melanoma asco review update 2016
TRANSCRIPT
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ASCO 2016 Melanoma Update
Thomas Olencki, DO Division of Medical Oncology
Department of Internal Medicine The Ohio State University Wexner Medical Center
Columbus, Ohio
June 18, 2016
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p <0.0001 15 14 13 12 11 10
Balch, JCO 19:3635, 2001.
9 8 7 Survival (years)
Pro
porti
on S
urvi
ving
6 5 4 3 2 1 0
1.0
0.8
0.6
0.4
0.2
0.0
Survival Curve Of Patients With Metastatic Melanoma
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What Are Benchmarks For Treatment Of Metastatic Melanoma ?
• Evaluated – 2100 patients – 70 arms of 42 trials in cooperative groups
• Results – OS
• median - 6.2 mos • 12 mos rate – 26%
– PFS • median – 1.7 mos • 6 mos rate – 15%
Korn, JCO 26:527, 2008
“Clinical benefit” CR+PR+SD
New “Benchmark” for phase 2 trails
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Advantages Of Immunotherapy
• Searching for tumor activating mutation less critical
• Immune system may “adapt” to specific tumor characteristics
• Potential for long-term durable response
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Immune Therapy
Also Now Known As Checkpoint Inhibitors
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Monoclonal Antibody Therapy • Nomenclature for monoclonal Ab checkpoint
inhibitors: – CTLA-4 – early inhibitor and most active in lymph node
• Ipilimumab (Yervoy®) – BMS
– PD -1 – later inhibitor in peripheral blood or tumor • Nivolumab (Opdivo®) – Bristol-Myers Squibb • Pembrolizumab (Keytruda®) - Merck
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Ipilimumab
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Phase III Ipilimumab – 2nd Line Tx
R A N D O M I Z E
Ipilimumab 3 mg/kg IV
Ipilimumab 3 mg/kg IV & gp 100
Open 9/2004 – 8/2008 Double blind
(3:1:1; for ipi, ipi & gp100 and gp100 alone)
Hodi, NEJM 363:711, 2010
676 pts with prior Tx
melanoma
70% had M1c poor risk
visceral disease gp 100 vaccine
All drugs à q 3 wks x 4 doses
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Phase III Ipilimumab – 2nd Line Tx
Ipilimumab alone OS 24% at 2+ yrs
Overall Survival
Hodi, NEJM 363:711 2010
OS at 1 yr 46%
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Phase III Ipilimumab – 2nd Line Tx
Overall Survival
Hodi, NEJM 363:711 2010
Flat survival curve 24 to 36 mos
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Long Term Survival With Ipilimumab
Schadendorf, JCO 33:1889, 2015
OS of 4,846 pts Tx on trial and from Expanded Access Program. Survival plateau starts at 3 yrs and extends to 10 yrs in some pts. Median OS was 9.5 mos
3 yr OS of 21%
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LDH May Be Most Accurate Predictor Of Response To Ipilimumab
Kelderman, Cancer Immuno Immunother 63:449. 2014
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Conclusions Regarding Ipilimumab • Tolerable to wide range of pt’s
– borderline PS − elderly – treated brain mets − uveal and mucosal primaries
• Combination with chemo Tx may not improve efficacy
• Associated with – RR 10-15% – PFS of about 3 mos – Stable OS of 21% at 3 yrs extending to 10 years in some pts
• Benefit of ipilimumab – increase in overall survival
• LDH may predict who will respond Ribas, JCO 33: 1865, 2015; Schadendorf, JCO 33:1889, 2015
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Nivolumab or Pembrolizumab
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Brief Review Of 3 Trials
• Nivolumab - Phase 1
• Pembrolizumab vs ipilimumab
• Nivolumab and Ipilimumab
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Phase I Nivolumab Dose Finding Study
• All 107 pts had to have had prior therapy
• 62% had 2 or more different therapies
• These were real world patients with bulky disease
• Stable brain metastasis were acceptable
• This is the 1st long-term follow-up study of the nivolumab therapy
Hodi, AACR April, 2016
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Hodi, AACR April, 2016
34% 5 yr OS
Phase I Nivolumab 5 Year OS Results
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Pembrolizumab vs Ipilimumab Keynote-006
R A N D O M I Z E
Pembrolizumab 10 mg/kg q 3 wks
Ipilimumab 3 mg/kg q 3 wks
834 pts 1:1:1 ratio ≤ 1 therapy
Robert, NEJM 372:320, 2015; Schachter, ASCO 2016 # 9504
Open 9/2013 - 3/2014
Pembrolizumab 10 mg/kg q 2 wks
Median FU – 23 mos
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Pembrolizumab vs Ipilimumab Keynote-006
• Response (23 mos median follow up) pembrolizumab (q3wk) ipilimumab
ORR 36% 13% CR 13% 5% PR 23% 8% SD 16% 18% PD 42% 49% Not eval 6% 18%
Schachter, ASCO 2016 #9504
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Schachter, ASCO 2016 #9504
Pembrolizumab vs Ipilimumab Keynote-006
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Pembrolizumab vs Ipilimumab Keynote-006
Schachter, ASCO 2016 #9504
Median PFS
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Pembrolizumab vs Ipilimumab Keynote-006
Schachter, ASCO 2016 #9504
Median OS
Median OS
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Pembrolizumab vs Ipilimumab Keynote-006
• In this study, ipilimumab pts faired better than in prior studies • No difference in PFS or OS was seen with the different
pembrolizumab schedules • Pembrolizumab (40% OS) found to be more effective than ipi
(22% OS) at 3 yr. OS in all subgrps. analyzed • Pembrolizumab PFS curve flattens at 20 months
• Pembrolizumab ( anti-PD-1 Tx) represents a new “standard of care” over ipilimumab for metastatic melanoma patient’s
Schachter, ASCO 2016 #9504
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Combination PD-1 Inhibition And Anti-CTLA-4
Or Nivolumab And Ipilimumab
(CheckMate 067)
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Phase III Nivolumab And Ipilimumab Or Monotherapy (CheckMate 067)
R A N D O M I Z E
Ipi 3 mg/kg & Nivo 1 mg/kg IV
Ipilimumab 3 mg/kg I
Open 7/2013 – 3/2014 Double blind
Larkin, NEJM 373:23, 2015 ; Wolchok, ASCO 2016 #9505
945 pts with No prior Tx
58% had M1c poor risk
visceral disease
Nivolumab 3 mg/kg
1:1:1 randomization
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Median PFS In Intention To Treat Pts
Nivo and Ipi 11.5 mos
Ipilimumab 2.9 mos
Larkin, NEJM 373:23, 2015; Wolchok, ASCO 2016 #9505
Nivolumab 6.9 mos
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Median PFS – CheckMate 067 Median 20.7 mos Follow-up
Nivo and Ipi 11.5 mos
Ipilimumab 2.9 mos
Nivo 6.9 mos
Wolchok, ASCO 2016 #9505
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Phase III Nivo And Ipi Or Monotherapy • Response results – at 20.7 mos FU
Ipi and Nivo Nivo Ipilimumab ORR 58% 44% 19% CR 12% 10% 2% PR 46% 34% 17% SD 13% 11% 22% PD 23% 38% 49% Unknown 7% 8% 10% Med resp dur NR 22 mos 14 mos Ongoing resp 73% 72% 52%
Larkin, NEJM 373:23, 2015 ; Wolchok, ASCO 2016 #9505
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Tumor-burden change
from baseline
Nivo
Nivo & Ipi
Ipi
35%↓
52%↓
6%↑ Larkin, NEJM 373:23, 2015
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Wolchok, ASCO 2016 #9505
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Median PFS In PD-L1 + Tumors
Ipi and Nivo 14 mos
Ipilimumab 3.9 mos
Nivolumab 14 mos
Now NR
Now 20 mos
Larkin, NEJM 373:23, 2015 ; Wolchok, ASCO 2016 #9505
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Median PFS In PD-L1 Negative Tumors
Ipi and Nivo 11.2 mos
Ipilimumab 2.8 mos
Nivolumab 5.3 mos
Larkin, NEJM 373:23, 2015; Wolchok, ASCO 2016 #9505
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Phase III Nivo And Ipi Or Monotherapy
• Response by PD-L1 status Nivo & Ipi Nivo Ipi
PD-L1 ≥ 5% 72% 58% 21% PD-L1 < 5% 55% 41% 18% • 69% of pts who DC’ed combination Tx due to AE developed
a response. • 50% of those responses were after Tx ended. Larkin, NEJM 373:23, 2015 ; Wolchok, ASCO 2016 #9505
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Early Phase 2 Randomized Study Of Nivolumab And Ipilimumab vs Ipilimumab
• Pt numbers small - 95 in combination and 47 in Ipi
• Follow-up is short at 2 years
• All patients previously not treated
Postow, AACR April 2016
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Postow, AACR, 2016
Phase II Study Of Nivolumab And Ipilimumab vs. Ipilimumab
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Postow, AACR 2016 months
Phase II Study Of Nivolumab And Ipilimumab vs. Ipilimumab
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Phase III Nivo And Ipi Or Monotherapy • Adverse events:
– combination arm • rash/ pruritis – 60% • diarrhea - 45% • hepatic – 32% • pulmonary – 7% • renal – 6% • incidence of Gr 3 and 4 – 56% • 39% of pts had AE that led to DC of TX • NO patient deaths
Larkin, NEJM 373:23, 2015; Wolchok, ASCO 2016 #9505
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Phase III Nivo And Ipi Or Monotherapy • Combination Tx with Nivo and Ipi represents a
dramatic therapeutic breakthrough for pts
• In PDL-1 status – for PDL1+ Nivo = Nivo & Ipi PFS – for PDL1− Need Nivo and Ipi for PFS benefit
• Nivo/ipi active in any sub grp. including ≥ 2 x LDH
• Responses and Overall Survival durable
• Toxicity moderate to severe but manageable – should not use in pts with “minimal reserve”
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Predictors Of Response And
Resistance
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Mutational Density As A Predictor Of Response
Alexandrov, Nature 500:415, 2013
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Factors Affecting Response And Resistance
Charen, ASCO 2016 Special Session - Rathmell
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Predictors Of Response – PD-1 • PD-L1 level evaluation
– Technically difficult – Tumor heterogeneity limits reliability – Expression inducible by PD-1 therapy – No standard assay comparable between companies – Significant variability
• Tumor versus CD8 PD-1 levels • Levels different on fresh versus frozen versus archival tissue • Levels maybe different on primary versus metastatic sites
• Should not be used at this time for clinical decisions
Adapted from Atkins, Plenary Session, ASCO 2015
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What About The Pt With Borderline PS?
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What About Grandma? • Pts who may not tolerate combination therapy include:
– poor social support – living a long distance from medical care – poorly controlled diabetes – deconditioned elderly
• Sequential use of checkpoint inhibitors is often better tolerated and safer than combination Tx
• Is there a preferred sequence? – PD-1 inhibitor followed by ipilimumab – Ipilimumab followed by a PD-1 inhibitor
• CheckMate 064 addressed this issue
Weber, Lancet Oncol pub online June 4, 2016
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CheckMate 064 – Phase 2
R A N D O M I Z E
Nivolumab
Open 4/2013 – 7/2014
Weber, Lancet Oncol pub online June 4, 2016
140 pts
≤ 1 prior Tx
Nivolumab
Ipilimumab
Ipilimumab
RR – 41% OS – NR
RR – 20% OS – 16.9 mos
Median follow-up of 19.8 months
12 wks
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CheckMate 064 - OS
Weber, Lancet Oncol pub online June 4, 2016
Nivo-Ipi
Ipi-Nivo
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CheckMate 064 • Results
– Overall survival follow-up is ongoing
• Given the opportunity, nivolumab followed by ipilimumab sequence may provide > clinical benefit to pts
• Toxicity comparable between both arms at 12 weeks, but greater in the Nivo à Ipi arm the latter 12 weeks
• Hazard ratio 0.57 in favor of Nivo à Ipi arm
• All prior assigned grps did better on Nivo à Ipi arm
Weber, Lancet Oncol pub online June 4,2016
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The B raf Mutation Pt
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What Is The Best Way To Tx Pts With B raf Mutation + Melanoma?
• No one really knows
• Emotional topic with no firm data
• Phase 3 study recently opened EA6134
• Optimal therapy may include up front: B raf, MEK and PD-1 inhibitor simultaneously
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EA 6134 - Intergroup
R A N D O M I Z E
B raf V600
mutation positive
Nivo and Ipi
Dabrafenib and tremetinib
PD
PD
C R O S S O V E R
Nivo and Ipi
Dabrafenib and tremetinib
OSU Contact: Joanne Jeter MD 614-293-4320
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Conclusions (1) • Combination Tx with nivolumab and ipilimumab indicated for
those pts who need a resp. and can tolerate the toxicity
• Single agent PD-L1 therapy indicated when toxicity a concern
• Nivolumab & ipilimumab are more effective than nivo alone
• Nivo/ Pembro alone or with ipilimumab are both more active than ipilimumab alone
• Nivo/ Pembro and nivolumab with ipilimumab represent a “new standard of care”
Adapted from Atkins, Plenary Session, ASCO 2015
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Conclusions (2) • Steroids to Tx toxicity does not negate therapeutic effect • B raf mutation status does not predict for response to
checkpoint blockade therapy • The most effective Tx (targeted vs immune vs combination)
for B raf mutation pt’s remains to be determined • High LDH (≥ 2 x nl) is not a negative indicator of response
to combination checkpoint therapy • HD IL-2 may be safely and effectively administered to those
pts that progress on any checkpoint inhibitor therapy (Buchbinder and McDermott, ASCO 2016 #e21006)
Adapted from Atkins, Plenary Session, ASCO 2015
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Summary Therapy Resp. Rate OS (5 yr) High dose IL-2 15% 6% Ipilimumab 10 - 20% 20% Nivo/pembro 30 – 40% 34% Nivo/Ipi 55 - 60% 64% (at 2 yrs)
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Research Lake at OSU (3.5 acres)