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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
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
• Previously untreated with any systemic therapy
• Karnofsky PS ≥70
Sunitinib
50 mg PO daily, 4 weeks on/2 weeks off
Phase III
N=900
IMmotion 151 - NCT02420821: Combination PD-L1 + VEGF inhibition
RANDOMIZATION
• Co-Primary endpoint: PFS, OS
Eligibility:
• Locally advanced or mRCC with clear cell component
• Previously untreated with any systemic therapy
• Karnofsky PS ≥70
Sunitinib
50 mg PO daily, 4 weeks on/2 weeks off
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
• Previously untreated with any systemic therapy
• 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
• Previously untreated with any systemic therapy
• Karnofsky PS ≥70
Sunitinib
50 mg PO daily, 4 weeks on/2 weeks off
Phase III
N=840
KEYNOTE 426 - NCT02853331: Pembrolizumab + Axitinib
RANDOMIZATION
• Co-Primary endpoint: PFS, OS
Pembrolizumab + Axitinib
200 mg IV every 3 weeks +5 mg PO BID
21
Eligibility:
• Advanced/mRCC with clear cell component
• Previously untreated with any systemic therapy
• Karnofsky PS ≥70 Sunitinib
50 mg PO daily, 4 weeks on/2 weeks off
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
Ipilimumab (10mg/kg)
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
Ipilimumab (10mg/kg)
Wks 1,4,7,10
Ipilimumab (10mg/kg)
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