Primo N. Lara, Jr., M.D. Professor of Medicine
University of California Davis School of Medicine
Associate Director for Translational Research
UC Davis Comprehensive Cancer Center
Sacramento, CA, USA
T-Cell Checkpoints in RCC: Musings from a non-immunologist
The “Cancer-Immunity Cycle”
Chen & Melman, Immunity 2013
Checkpoint Inhibitor Therapy
Nature, 2014
Both approaches activate anti-tumor T-cell activity
http://velica.deviantart.com/
Regulation of T-cell response is highly
complex • T-cell activation requires:
Interaction between T-cell receptor and antigen in context of MHC
CD28 co-stimulation
• T-cells are regulated by many overlapping stimulatory and inhibitory signaling pathways
• Targeting a single pathway may not be optimal
Sharma & Allison, Science 2015; Pardoll, Nature 2012
Donald Rumsfeld’s “Known Knowns”
• Known knowns: Things we know
• Known unknowns: Things we do not know
• Unknown unknowns: Things we don't know that we don't know
• “… it is the latter category that tend to be the difficult ones.”
Checkpoint inhibitor therapy in RCC: What we know
• PD1 or PDL-1 targeted therapies have activity
• Only 20% of patients respond
• Responses tend to be durable
• PD1 expression is associated with somewhat higher response
• Combination therapy appears to have greater efficacy but more toxic
• Secondary endpoints: tumor response for all subjects determined as
defined by RECIST v1.1 criteria
Nivolumab: Clinical activity Previously
treated (n=67)
Treatment-
naïve (n=23) All
(N=90)† Nivolumab
0.3 mg/kg
(n=22)
Nivolumab 2.0
mg/kg
(n=22)
Nivolumab
10 mg/kg
(n=23)
Nivolumab 10
mg/kg (n=23)
Objective response rate,
n (%); (95% CI)*
2 (9)
(1.1-29.2)
5 (23)
(7.8-45.4)
5 (22)
(7.5-43.7)
3 (13)
(2.8-33.6)
15 (17)
(9.6-26.0)
Best response, n (%)
Partial response (PR) 2 (9) 5 (23) 4 (17) 3 (13) 14 (16)
Unconfirmed PR 0 0 1 (4) 0 1 (1)
Stable disease (SD) 5 (23) 6 (27) 8 (35) 10 (43) 29 (32)
Progression-free survival rate, % (95% CI)
24 weeks 18 (6-36) 32 (14-51) 49 (27-68) 45 (24-64) 36 (26-46)
*CR, PR, unconfirmed CR, unconfirmed PR; †90 pts were evaluable for response
Motzer et al, ASCO 2014; Choueiri et al. ASCO 2014
Duration of response
Time to response Time (months)
0 3 6 9 12 15 18 21 24 27 30
0.3 mg/kg (n=12) 2 mg/kg (n=12) 10 mg/kg (n=11) R
esponders
Based on data cutoff of March 5, 2014. Ongoing response
Motzer, ASCO 2014; JCO 2014
PD-L1 status and response in mRCC
McDermott
(ESMO 2014)1
Choueiri
(ASCO 2014)2
Motzer
(JCO 2014)3,4
Drug MPDL3280A Nivolumab Nivolumab
ORR PD-L1 (+) 20% 22% 31%
ORR PD-L1 (-) 10% 8% 18%
Antibody Genentech/Roche Ab 28.8 28.8
Cell stained Immune Cell Tumor Tumor
Criteria for positivity Any >5% >5%
1. McDermott et al. ESMO 2014, abstract 8090; Choueiri et al. ASCO 2014, abstract 5012;
3. Motzer et al. ESMO 2014, abstract 810; 4. Motzer et al. JCO 2014.
B7-H1 (-) B7-H1 (+) P-value
# of Patients 95 18
ORR 19% 50% 0.012
PDL1 (B7-H1)/B7-H3: Impact on HD IL2 Response and PFS
B7-H1 (-)/B7-H3 (-) B7-H1 (+)/B7-H3 (+)
# of Patients 27 17
ORR 11.1% 52.9%
Response
PFS
Significantly longer PFS in B7-H1 positive tumors
Trend for longer PFS in B7-H1 and B7-H3 positive tumors
Bailey, ASCO 2013
VEGFR-TKI + Nivolumab in mRCC
80 100
60 40 20 0
-20 -40 -60 -80
-100
Ch
an
ge
in
ba
se
lin
e
targ
et
les
ion
s (
%)
Treatment S + N (n=29) P + N (n=19)
Sunitinib + N2 (n=7) 100
Ch
an
ge
in
ba
se
lin
e (
%)
80
60
40
20
-20
-40
-60
-80
-100 12 0 36 48 60 72 84 24
0
Sunitinib + N5 (n=26)
Time since first dose (weeks)
12 0 36 42 48 54 60 24 66 30 18 6
Pazopanib + N (n=20) First occurrence of new lesion
12 0 36 48 60 96 24 72 84
Amin et al. ASCO 2014, abstract 5010
• Primary endpoint: Safety (AEs, laboratory tests)
• Secondary endpoint: Efficacy (ORR, duration of response, PFS)
• Exploratory endpoint: Response by PD-L1 status
• Study assessments: Tumor response (RECIST v1.1) evaluated at screening, every 6 weeks (first 4 assessments), then every 12 weeks until disease progression
13 13 Q2W, every 2 weeks; Q3W, every 3 weeks
Patients with mRCC:
Arm N3 + I1 Nivolumab 3 mg/kg IV + Ipilimumab 1 mg/kg IV Q3W x4
Arm N1 + I3 Nivolumab 1 mg/kg IV+ Ipilimumab 3 mg/kg IV Q3W x4
Continuous Nivolumab 3 mg/kg IV Q2W
Previously treated or treatment naïve
Ran
do
mizatio
n
Hammers, ASCO 2014
Phase I study of nivolumab in combination with ipilimumab in metastatic renal cell carcinoma (mRCC)
Treatment-related AEs leading to discontinuation N3 + I1 (n=21) N1 + I3 (n=23)
Patients with an event 9.5 26.1
14
Treatment-related AEs (≥10% of patients) Event, % N3 + I1 (n=21) N1 + I3 (n=23)
All Grade 3-4 All Grade 3-4
Patients with an event 76.2 28.6 100 60.9
Safety and Tolerability: Summary
Treatment-related AE: selected categories
• No high-grade pulmonary AEs, including pneumonitis • No high grade endocrinopathy • Higher Grade 3-4 GI (26%) and hepatic (17%) toxicity seen with Ipi 3 mg/kg
Antitumor activity
15
N3 + I1 (n=21)
N1 + I3 (n=23)
Confirmed ORR, n (%) (95% CI)
9 (43) (21.8-66.0)
11 (48) (26.8-69.4)
Median duration of response, weeks (range) 31.1 (4.1+-42.1+)a NR (12.1+-35.1+)b
Ongoing responses, % (n/N) 78 (7/9) 82 (9/11)
Best objective response, n (%)
Complete response Partial response Stable disease Progressive disease Unable to determine
0
9 (43) 5 (24) 5 (24) 1 (5)
1 (4)
10 (43) 8 (35) 3 (13) 1 (4)
24 week PFS, % (95% CI) 65 (40, 82) 64 (41, 80) aMedian follow-up 36.1 weeks; bMedian follow-up 40.1 weeks
Response rates are among the highest reported for mRCC with any systemic therapy
MPDL3280A + Bevacizumab: Summary of Phase Ib Results
Safety and efficacy of patients in Arm A*
• Safety
– Treatment-related Grade 3 AEs occurred in 3% of
patients (1 case of neutropenia)
– No Grade 4 AEs or deaths were attributed to
MPDL3280A
• Efficacy in patients with 1L clear cell RCC
– 4 of 10 patients demonstrated an
objective response
– Additionally, 4 of 10 patients experienced SD ≥ 24
weeks
– Responding patients included 2 with
IHC (IC) 1, 1 with IHC (IC) 0 and 1 with IHC (IC)
unknown
– 9 of 10 patients with mRCC remain on
study treatment
*Patients in Arm A received MPDL3280A 20 mg/kg q3w + bevacizumab 15 mg/kg q3w; Patients dosed by 7 April 2014; data cut-off 7 July 2014; unconfirmed best responses
by RECIST v1.1
IHC 3: ≥10% of ICs are PD-L1+; IHC 2: ≥5% and <10% of ICs are PD-L1+; IHC 1: ≥1% and <5% of ICs are PD-L1+; IHC 0: <1% ICs are PD-L1+
Lieu et al. ESMO 2014, abstract 1049
Ch
an
ge
in
su
m o
f lo
ng
es
t
dia
me
ters
fro
m b
as
eli
ne
(%)
0
20
40
80
100
IHC 3 60
-20
-40
-60
-80
-100
Time on study (days)
0 42 84 126 168 210 252
IHC 1 IHC 0 IHC 1
IHC 0 IHC 0
IHC 1
IHC 0 IHC 1
Checkpoint inhibitor therapy in RCC: What we don’t know
• Can checkpoint inhibition cure mRCC?
• Which checkpoint inhibitor is best?
• Why is response rate only 20%?
– Who is destined to respond?
– Is there a molecular phenotype predictive of benefit?
• Why is RCC so immunogenic in the first place?
(Despite a lower mutational burden compared to melanoma or lung cancer)
Mutational burden across cancers
Alexandrov, et al. Nature 2013
Chromophobe Papillary RCC Clear cell RCC
Mutational load is associated with
benefit from checkpoint inhibitor
therapy in melanoma
19 Snyder, NEJM 2014
• Somatic neoepitopes are shared by patients who benefit from
CTLA4 blockade.
• Somatic mutations induce a subset of tumor proteins to be
recognized by the immune system as non-self
DCB: durable clinical benefit; NDB: no durable benefit
21
Number of missense mutations by tumor type Genome Res, 2014
Tumor missense mutations that have
predicted immunoreactivity* are
associated with increased survival
*based on high mutated gene expression, high
HLA-A expression, and predicted autologus HLA-A
(MHC1) binding affinity to the tumor antigen
Immunogenic
mutation count
CD8A expression (surrogate for CD8+ TIL cells)
All patients included
Selected PD-1 Pathway Trials in mRCC
Trial Sponsor Status NCT #
Nivolumab vs Everolimus Phase III BMS Completed accrual
01844505
Phase I/II Pazopanib + Pembro GSK Enrolling 02014636
Phase II PD-L1 vs Bev/PD-L1 vs Sunitinib Genentech Enrolling 01984242
Phase I Axitinib + Pembro Pfizer Enrolling 02133742
Nivo/Ipi vs Sunitinib Phase III BMS Enrolling 02231749
PD-1 Adjuvant Trial NCI/Coop In Development
Phase III Nivolumab vs everolimus (completed)
• Primary endpoint: OS
• Secondary endpoints: PFS, ORR, duration of response, OS in relation to
PDL-1 status, safety, patients-reported outcomes
Eligibility criteria:
• mRCC with clear cell component
• 1 to 2 prior VEGF-targeted
therapy
• Max = 3 lines
• Stratification:
• Regions
• MSKCC risk
Nivolumab
3 mg/kg q2 weeks
Everolimus 10 mg PO QD
R
A
N
D
O
M
I
Z
A
T
I
O
N
N=822
www.clinicaltrials.gov (NCT01668784)
MPDL3280A: Randomized Phase II Study
• Primary endpoint: PFS (central)
• Secondary endpoints: OS, ORR, DoR, OS, safety (original treatment group)
PFS, OS, ORR, DoR (crossover groups)
• Age ≥18 years
• Unresectable mRCC with component of clear cell and/or sarcomatoid histology that has not been treated with systemic agents
• KPS ≥70
N 150-300
Treat until disease
progression
MPDL3280A
+ BEV
MPDL3280A
+ BEV
Optional
crossover
www.clinicaltrials.gov (NCT01984242)
RA
ND
O
M
I
ZA
T
I
ON
MPDL3280A
Sunitinib
MPDL3280A
+ BEV
Conclusions: T-cell checkpoints
• There are many “unknown unknowns”
– Ponds of knowledge, oceans of ignorance
• T-cell checkpoint inhibitor therapy is highly active
– … but only in a subset of mRCC patients
• Immunologic basis of mRCC response still being
investigated
– Neoantigens (mutational landscape), MDSC inhibition, others
• Combination immunotherapy is now in phase III setting
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