondary: OS, ORR, safety ABI-007-NSCL-005 paclitaxel + carboplatin in patients > 70 years of age First-line study of 2 schedules of nab- (Ph IV, 284 pts) Primary: Percentage of pts with either Gr 2 PN or Gr 3 myelosuppression Secondary: Safety, PFS, ORR, OS ABI-007-NSCL-006 Second-line randomized study of nabpaclitaxel single agent vs. nabpaclitaxel + CC486 (Ph II, 160 pts) Primary: PFS Secondary: DCR, ORR, OS, safety nab-paclitaxel + pembrolizumab Planned Phase I/II study of combination of pembrolizumab plus nab-paclitaxel in unresectable stage III or stage IV NSCLC (Ph I/II, 36 pts) Primary: safety and tolerability of combination Secondary: ORR nab-paclitaxel + carboplatin in patients with poor PS ClinicalTrials.gov

50 nab-p & NSCLC: ongoing trials Soliman H, Oncotargets and Therapy 2017

51 nab-p: sviluppi clinici futuri ü Impiego di nab-p: NSCLC metastatico, mbc triple negative e LABC, PC localmente avanzato e setting adiuvante ü Impiego di nab-paclitaxel nel trattamento di altri tumori solidi: melanoma, testa collo, ovaio, stomaco, colangiocarcinoma, tumori primitivi del peritoneo e tumori genitourinari ü Numerosi studi di combinazione nab-paclitaxel e checkpoint inhibitors sono attualmente ongoing

52 Nab-paclitaxel & immunoterapia: sviluppi clinici futuri Soliman H, Oncotargets and Therapy 2017

53 nab-paclitaxel e non solo Ø A Phase I/II Trial of ABI-008 (Nab-docetaxel) in Patients With Hormone-refractory Prostate Cancer Ø A Combined Phase 1 and Phase 2 Study of Albumin-bound Rapamycin Nanoparticles (Nab-rapamycin, ABI-009) in the Treatment of BCG Refractory or Recurrent Nonmuscle Invasive Transitional Cell Bladder Cancer Ø A Phase I of ABI-010 (Nab-17-AAG) and ABI-007 (Abraxane) Administered Weekly in Patients With Advanced Non-Hematologic Malignancies NAB ClinicalTrials.gov

54 Il mestiere dell uomo è pensare. L importante non è sapere ma cercare. Continuate a cercare fino alla fine. Umberto Veronesi t.gamucci@libero.it