advances in cancer immunotherapy for solid tumors in immunotherapy... · 2016-06-10 · advances in...

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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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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