putting cancer in check with immunotherapy: melanoma and beyond michael postow, md melanoma and...
TRANSCRIPT
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Putting Cancer in Check with Immunotherapy: Melanoma and Beyond
Michael Postow, MDMelanoma and Immunotherapeutics Service
Memorial Sloan Kettering Cancer Center
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Bristol-Myers Squibb: -Research support-Participated in an advisory council (non-paid)
Amgen:-Participated in an advisory council (non-paid)
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2013 Breakthrough of the Year
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What happened in 1891?
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What happened in 1891?
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Main Questions
1. How can the immune system treat cancer?
2. What have we learned from clinical experience in melanoma?
3. How can we improve?
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Mellman et al. Nature 2011
Immunity in tumor control
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Mellman et al. Nature 2011
Immunity in tumor control
Vaccines
Cytokines
Adoptive cell transfer
Immunomodulatory antibodies
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Median OS benefit: 4.1 monthsHR : 0.78 (95% CI: 0.61-0.98; P = .03)
Sipuleucel-T vaccine improves survival in metastatic prostate cancer
Kantoff PW, et al. N Engl J Med. 2010
Prob
abili
ty o
f Sur
viva
l (%
)
Mos Since Randomization
80
60
40
20
0
100
0 12 24 36 48 60 72
Sipuleucel-T (n = 341)Median Survival: 25.8 Mos.
Placebo (n = 171)Median Survival: 21.7 Mos.
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HD IL-2 Therapy: Durable Responses
Atkins MB, et al. J Clin Oncol. 1999
Metastatic Melanoma (N = 270) Metastatic RCC (N = 255)
-HD IL-2 produces durable responses in 6% to 10% of patients with advanced melanoma or RCC-Few relapses in patients responding for over 2.5 years (likely cured)-FDA approval in 1992 (RCC) and 1997 (melanoma)
1.0
0.8
0.6
0.4
0.2
0.0Prob
abili
ty o
f Con
tinui
ng R
espo
nse
0 10 20 30 40 50 60 70 80 90 100 110 120 130
Duration of Response (Mos)
CR (n = 17)PR (n = 26)CR + PR (n = 43)
1.0
0.8
0.6
0.4
0.2
0.0Prob
abili
ty o
f Con
tinui
ng R
espo
nse
0 10 20 30 40 50 60 70 80 90 100 110 120 130
Duration of Response (Mos)
CRPR All
140 150 160 170 180
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Mellman et al. Nature 2011
Immunity in tumor control
Vaccines
Cytokines
Adoptive cell transfer
Immunomodulatory antibodies
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Turning up The Activating Blocking the Inhibiting
Ways to keeping the T cells “active”
Mellman et al. Nature 2011
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ARSS Question 1Which of the previously shown T cell co-regulatory targets has been targeted with FDA
approved antibodies?
1. CTLA-4
2. LAG-3
3. PD-1
4. CD 28
5. 1 and 3
6. 1, 3, and 4
7. 1, 2, 3, and 4
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Turning up The Activating Blocking the Inhibiting
Ways to keeping the T cells “active”
Mellman et al. Nature 2011
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DendriticCell T Cell
T-Cell Receptor
CD28
CTLA-4
B7
B7
Cytotoxic T Lymphocyte Antigen 4
MHC with Antigen
Lymph Node
Postow et al. JCO 2015
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DendriticCell T Cell
PD-L1/PD-L2
PD-1 Immune Checkpoints
TumorCD28B7
MHC and Antigen T-Cell Receptor
PD-1
PD-L1
PD-L1
PD-1 PD-L1
Lymph Node Tumor Microenvironment
PD-1
Postow et al. JCO 2015
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Blocking immunologic checkpoints
NivolumabPembrolizumab
PidilizumabIpilimumab and Tremelimumab
Kyi and Postow FEBS Letters 2014
MPDL3280AMEDI4736
MSB0010718C
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(1) Hodi et al. NEJM 2010(2) Hamid et al. NEJM 2013(3) Topalian et al. NEJM 2012(4) Weber et al. Lancet Oncol 2015(5) Kelly et al. JCO 2001
Adverse Events
• CTLA-4: Rash, diarrhea, hepatitis, endocrine– 24% grade 3/4 (1)
• PD-1/PD-L1: Rash, fatigue, arthralgias– 6-12% grade 3/4 (2-4)
• Chemotherapy: Alopecia, nausea, myelosuppression – ~50% grade 3/4 (5)
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Ipilimumab Rashes
Can be treated with topical corticosteroids
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Diarrhea and Colitis
Slangen et al., World J Gastrointest Pharmacol Ther, 2013
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Focal Active Colitis
Alterations in Crypt Epithelium
Maker AV, Ann Surg Oncol. 2005
Diarrhea and Colitis
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Weber et al. JCO 2012, reprinted from Blansfield J Immunother 2005
Enlarged pituitary due to hypophysitis
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Pneumonitis
3/30/20112/21/2011
Two doses of ipilimumab and four of nivolumab
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ARSS Question 2A 55 year old man has completed 3 doses of ipilimumab and
has developed significant diarrhea. Which do you recommend?
1. Ciprofloxacin and Flagyl
2. A several week course of oral steroids
3. Observation for 1 week, and then oral steroids only if worsening to avoid blunting of immunotherapy effect.
4. Infliximab
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Weber JS, J Clin Oncol 2012
Kinetics of irAEs with ipilumumab
Rash, pruritisLiver toxicityDiarrhea, colitisHypophysitis
Toxic
ity G
rad
e
Wks
14
0 2 4 6 8 10
12
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Diarrhea/Colitis Management
IPILIMUMAB
IPI
IPI
IPI
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Blocking immunologic checkpoints
NivolumabPembrolizumab
PidilizumabIpilimumab and Tremelimumab
Kyi and Postow FEBS Letters 2014
MPDL3280AMEDI4736
MSB0010718C
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Antibodies that block CTLA-4
Tremelimumab
Ipilimumab
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Median OS 10.1 mos
24% alive at 2 years
Hodi et al. NEJM 2010
Response rate of 10.9%
Ipilimumab confers OS benefit to gp100 vaccine in phase III study
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Long-term results of 2nd phase III study
Maio et al. J Clin Oncol 2010
Median OS 11.2 vs. 9.1 mosAt 5 years, 18.2 vs. 8.8% alive, p=0.002
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Ipilimumab “responses” can be delayed
10 mg/kg ipilimumab
Q3W X 4
Pre-treatment
Week 36: Still Regressing
Week 12: Progression
Week 20: Regression
New lesions
Wolchok ASCO 2008
July 2006
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Immune-related response criteria
• New lesions are not counted automatically as progressive disease.
• Increase in tumor burden must be confirmed on subsequent scan.
Wolchok et al. Clin Cancer Res 2009
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Blocking immunologic checkpoints
NivolumabPembrolizumab
PidilizumabIpilimumab and Tremelimumab
Kyi and Postow FEBS Letters 2014
MPDL3280AMEDI4736
MSB0010718C
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DendriticCell T Cell
PD-L1/PD-L2
PD-1 Immune Checkpoints
TumorCD28B7
MHC and Antigen T-Cell Receptor
PD-1
PD-L1
PD-L1
PD-1 PD-L1
Lymph Node Tumor Microenvironment
PD-1
Postow et al. JCO 2015
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PD-1/PD-L1 Agents in Development
Target Agent Class
PD-1
Nivolumab (MDX1106, BMS-936558)
IgG4 fully human Ab
Pembrolizumab (MK-3475)
IgG4 engineered humanized Ab
Pidilizumab (CT 011)‑ IgG1 humanized Ab
AMP 224‑ Fc of human IgG-PD-L2 fusion
PD-L1
BMS935559 (MDX 1105)‑ IgG4 fully human Ab
MPDL3280A IgG1 engineered fully human Ab
MEDI4736 IgG1 engineered fully human Ab
MSB0010718C IgG1 fully human Ab
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ARSS Question 3Which of the following statements about anti-PD-1 therapy in
melanoma is false?
1. Nivolumab has improved overall survival compared to dacarbazine.
2. Pembrolizumab has improved overall survival compared to ipilimumab.
3. Pembrolizumab has a higher rate of significant toxicity than ipilimumab.
4. Nivolumab and pembrolizumab are only available for patients who have progressed on ipilimumab and if relevant, a BRAF inhibitor.
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Responses with Nivolumab
Topalian et al, NEJM 2012Nivolumab: 1mg/kg every 2 weeks in melanoma patients
Response rate:~30%
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Nivolumab improves OS
Nivolumab vs. DTIC-- HR: 0.42
Ipi + DTIC vs. DTIC-- HR: 0.72
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Pembrolizumab: Clinical Activity Baseline: April 13, 2012
Images courtesy of A. Ribas, UCLA.
72-year-old male with symptomatic progression after bio-chemotherapy, HD IL-2, and ipilimumab
April 9, 2013
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Pembrolizumab improves OS compared to ipilimumab
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Drug Sponsor Target Disease Type Response (n) Reference
Nivolumab BMS PD-1
Solid Tumors 21% (42) Topalian et al. NEJM 2012
Melanoma 32% (44) Weber et al. JCO 2013
NSCLC 14% (63) Antonia et al. WCLC 2013
RCC 21% (168) Motzer et al. ASCO 2014
Ovarian 17% (18) Hamanishi ASCO 2014
Pembrolizumab Merck PD-1
Melanoma 40% (113) Daud et al. AACR 2014
NSCLC 19% (146) Gandhi et al. AACR 2014
Melanoma 34% (411) Ribas et al. ASCO 2014
NSCLC 26% (45) Rizvi et al. ASCO 2014
Head & Neck 18% (55) Selwert et al. ASCO 2014
CT-011 Curetech PD-1 Hematologic Cancers 33% (17) Berger et al. Clin Cancer Res 2008
Melanoma 6% (101) Atkins et al. ASCO 2014
AMP-224 Amplimmune/GSK
PD-1 Solid tumors Response, SD (42) Infante et al. ASCO 2013
Efficacy of PD-1 Agents
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Drug Sponsor Target Disease Type Response (n) Reference
Nivolumab BMS PD-1
Solid Tumors 21% (42) Topalian et al. NEJM 2012
Melanoma 32% (44) Weber et al. JCO 2013
NSCLC 14% (63) Antonia et al. WCLC 2013
RCC 21% (168) Motzer et al. ASCO 2014
Ovarian 17% (18) Hamanishi et al. ASCO 2014
Pembrolizumab Merck PD-1
Melanoma 40% (113) Daud et al. AACR 2014
NSCLC 19% (146) Gandhi et al. AACR 2014
Melanoma 34% (411) Ribas ASCO 2014
NSCLC 26% (45) Rizvi et al. ASCO 2014
Head & Neck 18% (55) Selwert et al. ASCO 2014
CT-011 Curetech PD-1 Hematologic Cancers 33% (17) Berger et al Clin Cancer Res 2008
Melanoma 6% (101) Atkins ASCO 2014
AMP-224 Amplimmune/GSK
PD-1 Solid tumors Response, SD (42) Infante et al. ASCO 2013
Efficacy of PD-1 Agents
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Drug Sponsor Target Disease Type Response (n) Reference
MPDL3280a Genentech PD-L1
Solid Tumors 21% (103) Herbst et al. ASCO 2013
Melanoma 23% (30) Hamid et al. ASCO 2013
NSCLC 23% (53) Sorial et al. ECC 2013
Bladder 26% (65) Powels et al. ASCO 2014
MEDI4736 MedImmune PD-L1
Solid Tumors 11% (179) Segal et al. ASCO 2014
NSCLC 16% (58) Brahmer et al ASCO 2014
Head & Neck 14% (22) Segal et al. ASCO 2014
Gastric 19% (16) Segal et al. ASCO 2014
MSB0010718C EMD Serono PD-L1 Solid tumors Response (27) Heery et al. ASCO 2014
MDX - 1105 BMS PD-L1 Solid Tumors 17% (135) Brahmer et al. NEJM 2012
Efficacy of PD-L1 Agents
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Drug Sponsor Target Disease Type Response (n) Reference
MPDL3280a Genentech PD-L1
Solid Tumors 21% (103) Herbst et al. ASCO 2013
Melanoma 23% (30) Hamid et al. ASCO 2013
NSCLC 23% (53) Sorial et al. ECC 2013
Bladder 26% (65) Powels et al. ASCO 2014
MEDI4736 MedImmune PD-L1
Solid Tumors 11% (179) Segal et al. ASCO 2014
NSCLC 16% (58) Brahmer et al ASCO 2014
Head & Neck 14% (22) Segal et al. ASCO 2014
Gastric 19% (16) Segal et al. ASCO 2014
MSB0010718C EMD Serono PD-L1 Solid tumors Response (27) Heery et al. ASCO 2014
MDX - 1105 BMS PD-L1 Solid Tumors 17% (135) Brahmer et al. NEJM 2012
Efficacy of PD-L1 Agents
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96 y.o. female– Progressed on previous cetuximab– HPV negative, PD-L1 positive– Treatment ongoing at 8 weeks
Segal et al., ASCO 2014
Baseline Day 28
Response in Patient with Head and Neck Cancer
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MPDL3280A: Urothelial Bladder Cancer
• Median time to first response was 42 days (range, 38 to 85 days)• Median duration of response has not been reached
Powles T, et al. ASCO 2014
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Pembrolizumab: AEs in > 5% of Patients
Adverse Event (N = 135) All Grades, n (%) Grades 3/4, n (%)
Any 107 (79.3) 17 (12.6)
Fatigue 41 (30.4) 2 (1.5)
Rash 28 (20.7) 3 (2.2)
Pruritus 28 (20.7) 1 (0.7)
Diarrhea 27 (20.0) 1 (0.7)
Myalgia 16 (11.9) 0
Headache 14 (10.4) 0
Increased AST 13 (9.6) 2 (1.5)
Asthenia 13 (9.6) 0
Nausea 13 (9.6) 0
Vitiligo 12 (8.9) 0
Hypothyroidism 11 (8.1) 1 (0.7)
Increased ALT 11 (8.1) 0
Cough 11 (8.1) 0
Pyrexia 10 (7.4) 0
Chills 9 (6.7) 0
Abdominal pain 7 (5.2) 1 (0.7)
Ribas A, et al. ASCO 2013
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PD-L1 tumor cell membranestaining: 5%,
heterogeneous0 80%,
homogeneous3%, focal
PD-L1 Negative PD-L1 Positive
Slide courtesy of Margaret Callahan
Immunohistochemistry for PD-L1 expression
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ARSS Question 4Which of the following statements about PD-L1 is
true?
1. PD-L1 is required to benefit from anti-PD1 therapy.
2. PD-L1 is required to benefit from ipilimumab.
3. PD-L1 is tested using similar methodology across clinical trials.
4. PD-L1 may reflect an immunologically active tumor
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Nivolumab in NSCLC: PD-L1 is not associated with overall survival
PD-L1 +
PD-L1 -
Julie Brahmer ASCO 2014
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PD-L1 ≠ EGFR, BRAF, HER2, ER, KRAS
• Many different assays measure PD-L1 differently
• PD-L1 negative tumors can still respond
• PD-L1 is a dynamic immunologic marker
• Heterogeneity exists within individual patients [1]
[1] Madore et al. Pigment Cell Melanoma Res 2014
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Pretreatment immunologic biomarkers
Square peg into a round hole?
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Immune Checkpoint CombinationsChemotherapy
Carboplatin/Paclitaxel (Lynch et al., J Clin Oncol 2012)
Anti-angiogenic agentsBevacizumab (Hodi et al., Cancer Immunol Res 2014)
Hormonal TherapyExemestane (Vonderheide et al., Clin Cancer Res 2010)Androgen deprivation (MDACC)
Targeted therapyVemurafenib (Ribas et al., NEJM 2013)
Other immunotherapyGM-CSF (Hodi et al., JAMA 2014)Nivolumab (Wolchok et al., NEJM 2013)
RadiotherapyPostow et al. NEJM 2013
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Ipilimumab + Nivolumab
Therapy, % ORR
Ipilimumab 7
Nivolumab 28
Combination 42
Wolchok et al., NEJM 2013
First occurrence of new lesion
Cohort 2: 1 mg/kg nivolumab + 3 mg/kg ipilimumab
All patients in concurrent cohorts 250
200
150
100
50
0
-50
-100C
han
ge in
targ
et
lesio
ns
from
baselin
ePatients
300250200150100
50
-20
-40
-60
-80
-100
0
Chan
ge in
targ
et le
sion
s fr
om
base
line
(%)
0 10 20 30 40 50 60 70 80 90 100 110 120
Weeks since treatment initiation
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• Proof-of-concept for the promise of immune checkpoint blocking antibodies
• Durable responses in melanoma and other cancers
• Biomarkers inform biology but not yet treatment selection
• Combinations may be better than single agent
Summary
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• How should we target the next T cell co-regulatory receptors?
Future Questions
Mellman et al. Nature 2011
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• How should we target the next T cell co-regulatory receptors?
• What endpoints should the FDA consider for regulatory approval?
Future Questions
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• How should we target the next T cell co-regulatory receptors?
• What endpoints should the FDA consider for regulatory approval?
• Can targeting T-cells enhance other cancer therapeutics?
Future Questions
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1891 to 2015
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1891 to 2015
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Postow M, et al. New Engl J Med 2012
Case reports of the abscopal effect