MELANOMA NUOVI FARMACI

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1 MELANOMA NUOVI FARMACI Mario Mandalà Unità Operativa Oncologia Medica Dipartimento Oncologia-Ematologia Ospedali Riuniti Bergamo

2 Studi di fase II nel melanoma avanzato negli ultimi 24 anni Korn JCO 2008

3 MIA AGENDA BRAF/MEK INIBITORI ANTICORPI IMMUNOMODULANTI CKIT

4 Courtesy Daniela Massi

5 . Romano E. Lancet Oncol 2011

6 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

7 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

8 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)

9 RISPOSTE ALLA TERAPIA Mtr: 2.7; 5% Mtr: 1.45; 48%

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12 Progression-free survival (%) Progression-free survival (February 01, 2012 cut-off) censored at crossover No. at risk Dacarbazine Vemurafenib Time (months) Dacarbazine (n=338) Vemurafenib (n=337) Hazard ratio 0.38 (95% CI: ) Log-rank p<0.001 (post-hoc) Chapman P. et al. abs 8502 ASCO Ann. Meeting Chicago 2012

13 Summary of overall survival data ASCO 2011 ASCO 2012 (post-hoc) DTIC Vemurafenib DTIC a Vemurafenib Median follow-up, months Median OS, months Not reliably estimated month survival, % month survival, % Hazard ratio, OS % reduction in risk of death a Censored at crossover Chapman P. et al. abs 8502 ASCO Ann. Meeting Chicago 2012

14 Overall survival (%) Vemurafenib phase I overall survival: Updated KM estimates (Aug. 2011) year 2 years 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

15 Dabrafenib: Maximum tumor percent change from baseline investigator-assessed Maximum percent change in baseline target lesions

16 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< Dabrafenib: median PFS 5.1 mos DTIC: median PFS 2.7 mos Number at risk Time from Randomization (Months) 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.)

17 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 <1 - Rash Fatigue <1 Photosensitivity LFTs 22 8 <1 5* 1* -* Cutaneous SCC <1 <1 - Keratoacanthoma Skin papilloma 21 < Nausea Neutropenia <1 - < Uveitis** 3 < 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.

18 MEK INIBITORI AZD 6244 Studio fase II randomizzato vs Temozolamide No Differenza in PFS, OS, No Beneficio in BRAF mutati Kirkwood CCR 2011, Nov

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21 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

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23 BRAF vs Combo Drug(s) CR+PR % Median PFS First author Ref Vemurafenib (III) Chapman (NEJM) Dabrafenib (III) Hauschild (Lancet) Trametinib (III) Flaherty (NEJM) Combos Vemu + GDC-0973 Fase 1b > 90%? Gonzales ESMO 2012 Dabrafenib+ Trametinib Part B Dabrafenib+ Trametinib Part C (1) Weber ASCO Long ESMO 2012 Dabrafenib+ Trametinib Part C (2) Long ESMO 2012

24 IPILIMUMAB

25 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

26 IPILIMUMAB PATTERN DI RISPOSTA -IrRC EFFETTO SULLA SOPRAVVIVENZA TOSSICITA

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28 Proportion alive Kaplan-Meier Analysis of Survival: MDX lpi + Gp100 lpi Alone (A) (B) Gp100 Alone (C) Comparison HR p-value Arms A vs. C Arms B vs. C 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

29 Study CA : 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:

30 DATI DI EFFICACIA

31 Time to onset of iraes Median time to onset, weeks (n, 95% CI) Type Grade 2-5 Grade 3-5 Skin 3.6 (61, ) GI 6.6 (76, ) Liver 6.7 (23, ) Endocrine 9.2 (16, ) 4.4 (9, ) 6.9 (40, ) 6.7 (23, ) 10.1 (8, ) Version date: Lebbé, C et al. Perspectives in Melanoma XII 2008; Abstract O-015. Review Date: X Document Owner: Patrick Garcia IPI

32 Proportion not resolved Proportion not resolved Time to Resolution of Grade 2 4 iraes GI Median: 2.3 weeks Patients at risk Weeks Tx 10mg/kg Endocrine Median: 20.1 weeks Weeks Lebbé, C et al. Perspectives in Melanoma XII 2008; Abstract O-015. Monotherapy 10mg/kg treated patients 1.0 Censored 0.9 Liver Median: 4.0 weeks Weeks Skin Median: 6.1 weeks Version date: Review Date: X Document Owner: Patrick Garcia IPI

33 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

34 PD-1 RO 28% Minore tox rispetto a Ipi Marcatore predittivo PD-L1

35 KIT COME TARGET

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37 KIT AS A THERAPEUTIC TARGET IN MELANOMA JAMA 2011 Carvajal 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

38 PET-CT scan before Imatinib treatment PET-CT scan after Imatinib treatment

39 COSA FARE? PRIMA SCELTA INVIARE I PAZIENTI IN CENTRI DI RIFERIMENTO PER VALUTAZIONE IN STUDI CLINICI

40 PAZIENTI NAIVE PRIMA LINEA BRAF MUTATI V600 PRIMA LINEA VEMURAFENIB SECONDA LINEA IPILIMUMAB 3 mg/kg w 1, 4, 7, 10 TERZA LINEA CHEMIOTERAPIA

41 PAZIENTI NAIVE PRIMA LINEA BRAF NON MUTATI PRIMA LINEA CHEMIOTERAPIA SECONDA LINEA IPILIMUMAB 3 mg/kg w 1, 4, 7, 10 TERZA LINEA?

42 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

43 CONCLUSIONI GIUSTO TARGET GIUSTO FARMACO GIUSTO PAZIENTE GIUSTO CENTRO

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