3 rd Session MELANOMA. Michele La Greca Francesco Ferraù. Dipartimento III Livello Oncologia UOC Oncologia Medica Ospedale S.

Transcript

1 3 rd Session MELANOMA V EUROPEAN CONFERENCE ON SURVIVORS AND CHRONIC CANCER PATIENTS June 6 th 7 th 2014 Palazzo Vermexio - Siracusa, Italy Michele La Greca Francesco Ferraù! " # 8 " $%! &' "!! ( $) * +!,"! * $-! %$! #%. /$* &$! 0) %) - ),+ $,! " " $" - ) * (!. * & $&! Dipartimento III Livello Oncologia UOC Oncologia Medica Ospedale S.Vincenzo Taormina

2 MELANOMA CUTANEO E PROGNOSI MELANOMA SOTTILE (Breslow <1 mm.) DUE GRUPPI BRESLOW> 3 mm. LOCALIZZAZIONI LINFONODALI METS SINCRONE

3 Comparison of different schedules of systemic treatment (41 TRIALS) in disseminated melanoma RESPONSE RATE OVERALL SURVIVAL TK Eigentler et al., The Lancet Oncology 2003

4 First DTIC study 1971 Principali capisaldi terapeutici nel melanoma metastatico Studies on associations therapies to improve overall survival 1980s LA RIVOLUZIONE BIOLOGICA Interferon is approved by FDA 1995 Ipilimumab approved by FDA e EMA DTIC is approved by FDA for metastatic melanoma 1980s-1990s Fotemustine studies on brain mets 1998 Interleukin- 2 is approved by FDA 2011/ Dabrafenib Vemurafenib approved approved by FDA by FDA and EMA Burke PJ, et al. Cancer 1971;27: Mouawad R, et al. Crit Rev Oncol Hematol 2010;74: Khayat D, et al. Cancer Invest 1994;12: National Cancer Institute. Melanoma treatment (PDQ ): stage III melanoma. Available on US Food and Drug Administration. FDA news release: FDA approves new treatment for a type of late-stage skin cancer [press release]. Available on European Medicines Agency recommends approval of first-in-class treatment for metastatic or unresectable melanoma. Available on 4

5 SECONDA DECADE DEGLI ANNI 2000 LE DUE GRANDI NOVITA FARMACI INIBITORI DI CHECK-POINTS IMMUNITARI (Ipilimumab Nivolumab/Pembrolizumab anti CD137 etc) FARMACI AD ATTIVITA TARGETED GENETIC-DRIVEN (BRAFi MEKi)

6 Modulation of T-cell function T-cell activation occurs through the interaction with an APC Additional signals occur through interactions of costimulatory molecules T-cell functions are tightly regulated through various costimulatory and inhibitory molecules Modulation of T-cell activation by targeting these regulatory molecules is an area of active research

7 Frequently asked questions: theory that through blockade of the CTLA-4-mediated Ipilimumab, mechanism of action CTLA-4 Blocking mab, augments T- The mechanism of action of ipilimumab differs from those Cell Activation of traditional chemotherapy or small-molecule inhibitors, CTLA-4 were developed as anticancer therapies under the inhibitory signal, the activity of T-cells may be activated against tumor antigens and their activity harnessed for treatment of cancer. 3,13 A T-cell activation T-cell inhibition T-cell remains activ ated CTLA-4 Activation TCR CD28 Activation TCR CD28 CTLA-4 Inhibition Activation TCR CD28 CTLA-4 Activation MHC APC B7 MHC APC B7 MHC B7 APC Ipilimumab blocks CTLA-4 B TCR: MHC antigen CD28: B7 CTLA-4: B7 lpilimumab T-cell activation T-cell inhibition CTLA-4 blockade/ T-cell proliferation Figure 1 (A and B) Role of CTLA-4 in T-cell responses and the impact of CTLA-4 blockade with ipilimumab. Ipilimumab mechanism of action (A) and brake and pedal analogy (B) as used to explain the mechanism to patients and caregivers. Abbreviations: CTLA, cytotoxic T-lymphocyte antigen; APC, antigen-presenting cell; MHC, major histocompatibility complex; TCR, T-cell receptor. Ledezma B, Cancer Manag Res 2014

8 The target: BRAF kinase An important mediator of cellular proliferation RTK RAS ATP ATP BRAF V600E Raf MEK Vemurafenib Dabrafenib ERK Cellular proliferation Vemurafenib / Dabrafenib co-structure with the kinase domain of BRAF V600E (Bollag et al., Nature 2010)

9 Pr opor t i Al on i v e Ipilimumab Study 024: Overall Survival Ipilimumab + DTIC Placebo + DTIC Ye a r s Estimated Survival Rate 1 Year 2 Year 3Year 4 Year* Ipilimumab + DTIC n= Placebo + DTIC n= *M.Maio, ESMO Meeting 2012

10 Overall survival rates with ipilimumab at 10 mg/kg Survival rate, % (95% CI) Study 1-year 2-year 3-year 4-year 5-year * CA CA CA EAP 10 mg Lebbè C, ESMO2012

11 CAMBIAMENTI CULTURALI VALUTAZIONE DELLE RISPOSTE (ircr di Wolchok) CONTROLLO DI MALATTIA POST-TREATMENT SD DURATURE E SOPRAVVIVENZA UGUALE AI PAZ IN RISPOSTA OBIETTIVA GESTIONE DEGLI EVENTI AVVERSI A MEDIO- LUNGO TERMINE TERAPIE COMBINATORIE BEN TOLLERATE (antibraf+antimek; anti-ctla4+antipd1)

12 Ipilimumab 4846 Pts (ESMO ECCO 2013): ORR 7-15% plateau OS in 17-25% dopo 3 anni, prolungata fino a 10 aa. Schadendorf D et Al, abst # 241BA Vemurafenib (BRIM 3) ORR 53 % (RC 6%), m OS 13,6 mesi Dabrafenib (BREAK 3) ORR 50% (RC 3%), m OS 18,2 mesi

13 Pooled overall survival data from 1861 ipilimumab-treated patients in 12 clinical trials Proportion Alive Ipilimu mab CENSORED Median OS, months (95% CI): 11.4 ( ) 3-year OS rate, % (95% CI): 22 (20 24) Months year estimated survival rate of 22% observed in patients treated with ipilimumab A plateau in the survival curve begins at approximately 3 years, with some patients followed for up to 10 years Consistency of long-term survival data for ipilimumab in metastatic melanoma, regardless of doses, regimens and treatment line Schadendorf D, et al. Presented at ECC 2013: oral presentation 24LBA

14 Proportion Alive Pooled overall survival analysis including Expanded Access Program data: 4846 patients Median OS, months (95% CI): 9.5 ( ) year OS rate, % (95% CI): 21 (20 22) Ipilimumab CENSORED Months Schadendorf D, et al. Presented at ECC 2013: oral presentation 24LBA

15 immunologic agents induce long-lasting complete responses in a limited number of patients, to the point where the question of cure in these cases must be entertained. Paul Chapman ASCO Educational Book, 2014

16

17 Paziente vivente in RC, 19 mesi di terapia con vemurafenib

18 La persistenza della memoria, Salvador Dalì

19 OLTRE IPILIMUMAB: MoAb ANTI-PD-1 PEMBROLIZUMAB, 135 pts: RO (recist): 38% Hamid O, NEJM 2013 PEMBROLIZUMAB, 411 pts: RO (recist): 40% IPI naive RO (recist): 28% IPI previous mos not reached sopravv.1 anno: 71% AEs GIII-IV: 12% Ribas A, ASCO 2014

20 OLTRE IPILIMUMAB: MoAb ANTI-PD-1 NIVOLUMAB, 107 pts: RO (recist): 31%, durata mediana 22 mesi OS mediana: 17 mesi sopravv. 1 anno: 62% sopravv. 2 anni: 43% Sznol M, ASCO 2013 NIVOLUMAB, 107 pts: - RO (recist): 32%, durata mediana 23 mesi - 46% mantiene risposta oltre sei mesi - sopravv. 2 anni: 48% - sopravv. 3 anni: 41% - PFS e OS per PD-L1 pos. Hodi FS, ASCO 2014

21 OLTRE IPILIMUMAB: MoAb ANTI-PD-1 NIVOLUMAB + IPILIMUMAB, 53 Pts concurrent, 33 Pts sequential RO (Recist): 40% Clinical Activity (RO, irr): 65% quasi tutte risposte con regressione dell 80% AEs GIII-IV: 53% Wolchock JD, NEJM 2013

22 Melanoma Immunotherapy: Future Directions Targeted monoclonal antibody therapy Anti CTLA-4 therapy Dose, schedule, toxicity Novel antibodies: anti PD-1, anti-cd137, anti-cd40 Adoptive-cell therapy Combined use of CD4+ and CD8+ T cells Combination therapy with anti CTLA-4/anti PD-1 antibodies Stimulating transferred lymphocytes with new/better combinations of agents Combinatorial immunotherapy with targeted therapy, antiangiogenic agents, and chemotherapy

23 NUOVI SCENARI Per il Chirurgo: Elettrochemioterapia; Metastasectomia di melanoma oligometastatico (NCCN 2014). Per l Oncologo: trattamento neoadiuvante, adiuvante e delle sequele a lungo termine. Per lo Psicologo: trattamento dell ansia cronica.

24 CONCLUSIONI Il Paziente con melanoma avanzato inizia ad avere miglior qualità di vita e spravvivenza prolungata Risposte obiettive significative, miglior controllo del dolore, prolungamento della dormant phase L oncologo inizia a focalizzare l attenzione su problematiche croniche Format psico-assistenziale per Pazienti con particolare autocoscienza di malattia

25 Grazie per l attenzione