TKCC/Garvan Cancer Biology Seminars Melanoma & Cancer Immunotherapy

19/02/2016

A/Prof Anthony Joshua Head, Dept of Medical Oncology

St Vincent’s Hospital, Sydney

ImmunotherapyProgress:ALongTimeComing

Joost W et al. Nature Reviews Drug Discovery;10:591-600, 2011.

ThreeRequirementsforSpontaneousorTherapeu;cImmuneResponse

Immunization T-cell response

Overcome Immune

Suppression

Mellman, Coukos, Dranoff. Nature 2011;480:480-489

ImmunotherapyBalance

•  Anti-Cancer – Lymphocytes (CD8

T cells) – Cytokines: IFN-γ,

IL2 – Dendritic cells (DC) – CD40, OX40, TLR

•  Tumor Promoting – Lymphocytes (T reg) – Cytokines: TGF-beta,

IL-10, IDO – Suppressive

macrophage – CTLA-4, PD1, LAG3,

TIM3

TumorAn;gens Tissue associated antigens

•  MART1, gp100, tyrosinase; PSA, her2/neu, mesothelin, CEA, folate receptor-α

Oncofetal/cancer-testis •  MAGE family •  BAGE family •  GAGE family •  NY-ESO-1

Universal Antigens •  Survivin, hTERT

Neo-antigens •  CDK4, β-catenin, mutated introns •  New sequences resulting from mutations

MSLawrenceetal.Nature000,1-5(2013)doi:10.1038/nature12213

Soma>cmuta>onfrequenciesobservedinexomesfrom3,083tumor-normalpairs.

TumorswithaHighMuta;onalLoad

[TITLE]

Presented By Padmanee Sharma, MD, PhD at 2013 ASCO Annual Meeting

ImmuneCheckpointPathways

CentralLoca;onAn;gen-Presen;ngCell

CTLA-4Blockade(ipilimumab) PD-1Blockade(nivolumab)CTLA-4Blockade(ipilimumab) PD-1Blockade(pembrolizumab,nivolumab)

Presented By Jedd D. Wolchok, MD, PhD at 2013 ASCO Annual Meeting

1stGenerationAgents

ImprovedSurvivalwithIpilimumab(An;-CTLA-4)

•  Stage IV or unresectable Stage III Melanoma

•  Now Health Canada approved 1st line

Long-termSurvivalin4846Metasta;cMelanomaPa;entsTreatedwithIpilimumab

Pa;entsatRiskIpilimumab 4846 1786 612 392 200 170 120 26 15 5 0

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 84 96 108 120

Ipilimumab

CENSORED

Median OS, months (95% CI): 9.5 (9.0–10.0) Pooled Data: Phase II, III, EAP

3-year OS rate, % (95% CI): 21 (20–22)

Prop

or;o

nAlive

Months

Schadendorf, Hodi FS, Robert et al. ESMO 2013

Gattinoni et al. Nature Reviews Immunology 6: 383–393, 2006.

Adop;veCellTherapy(ACT)withTIL

NCI Strategy !• Highly selected TIL!• Rapid expansion protocol!

Lymphodepletion: Cytoxan/Fludarabine!

- Increase IL2, IL7, IL15 availability!- Reduce regulatory T cells!

Administration of high dose IL-2!- Toxic, but fewer doses given!

Rosenberg,AACRAnnualMee>ng,2014

TILTherapyAcrosstheWorld

1)  Dudley/Rosenberg - 50-70% response rates, 22% complete responses (years)

2)  Besser/Schacter – 40-50% response rates (57, 5 CR 18, PR) 10% CR

3)  Radyvani/Hwu – 48% response rates (15/31, 2 CR) 4)  Ellebaek/Svane – 30% response rates (2/6, 2 CR)

5)  Pilon-Thomas/Sarnaik – 38% response rates (13 patients; 2 CR, 3 PR

6)  Princess Margaret – Canadian trials initiated

2ndGenerationAgents

Robert C et al. N Engl J Med 2015;372:320-330

Original Article Nivolumab in Previously Untreated Melanoma without BRAF Mutation

UPDATE-the2-yearOSratewithfrontlinenivolumabwas57.7%comparedwith26.7%fordacarbazine.

Characteristics of Response.

Robert C et al. N Engl J Med 2015;372:320-330

Case

Presentation

•  41yearoldpreviouslywell

•  Irregularlesiononrightthighforapproximately12months

•  Shavebiopsy3.2mm,ulcerated,mitoticrate3/mm2,followedbyWLEandSNB(0/2)

•  DeterminedtobeBRAFNeg,NRAS+ve

MetastaticPresentation

•  InitialCTsclear

•  1yearpostdiagnosisnotedtohavenewmetastaticinfrahilarnode(1.4cm),6mmRLL

nodule

•  ReferredforPETscan/EBUS-+veformelanoma

Movingtowardstherapy

•  ShortintervalCTdemonstratedrighthilarnode(15mm),rightfissuralnodule,RLL

noduleallincreasinginsize

•  Alsonewrightinguinalnode(16mm)

Pretreatment 2 Months

PartialResponse(78%decreaseinindexlesion@2months):

TILpa;ent1:Clinicalresponse

Otherlesions@2months:Pulmonarynodules-stableRighthilarnodes–absentSubcutlesionRtupperthigh-absent

AfterTILinfusion:Diseaseprogression@6months.Ipilimumab(progression).Pembrolizumab(response).

Clinical Experience With NIVO Plus IPI Combination

•  Phase I study of NIVO plus IPI in advanced melanoma:1,2 –  ORR up to 53% (CR rate of 18%) –  2-year OS rate up to 88%

•  Phase II study of NIVO plus IPI in untreated melanoma:3 –  ORR of 61% with the combination vs. 11% for IPI alone; CR rate of 22% with

the combination –  Treatment-related grade 3–4 adverse events (AEs): 54% for the combination

vs. 24% for IPI

•  In the above studies, response rates were similar regardless of PD-L1 expression1-3

1. Wolchok et al. N Engl J Med 2013;369:122-33; 2. Oral presentation by Dr. Mario Sznol at the ASCO 2014 Annual Meeting; 3. Postow et al. N Engl J Med 2015;372:2006-17.

28

CA209-067: Study Design

29

Randomized, double-blind, phase III study to compare NIVO + IPI or NIVO alone to IPI alone

Unresectable or Metatastic Melanoma

•  Previously untreated

•  945 patients

Treat until progression**

or unacceptable

toxicity

NIVO 3 mg/kg Q2W + IPI-matched placebo

NIVO 1 mg/kg + IPI 3 mg/kg Q3W for 4 doses then

NIVO 3 mg/kg Q2W

IPI 3 mg/kg Q3W for 4 doses +

NIVO-matched placebo

Randomize 1:1:1

Stratify by:

•  PD-L1 expression*

•  BRAF status

•  AJCC M stage

*Verified PD-L1 assay with 5% expression level was used for the stratification of patients; validated PD-L1 assay was used for efficacy analyses.

**Patients could have been treated beyond progression under protocol-defined circumstances.

N=314

N=316

N=315

PFS (Intent-to-Treat)

NIVO + IPI (N=314)

NIVO (N=316)

IPI (N=315

)

Median PFS, months (95% CI)

11.5 (8.9–16.7)

6.9 (4.3–9.5)

2.9 (2.8–3.4)

HR (99.5% CI) vs. IPI

0.42 (0.31–0.57)*

0.57 (0.43–0.76)*

--

HR (95% CI) vs. NIVO

0.74 (0.60–0.92)**

-- --

*Stratified log-rank P

Response to Treatment

NIVO + IPI (N=314)

NIVO (N=316)

IPI (N=315)

ORR, % (95% CI)* 57.6 (52.0–63.2)43.7 (38.1–

49.3)19.0 (14.9–

23.8) Two-sided P value vs IPI

Tumor Burden Change From Baseline

NIVO + IPI Median change: -51.9%

NIVO Median change: -34.5%

IPI Median change: +5.9%

Confirmed responder 30% reduction in tumor burden by RECIST v1.1

32

Bas

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(%)

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ons

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155 171 164

91 97 47

32 34 16

113 115 83

78 83 36

1 1

4 7 3

No. at Risk NIVO + IPI

NIVO IPI

0

0 3 6 9 12 15 18 21 Months

Prop

ortio

n al

ive

and

prog

ress

ion-

free

1.0

0.8

0.6

0.4

0.2

0.0 NIVO + IPI NIVO IPI

0 3 6 9 12 15 18

0.2

0.4

0.6

0.8

1.0

0.0

PFS by PD-L1 Expression Level (1%)

Prop

ortio

n al

ive

and

prog

ress

ion-

free

NIVO + IPI NIVO IPI

123 117 113

65 42 19

26 13 5

82 50 39

57 34 12

0 0

6 2 0

No. at Risk NIVO + IPI

NIVO IPI

Months

mPFS HR

NIVO + IPI 12.4

0.44

NIVO 12.4 0.46

IPI 3.9 --

mPFS HR

NIVO + IPI 11.2

0.38

NIVO 2.8 0.67

IPI 2.8 --

PD-L1 ≥1%* PD-L1

Safety Summary

Patients Reporting Event, %

NIVO + IPI (N=313) NIVO (N=313) IPI (N=311)

Any Grade

Grade 3–4

Any Grade

Grade 3–4

Any Grade

Grade 3–4

Treatment-related adverse event (AE) 95.5 55.0 82.1 16.3 86.2 27.3

Treatment-related AE leading to discontinuation 36.4 29.4 7.7 5.1 14.8 13.2

Treatment-related death* 0 0.3 0.3

*One reported in the NIVO group (neutropenia) and one in the IPI group (cardiac arrest).

34

•  67.5% of patients (81/120) who discontinued the NIVO + IPI combination due to treatment-related AEs developed a response

AdoptiveTcelltherapy

•  UnderwentResectionofinguinalnode

•  UnderwentApharesis

•  AdmittedforTreatment6weekslaterforTILtherapy

•  Fludarabine/CyclophosphamidethereaftersubcutaneousIL2

Recovery

•  Recoveredwell,playinghockey

•  Remainsonpneumocystisprophylaxis

•  CTscansshowsignificantimprovement3

monthsposttreatment

Relpase

•  RestagingMRIalsodemonstratesa1.1cmprecentralbrainlesion

•  TreatedwithSRS9monthsfromTILStherapy

Relapse2

•  Restagingdemonstrateda4.9X1.8cmrightdiaphragmaticmassalongwithgrowthinthe

RLLnodule

RESPONSE

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PeripheralBlood1W 4W

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ResponsetoPembrolizumab

Baseline

Otherpoints

43

ProgressionversusPseudo-progression

Ribas A et al. Clin Cancer Res 2009;15:7116-7118©2009 by American Association for Cancer Research

45

irAEsObservedwithNovelImmuno-oncologyTherapy

Ifnotvigilant,mayresultinmoreseriousimmune-relatedadverseevents

Endocrine • Headache• Visualchanges• Fever• Fatigue/weakness• Confusion

Neurologic • Sensoryormotorneuropathy

• Muscleweakness• Fatigue• Difficultywakingup

Hepatic • AbnormalLFTs(eg,AST,ALT,totalbilirubin)

Skin • Skinrashorpruritus

Gastrointestinal (GI) • Diarrhea• Stomachpain• Nausea/vomiting/pain• Bloodinstool• Constipation

ALT:alanineaminotransferaseAST:aspartateaminotransferaseirAE:immune-relatedadverseevent

Perc

ent a

live

Immunotherapy Targeted therapy

1 2 Years

3 0 1 3 0 2 Years

Combination

1 3 0 2 Years

Combining immunotherapy and targeted therapy for melanoma?

Perc

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