Post-ASCO. Behandeling van melanoom en niercelcarcinoom John Haanen

Transcriptie

1 Post-ASCO Behandeling van melanoom en niercelcarcinoom John Haanen

2 Disclosure belangen John Haanen (potentiële) belangenverstrengeling Voor bijeenkomst mogelijk relevante relaties met bedrijven Onderzoeksgeld Adviesrol Zie hieronder Bedrijfsnamen BMS, Novartis, GSK BMS, MSD, Roche, GSK

3 Targeted therapy: Melanoom Fase Ib studie met LEE-001 en binimetinib 1e uitkomsten van de Combi-D studie PET resultaten van BRIM-7 Immunotherapie: Update van de nivolumab, pembrolizumab en de ipilimumab + nivolumab en T-VEC studies Adjuvante studie (E18071)

4 Targeted therapy bij melanoom

5 Combinatie TT Long et al.: Fase III studie met dabrafenib + trametinib vs dabrafenib + placebo

6 Study Rationale Presented By Georgina Long at 2014 ASCO Annual Meeting

7 COMBI-d: Study Design Presented By Georgina Long at 2014 ASCO Annual Meeting

8 Baseline Patient Characteristics Presented By Georgina Long at 2014 ASCO Annual Meeting

9 COMBI-d: Investigator-Assessed PFS<br />Data cut August 2013* Presented By Georgina Long at 2014 ASCO Annual Meeting

10 COMBI-d: Investigator-Assessed PFS Presented By Antoni Ribas at 2014 ASCO Annual Meeting

11 COMBI-d: Best Confirmed Response Presented By Georgina Long at 2014 ASCO Annual Meeting

12 COMBI-d: Overall Survival<br />Data cut August 2013 Presented By Georgina Long at 2014 ASCO Annual Meeting

13 COMBI-d: Adverse Events Presented By Georgina Long at 2014 ASCO Annual Meeting

14 Conclusies Combi-D studie haalt primaire eindpunt met 25% verbetering in PFS (HR: 0,75 met p= 0,035) Hogere RR van 67% vs 51% Nog geen mature data voor OS GSK heeft registratie voor de combinatie teruggetrokken bij EMA CBG heeft NPP voor de combinatie gesloten

15 PET studieresultaten BRIM7 BRIM7: fase I studie met vemurafenib + cobimetinib (MEK-i) PET metingen vooraf en aan eind van cyclus 1 en cyclus 2

16 BRIM7 FDG-PET: Complete Metabolic Response and clinical outcome Presented By Keith Flaherty at 2014 ASCO Annual Meeting

17 Targeted therapy: Melanoom Fase Ib studie met LEE-001 en binimetinib 1e uitkomsten van de Combi-D studie PET resultaten van BRIM-7 Immunotherapie: Update van de nivolumab, pembrolizumab en de ipilimumab + nivolumab en T-VEC studies Adjuvante studie (E18071)

18 Mechanism of action Presented By Hans Hammers at 2014 ASCO Annual Meeting

19 Efficacy and Safety of the <br />Anti-PD-1 Monoclonal Antibody MK-3475 in <br />411 Patients With Melanoma Presented By Jeffrey Weber at 2014 ASCO Annual Meeting

20 Treatment-Related AEs With Incidence >5% Presented By Jeffrey Weber at 2014 ASCO Annual Meeting

21 Response Based on Tumor PD-L1 Expression (Central Review, RECIST v1.1) Presented By Jeffrey Weber at 2014 ASCO Annual Meeting

22 Antitumor Activity by Prior Ipilimumab and MK-3475 Dose/Schedule Presented By Jeffrey Weber at 2014 ASCO Annual Meeting

23 Kaplan-Meier Estimate of Overall Survival Presented By Jeffrey Weber at 2014 ASCO Annual Meeting

24 Pooled OS Analysis for Ipilimumab Including EAP Data: 4846 Patients Median OS (95% CI): 9.5 ( ) 3-year OS rate (95% CI): 21% (20 22%) Hodi et al ESMO 2013

25 Long-term survival of ipilimumab-naïve patients (pts) with advanced melanoma (MEL) treated with nivolumab (anti-pd-1; BMS ; ONO-4538) in a phase I trial. Presented By Jeffrey Weber at 2014 ASCO Annual Meeting

26 Select Drug-Related Adverse Events ( 1%) Occurring in Melanoma Patients Treated with Nivolumab1 Presented By Jeffrey Weber at 2014 ASCO Annual Meeting

27 PFS and Survival Endpoints in Melanoma Patients Receiving Nivolumab Therapy Presented By Jeffrey Weber at 2014 ASCO Annual Meeting

28 ORR by PD-L1 Expression in Melanoma Patients Presented By Jeffrey Weber at 2014 ASCO Annual Meeting

29 Survival, response duration, and activity by BRAF mutation status of nivolumab and ipilimumab concurrent therapy in advanced melanoma Presented By Jeffrey Weber at 2014 ASCO Annual Meeting

30 Most Common Grade 3 4 Related AE Presented By Jeffrey Weber at 2014 ASCO Annual Meeting

31 Characteristics of Responses Presented By Jeffrey Weber at 2014 ASCO Annual Meeting

32 Overall Survival for Concurrent Therapy by Dose Cohort Presented By Jeffrey Weber at 2014 ASCO Annual Meeting

33 ORR by BRAF Status for Concurrent Cohorts Presented By Jeffrey Weber at 2014 ASCO Annual Meeting

34 ORR by PD-L1 Status (5% cutoff) Presented By Jeffrey Weber at 2014 ASCO Annual Meeting

35 Conclusies Data uit ASCO 2013 worden bevestigd in grotere cohorten patienten en langere follow-up Nivolumab en pembrolizumab hebben een indrukwekkende en lange kans op respons, worden goed verdragen en geven een opvallende overleving Ipi voorbehandelde ptn hebben een lagere kans op effect dan ipi naïve ptn PD-L1 is geen goede marker voor respons Combinatie van ipi/nivo is toxisch maar induceert indrukwekkende responsen en lange overleving Wachten op de fase III studies

36 Veel open vragen Hoe lang moet met anti-pd1 worden behandeld? Zijn er goede predictieve markers voor respons (of tox)? Is inductie behandeling (zoals bij ipi) mogelijk? Hoe verhoudt zich anti-pd1 t.o.v. de combinatie anti- CTLA4/anti-PD1 Weegt de tox van de combinatie op tegen de voordelen? Kan anti-pd1 veilig worden doorgegeven bij graad 3/4 door de combinatie? Wat wordt de prijs van anti-pd1 en van de combinatie?

37 Ipilimumab Versus Placebo After <br />Complete Resection of Stage III Melanoma: <br />Initial Efficacy and Safety Results from the EORTC Phase III Trial Presented By Alexander Eggermont at 2014 ASCO Annual Meeting

38 EORTC 18071/CA : Study Design Presented By Alexander Eggermont at 2014 ASCO Annual Meeting

39 Key Eligibility Criteria Presented By Alexander Eggermont at 2014 ASCO Annual Meeting

40 Primary Endpoint: Recurrence-free Survival (IRC) Presented By Alexander Eggermont at 2014 ASCO Annual Meeting

41 Slide 12 Presented By Alexander Eggermont at 2014 ASCO Annual Meeting

42 Slide 14 Presented By Alexander Eggermont at 2014 ASCO Annual Meeting

43 Conclusie Eerste analyse toont een verbetering van de RFS voor ipilimumab, maar forse toxiciteit Vraag is of dit zich vertaalt in verbetering van de DMFS en OS

44 Niercelcarcinoom 1e resultaten van fase II studie met anti- PD1 Combinaties: TKI + anti-pd1 Ipilimumab + nivolumab Oncotype DX RS Anti-PD-L1 in blaaskanker

45 Nivolumab for metastatic renal cell <br />carcinoma (mrcc): results of a randomized, dose-ranging phase II trial Presented By Robert Motzer at 2014 ASCO Annual Meeting

46 Phase II study design Presented By Robert Motzer at 2014 ASCO Annual Meeting

47 Study objectives Presented By Robert Motzer at 2014 ASCO Annual Meeting

48 Key inclusion criteria Presented By Robert Motzer at 2014 ASCO Annual Meeting

49 Patient demographics Presented By Robert Motzer at 2014 ASCO Annual Meeting

50 Prior treatment in metastatic setting Presented By Robert Motzer at 2014 ASCO Annual Meeting

51 Progression-free survival Presented By Robert Motzer at 2014 ASCO Annual Meeting

52 Slide 13 Presented By Robert Motzer at 2014 ASCO Annual Meeting

53 Duration of response Presented By Robert Motzer at 2014 ASCO Annual Meeting

54 Treatment-related select adverse events Presented By Robert Motzer at 2014 ASCO Annual Meeting

55 Overall survival Presented By Robert Motzer at 2014 ASCO Annual Meeting

56 Overall survival by MSKCC risk group and number of prior treatments Presented By Robert Motzer at 2014 ASCO Annual Meeting

57 Slide 19 Presented By Robert Motzer at 2014 ASCO Annual Meeting

58 Nivolumab (anti-pd-1; BMS ; ONO-4538) in combination with sunitinib or pazopanib in patients (pts) with metastatic renal cell carcinoma (mrcc) Presented By Asim Amin at 2014 ASCO Annual Meeting

59 Dose escalation Presented By Asim Amin at 2014 ASCO Annual Meeting

60 Antitumor activity (per RECIST 1.1) Presented By Asim Amin at 2014 ASCO Annual Meeting

61 Maximum tumor burden reduction in baseline target lesions by nivolumab dose Presented By Asim Amin at 2014 ASCO Annual Meeting

62 Change from baseline in target tumor burden by prior treatment status Presented By Asim Amin at 2014 ASCO Annual Meeting

63 Progression-free survival Presented By Asim Amin at 2014 ASCO Annual Meeting

64 Time to response and duration <br />of response Presented By Asim Amin at 2014 ASCO Annual Meeting

65 Conclusions Presented By Asim Amin at 2014 ASCO Annual Meeting

66 CA (NCT ): <br />phase I study design (N + I cohort) Presented By Hans Hammers at 2014 ASCO Annual Meeting

67 Treatment administration Presented By Hans Hammers at 2014 ASCO Annual Meeting

68 Key inclusion and exclusion criteria Presented By Hans Hammers at 2014 ASCO Annual Meeting

69 Treatment-related select AE categories Presented By Hans Hammers at 2014 ASCO Annual Meeting

70 Treatment-related AEs leading to discontinuation Presented By Hans Hammers at 2014 ASCO Annual Meeting

71 Antitumor activity Presented By Hans Hammers at 2014 ASCO Annual Meeting

72 Progression-free survival Presented By Hans Hammers at 2014 ASCO Annual Meeting

73 Maximum tumor burden change in baseline target lesions Presented By Hans Hammers at 2014 ASCO Annual Meeting

74 Time to response and duration <br />of response Presented By Hans Hammers at 2014 ASCO Annual Meeting

75 Change from baseline in target tumor burden Presented By Hans Hammers at 2014 ASCO Annual Meeting

76 Conclusies Anti-PD1 behandeling bij mrcc heeft acceptabele toxiciteit en indrukwekkende effectiviteit bij voorbehandelde patienten OS in fase II studie lijkt zeer veel belovend Combinatie TKI + anti-pd1 is mogelijk. Meer lever en niertox. Effectiever? Combinatie van ipi + nivo is mogelijk, wel >40% graad 3/4 tox, maar indrukwekkenden ORR.

77 Inhibition of PD-L1 by MPDL3280A<br />leads to clinical activity in<br />patients with metastatic urothelial bladder cancer (UBC) Presented By Thomas Powles at 2014 ASCO Annual Meeting

78 MPDL3280A Phase Ia Presented By Thomas Powles at 2014 ASCO Annual Meeting

79 MPDL3280A: Activity in Human Cancer Presented By Thomas Powles at 2014 ASCO Annual Meeting

80 PD-L1 Prevalence in Solid Tumors Presented By Thomas Powles at 2014 ASCO Annual Meeting

81 Metastatic Urothelial Bladder Cancer Presented By Thomas Powles at 2014 ASCO Annual Meeting

82 MPDL3280A: UBC Baseline Characteristics<br />Efficacy-evaluable population with UBC in Phase I expansion Presented By Thomas Powles at 2014 ASCO Annual Meeting

83 MPDL3280A: Treatment-Related AEs<br />Safety-evaluable population with UBC in Phase I expansion Presented By Thomas Powles at 2014 ASCO Annual Meeting

84 MPDL3280A: Summary of ORR in UBC <br />Efficacy-evaluable population with UBC in Phase I expansion Presented By Thomas Powles at 2014 ASCO Annual Meeting

85 MPDL3280A: Tumor Burden Over Time in UBC Presented By Thomas Powles at 2014 ASCO Annual Meeting

86 Conclusies MPDL3280A is actief bij platinumvoorbehandelde urotheelcelcarcinoompatienten 43% van de PDL1+ (IC) patienten hadden een objectieve respons Responsen hadden lange duur Goede tolerantie met slechts 4% graad 3 of 4 toxiciteit