ASCO 2015 Melanoma Immunotherapy
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Transcript of ASCO 2015 Melanoma Immunotherapy
ASCO 2015 Melanoma Immunotherapy
Thomas Olencki, DO Division of Medical Oncology
Department of Internal Medicine The Ohio State University Wexner Medical Center
Columbus, Ohio
June 13, 2015
Melanoma Is What Gives Cancer A Bad Name
George Canellos
Adapted from Michael Atkins
p <0.0001
15 14 13 12 11 10
Balch, JCO 19:3635, 2001.
9 8 7 Survival (years)
Prop
ortio
n Su
rviv
ing
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
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
High Dose IL-2 In Metastatic Melanoma
Response durations for pts who achieved a CR/ PR
Atkins, JCO 17:2105, 1999
3.7%
High Dose IL-2 In Metastatic Melanoma
Survival for the whole study population (270 patients) OS – 11.4 months at median follow up of 62 mos
Atkins, JCO 17:2105, 1999
Stage IV
Advantages Of Immunotherapy
• Searching for tumor activating mutation less critical
• Immune system may “adapt” to specific tumor characteristics
• Potential for long-term durable response
Immune Therapy
Also Now Known As Checkpoint Inhibitors
Monoclonal Antibody Therapy • Nomenclature for monoclonal Ab:
– CTLA-4
• Ipilimumab (Yervoy®) - BMS – PD -1
• Nivolumab (Opdivo®) – Bristol-Myers Squibb • Pembrolizumab (Keytruda®) - Merck
Ipilimumab
Ipilimumab
Ag presenting Dendritic cell
Or Tumor cell MHC II Ag TCR
CD 28 – T cell stimulation (with IL-2 production) CD 80 B 7.1 CD 86 B 7.2
Activated T Cell
CTLA-4 – T cell inhibition (induction of tolerance) − CD152
Ipilimumab (2)
Ag presenting Dendritic cell
Or Tumor cell MHC II Ag TCR
CD 28 – Unopposed T cell stimulation CD 80 B 7.1 CD 86 B 7.2
Activated T Cell
Unopposed autoimmune effects: - rash and vitiligo - hypopituitarism - diarrhea and colitis - hepatitis
Ipilimumab (3)
• Humanized IgG1k – T1/2 20 - 30 days – administered IV q 3 wks x 4 doses
• Breaks immune system tolerance for the tumor
• Ipilimumab an early check point regulator of T cell Fx
– thought to be active in the lymph node
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 q 3 wks x 4 doses
Phase III Ipilimumab – 2nd Line Tx
Ipilimumab alone OS 24% at 2+ yrs
Overall survival
Hodi, NEJM 363:711 2010
Phase III Ipilimumab – 2nd Line Tx
Overall Survival
Hodi, NEJM 363:711 2010
Flat survival curve 24 to 36 mos
Phase III Ipilimumab – 2nd Line Tx • Results ipi ipi and gp100 gp100 Korn PFS 2.8 mos 2.8 mos 2.8 mos 1.7 med OS 10.1 mos 10 mos 6.4 mos 6.2 12 mos 46% 44% 25% 26% 24 mos 24% 22% 14% RR 11% 6% 2% Clin Benefit * 29% 22% 11%
* CR, + PR, + SD Hodi, NEJM 363:711, 2010
Phase III Dacarbazine +/- Ipilimumab 1st Line Tx
R A N D O M I Z E
Ipilimumab 10 mg/kg + DTIC
DTIC
502 pts 1:1 ratio
Robert, NEJM 364:2517, 2011
Open 8/2006 - 1/2008
Phase III Dacarbazine +/- Ipilimumab 1st Line Tx
Robert, NEJM 364:2517, 2011
Overall Survival
Phase III Dacarbazine +/-Ipi 1st Line • Results Ipi and DTIC DTIC Korn PFS NA NA 1.7 med OS 11.2 mos 9.1 mos 6.2 12 mos 47% 36% 26% 24 mos 28% 18% 36 mos 21% 12% RR 15% 10%
Robert, NEJM 364:2517, 2011
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.
3 yr surv of 21%
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
Ribas, JCO 33: 1865, 2015; Schadendorf, JCO 33:1889, 2015
Nivolumab or Pembrolizumab
PD-1 / PD-L1 Interaction
Tumor
MHC II Ag TCR
Activated T Cell
(B7-H1) PD-L1 PD-1 - T cell inhibition
PD-1/PD -L1 is a regulator of T cell function in the tumor and peripheral blood
PD-1 / PD-L1 Interaction
Tumor
MHC II Ag TCR
Activated T Cell
B7-H1 – PD-L1 PD-1 - T cell inhibition
Nivolumab / Pembrolizomab
Brahmer, JCO 28:3167, 2010
Induction of tolerance
Results: PR and SD with few side effects
Brief Review Of 3 Trials
• Nivolumab 1st line
• Pembrolizumab vs ipilimumab
• Nivolumab and Ipilimumab
Phase III Nivolumab vs DTIC As 1st Line Therapy
R A N D O M I Z E
Ipilimumab 3 mg/kg
DTIC 1000 mg/m2
418 pts 1:1 ratio
Robert, NEJM 372:320, 2015
Open 1/2013 - 2/2014 All patients BRAF
wild type
Phase III Nivolumab vs DTIC As 1st Line Therapy
• Results Nivolumab DTIC PFS 5.1 mos 2.2 mos med OS not reached 10.8 mos 12 mos 73% 40% RR 40% 14%
• Conclusions: Trial significant for ↑ PFS, OS & RR
Robert, NEJM 372:320, 2015
Phase III Nivolumab vs DTIC As 1st Line Therapy - OS
Robert, NEJM 372:320, 2015
Phase III Nivolumab vs DTIC As 1st Line Therapy - PFS
Robert, NEJM 372:320, 2015
Pembrolizumab vs Ipilimumab
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
Robert, NEJM 372:320, 2015
Open 9/2013 - 3/2014
Pembrolizumab 10 mg/kg q 2 wks
Pembrolizumab vs Ipilimumab
Robert, NEJM 2015
Ipilimumab
Pembrolizumab
Progression free survival
Pembrolizumab vs Ipilimumab
Robert, NEJM 2015
Ipilimumab
Overall survival
Pembrolizumab vs Ipilimumab
• Results pembrolizumab (q3wk) ipilimumab PFS 4.1 mos 2.8 mos med OS not reached not reached 12 mos 68% 58% RR 33% 12% • Conclusions: Trial stopped early by the DSMB because of
superiority of pembrolizumab
Robert, NEJM 372:320, 2015
Combination PD-1 Inhibition And Anti-CTLA-4
Or Nivolumab And Ipilimumab
Phase III Nivolumab And Ipilimumab Or Monotherapy
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 May 31, 2015 Epub
945 pts with No prior Tx
58% had M1c poor risk
visceral disease
Nivolumab 3 mg/kg
1:1:1 randomization
Median PFS In Intention To Treat Pts
Nivo and Ipi 11.5 mos
Ipilimumab 2.9 mos
Larkin, NEJM May 31, 2015 Epub
Nivolumab 6.9 mos
Phase III Nivo And Ipi Or Monotherapy • Response results Ipi and Nivo Nivo Ipilimumab ORR 58% 44% 19% CR 12% 9% 2% PR 46% 35% 17% SD 13% 11% 22% PD 23% 38% 49% Unknown 7% 8% 10%
Larkin, NEJM May 31, 2015 Epub
Tumor-burden change
from baseline
Nivo
Nivo & Ipi
Ipi
35%↓
52%↓
6%↑
Larkin, NEJM May 31, 2015 Epub
Median PFS In PD-L1 + Tumors
Ipi and Nivo 14 mos
Ipilimumab 3.9 mos
Nivolumab 14 mos
Larkin, NEJM May 31, 2015 Epub
Median PFS In PD-L1 Negative Tumors
Ipi and Nivo 11.2 mos
Ipilimumab 2.8 mos
Nivolumab 5.3 mos
Larkin, NEJM May 31, 2015 Epub
Phase III Nivo And Ipi Or Monotherapy
• Response by PD-L1 status Nivo & Ipi Nivo Ipi PD-L1 ≥ 5% 72% 57% 21% PD-L1 < 5% 54% 41% 18% 67% of pts who DC’ed combination Tx due to AE developed a response. One half of those responses were after Tx ended. Only about 25% pts are PD-L1+ (BMS testing)
Larkin, NEJM May 31, 2015 Epub
Phase III Nivo And Ipi Or Monotherapy • Adverse events:
– combination arm • diarrhea- 44% • fatigue – 35% • puritus – 33% • incidence of Gr 3 and 4 – 55% • 36% of pts had AE that led to DC of TX – diarrhea & colitis • NO patient deaths
– use of steroids did NOT prevent responses – absolutely need to wean steroids over a minimum of 4 wks
Larkin, NEJM May 31, 2015 Epub Atkins, Plenary Session, ASCO 2015
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
• Response and PFS presented today • Overall survival pending longer follow up • Toxicity moderate to severe but manageable
Mutational Density As A Predictor Of Response
Alexandrov, Nature 500:415, 2013
Predictors Of Response • Primed tumor – CD8 infiltrate within tumor
– Can be primed by prior or concurrent therapy with ipilimumab
– Increased number of T reg cells and expression of suppressive IDO (surrogate for immune infiltrate)
• Absolute lymphocyte count at beginning of 2nd course of > 1,000 (for ipilimumab) Allison, Plenary Session of ASCO 2015
Postow, JCO 33:1974, 2015
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 different on primary versus metastatic sites
• Should not be used at this time for clinical decisions Adapted from Atkins, Plenary Session, ASCO 2015
Other T Cell/Tumor Interactions
Allison, Plenary Session of ASCO 2015
Conclusions (1) • Combination Tx with nivolumab and ipilimumab indicated for
those pts who need a resp. and can the tolerate toxicity • Single agent PD-L1 therapy indicated when toxicity a
concern • Nivolumab & ipilimumab are more effective than nivo alone • Nivo/ Pembro or nivolumab 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
Conclusions (2) • Use of steroids to treat toxicity does not negate therapeutic
effect • B raf mutation status does not predict for response to
checkpoint blockade therapy • High LDH may not be an absolute negative indicator of
response to 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 2015)
Adapted from Atkins, Plenary Session, ASCO 2015
Melanoma Is What Gives Cancer A Bad Name
But now we can do something about it!