advances in cancer immunotherapy for solid tumors in immunotherapy... · 2016-06-10 · advances in...
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Advances in Cancer Immunotherapy for
Solid TumorsExpert Perspectives on The
New DataSunday, June 5, 2016
Supported by an independent educational grant from AstraZeneca
Not an official event of the 2016 ASCO Annual Meeting
Not sponsored or endorsed by ASCO or the Conquer Cancer Foundation
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• This slide deck in its original and unaltered format is for educational purposes and is current as of Sunday, June 5, 2016. The content and views presented in this educational activity are those of the authors/presenters and do not necessarily reflect those of Creative Educational Concepts, Inc. or the supporter.
• These materials may discuss therapeutic products that have not been approved by the US Food and Drug Administration and off-label uses of approved products. A qualified healthcare professional should be consulted before using any therapeutic product discussed. Readers should verify all information and data before treating patients or employing any therapies or strategies described in this educational activity.
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1. Evaluate the principles of tumor immunology and the mechanisms of action of current and emerging cancer immunotherapies used in solid tumors.
2. Appraise the latest clinical trial data regarding emerging cancer immunotherapies in SCCHN, NSCLC, mesothelioma, gastric cancer, melanoma, and other solid tumors, including use of both monotherapy and combination regimens.
3. Explore the role of biomarkers in patient selection to improve targeted use of immune checkpoint inhibitors.
4. Identify practical strategies for using current and emerging cancer immunotherapies, including prevention, early detection, and management of immune-related adverse effects.
Learning Objectives
Advances in Immunotherapy for Solid TumorsExpert Perspectives on Applying The Latest Data to Clinical Practice
Antoni Ribas, MD, PhD Professor of MedicineProfessor of SurgeryProfessor of Molecular and Medical PharmacologyDirector, Tumor Immunology Program, Jonsson Comprehensive Cancer CenterUniversity of California Los AngelesChair, Melanoma Committee at SWOGLos Angeles, CA
• I consult for Advaxis, Compugen, CytomX, Five Prime, and FLX Bio
• I am a major stockholder in Kite Pharma• I am not on any scientific advisory boards• I am not a member of any speakers’ bureau
Disclosures
Immune Checkpoint Blockade
Results in Melanoma
Study Drug Control Tx
Ribas 2013 Tremelimumab Temozolomide or dacarbazine
Hodi 2010 Ipilimumab +/- gp100 gp100
Robert 2011 Ipilimumab + dacarbazine Dacarbazine + placebo
Weber 2015 Nivolumab Dacarbazine or paclitaxel + carboplatin
Ribas 2015 Pembrolizumab Chemotherapy
Robert 2015 Nivolumab Dacarbazine
Total (95% Cl)
Anti-CTLA-4 and Anti-PD-1 TrialsMeta-Analysis: PFS
0.2 0.5 1 2 5Favors immune
TxFavors control
Tx
Risk ratioM-H, Random, 95% Cl
Yun S, et al. Cancer Med. 2016.
P=.0004
Study Drug Control Tx
Ribas 2013 Tremelimumab Temozolomide or dacarbazine
Hodi 2010 Ipilimumab +/- gp100 gp100
Robert 2011 Ipilimumab + dacarbazine Dacarbazine + placebo
Robert 2015 Nivolumab Dacarbazine
Total (95% Cl)
Anti-CTLA-4 and Anti-PD-1 TrialsMeta-Analysis: OS
0.2 0.5 1 2 5Favors immune
TxFavors control
Tx
Risk ratioM-H, Random, 95% Cl
Yun S, et al. Cancer Med. 2016.
P=.001
Robert C, et al. N Engl J Med. 2015.
NivolumabBRAFwt Untreated Melanoma
Robert C, et al. N Engl J Med. 2015.
Pembrolizumab vs IpilimumabAdvanced Melanoma
Ove
rall
Surv
ival
(%)
Month
Pembrolizumab, Q3W
Pembrolizumab, Q2W
Ipilimumab
Efficacy in 611 patients
Ribas A, et al. JAMA. 2016.
Pembrolizumab KEYNOTE 001
As of October 18, 2014; median follow-up: 21 monthsCentral radiology review by RECIST v1.1
ORR: 33%ORR in previously untreated: 45%
Ipilimumab treatedIpilimumab naive
Chan
ge fr
om B
asel
ine,
%
-100
-80
-60
-40
-20
0
20
40
60
80
100
Kaplan-Meier estimates of duration of response among responders in the total population (n=205) and the treatment-naive population (N=65), as assessed by RECIST v1.1 by independent central review for patients with confirmed response who had ≥1 dose of study treatment
Ribas A, et al. JAMA. 2016.
KEYNOTE 001 Duration of Response
Prob
abili
ty o
f Sur
viva
l
Months
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
0 12 24 36 48 60 72 846 18 30 42 54 66 78
Database lock Oct 2015
107 6486 51 49 41 29 031543 36 17 12 1Number of Patients at Risk
All Patients
All Patients (events: 69/107), median and 95% CI: 17.3 (12.5–37.8)
NIVO 3 mg/kg (events: 11/17), median and 95% CI: 20.3 (7.2–NR)
17 1115 9 8 7 6 167 6 6 6 0NIVO 3 mg/kg
Hodi FS, et al. AACR. 2016. (Abstract CT001)
Nivolumab Follow-upOverall Survival at 5 Years
Immune CheckpointsManaging Toxicities
PembrolizumabirAEs with Incidence >5%
Adverse Event, N (%)
TotalN=411 Adverse Event,
N (%)
TotalN=411
Any Grade Grade 3/4 Any Grade Grade 3/4
Fatigue 36 2 Myalgia 9 0
Pruritus 24 <1 Headache 8 <1
Rash 20 <1 Hypothyroidism 8 <1
Diarrhea 16 <1 Decreased appetite 7 <1
Arthralgia 16 0 Dyspnea 7 <1
Nausea 12 <1 Chills 6 0
Vitiligo 11 0 Pyrexia 6 0
Asthenia 9 0 ALT increased 5 <1
Cough 9 0 Total 83 12Similar safety profiles in IPI-N and IPI-T patientsRibas A, et al. ASCO. 2014.
KEYNOTE-001
• CBCs, metabolic panels, LFTs and thyroid function tests should be obtained at each treatment and q6-12 wks for 6 mos post-treatment in all pts receiving checkpoint inhibiting antibodies.
• ACTH and cortisol should also be checked in pts with fatigue and nonspecific symptoms, plus testosterone in men.
• Frequency of follow-up testing should be adjusted to individual response and AEs that occur.
• Corticosteroids can reverse nearly all toxicities associated with these agents, but should be reserved for grade 3/4, or prolonged grade 2, irAEs.
Immune Checkpoints Toxicity Management Guidelines
Weber JS, et al. J Clin Oncol. 2015.
• Pulmonary• Hepatic• Renal • GI• Endocrine• Neurological
Immune Checkpoints Toxicity Management
irAEs Requiring Greater Vigilance And Early Intervention
Checkpoint InhibitionManaging Gr 3/4 Treatment-Related irAEs
*In pts with liver metastasis who begin treatment with Grade 2 elevation of AST/ALT.†Pts receiving ipilimumab may tolerate treatment with PD-1/PD-L1 inhibitor alone.
‡Steroids do not appear to accelerate the rate of improvement.
FDA Pembrolizumab, Nivolumab, Ipilimumab Prescribing Information.
Grade 3/4 pneumonitis, nephritis, enterocolitis, hepatitis, or infusion-related reactionNew or worsening neuropathyAny life-threatening or Grade 4 AEAny severe or Grade 3 recurrent AE
Hepatitis associated with:AST/ALT > 5 x ULNAST/ALT ≥ 50% ↑ from baseline lasting ≥ 1 wk* Total bilirubin > 3 x ULN
Initiate steroid therapy
Permanently discontinue a PD-1 tx
If no improvement in colitis or
pneumonitis, infliximab or
mycophenolate†
If no improvement in hepatitis,
consider mycophenolate;
infliximab contraindicated
Grade 4 elevation of pancreatic enzymes
Usually resolves with tx
interruption‡
Immune Checkpoint Blockade irAEs and Response to Therapy Frequent Development Of Vitiligo (Skin Depigmentation) In Responding Patients
PD-1 Blockade irAEs and Response to Therapy
Disappearance of a Pigmented Birth Mark
Before After
PD-1 BlockadeBiomarkers of Response
• A T-cell specific for cancer− Have the appropriate TCR to specifically recognize cancer
cells− Have been licensed to kill that cancer− Be turned off by PD-1:PD-L1 interaction
• A cancer cell that is recognized by the T-cells− The cancer cell needs to have antigens that differentiate it
from normal cell (eg, neoantigens, viral antigens, shared tumor antigens)
− The cancer cell needs to be sensitive to T-cell attack− The cancer needs to be limiting T-cells through the PD-
1:PD-L1 interaction
PD-1 BlockadePrerequisites for Killing Cancer
Dendritic cell
MHC TCR
B7
Lymph node
T cell
Signal 1Signal 2
Inhibitor of signal 2
Cancer
MHC
CD28
TCR
PD-L1PD-1
Anti-PD-1Anti-PD-L1
Tumeh et al. Nature 2014
Melanoma cell or tumor macrophage
Interferons
PD-1 blockadeInhibiting Adaptive Immune Resistance
Anti-PD-1Anti-PD-L1
Tumeh et al. Nature 2014
Melanoma cell or tumor macrophage
Interferons
PD-1 blockadeInhibiting Adaptive Immune Resistance
Tumeh PC, et al. Nature. 2014.
Inhibiting Adaptive Immune ResistancePD-1 Blockade-Induced Responses
Progression
Melanoma cellor tumor macrophage
Interferons
Melanoma cellor tumor macrophage
Hypothesis formulated based on quantitative IHC analyses of 46 cases from UCLA PD
-L1
PD-1
CD8
Response
Pt CD8+ Density, Invasive Margin Before Tx
Predicted Prob. of Response Blinded Prediction
1 58 0.35 Progression
2 159 0.37 Progression
3 329 0.4 Progression
4 341 0.41 Progression
5 2120 0.75 Response
6 5466 0.98 Response
7 2211 0.76 Response
8 3810 0.92 Response
9 4294 0.95 Response
10 4948 0.97 Response
11 5565 0.98 Response
12 6004 0.99 Response
13 5951 0.99 Response
14 7230 0.99 Response
15 6320 0.99 Response
Predicting Responses Gustave Roussy Validation Set
Paul C. Tumeh, UCLA; Christine Mateus, Caroline Robert, Gustave Roussy
Pt CD8+ Density, Invasive Margin Before Tx
Predicted Prob. of Response Blinded Prediction Clinical Response
(RECIST 1.1)1 58 0.35 Progression Progression
2 159 0.37 Progression Progression
3 329 0.4 Progression Progression
4 341 0.41 Progression Progression
5 2120 0.75 Response Response
6 5466 0.98 Response Progression
7 2211 0.76 Response Response
8 3810 0.92 Response Response
9 4294 0.95 Response Response
10 4948 0.97 Response Response
11 5565 0.98 Response Response
12 6004 0.99 Response Response
13 5951 0.99 Response Response
14 7230 0.99 Response Response
15 6320 0.99 Response Response
Predicting Responses Gustave Roussy Validation Set
Paul C. Tumeh, UCLA; Christine Mateus, Caroline Robert, Gustave Roussy
0.35
0.3
0.25
0.2
0.15
0.1
0.05
0
0 0.1 0.2 0.3 0.4 0.5
TCR ClonalityPembrolizumab
Tumeh PC, et al. Nature. 2014.
TIL
infil
trat
e (r
earr
ange
men
ts/g
enom
e)
Clonality
Only progressors in bottom left quadrant
(below median Clonality and % T cell) P=0.005 by
Fisher’s Exact
Progressors (N=13)Responders (N=12)
Response ProgressionCl
onal
ity
**
0.4
0.3
0.2
0.1
IFN SignaturePembrolizumab
Ribas A, et al. ASCO. 2015.
Nonresponder Responder0.8
1.0
1.2
1.4
1.6
1.8
2.0
2.2
2.4 Best Overall Response, RECISTv1.1
PDL AmpliconNivolumab
Ansell SM, et al. N Engl J Med. 2015.
chr9:5,270,000PDL1 PDL2
chr9:5,700,000
PDL1/2 Gain
PDL1/2 Amplification
RP11-599h20 RP11-635N21
100 kb
Mutational LoadPembrolizumab
Rizvi NA, et al. Science. 2015; Le DT, et al. N Engl J Med. 2015.
All Tumors
# N
onsy
nony
mou
s mut
atio
ns/t
umor
1200
800
400
200
0DCB NDB
P=.02
Som
atic
mut
atio
ns p
er tu
mor
5000
4000
3000
2000
1000
0
Progressive Disease
ObjectiveResponse
StableDisease
PD-1 BlockadeMesenchymal Transcriptome
Hugo W, et al. Cell. 2016.
JAEGER_METASTASIS_UPMAPKi_INDUCED_EMT (*FDR=0.9)LEF1_UP.V1_UP (*FDR=0.11)POOLA_INVASIVE_BREAST_CANCER_UPYE_METASTATIC_LIVER_CANCERANASTASSIOY_CANCER_MESENCHYMAL_TRANSTITIONALCHARAFE_BREAST_CANCER_BASAL_VS_MESEN(*FDR=0.24)MAHADEVAN_GIST_MORPHOLOGICAL_SWITCHVECCHI_GASTRIC_CANCER_ADVANCED_VS_EARLY_UPLIEN_BREAST_CARCINOMA_METAPLASTICLU_TUMOR_ENDOTHELIAL_MARKERS_UPLU_TUMOR_VASCULATURE_UPLU_TUMOR_ANGIOGENESIS_UPROY_WOUND_BLOOD_VESSEL_UP (*FDR=0.05)MAPKi_INDUCED_ANGIOGENESIS (*FDR=0.11)EP_BLOOD_VESS_DEVIL_DN_IN_RWESTON_VEGFA_TARGETS_12HR (*FDR=0.11)WESTON_VEGFA_TARGETS_6HRMAINA_VHL_TARGETS_DNMS_RESP_TO_HYPOXIA_UP_IN_MAPKi_aPDL1_NRHARRIS_HYPOXIAKARAKAS_TGFB1_SIGNALINGJEON_SMAD6_TARGETS_DNPOST_OP_WOUNDHEALINGMISHRA_CARCINOMA_ASSOCIATED_FIBROBLAST_UPMS_RESP_TO_WOUNDHEALING_UP_IN_MAPKi_aPDL1_NR DER_IFN_GAMMA_RESPONSE_UPDER_IFN_ALPHA_RESPONSE_UPDER_IFN_BETA_RESPONSE_UPGRANDVAUX_IFN_RESPONSE_NOT_VIA_IRF3ZHANG_INTERFERON_RESPONSENATSUME_RESPONSE_TO_INTERFERON_BETA_UPRADAEVA_RESPONSE_TO_IFNA1_UPMOSERLE_IFNA_RESPONSESANA_RESPONSE_TO_IFNG_UPHECKER_IFNB1_TARGETS
Inte
rfero
n in
duce
dW
ound
heal
ing
TGFβ
Hypo
xia
Angi
ogen
esis
EMT/
M
etas
tasis
Non-responding (n=13) Responding (n=15)
Row Z-score
-2 -1 0 1 2
Future Cancer Management Post-Anti-PD-1/PD-L1 Era
Anti-PD-1/anti-PD-L1
Generate T cells:
+ Anti-CTLA4+ Immune activating antibodies or cytokines+ TLR agonists or oncolytic viruses+ IDO or macrophage inhibitors+ Targeted therapies
Bring T cells into tumors:
+ Vaccines+ TCR engineered ACT+ CAR engineered ACT
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