Transcript Ontwikkelingen immunotherapie

Post-ASCO
Behandeling van melanoom en
niercelcarcinoom
John Haanen
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
Melanoom
• Targeted therapy:
– 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)
Targeted therapy bij melanoom
Combinatie TT
• Long et al.: Fase III studie met dabrafenib
+ trametinib vs dabrafenib + placebo
Study Rationale
Presented By Georgina Long at 2014 ASCO Annual Meeting
COMBI-d: Study Design
Presented By Georgina Long at 2014 ASCO Annual Meeting
Baseline Patient Characteristics
Presented By Georgina Long at 2014 ASCO Annual Meeting
COMBI-d: Investigator-Assessed PFS<br />Data cut August 2013*
Presented By Georgina Long at 2014 ASCO Annual Meeting
COMBI-d: Investigator-Assessed PFS
Presented By Antoni Ribas at 2014 ASCO Annual Meeting
COMBI-d: Best Confirmed Response
Presented By Georgina Long at 2014 ASCO Annual Meeting
COMBI-d: Overall Survival<br />Data cut August 2013
Presented By Georgina Long at 2014 ASCO Annual Meeting
COMBI-d: Adverse Events
Presented By Georgina Long at 2014 ASCO Annual Meeting
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
PET studieresultaten BRIM7
• BRIM7: fase I studie met vemurafenib +
cobimetinib (MEK-i)
• PET metingen vooraf en aan eind van
cyclus 1 en cyclus 2
BRIM7 FDG-PET: Complete Metabolic Response and clinical outcome
Presented By Keith Flaherty at 2014 ASCO Annual Meeting
Melanoom
• Targeted therapy:
– 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)
Mechanism of action
Presented By Hans Hammers at 2014 ASCO Annual Meeting
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
Treatment-Related AEs With Incidence >5%
Presented By Jeffrey Weber at 2014 ASCO Annual Meeting
Response Based on Tumor PD-L1 Expression (Central Review, RECIST v1.1)
Presented By Jeffrey Weber at 2014 ASCO Annual Meeting
Antitumor Activity by Prior Ipilimumab and MK-3475 Dose/Schedule
Presented By Jeffrey Weber at 2014 ASCO Annual Meeting
Kaplan-Meier Estimate of Overall Survival
Presented By Jeffrey Weber at 2014 ASCO Annual Meeting
Pooled OS Analysis for Ipilimumab Including EAP Data:
4846 Patients
Median OS (95% CI): 9.5 (9.0–10.0)
3-year OS rate (95% CI): 21% (20–22%)
Hodi et al ESMO 2013
Long-term survival of ipilimumab-naïve patients (pts) with advanced melanoma (MEL) treated with nivolumab (anti-PD-1; BMS-936558; ONO-4538) in a phase I trial.
Presented By Jeffrey Weber at 2014 ASCO Annual Meeting
Select Drug-Related Adverse Events (≥1%) Occurring in Melanoma Patients Treated with Nivolumab1
Presented By Jeffrey Weber at 2014 ASCO Annual Meeting
PFS and Survival Endpoints in Melanoma Patients Receiving Nivolumab Therapy
Presented By Jeffrey Weber at 2014 ASCO Annual Meeting
ORR by PD-L1 Expression in Melanoma Patients
Presented By Jeffrey Weber at 2014 ASCO Annual Meeting
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
Most Common Grade 3–4 Related AE
Presented By Jeffrey Weber at 2014 ASCO Annual Meeting
Characteristics of Responses
Presented By Jeffrey Weber at 2014 ASCO Annual Meeting
Overall Survival for Concurrent Therapy by Dose Cohort
Presented By Jeffrey Weber at 2014 ASCO Annual Meeting
ORR by BRAF Status for Concurrent Cohorts
Presented By Jeffrey Weber at 2014 ASCO Annual Meeting
ORR by PD-L1 Status (5% cutoff)
Presented By Jeffrey Weber at 2014 ASCO Annual Meeting
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
Veel open vragen…
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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 antiCTLA4/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?
Ipilimumab Versus Placebo After <br />Complete Resection of Stage III Melanoma: <br />Initial Efficacy and Safety Results from the EORTC 18071 Phase III Trial
Presented By Alexander Eggermont at 2014 ASCO Annual Meeting
EORTC 18071/CA184-029: Study Design
Presented By Alexander Eggermont at 2014 ASCO Annual Meeting
Key Eligibility Criteria
Presented By Alexander Eggermont at 2014 ASCO Annual Meeting
Primary Endpoint: Recurrence-free Survival (IRC)
Presented By Alexander Eggermont at 2014 ASCO Annual Meeting
Slide 12
Presented By Alexander Eggermont at 2014 ASCO Annual Meeting
Slide 14
Presented By Alexander Eggermont at 2014 ASCO Annual Meeting
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
Niercelcarcinoom
• 1e resultaten van fase II studie met antiPD1
• Combinaties:
– TKI + anti-PD1
– Ipilimumab + nivolumab
• Oncotype DX RS
• Anti-PD-L1 in blaaskanker
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
Phase II study design
Presented By Robert Motzer at 2014 ASCO Annual Meeting
Study objectives
Presented By Robert Motzer at 2014 ASCO Annual Meeting
Key inclusion criteria
Presented By Robert Motzer at 2014 ASCO Annual Meeting
Patient demographics
Presented By Robert Motzer at 2014 ASCO Annual Meeting
Prior treatment in metastatic setting
Presented By Robert Motzer at 2014 ASCO Annual Meeting
Progression-free survival
Presented By Robert Motzer at 2014 ASCO Annual Meeting
Slide 13
Presented By Robert Motzer at 2014 ASCO Annual Meeting
Duration of response
Presented By Robert Motzer at 2014 ASCO Annual Meeting
Treatment-related select adverse events
Presented By Robert Motzer at 2014 ASCO Annual Meeting
Overall survival
Presented By Robert Motzer at 2014 ASCO Annual Meeting
Overall survival by MSKCC risk group and number of prior treatments
Presented By Robert Motzer at 2014 ASCO Annual Meeting
Slide 19
Presented By Robert Motzer at 2014 ASCO Annual Meeting
Nivolumab (anti-PD-1; BMS-936558; 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
Dose escalation
Presented By Asim Amin at 2014 ASCO Annual Meeting
Antitumor activity (per RECIST 1.1)
Presented By Asim Amin at 2014 ASCO Annual Meeting
Maximum tumor burden reduction in baseline target lesions by nivolumab dose
Presented By Asim Amin at 2014 ASCO Annual Meeting
Change from baseline in target
tumor burden by prior treatment status
Presented By Asim Amin at 2014 ASCO Annual Meeting
Progression-free survival
Presented By Asim Amin at 2014 ASCO Annual Meeting
Time to response and duration <br />of response
Presented By Asim Amin at 2014 ASCO Annual Meeting
Conclusions
Presented By Asim Amin at 2014 ASCO Annual Meeting
CA209-016 (NCT01472081): <br />phase I study design (N + I cohort)
Presented By Hans Hammers at 2014 ASCO Annual Meeting
Treatment administration
Presented By Hans Hammers at 2014 ASCO Annual Meeting
Key inclusion and exclusion criteria
Presented By Hans Hammers at 2014 ASCO Annual Meeting
Treatment-related select AE categories
Presented By Hans Hammers at 2014 ASCO Annual Meeting
Treatment-related AEs leading to discontinuation
Presented By Hans Hammers at 2014 ASCO Annual Meeting
Antitumor activity
Presented By Hans Hammers at 2014 ASCO Annual Meeting
Progression-free survival
Presented By Hans Hammers at 2014 ASCO Annual Meeting
Maximum tumor burden change in baseline target lesions
Presented By Hans Hammers at 2014 ASCO Annual Meeting
Time to response and duration <br />of response
Presented By Hans Hammers at 2014 ASCO Annual Meeting
Change from baseline in target
tumor burden
Presented By Hans Hammers at 2014 ASCO Annual Meeting
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.
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
MPDL3280A Phase Ia
Presented By Thomas Powles at 2014 ASCO Annual Meeting
MPDL3280A: Activity in Human Cancer
Presented By Thomas Powles at 2014 ASCO Annual Meeting
PD-L1 Prevalence in Solid Tumors
Presented By Thomas Powles at 2014 ASCO Annual Meeting
Metastatic Urothelial Bladder Cancer
Presented By Thomas Powles at 2014 ASCO Annual Meeting
MPDL3280A: UBC Baseline Characteristics<br />Efficacy-evaluable population with UBC in Phase I expansion
Presented By Thomas Powles at 2014 ASCO Annual Meeting
MPDL3280A: Treatment-Related AEs<br />Safety-evaluable population with UBC in Phase I expansion
Presented By Thomas Powles at 2014 ASCO Annual Meeting
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
MPDL3280A: Tumor Burden Over Time in UBC
Presented By Thomas Powles at 2014 ASCO Annual Meeting
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