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

26