renal cell cancer and prostate cancer: clinical ... · instituto de biomedicina de sevilla (ibis)...

Renal Cell Cancer

and Prostate

Cancer: Clinical

Development in I-O

Ignacio Duran, MD, PhDDepartment of Medical Oncology

Hospital Univ. Virgen del RocíoInstituto de Biomedicina de Sevilla (IBIS)

Seville, Spain

Disclosures

• I have participated in compensated advisory boards for Roche and BMS

• I have received speaker honoraria from Roche, BMS and MSD

Aims & Objectives

• To be able to understand the rationalebehind immunotherapy in renal cell cancer(RCC) and metastatic prostate cancer (mPC)and to be up-to-date with the most recentclinical data in these two settings

Immunotherapy in RCC: Does it

make sense?Clinical

perspective

Biological perspective

1. Fyfe G, et al. J Clin Oncol 1995;13:688-696.2. Escudier B, et al. J Clin Oncol 2009;27:1280-1289.3. Motzer RJ, et al. J Clin Oncol 2007;25(Suppl):Abstract 5024.4. Hudes G, et al. N Engl J Med 2007;356:2271-2281.

5. Escudier B, et al. Lancet 2007;370:2103-2111.6. Motzer RJ, et al. Cancer 2010;116:4256-4265.7. Sternberg CN, et al. J Clin Oncol

2010;28:1061-1068.8. Rini BI, et al. Lancet 2011;378:1931-1939.

High-dose interleukin-

21

Sorafenib2

IFN-α

Sunitinib3

Bevacizumab + IFN-α5

Temsirolimus4

Pazopanib7

Everolimus6

Axitinib8

1992-2005 2005 2006 2007 2008 2009 2010 2011 2012

Clinical Analysis: Treatment

evolution in the last 2 decades

Treatment Algorithm; 2000`s

Setting Agent

Treatmen

t-naїve

Good or intermediate

risk

Sunitinib

Bevacizumab + IFN-α

Pazopanib

Poor risk Temsirolimus

1. Ljungberg B, et al. Eur Urol 2010;58:398-406.2. Escudier B, et al. Ann Oncol 2012;23(Suppl7):vii65-

vii71.

Previously

treated

Prior cytokine

Prior VEGFR-TKI

Prior mTOR inhibitor

PazopanibSorafenibAxitinib

EverolimusAxitinib

No recommendation

Treatment Revolution but …• In the first decade of the 2000’s we witnessed a

treatment revolution in mRCC

• Responses, PFS improvement, some long responders

• However, that initial excitement progressivelydiminished as some barriers appeared

• No clear benefit in OS both in 1st/2nd Line [exc Tem]

• Toxicity as a limiting factor

• Primary Refractories to 1st line

• Scarce improvement in 2nd Line

• PFS ~5 mos, OS ~ 15-20 mos

Treatment Revolution but …• In the first decade of the 2000’s we

witnessed a treatment revolution in mRCC

• Responses, PFS improvement, some longresponders

• However, that initial excitementprogressively diminished as some barriersappeared

• No clear benefit in OS both in 1st/2nd Line[exc Tem]

• Toxicity as a limiting factor• Primary Refractories to 1st line• Scarce improvement in 2nd Line:

• PFS ~5 mos, OS ~ 15-20 mos

RCC and the immune system: A

strange couple

• RCC is an immunogenic cancer and is frequentlyinfiltrated with immune cells, including macrophagesand T lymphocytes

• Different from other tumor types, higher TumorInfiltrating Lymphocytes [TILs] correlated with poorerprognosis and shorter survival in RCC

• The mechanism underpinning the controversialpathophysiologic significance of TILs in RCC remainsunclear

Fridman WH, Pages F ,Sautes-Fridman C ,Galon J. Theimmune contexture in human tumours: impact on clinical outcome. Nat Rev Cancer

2012; 12:298–306. 2 Nakano O, Sato M, et al. Proliferative activity of intratumoral CD8(þ) T-lymphocytes as a prognostic factor in human

renal cell carcinoma: clinicopathologic demonstration of antitumor immunity. Cancer Res 2001;61: 5132–6. 3.

RCC and the immune system: A

strange couple

• Primary tumors from patients with mRCC treated withantiangiogenics showed increased CD4 and CD8 T-lymphocyte infiltration compared with that in uninvolvedtissue and untreated controls

• This finding was inversely correlated with patient overallsurvival (OS) and progression-free survival (PFS)

• T-lymphocyte infiltration was correlated with infiltration ofimmunosuppressive Tregs and upregulation of thecheckpoint ligand PD-L1

Xian-De Liu1, Anh Hoang1, Lijun Zhou et al. Cancer Immunol Res; 3(9) September 2015

Both sunitinib- and bevacizumab-treated cases showed increased CD3+ T-

lymphocyte infiltration relative to untreated primary RCC controls: 19.3% and 16.6%

versus 11.3% (P < 0.01) and increased CD45RO+ T-lymphocyte infiltration:2 7.2%

and 24.3% versus 16.8% (P < 0.01)

Xian-De Liu1, Anh Hoang1, Lijun Zhou et al. Cancer Immunol Res; 3(9) September 2015

More T Lymphocytes worse?

Why?

• The answer could be in Tregs, a subset of CD4+ T lymphocytes that express FOXP3

• T regs are going to inhibit the function of effector T Lymphocytes or induce their apoptotic death

• Patients treated with Sunitinib with shorter OS or PFS showed higher infiltrating Tregs.

• Analyses revealed that inpatients treated withantiangiogenics a highconcentration ofCD4+/CD8+ T Lymphocytescorrelated with worseoutcome

• Why?

Antiangiogenics promote PD-L1

expression

Both sunitinib and bevacizumab treated cases showed increased expression of PD-L1 relative to that of untreated RCC controls: 8.0% and 6.3% versus 1.3% (P < 0.01),respectively

Correlation between CD8+T-lymphocyte infiltration andPD-L1 expression in sunitinibtreatedsamples [IF gammasecretion?]

Antiangiogenic therapy increased

T-lymphocyte infiltration to

eliminate cancer cells. [altough

also increases Tregs]

Antiangiogenic therapy promotes

tumorigenesis by generating an

immunosuppressive tumor

microenvironment with PD-L1

upregulation.

Rationale of immunotherapy in

mRCC

Combination or sequencing therapy with antiangiogenics and with

anti–PD-L1 /PD-1 therapy will reactivate tumor-infiltrating T cells to

exert anticancer cytotoxicity.

From the rationale to the clinicCheckMate 025:

A randomized, open-label, phase III

study of nivolumab versus

everolimus in advanced RCC

Previously treated mRCC

anti-angiogenic therapies

Previously treated mRCC

1-2 prev tx lines

Stratification factorsRegion

MSKCC risk group

Number of prior anti-angiogenic

therapies

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 tolerated and clinical benefit was noted

• 1ary end-point: OS; 2ary end-points: ORR, PFS, QoL, AEs,

NivolumabN = 410

EverolimusN = 411

MSKCC risk group, %Favorable IntermediatePoor

354916

364915

# of prior anti-angiogenic regimens, %12

7228

7228

Nivolumab

n=410

Everolimus

n=411

Confirmed Investigator Confirmed Investigator

Objective response rate, % (95%

CI)*21.5 25 3.9 5

Complete response 0.7 1 0.5 1

Partial response 20.7 24 3.4 5

Stable disease 35.9 34 54.5 55

Progressive disease 33.2 35 25.5 28

Median duration of response,

months (range)† 23.0 (12.0–NE) 12.0 (0–27.6) 13.7 (8.3–21.9) 12.0 (0–22.2)

Any Grade

Grade 3-4

Any Grade

Grade 3-4

Treatment-related AEs, %

79 19 88 37

TOXICITY BY

DRUG Nivolumab

Everolimus

CheckMate 025: PFS and OS

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

Number of patients at riskNivolumab41023014511681 66 48 29 11 4 0Everolimus411227129 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

1.0

Pro

gre

ssio

n-f

ree

surv

ival

(p

rob

abili

ty)

Median PFS, months (95% CI)

Nivoluma

b4.6 (3.7–5.4)

Everolimu

s4.4 (3.7–5.5)

HR 0.88, 95% CI 0.75–1.03, P=0.11

Based on data cut-off of June 2015.

CI, confidence interval; OS, overall survival; PFS, progression-free survival.

Motzer et al. N Engl J Med. 2015;373(19):1803-1813.

Adapted from Motzer et al, 2015.

18

Number of patients at riskNivolumab41038935933730527521313973 29 0Everolimus41136632428726524118711561 20 0

0 3 6 129 15Months

18 21 24 27 33

0.0

0.3

0.1

0.2

0.4

0.5

0.6

0.7

0.8

0.9

1.0

30

Ove

rall

surv

ival

(p

rob

abili

ty) Median OS, months (95% CI)

Nivoluma

b25.0 (21.7–NE)

Everolimu

s19.6 (17.6–23.1)

HR 0.73, 95% CI 0.57–0.93, P=0.002

32

27% reduction in the risk of death

Long-Term Efficacy of Nivolumab in

pretreated RCC patients from Phase

I and II Studies: OS

• In phase I and II studies, minimum follow-up was 50.5 months and 49.2 months, respectively

34 28 24 18 14 13 12 12 11 8 6 6 2 1 0

16

7

14

2

11

3

93 80 65 58 51 47 2 0 0 0 0 0

Number of patients at risk

Phase I

Phase II

StudyMedian OS,

months (95% CI)

Phase I Checkmate 003

22.4 (12.5–NE)

Phase II Checkmate 010

23.4 (17.7–26.9)

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0 6 12 18 24 30 36 42 48 54 60 66 72 78 84

Ov

era

ll s

urv

iva

l (p

rob

ab

ilit

y)

Months

38%

29%

34%

CI, confidence interval; NE, not estimable; OS, overall survival.

McDermott DF et al. Oral presentation at ASCO 2016. 4507.

Adapted from McDermott et

al, 2016.

19

Long Tail of I-O

More to come: Clinical Research

with I-O in 1st Line

Eligibility:

• Locally advanced or mRCC

• Previously untreated with any systemic therapy

• Karnofsky PS ≥70Sunitinib

50 mg PO daily, 4 weeks on/2 weeks off

Phase III

N=1070

CheckMate214 - NCT02231749: Combination PD-1 + CTLA-4 inhibition

RANDOMIZATION

• Co-Primary endpoint: PFS, OS

Eligibility:

• Locally advanced or mRCC with clear-cell and/or sarcomatoidcomponent


• Karnofsky PS ≥70

Sunitinib


Phase III

N=900

IMmotion 151 - NCT02420821: Combination PD-L1 + VEGF inhibition

RANDOMIZATION


Eligibility:

• Locally advanced or mRCC with clear cell component



Sunitinib


Phase III

N=583

Javelin Renal 101 - NCT02684006: Combination PD-L1 + VEGFR TKI

RANDOMIZATION

• Primary endpoint: PFS

BID, twice daily; IV, intravenous; mRCC, metastatic renal cell carcinoma; OS, overall survival; PO, orally; PFS, progression-free survival; PS, performance status; q2w, every 2 weeks; q3w, every 3 weeks.

Information collected from Clinicaltrials.gov. 20

Nivolumab + Ipilimumab

3mg/kg IV + 1mg/kg IVevery 3 weeks X4

then Nivolumab 3mg/kg IV q2w

Atezolizumab + Bevacizumab

1200 mg IV +15 mg/kg IV q3w

Avelumab + Axitinib

10mg/kg IV q2w+ 5mg PO BID

Clinical Research with I-O in 1st

Line

Eligibility:

• Advanced/mRCC, predominantly clear cell histology


• Karnofsky PS ≥70Sunitinib

Phase III

N=450

ADAPT - NCT01582672: Autologous Dendritic Cell Vaccine

RANDOMIZATION

• Primary endpoint: OS

BID, twice daily; IV, intravenous; mRCC, metastatic renal cell carcinoma; OS, overall survival; PO, orally; PFS, progression-free survival; PS, performance status; q3w, every 3 weeks.

Information collected from Clinicaltrials.gov.

Eligibility:

• Advanced/mRCC with clear cell component



Sunitinib


Phase III

N=840

KEYNOTE 426 - NCT02853331: Pembrolizumab + Axitinib

RANDOMIZATION


Pembrolizumab + Axitinib

200 mg IV every 3 weeks +5 mg PO BID

21

Eligibility:

• Advanced/mRCC with clear cell component


• Karnofsky PS ≥70 Sunitinib


Phase III

N=735

NCT02811861: Lenvatinib + Everolimus or Pembrolizumab

RANDOMIZATION

• Primary endpoint: PFS

Lenvatinib + Everolimus

18 mg PO daily +

5 mg PO daily

Lenvatinib + Pembrolizumab

20 mg PO daily +

200 mg IV q3w

AGS-003

8 intradermal injections in first year

followed by quarterly boosters

Conclusions• There is a biologic rationale to support the clinical

development of immunotherapy alone or in combinationin mRCC

• Targeting immune checkpoint pathways has beenconfirmed as a valid strategy with improvement in ORRand OS in patients with mRCC upon progression toprevious therapy and currently represents one of theoptions in this setting

• Multiple studies are ongoing testing combinations ofdiverse strategies and their results might change thetherapeutic scenario

Prostate Cancer and

Immunotherapy:Does it make sense?

Sisyphys (1548–49) Titian. Prado Museum

Is it the search of Immunotherapy in PC

a useless task as Sisyphu’s?

Probably not, but the work needs to be refined

Four active IT have been developed and tested

Anti-CTLA-4

Cell based vaccines [GVAX]

Viral Vector Based [Prostvac]

Autologous Vaccines

Anti-CTLA-4 failed to demonstrate an

OS benefit in docetaxel pretreated

Post Docetaxel mCRPC

N=799

Single dose

Bone-

directed RT

(8Gy)

Ipilimumab (10mg/kg)

Wks 1,4,7,10


Every 12 wks

Placebo

Wks 1,4,7,10

Placebo

Every 12 wks

Patients stratified by investigator site, Alkaline

Phosphatase, Hemoglobin and ECOG PS

Treatment until disease

progression or intolerable toxicity

Primary endpoint: OS

Secondary: PFS & safety

Exploratory: PSA reduction

mOS: 12.2m vs. 10.m

HR: 0.85, 95%CI: 0.72-1.00; p=0.053mPFS: 4m vs. 3.1m

HR: 0.70, 95%CI: 0.61-0.82; p<0.0001

Kwon, E.D. The Lancet 2014

PSA reduction in 13.1% of patients on Ipilimumab

CA184-043 Ipilimumab Phase 3 trial after Docetaxel

non-visceral mCRPC

N=400R2:1


Wks 1,4,7,10


Every 12 wks

Placebo

Wks 1,4,7,10

Placebo

Every 12 wks

Patients stratified by investigator site, pain

none vs. minimal, hemoglobin, LDH and ECOG

PS

Treatment until disease

progression or intolerable toxicity

Primary endpoint: OS

Secondary: PFS, T to subsequent systemic therapy, pain progression & safety

Exploratory: PSA reduction

mOS: 21.7m for placebo

No significant OS benefit

Beer, T. M. J Clin Oncol 2017

PSA reduction in 23% vs. 8% of patients on Ipilimumab & placebo, respectively

mFU 2yrs

mPFS: 5,6m vs. 3.8m

Anti-CTLA-4 failed also to demonstrate

an OS benefit in chemonaiveCA184-095 Ipilimumab Phase 3 trial in chemo-naïve pts

Prostate Cancer and Immunotherapy

…The first-in-human trial for ipilimumab was performed in metastatic castration-resistant prostate cancer (mCRPC) and showed early clinical efficacy, including prostate-specific antigen (PSA) modulation, and in some cases, objective response

Kim W and Fong L, J Clin Oncol. 2017; Small EJ, Tchekmedyian NS, Rini BI, et al: A pilot trial of CTLA-4 blockade with human

anti-CTLA-4 in patients with hormone-refractory prostate cancer. Clin Cancer Res 13:1810-1815, 2007

Other negative story: Cell-Based

Vaccines

GVAX was developed by using an androgen-sensitive and an

mCRPC cancer cell line (LNCaP and PC-3, respectively), and

expressing GM-CSF

Cell-based Vaccines

• VITAL-1 and VITAL-2 were studies testing GVAX in different settings

• Neither trial was able to show an OS advantage for GVAX

• Both studies were prematurely terminated

• VITAL-1 due to efficacy concerns (a less than 30 % chance of

meeting an improved survival)

• VITAL-2 due to an increased mortality rate in the GVAX plus

docetaxel arm (67 deaths) compared to the D/P arm (47

deaths)

Genitourinary Cancer Symposium: Proc Am Soc Clin Oncol. 2009 abstract # LBA150.

American Society of Clinical Oncology–Genitourinary Cancers Symposium; 2009. p. 26–8.Fernadez EM, Vera-Badillo F et al. Clin Transl Oncol (2015) 17:339–357

Viral Vector based-vaccines: Promising

A gene is inserted into a recombinant virus vector, often a

poxvirus. The Ags encoded in the viral vector (with or without co-

stimulatory molecules) will then be lysed and taken up by APCs,

which will present their peptides to CD4 and CD8 T cells.

Viral Vector based-vaccines:

Promising

Previous positive results in Phase II

[Recently updated]

Kantoff P et al. J Clin Oncol, Vol 35, No 1 (January 1),

2017: pp 124-125

Phase III data expected to be released Q2-3 2017

Autologous vaccines: Sipuleucel-T

1

2

The vaccine process

includes the collection of

the patient’s peripheral

dendritic cells via

leukapheresis and its

incubation with a fusion

protein (PA2024)

composed of PAP (which

targets the IR to PC cells)

and granulocyte/

macrophage-colony

stimulating factor (GM-

CSF) (which enhances the

IR)

US Food and Drug Administration. FDA labelling information—Provenge. FDA website [online]. 2010.

“Sipuleucel-T represents the first cell based immunotherapy

able to demonstrate an improvement in OS in cancer patients,

opening a new treatment paradigm”

Immunotherapy in Prostate Cancer

Kantoff PW, Higano CS, Shore ND, et al: Sipuleucel-T immunotherapy for

castration-resistant prostate cancer. N Engl J Med 363:411-422, 2010

Should we keep on trying?

Mercader, M. Proc Natl Acad Sci USA. 2001; Bronte V. JEM 2005

Androgen ablation induces CD3+ T cell infiltration of the

prostate at glandular and intratumoral sites

T cells infiltrate within treated prostate tissues

are comprised predominantly of CD4 T cells

Higher expression of NOS2 & ARG2 in PC tissues than in tumor-free prostatic tissues

Somebody believe so…

• Atezolizumab• Atezo + RAD-223• Atezo +

Enzalutamide• Atezo +

Sipuleucel-T

Source: Clinical Trials.Gov January 2017

Pembrolizumab• Pembro after [docetaxel;

Enzalutamide]

• Pembro + [Olaparib; Enzalutamide]

• Pembro + pTVG-

HP Plasmid DNA Vaccine

• Pembro + RT

• Nivolumab• Nivo in mCRPC with DNA

repair defects

• Nivo in mCRPC with AVR-7

• Nivo + Prostvac

• Nivo + Ipililumab

• Durvalumab• Durva + Tremelimumab

• Durva in mCRPC with DNA

repair defects

• Durva + Olaparib

• Durva + Vaccines

Summary

• Immunotherapy has a rationale in prostate cancer

• Nevertheless, the different strategies tested so far havehad variable degrees of success

• Toxicity remains an issue with some compounds such asAnti-CTLA4 and the combination of differentapproaches seems the way to go

• Results from recently concluded studies and ongoingtrials are awaited

Thank you for your attention

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