Immuno-Oncology of Renal Canceroncologypro.esmo.org/content/download/69823/1244759/file/2015... · Trial landscape for Immune Checkpoint Inhibitors in RCC ... 276 265 245 233 210

The Christie NHS Foundation Trust

Immuno-Oncology ofRenal Cancer

Dr Fiona ThistlethwaiteConsultant Medical Oncologist and Honorary Senior Lecturer

The Christie NHS Foundation Trust and University of Manchester

•


Disclosures

Advisory role

Nordic, BMS

Travel, accommodation, Expenses

Ipsen, BMS

Research collaborations

Adaptimmune

MedImmune


Introduction• Renal cell carcinoma (RCC) accounts for

2-3% malignant diseases in adults

• 115,000 new cases in Europe in 2012

• Nephrectomy can be curative for earlystage disease but most patients developmetastatic disease

• 30% at diagnosis• 30% relapse

• RCC has long been recognized as apotential target for immunotherapy

• Observation that it is one of themost common tumour types toundergo spontaneous regression(Bumpus 1928)


Interferon alpha (IFN- )

IFNMPA

Events Total152163

174176

0.0

0.2

0.4

0.6

0.8

Pro

port

ion

aliv

e 1.0

Months0 12 24 36

REO1: IFN- vs Medroxyprogesterone acetate(MPA)1 year survival 43% IFN- 32% MPA

2 year survival 22% IFN- 13% MPAOS HR: 0.75 (95% CI 0.60-0.94, p=0.013)


FDA approved high dose il-2 in 1992

14% response rate withdurable responses in a small percentage ofpatients

Difficult to give

Focus on a selectedgroup•Clear cell •Nephrectomy•Good risk disease•Lung metastasis


Milestones in RCC

1983

1984

1993

SorafenibSunitinib

PazopanibAxitinib

Everolimus

TemsirolimusBevicizumab +IFN


Immune System and Potential for Intervention

T reg cellCD25+CD4+FoxP3

CTL

APC

B7.1

CD28

T cell

T cell

CTLA4

B7.1

MHCAPC

CTL

IL-2

IL-2

CTLA4 B7.1

Vaccination

Interference withRegulationeg CTLA4

CytokineIL2

Depletion ofTregs

Interference with Regulation

eg PD1/PDL1Adoptive Cell therapy


Immune Checkpoint Blockade

Ribas NEJM 2012


Immune Checkpoint inhibitorsin RCC

Target Drug Company

CTLA4 Ipilimumab BMS

Tremelimumab MedImmune/AZ

PD1 Nivolumab (BMS-936558) BMS

Pembrolizumab (MK-3475) Merck

Pidilizumab (CT-011) Teva/CureTech

AMP-224 GSK/Novartis

AMP-514 MedImmune/AZ

PDL1 Atezolizumab (MPDL3280A) Genentech/Roche

Duvalumab (MEDI4736) MedImmune/AZ

BMS-936559 BMS


Immune Checkpoint inhibitorsin RCC

• ClinicalTrials.gov >450 trials of ‘immune agents’in RCC

• All stages of clinical development • Biomarker studies• Phase I-III• Combination studies


Trial landscape for Immune Checkpoint Inhibitors in RCC

Based on Grunwald ECC 2015Clin trials.gov

Phase I Phase 2 Phase 3Nivolumab

•Monotherapy•Combination with ipilimumab orsunitinib or pazopanib

Nivolumab•Monotherapy•Monotherapy, biomarker study

Nivolumab•2L monotherapy vs everolimus•1L combination with ipilimumab•2L+ safety study (Ph4)

Nivolumab•Combination with other I-O agents in solid tumours

Atezolizumab•Monotherapy•Combination with bevacizumab•Combination with IFN- -2b•Combination with other I-O and non-I-O agents in solid tumours

Atezolizumab•1L monotherapy with bevacizumab

Atezolizumab•1L combination with bevacizumab

Pidilizumab•Combination with dendritic cellvaccine

Pembrolizumab•2L combination with ipilimumab or peg IFN- -2b (Ph1/2)

•1L monotherapy or combination with pazopanib (Ph1)•Combination with targeted agents in solid tumours (Ph1/2)

Durvalumab•Combination with tremelimumab and other I-O in solid tumours (Ph1)•Monotherapy in solid tumours including RCC (Ph 1/2)

PDR001•Combination with I-O in solid tumours including RCC (Ph 1/2)

CheckMate 025: A randomized, open-label, phase III study ofnivolumab versuseverolimus in advancedrenal cell carcinoma

Padmanee Sharma, Bernard Escudier, David F. McDermott, Saby George, Hans J. Hammers, Sandhya Srinivas, Scott S. Tykodi, Jeffrey A. Sosman,

Giuseppe Procopio, Elizabeth R. Plimack, Daniel Castellano, Howard Gurney, Frede Donskov, Petri Bono, John Wagstaff, Thomas C. Gauler, Takeshi Ueda,

Li-An Xu, Ian M. Waxman, Robert J. Motzer, on behalf of the CheckMate 025 investigators

13

Study design

Nivolumab 3 mg/kg intravenously

every two weeks

Nivolumab 3 mg/kg intravenously

every two weeks

Everolimus10 mg orally

once daily

Everolimus10 mg orally

once daily

Ran

do

miz

e 1:

1

• Patients were treated until progression or intolerable toxicity occurred

• Treatment beyond progression was permitted if drug was toleratedand clinical benefit was noted

MSKCC, Memorial Sloan-Kettering Cancer Center.

▪ Primary endpoint

▪ Overall survival (OS)

▪ Secondary endpoints included

▪ Objective response rate (ORR)

▪ Progression-free survival (PFS)

▪ Adverse events

▪ Quality of life (QoL)

▪ OS by PD-L1 expression

Study endpoints

•14

•15

Overall survivalMedian OS, months (95% CI)

Nivolumab 25.0 (21.8–NE)Everolimus 19.6 (17.6–23.1)

HR (98.5% CI): 0.73 (0.57–0.93)P = 0.0018

0 3 6 129 15

Months

18 21 24 27 30 33

No. of patients at riskNivolumab 410 389 359 337 305 275 213 139 73 29 3 0

411 366 324 287 265 241 187 115 61 20 2 0Everolimus

0.0

0.3

0.1

0.2

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Ove

rall

Su

rviv

al (

Pro

bab

ility

)

Nivolumab

Everolimus

Minimum follow-up was 14 months.

NE, not estimable.

Overall survival by subgroup analysesSubgroup

Nivolumabn/N

Everolimusn/N

MSKCC risk group

Favorable 45/145 52/148

Intermediate 101/201 116/203

Poor 37/64 47/60

Prior anti-angiogenic regimens

1 128/294 158/297

2 55/116 57/114

Region

US/Canada 66/174 87/172

Western Europe 78/140 84/141

Rest of the world 39/96 44/98

Age, years

<65 111/257 118/240

≥65 to <75 53/119 77/131

≥75 19/34 20/40

Sex

Female 48/95 56/107

Male 135/315 159/304

•16Nivolumab

•0.25 •0.5 •0.75 •1.5 •2.25•1

EverolimusFavors

•Analyses based on interactive voice response system data.

Overall survival by PD-L1 expressionPD-L1 <1% (n = 76%)

Median OS, months (95% CI)Nivolumab 21.8 (16.5–28.1)

Everolimus 18.8 (11.9–19.9)

No. of patients at riskNivolumab 94 86 79 73 66 58 45 31 18 4 1 0Everolimus 87 77 68 59 52 47 40 19 9 4 1 0

0.0

0 3 6 129 15

Months

18 21 24 27 30 33

0.3

0.1

0.2

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Ov

era

ll S

urv

ival

(P

rob

ab

ility

)

Nivolumab

Everolimus

PD-L1 ≥1% (n = 24%)

•17

Median OS, months (95% CI)

Nivolumab 27.4 (21.4–NE)

Everolimus 21.2 (17.7–26.2)

276 265 245 233 210 189 145 94 48 22 2 0299 267 238 214 200 182 137 92 51 16 1 0

Nivolumab

0 3 6 129 15

Months

18 21 24 27 30 33

0.3

0.1

0.2

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0.0

Everolimus

HR (95% CI): 0.79 (0.53–1.17) HR (95% CI): 0.77 (0.60–0.97)

•18

Antitumor activity

Nivolumab

N = 410Everolimus

N = 411

Objective response rate, % 25 5

Odds ratio (95% CI)P value

5.98 (3.68–9.72)<0.0001

Best overall response, %Complete responsePartial responseStable diseaseProgressive diseaseNot evaluated

1

2434356

15

552812

Median time to response,months (range)

3.5 (1.4–24.8) 3.7 (1.5–11.2)

Median duration of response,months (range)*

12.0 (0–27.6) 12.0 (0–22.2)

Ongoing response, n/N (%) 49/103 (48) 10/22 (45)

*For patients without progression or death, duration of response is defined as the time from the first response(CR/PR) date to the date of censoring.

•19

Response characteristics

0 16 32 6448 80

Time (Weeks)96 112 128

Re

spo

nd

ers

Ongoing response

First responseOff treatment

Nivolumab

EverolimusOn treatment

Progression-free survival

No. of patients at riskNivolumab 410 230 145 116 81 66 48 29 11 4 0Everolimus 411 227 129 97 61 47 25 16 3 0 0

0 3 6 129 15Months

18 21 24 27 30

0.0

0.3

0.1

0.2

0.4

0.5

0.6

0.7

0.8

0.9

1.0P

rog

ress

ion

-Fre

e S

urv

ival

(P

rob

abili

ty)

Nivolumab

Everolimus

Median PFS, months (95% CI)

Nivolumab 4.6 (3.7–5.4)Everolimus 4.4 (3.7–5.5)

HR (95% CI): 0.88 (0.75–1.03)P = 0.1135

In a post-hoc analysis of patients who had not progressed or died at 6months, median PFS was 15.6 months for nivolumab vs 11.7 months foreverolimus (HR (95% CI): 0.64 (0.47–0.88)) •20

•21

Safety Summary

NivolumabN = 406

EverolimusN = 397

Any Grade Grade 3-4 Any Grade Grade 3-4

Treatment-related AEs, % 79 19 88 37

Treatment-related AEsleading to discontinuation, % 8 5 13 7

Treatment-related deaths, n 0 2a

•a Septic shock (1), bowel ischemia (1).

44% of patients in the nivolumab arm and 46% of patients in theeverolimus arm were treated beyond progression

•22

Change from baseline in quality of lifescores on FKSI-DRS

Questionnaire completion rate: ≥80% during the first year of follow-up.

• Mea

n C

han

ge

Fro

m B

asel

ine

Nivolumab

Everolimus

40 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72 76 80 84 88 92 96 100 104

Week

-6

0

-4

-2

2

4

6

No. of patients at riskNivolumab 362 334 302 267 236 208 186 164 159 144 132 119 112 97 90 89 81 72 63 59 53 44 43 31 30 26 20Everolimus 344 316 270 219 191 157 143 122 102 97 87 74 73 63 58 49 44 35 30 28 24 21 15 12 12 9 9

Wo

rse

Bet

ter

▪ Mean change from baseline in the nivolumab group increased over timeand differed significantly from the everolimus group at each assessmentthrough week 76 (P<0.05)

▪ CheckMate 025 met its primary endpoint, demonstratingsuperior OS with nivolumab versus everolimus (25.0 vs19.6 months)

▪ This is the only phase III trial to demonstrate a survivaladvantage in previously-treated patients with mRCC versusstandard therapy

▪ Nivolumab was associated with fewer grade 3 and 4treatment-related AEs compared to everolimus andimprovement in QOL

▪ ORR 25% vs 6 % but CR rate low at only 1% in each arm

•23

Conclusions (1)

▪ Practice changing for 2nd line therapy forRCC

▪ Still many unanswered questions forimmunotherapy in RCC▪ Checkpoint inhibitor drugs▪ Other immunotherapy approaches

What is the impact of Checkmate 025?

•24

▪ Checkpoint inhibitors in1st line therapy?▪ Combination therapy?▪ Treatment beyond progression?▪ Next generation targets?

Unanswered questions for checkpointinhibitor drugs in RCC

•25

T cell targets

•26

Mellman et al Nature Vol 480 2011

▪ Checkpoint inhibitors in 1st line therapy?▪ Combination therapy?▪ Treatment beyond progression?▪ Next generation targets?▪ Immunotherapy biomarkers in RCC?▪ What about patients who do not respond?▪ How long to continue checkpoint inhibitors?▪ What about the adjuvant setting?


•27

▪ Checkpoint inhibitors in1st line therapy?▪ Combination therapy?


•28

•29

•30

▪ 10 most common treatment related AEs

•31

Ipi+Nivo vs Sunitinib Phase III in Front-line mRCC

•32

•aStratified by International Metastatic RCC Database Consortium (IMDC) prognostic score (0 vs 1–2 vs 3–6) and by region (US vs Canada/Europe vs rest of world)•bPatients may continue treatment beyond progression (Response Evaluation Criteria in Solid Tumors [RECIST] v1.1) if investigator-assessed clinicalbenefit is achieved and the treatment is well tolerated

• Treatment-naïveadvanced ormetastatic RCC

• Measurabledisease

• KPS > 70%

Arm A3 mg/kg nivolumab IV + 1mg/kg ipilimumab IV Q3W

for four doses, then 3mg/kg nivolumab IV Q2W

Arm B50 mg sunitnib PO once

daily for 4 weeks followedby 2 weeks of, every cycle

• Primary: PFS and OS in intermediate- and poor-risk patients• Secondary:ORR in intermediate- and poor-risk patients; PFS, OS, and ORR inany-risk patients, AEs

Atezolizumab in RCC

•33

Atezolizumab in Rcc

•34

Atezolizumab in RCC

•35

Atezolizumab in Combination with Bevacizumab vsSunitinib: Phase III Study in Untreated Advanced RCC

Primary endpoints: PFS per RECIST v.1.1 via central ICR assessment

Secondary endpoints: PFS using investigator assessment per immune-related criteria,ORR, duration of response, OS, duration of response and PFS in patients progressing onsunitinib and MPDL alone arms who subsequently cross over to combination, safety, PKof MPDL3280A alone and in combination with bevacizumab

Eligibility Locally advanced or

mRCC with clear-cell and/orsarcomatoidcomponent

Previouslyuntreated with anysystemic therapy

Karnofsky PS ≥70

MPDL3280A +bevacizumab

RANDOMIZATION

•N=550

Sunitinib

•36

▪ What about 1st line therapy?▪ Combination therapy?▪ Treatment beyond progression?


•37

▪ With immunotherapy, tumor flare (growth of existing lesions or theappearance of the new lesions) may precede antitumor effects1

▪ This phenomenon may result in RECIST–defined progression leadingto premature discontinuation of therapy

Tumor flare with immunotherapy

•381. Wolchok JD et al. Clin Cancer Res. 2009;15:7412-7420.

Study design

aStratified by Memorial Sloan Kettering Cancer Center (MSKCC) risk group and number of prior therapies in metastatic setting.

0.3, 2, or 10 mg/kg

of nivolumab IV Q3W

0.3, 2, or 10 mg/kg

of nivolumab IV Q3WR

an

do

miz

e 1:

1:1aKey Criteria

•mRCC with clear-cell component•≥1 prior anti-angiogenic agent •Karnofskyperformance status(KPS) ≥70%

Key Criteria•mRCC with clear-cell component•≥1 prior anti-angiogenic agent •Karnofskyperformance status(KPS) ≥70%

Treat untilprogression or

intolerabletoxicity

Endpoints•Primary: Doseresponse by PFS•Key secondary:PFS, ORR, OS,safety

•39

• Treatment beyond progression was permitted if nivolumabwas tolerated and clinical benefit was noted

Motzer RJ. J Clin Oncol 2015.

Tumor burden change from first progression inpatients treated beyond progression

•40

Patients

40

20

–20

–40

–60

–80

–100

0

Ch

ang

e F

rom

Pro

gre

ssio

n (

%)

•+ Indicates patient who had at least a 20% increase in target lesions at time of first progression.


Immune System and Potential for Intervention

T reg cellCD25+CD4+FoxP3

CTL

APC

B7.1

CD28

T cell

T cell

CTLA4

B7.1

MHCAPC

CTL

IL-2

IL-2

CTLA4 B7.1

Vaccination

Interference withRegulationeg CTLA4

CytokineIL2

Depletion ofTregs

Interference with Regulation

eg PD1/PDL1Adoptive Cell therapy


Other approaches• Vaccination

• Autologous/allogeneic RCC vaccination• Dendritic cell vaccines• Heat Shock protein vaccines• Peptide (eg IMA901 Immatics NCT01265901)• DNA/RNA viral vaccines (eg TroVax NCT00397345)

• T cell therapy• Depletion of Treg (Thistlethwaite Can Immunol Immunother 2008)

• CAR/TCR

• TIL

An open-label, randomized, phase 3 studyinvestgatng IMA901 multpeptde cancer vaccinein combinaton with sunitnib vs. sunitnib alone as

frst-line therapy for metastatc RCC

B. Rini1, A. Stenzl2, R. Zdrojowy3, M. Kogan4, M. Shkolnik5, S. Oudard6, S. Weikert7, S. Bracarda8, S. Crabb9, J. Bedke2, J. Ludwig10, D. Maurer10, R.

Mendrzyk10, A. Mahr10, J. Fritsche10, T. Weinschenk10, H. Singh10, A. Kirner10, C. Reinhardt10, T. Eisen11

•1Cleveland Clinic Taussig Cancer Center, Cleveland, USA; 2University of Tuebingen, Tuebingen, Germany; 3Wroclaw MedicalUniversity, Wroclaw, Poland; 4Rostov State Medical University of Roszdrav, Rostov-on-Don, Russia; 5Russian Scientfc Centerof Radiology and Surgery Technologies, St. Petersburg, Russia; 6Hopital Europeen Georges Pompidou, Paris, France; 7Vivantes

Humboldt Clinic, Berlin, Germany; 8Ospedale San Donato, Arezzo, Italy; 9Southampton General Hospital, Southampton, UK;10immatcs biotechnologies GmbH, Tuebingen, Germany; 11University of Cambridge, Cambridge, UK

IMA901 multi-peptide cancer vaccine

Selecton of IMA901 peptdes (9 HLA-A2, 1 pan-DR) based on over-expression of peptdes in tumors and proof of immunogenicity

•*Weinschenk et al., Cancer Res2002

IMA901 phase 2 results

Second-line mRCC pts (n = 68) were randomized to receive or notcyclophosphamide (Cy) prior to vaccinaton with IMA901

Patents who have received Cy and had T cell responses to IMA901showed longer survival

•*Walter et al., Nature Med. 2012

Study Design

1,171 pts screened 366 started 1st sunitnib cycle (HLA-A2-negatvity main exclusion) 339 pts randomized

Study was not blinded

IMA901 plus GM-CSF (i.d.)

R3:2

Sunitinib

Cyclophosphamide(300 mg/m2 x 1)

SunitinibSunitinib (1 cycle)

• IMDC risk group• Nephrectomy• Region

• 1st-line metastatic ccRCC• HLA-A*02-positive• Fav. / Inter. risk (IMDC)

Overall Survival

•# n.r. = not reached* logRank statified on risk group

•HR: 1.34 p = 0.08*

Con: Median OS: n.r.#

Vac: Median OS: 33.1 mo

All patients

Con: 33.7 mo

Vac: n.r.

•HR: 0.82 p = 0.59**

Favorable

Con: n.r.

Vac: 27.8 mo

•HR: 1.52 p < 0.05**

Intermediate

•** unstratified logRank

Immune-response correlation

• No signifcant OS associaton with immune responses observed

• The comparable survival in immune responder vs. non-

responders argues against a harmful efect of the vaccinaton•* unstratified LogRank

Immune responders(≥2 TUMAP)

HR: 0.92 p = 0.84*

Immune responders(min. 1 TUMAP)

HR: 0.68 p = 0.18*

Summary and Conclusions

• No improvement of OS when adding IMA901 to 1st line sunitnib

• An overall favorable safety profle of IMA901 was confrmed

• IMA901 with sunitnib resulted in impaired immune responses

• Specifc T cells with 3-fold lower frequency compared to phase 2

• No clear associaton of (weak) T cell responses with clinical outcome

• Immune responses need to be signifcantly improved before

further development of IMA901 is indicated


Interleukin-2 (IL2)

• Cytokine• Regulator of immune system• T-cell growth factor

• T-cell activity• NK cell activity

• Noted to result in tumourregression in mouse models


Treatment Effects

0 3 hours 6 hours 8 hours

IL2 Infusion

39°C

37°CBP120

80

•Fluid 50 100 150 200 200 150 100 50

IL2 Infusion

http://bp0.blogger.com/_E_CvZl9kH9Q/RsixZHCO4MI/AAAAAAAAAEA/TQQKsSsK5Y0/s1600-h/30072007+q+hosp.jpg


HD IL2 toxicities• Fever• Hypotension• Tachycardia• Malaise

• Capillary leak syndrome• Oliguria• Nausea/vomiting• Diarrhoea• Thrombocytopenia

• Thyroid dysfunction• Arrhythmias• Myocarditis• Transaminitis• Confusion/hallucinations


Significant responses


HD IL2 for RCC at The Christie180 consecutive patients

Group A: First Line (2003 – 2013)

Group B: After VEGFtargeted therapy (2007-2013)

Total(%)

ORR(%)

CR (%) Total(%)

ORR(%)

CR (%)

Whole cohort 145 62 (43) 30 (21) 35 13 (37) 6 (17)

Pathology-basedselection ‘Favourable’ ‘Other’

127 (88)18 (12)

59 (46)3 (17)

29 (23)1 (6)

31 (89) 4 (11)

13 (42)0

6 (19)0

Professor Hawkins and the RCC DG


OS – Response (favourable group)

Group A (first line) Group B (post first line)

P<0.001*** P<0.001***


TIL for Renal Cancer

0 5 10 150

20

40

60 V1V6V12V13V14V15

Days after iniation of REP

Nu

mb

er o

f ce

lls (

x106 )

0

10000

20000

30000

40000

T cells aloneAutologous tumour

*** *** ***

IFN

rele

ase

(pg

/ml)

• 6 TIL subjected to Rapid expansion mimicking the process required to generate sufficient TIL for clinical use

• Where autologous tumour was available – all samples maintained anti-tumour specificity as determined by interferon gamma release when co-cultured with autologous tumour


Conclusions• Renal cancer is at the centre of the

immunotherapy for cancer revolution• Still searching for the Holy Grail of maximum

durable response rate, with limited toxicities• HDIL2 in RCC can achieve the former but at the

cost of the later• Checkpoint inhibitors are shaping the future of

mainstream treatment for RCC• How they will be combined together/with

cytokines/with small molecues/Tcell therapyremains to be defined


Any Questions?

[email protected]

Documents

Immuno-Oncology of Renal Canceroncologypro.esmo.org/content/download/69823/1244759/file/2015... · Trial landscape for Immune Checkpoint Inhibitors in RCC ... 276 265 245 233 210