MELANOMA NUOVI FARMACI Mario Mandalà Unità Operativa Oncologia Medica Dipartimento Oncologia-Ematologia Ospedali Riuniti Bergamo
Studi di fase II nel melanoma avanzato negli ultimi 24 anni Korn JCO 2008
MIA AGENDA BRAF/MEK INIBITORI ANTICORPI IMMUNOMODULANTI CKIT
Courtesy Daniela Massi
. Romano E. Lancet Oncol 2011
BRAF-MEK An important mediator of cellular proliferation Fattori di crescita Segnale normale Segnale oncogenico Membrane RTK RAF BRAF V600E Y-P Y-P Ras GTP MEK MEK BRAF INHIBITORS Altri effettori P P MEK INHIBITORS BRAF mutations are exclusive to tumors > 50% malignant melanomas ~10% of CRC ~8% all solid tumors P ERK Traslocazione nucleare Espressione genica P ERK Abnormal Cellular Proliferation
The ERK/MAPK pathway and the pharmacologic agents in clinical development targeting RAF kinases or MEK MEK INIBITORE: INIBITORE ALLOSTERICO E INIBISCE UNA PROTEINA NORMALE RAF INIBITORE: INIBITORE COMPETITIVO ATP E INIBISCE UNA PROTEINA MUTATA Mek162 Ribas, A. & Flaherty, K. T. (2011) BRAF targeted therapy changes the treatment paradigm in melanoma Nat. Rev. Clin. Oncol. 2011
BRIM-3 Chapman et al. NEJM 2011 Screening BRAF V600E mutation Randomization N=675 Vemurafenib 960 mg po bid (N=337) Stratification Stage ECOG PS (0 vs 1) LDH level ( vs nl) Geographic region Dacarbazine 1000 mg/m 2 iv q3w (N=338)
RISPOSTE ALLA TERAPIA Mtr: 2.7; 5% Mtr: 1.45; 48%
Progression-free survival (%) Progression-free survival (February 01, 2012 cut-off) censored at crossover No. at risk Dacarbazine Vemurafenib 100 90 80 70 60 50 40 30 20 10 0 0 6 12 18 24 Time (months) 338 337 Dacarbazine (n=338) 1.6 6.9 100 269 Vemurafenib (n=337) 63 186 37 113 22 77 Hazard ratio 0.38 (95% CI: 0.32 0.46) Log-rank p<0.001 (post-hoc) 14 49 3 16 0 3 0 0 Chapman P. et al. abs 8502 ASCO Ann. Meeting Chicago 2012
Summary of overall survival data ASCO 2011 ASCO 2012 (post-hoc) DTIC Vemurafenib DTIC a Vemurafenib Median follow-up, months 2.3 3.8 9.5 12.5 Median OS, months Not reliably estimated 9.7 13.6 6-month survival, % 64 84 66 84 12-month survival, % 44 56 Hazard ratio, OS 0.37 0.70 % reduction in risk of death 63 30 a Censored at crossover Chapman P. et al. abs 8502 ASCO Ann. Meeting Chicago 2012
Overall survival (%) Vemurafenib phase I overall survival: Updated KM estimates (Aug. 2011) 100 90 80 70 60 50 40 30 20 10 0 1 year 2 years 0 3 6 9 12 15 18 21 24 27 30 33 36 Time since first dose (months) V600E dose escalation (n=16) Extension (n=32) WT or sub-therapeutic exposure (n=33) Median OS (month) Dose escalation 25.2 Extension 13.8 Extension cohort landmark Estimated survival: 1 year = 50%, 2 years = 38% WT or sub-therapeutic. 4.18
Dabrafenib: Maximum tumor percent change from baseline investigator-assessed Maximum percent change in baseline target lesions
Proportion Alive Without Progression Primary endpoint: PFS Investigator-assessed (cut-off: 19 December 2011) 1.0 Hazard ratio 0.30 (95% CI: 0.18, 0.51); p<0.0001 0.9 0.8 0.7 Dabrafenib: median PFS 5.1 mos 0.6 0.5 0.4 0.3 0.2 DTIC: median PFS 2.7 mos 0.1 0.0 Number at risk 0 1 2 3 4 5 6 7 8 9 Time from Randomization (Months) 187 184 173 113 100 41 31 5 3 0 63 53 31 14 11 6 4 2 0 0 On randomized study treatment at cut-off: dabrafenib 57%, DTIC 27% Median follow-up time: 4.9 months (dabrafenib 5.1 mos, DTIC 4.8 mos.)
Selected adverse events (% of patients) (March 31, 2011 cutoff) Vemurafenib, n=336 Dacarbazine, n=287 Adverse events All Grade 3 Grade 4 All Grade 3 Grade 4 Arthralgia 53 4-3 <1 - Rash 37 8-2 - - Fatigue 38 2-33 2 <1 Photosensitivity 33 3-4 - - LFTs 22 8 <1 5* 1* -* Cutaneous SCC 17 16 - <1 <1 - Keratoacanthoma 9 9 - - - - Skin papilloma 21 <1 - - - - Nausea 35 2-43 2 - Neutropenia <1 - <1 12 6 3 Uveitis** 3 <1 - - - - Discontinuations due to AE: 7% vemurafenib; 4% dacarbazine *Data from OS IA Dec 30, 2010, not updated for March 1, 2011 cutoff. **Data obtained from a manual count rather than a statistical output.
MEK INIBITORI AZD 6244 Studio fase II randomizzato vs Temozolamide No Differenza in PFS, OS, No Beneficio in BRAF mutati Kirkwood CCR 2011, Nov
BRAF E MEK INIBITORI A CONFRONTO BRAF OR PFS? MEK Attività su BRAF Mutati e Non Mutati Attività su Melanoma uveale Non transattivazione RAS Mutati Non secondi tumori
BRAF vs Combo Drug(s) CR+PR % Median PFS First author Ref Vemurafenib (III) 53 6.9 Chapman (NEJM) Dabrafenib (III) 50 6.7 Hauschild (Lancet) Trametinib (III) 22 4.8 Flaherty (NEJM) Combos Vemu + GDC-0973 Fase 1b > 90%? Gonzales ESMO 2012 Dabrafenib+ Trametinib Part B Dabrafenib+ Trametinib Part C (1) 57 10.8 Weber ASCO 2012 50 9.2 Long ESMO 2012 Dabrafenib+ Trametinib Part C (2) 78 9.4 Long ESMO 2012
IPILIMUMAB
Ipilimumab: Mechanism of Action T-cell activation T-cell inhibition T-cell potentiation T cell CTLA4 T cell T cell APC TCR MHC CD28 B7 APC TCR MHC CD28 CTLA4 B7 APC TCR MHC B7 CTLA4 IPILIMUMAB blocks CTLA-4 O Day S et al. ASCO 2010 plenary session (#4) IPI-004-2010 25 25
IPILIMUMAB PATTERN DI RISPOSTA -IrRC EFFETTO SULLA SOPRAVVIVENZA TOSSICITA
Proportion alive Kaplan-Meier Analysis of Survival: MDX010-20 1.0 0.9 0.8 0.7 0.6 0.5 0.4 lpi + Gp100 lpi Alone (A) (B) Gp100 Alone (C) Comparison HR p-value Arms A vs. C 0.68 0.0004 Arms B vs. C 0.66 0.0026 0.3 0.2 0.1 0.0 1 2 3 4 Years Survival Rate Ipi + gp100 N=403 Ipi + pbo N=137 gp100 + pbo N=136 1 year 44% 46% 25% 2 year 22% 24% 14% Hodi S et al. NEJM 2010;363(8):711-23
Study CA184-024: Randomized, Double-blind Phase III Trial of ipilimumab with dacarbazine vs. dacarbazine Screening Induction Maintenance F/U Unresectabl e Stage III and IV melanoma n=500 Ipilimumab 10 mg/kg q3w 4 + DTIC (850mg/m 2 ) q3w for 22 w Placebo IV q3w 4 + DTIC (850mg/m 2 ) q3w for 22 w 36.8%? Ipilimumab 10 mg/kg q12w Placebo IV q12w 17% Until 416 events Week 0 Week 12 Week 24 Primary endpoint: Overall survival Secondary objectives: PFS, DCR, BORR, survival rates, safety profile, time to response, duration of response, health-related QoL, Population PK PFS: progression-free survival; DCR: disease control rate (CR+PR+SD); BORR: best objective response rate (CR+PR); QoL: quality of life Robert C et al. NEJM 2011;364:2517-2526
DATI DI EFFICACIA 11.2 9.1 19.3 8.1
Time to onset of iraes Median time to onset, weeks (n, 95% CI) Type Grade 2-5 Grade 3-5 Skin 3.6 (61, 3.1 4.1) GI 6.6 (76, 5.1 8.0) Liver 6.7 (23, 6.1 9.3) Endocrine 9.2 (16, 6.7 11.1) 4.4 (9, 3.1 4.4) 6.9 (40, 5.7 8.9) 6.7 (23, 6.1 9.7) 10.1 (8, 7.0 11.4) Version date: 20-10-09 Lebbé, C et al. Perspectives in Melanoma XII 2008; Abstract O-015. Review Date: X-10-09 Document Owner: Patrick Garcia IPI-67-2009 31
Proportion not resolved Proportion not resolved Time to Resolution of Grade 2 4 iraes 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 GI Median: 2.3 weeks 0 0 4 8 12 16 20 24 28 32 36 40 44 48 52 Patients at risk Weeks Tx 10mg/kg 76 28 16 8 5 5 4 4 2 2 2 2 1 1 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 Endocrine 0 4 8 12 16 20 24 28 Median: 20.1 weeks Weeks 32 36 40 44 48 52 Lebbé, C et al. Perspectives in Melanoma XII 2008; Abstract O-015. Monotherapy 10mg/kg treated patients 1.0 Censored 0.9 Liver 0.8 0.7 0.6 Median: 4.0 weeks 0.5 0.4 0.3 0.2 0.1 0 0 4 8 12 16 20 24 28 32 36 40 44 48 52 Weeks 1.0 22 11 7 5 1 1 0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 Skin Median: 6.1 weeks 0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 Version date: 20-10-09 Review Date: X-10-09 Document Owner: Patrick Garcia IPI-67-2009 32
Immunoterapia con Ipi : basso tasso di RO (10 15%), ma risposte di lunga durata Inibitori BRAF alto tasso RO (50 60%), ma resistenza mediamente entro 7 mesi
PD-1 RO 28% Minore tox rispetto a Ipi Marcatore predittivo PD-L1
KIT COME TARGET
KIT AS A THERAPEUTIC TARGET IN MELANOMA JAMA 2011 Carvajal 2011 328 PTS: 295 Studiati 10-15% dei melanomi 28 trattati (8%) Mutazione o amplificazione Acrali (23%)-mucosi 25 (7%) valutati per (25%)-CSD (9%) risposta 51 (15%): Amplificati e mutati 42 (13%) mutati 4 (1%) pazienti con Risposta sostenuta: solo mutati
PET-CT scan before Imatinib treatment PET-CT scan after Imatinib treatment
COSA FARE? PRIMA SCELTA INVIARE I PAZIENTI IN CENTRI DI RIFERIMENTO PER VALUTAZIONE IN STUDI CLINICI
PAZIENTI NAIVE PRIMA LINEA BRAF MUTATI V600 PRIMA LINEA VEMURAFENIB SECONDA LINEA IPILIMUMAB 3 mg/kg w 1, 4, 7, 10 TERZA LINEA CHEMIOTERAPIA
PAZIENTI NAIVE PRIMA LINEA BRAF NON MUTATI PRIMA LINEA CHEMIOTERAPIA SECONDA LINEA IPILIMUMAB 3 mg/kg w 1, 4, 7, 10 TERZA LINEA?
II-III LINEA BRAF MUTATI COSA BRAF INIBITORE se Malattia rapidamente progrediente Paziente sintomatico Malattia viscerale estesa Se vuoi ottenere una RO quanto prima Vantaggio: risposta rapida ma forse TTP circa 8 mesi FARE? Ipilimumab se Hai tempo di aspettare la risposta Paziente paucisintomatico Volume di malattia non elevato Vantaggio: Possibilità di controllo a lungo temine
CONCLUSIONI GIUSTO TARGET GIUSTO FARMACO GIUSTO PAZIENTE GIUSTO CENTRO