redefining the management of advanced rcc

Not an official event of the 2019 ASCO Annual Meeting.

Not sponsored, endorsed, or accredited by ASCO, CancerLinQ, or Conquer Cancer.

Redefining the Management

of Advanced RCC An Expert Tumor Board on Rational

Selection, Sequencing, and Combination

of Targeted Agents and Immunotherapy

Welcome and Introduction

David F. McDermott, MD

Chief, Medical Oncology

Cancer Center and Rosenberg Clinical Cancer Center

Co-Director, Immunotherapy Institute

Director, Cutaneous and Immuno-Oncology Programs

Beth Israel Deaconess Medical Center

Leader, Dana-Farber Harvard Cancer Center Kidney Cancer Program

Professor of Medicine

Harvard Medical School

Boston, Massachusetts

Disclosures

David F. McDermott, MD, has a financial interest/relationship or affiliation in the form of:

Consultant and/or Advisor for Alkermes; Array BioPharma; Bristol-Myers Squibb; Eli Lilly and Company;

EMD Serono, Inc.; Exelixis, Inc.; Genentech USA, Inc.; Jounce Therapeutics, Inc.; Merck & Co., Inc.;

Novartis Pharmaceuticals Corporation; Peloton Therapeutics, Inc.; Pfizer, Inc.; and X4 Pharmaceuticals,

Inc.

Other financial interest/relationship Alkermes; Bristol-Myers Squibb; Exelixis, Inc.; Genentech USA, Inc.;

Merck & Co., Inc.; Novartis Pharmaceuticals Corporation; Peloton Therapeutics, Inc.; Pfizer, Inc.;

Prometheus Laboratories Inc.; and X4 Pharmaceuticals, Inc. for Cancer Research.

David F. McDermott, MD, does intend to discuss either non–FDA-approved or investigational use for the

following products/devices: immune checkpoint inhibitors and VEGF pathway inhibitors in the

management of advanced RCC.

This CME/MOC activity is jointly provided by Medical Learning Institute, Inc. and PVI, PeerView Institute for Medical Education.

This activity is supported through independent medical education grants from Bristol-Myers Squibb, Eisai Inc., Exelixis, Inc., and

Merck & Co., Inc.

Disclosures

Toni K. Choueiri, MD, has a financial interest/relationship or affiliation in the form of: Consultant and/or Advisor for Alexion; Analysis Group; AstraZeneca; Bayer Corporation; Bristol-Myers Squibb and Sons LLC.; Calithera; Cerulean; Corvus Pharmaceuticals; Eisai Inc.; Eli Lilly and Company; EMD Serono, Inc.; Exelixis, Inc.; F. Hoffmann-La Roche Ltd; Foundation Medicine, Inc.; Genentech, Inc.; GlaxoSmithKline; Heron Therapeutics, Inc.; Ipsen Biopharmaceuticals, Inc.; Merck & Co., Inc.; National Comprehensive Cancer Network; Novartis Pharmaceuticals Corporation; Peloton Pharmaceuticals, Inc.; Pfizer, Inc.; Prometheus Laboratories Inc.; Roche Products Limited; and UpToDate, Inc. Grant/Research Support from Sanofi-Aventis U.S. LLC; Takeda Pharmaceutical Company Limited; and Tracon Pharmaceuticals, Inc. Toni K. Choueiri, MD, does intend to discuss either non–FDA-approved or investigational use for the following products/devices: immune checkpoint inhibitors and VEGF pathway inhibitors in the management of advanced RCC.



Merck & Co., Inc.

Disclosures

Nizar M. Tannir, MD, FACP, has a financial interest/relationship or affiliation in the form of:

Consultant and/or Advisor for Bristol-Myers Squibb; Eli Lilly and Company; Exelixis, Inc. and Nektar.

Other financial interest/relationship Clinical trial grant for Exelixis, Inc. and Nektar. Strategic council meeting with Eisai Inc. Steering Committee Meeting with Pfizer, Inc. Ono Pharmaceutical CO., Ltd. for seminar presentations.

Nizar M. Tannir, MD, FACP, does intend to discuss either non–FDA-approved or investigational use for the following products/devices: immune checkpoint inhibitors and VEGF pathway inhibitors in the management of advanced RCC.



Merck & Co., Inc.

Disclosures

Content Reviewers

Julia Rotow, MD, has no financial

interests/relationships or affiliations in relation to

this activity.

Janice Trainor-Tellier, MSN, RN, has no

financial interests/relationships or affiliations in

relation to this activity.

Medical Director

PVI, PeerView Institute for Medical Education

Aarati Ranganathan, PhD, has no financial

interests/relationships or affiliations in relation to

this activity.

Other PVI associates who are in a position to have control over the content of this activity do not have any financial

relationships or relationships to products or devices with any commercial interest related to the content of this CME/MOC

activity during the past 12 months.

The associates of the Medical Learning Institute, Inc., the accredited provider for this activity, do not have any financial

relationships or relationships to products or devices with any commercial interest related to the content of this CME/MOC

activity during the past 12 months.

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Rethinking the Choice of Frontline

Regimens for Individual Patients

With Advanced RCC



Dana-Farber Harvard Cancer Center

Kidney Cancer Program



Toni K. Choueiri, MD

Lank Center for Genitourinary Oncology

Dana-Farber Cancer Institute



Nizar M. Tannir, MD, FACP

The University of Texas

MD Anderson Cancer Center

Houston, Texas

Tumor Board 1: A Patient With

Newly Diagnosed Metastatic RCC

Tina, a 43-year-old female

• Presented with chronic

cough x 4 mo, fatigue,

dyspnea, headache,

chills, and night sweats

• KPS 80% (ECOG PS 1)

Assessment • Labs

• CT of CAP

• Hb 11.2

• ANC 11,500

• Serum LDH 866

(ULN 618)

• Platelet count normal

• Corrected serum

calcium level normal

• 8-cm lower pole left

renal mass

• Multiple lesions in the

liver and lung

Diagnosis • Left renal mass

biopsy

• Clear-cell RCC,

Fuhrman nuclear

grade 3

• Poor risk

Tumor Board 1: Initial CT Scans

Images courtesy of Dr. Tannir.

11/28/2018

Tumor Board 1: Treatment Options

Given this patient’s features and current evidence, what are his options for upfront systemic therapy?

Dual immune checkpoint inhibition

Immune checkpoint inhibitor plus TKI

Single agent

(TKI or immune

checkpoint inhibitor)

IO + IO Is a Valid

Frontline Option


Professor and Chair Ad Interim

Genitourinary Medical Oncology

Ransom Horne, Jr. Endowed Professorship

in Cancer Research



Houston, Texas

• CTLA-4 activation

downregulates the

function of T cells

• Blockade of CTLA-4

ultimately allows

upregulation of

immune response

targeting tumor

antigens

Is CTLA-4 Blockade Synergistic With Anti–PD-1?1,2

1. Postow MA et al. J Clin Oncol. 2015;33:1974-1982. 2. Lee L et al. J Clin Pharmacol. 2016;56:157-169.

Lymph Node

CD28 B7

T-cell receptor

MHC with antigen

Dendritic Cell T Cell

B7

CTLA-4

Is CTLA-4 Blockade Synergistic With Anti–PD-1?1,2

(Cont’d)

1. Postow MA et al. J Clin Oncol. 2015;33:1974-1982. 2. Lee L et al. J Clin Pharmacol. 2016;56:157-169.

Lymph Node

CD28 B7

T-cell receptor

MHC with antigen

Dendritic Cell T Cell

Tumor

Microenvironment

PD-L1/PD-L2 PD-1

Tumor

PD-1

PD-1 PD-L1

PD-L1

PD-L1

• PD-1 receptor on

T cells act as “off

switch” to downregulate

immune response

• PD-1/PD-L1 inhibitors

act to destroy cancer

cells in both the lymph

node and the tumor

microenvironment

CheckMate -214: Nivolumab + Ipilimumab in

Newly Diagnosed Advanced RCC—Study Design1

1. Tannir NM. 2019 American Society of Clinical Oncology Genitourinary Cancers Symposium (ASCO-GU 2019). Abstract 547.

N = 1,096

Key eligibility criteria

• Treatment-naïve

inoperable, locally

advanced, or metastatic

• Clear-cell histology

• KPS ≥70

Nivolumab (3 mg/kg, IV Q3W)

+

Ipilimumab (1 mg/kg, IV Q3W) x

4 doses, then

Nivolumab 3 mg/kg Q2W

Sunitinib 50 mg (4 wk on, 2 wk off)

Stratification

• IMDC

prognostic

score (0 vs 1-2

vs 3-6)

• Region (US vs

Canada/Europe

vs rest of the

world)

Endpoints

• Coprimary (intermediate/poor risk): PFS, OS, ORR

• Secondary: safety

1:1

R

Time, mo

0 6 12 18 24 30 36 39 4 2 4 5 3 9 15 21 27 33

Overa

ll S

urv

iva

l, P

rob

ab

ilit

y

No. at risk

NIVO + IPI 550 523 492 464 443 425 410 389 371 351 327 271 161 58 4 0

SUN 546 507 472 435 404 367 345 325 310 295 275 232 145 55 5 0

NIVO + IPI

SUN

NIVO + IPI NR (NE) SUN 37.9 (32.2-NE)

Median OS, mo (95% CI)

HR (95% CI): 0.71 (0.59-0.86)

P = .0003

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0

83%

78%

71%

61%

64%

56%

CheckMate -214: Overall Survival

Intent-to-Treat Patients1

1. Tannir NM. ASCO-GU 2019. Abstract 547.

Intermediate/Poor Risk Favorable Risk

Time, mo 0 6

No. at risk

NIVO + IPI 425 399 372 348 332 317 306 287 270 253 233 183 90 34 2 0

SUN 422 388 353 318 290 257 236 220 207 194 179 144 75 29 3 0

12 18 24 30 36 4 2 3 9 15 21 27 33 4 5 3 9

Overa

ll S

urv

ival,

Pro

bab

ilit

y

1.0

0.8

0.9

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0

NIVO + IPI

SUN

NIVO + IPI

SUN

Time, mo

0 6

No. at risk

NIVO + IPI 125 124 120 116 111 108 104 102 101 98 94 88 71 24 2 0

SUN 124 119 119 117 114 110 109 105 103 101 96 88 70 26 2 0

12 18 24 30 36 4 2 3 9 15 21 27 33 4 5 3 9

Overa

ll S

urv

ival,

Pro

bab

ilit

y

1.0

0.8

0.9

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0

80%

72%

66%

53%

60%

47%

NIVO + IPI NR (35.6-NE)

SUN 26.6 (22.1-33.4)


HR (95% CI): 0.66 (0.54-0.80)

P < .0001

96%

94%

88%

85%

85%

80%

NIVO + IPI NR (NE)

SUN NR (NE)


HR (95% CI): 1.22 (0.73-2.04)

P = .4426

CheckMate -214: Overall Survival by IMDC Risk1


Time, mo

0 6 12 18 24 30 36 4 2 3 9 3 9 15 21 27 33

Pro

gre

ss

ion

-Fre

e S

urv

iva

l,

Pro

bab

ilit

y

No. at risk

NIVO + IPI 550 403 306 242 204 188 167 143 131 120 108 70 25 4 0

SUN 546 404 298 225 185 157 130 106 85 74 62 47 21 2 0

NIVO + IPI

SUN

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0

44%

44%

31%

23%

28%

18%

NIVO + IPI 9.7 (8.1-11.1) SUN 9.7 (8.3-11.1)

Median PFS, mo (95% CI)

HR (95% CI): 0.85 (0.73-0.98)

P = .0267

CheckMate -214: Progression-Free Survival

Intent-to-Treat Patients1


Intermediate/Poor Risk Favorable Risk

Time, mo

0 6 12 18 24 30 36 4 2 3 9 3 9 15 21 27 33

Pro

gre

ss

ion

-Fre

e S

urv

ival,

Pro

bab

ilit

y

Time, mo

0 6 12 18 24 30 36 4 2 3 9 3 9 15 21 27 33

Pro

gre

ss

ion

-Fre

e S

urv

ival,

Pro

bab

ilit

y

No. at risk

NIVO + IPI 425 296 218 173 147 135 125 106 95 87 81 48 17 3 0

SUN 422 295 200 142 111 93 75 60 44 34 26 16 6 0 0

No. at risk

NIVO + IPI 125 107 88 69 57 53 42 37 36 33 27 22 8 1 0

SUN 124 109 98 83 74 64 55 46 41 40 36 31 15 2 0

1.0

0.8

0.9

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0

1.0

0.8

0.9

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0

NIVO + IPI

SUN

NIVO + IPI

SUN

41%

36%

30%

17%

28%

12%

NIVO + IPI 8.2 (6.9-10.0)

SUN 8.3 (7.0-8.8)


HR (95% CI): 0.77 (0.65-0.90)

P = .0014 70%

53%

40%

35%

35%

29%

NIVO + IPI 13.9 (9.9-17.9)

SUN 19.9 (15.1-23.5)


HR (95% CI): 1.23 (0.90-1.69)

P = .1888

CheckMate -214: PFS by IMDC Risk1


30.7 32.2 30.6 28.2 31.2

46.0

10.5 1.8 11.3 1.2

8.0

4.0

0

10

20

30

40

50

• Among ITT patients, 185 (34%) versus 114 (21%) achieved ≥50% best tumor burden reduction with NIVO + IPI versus SUN

ITT Population Intermediate/Poor Risk1 Favorable Risk

NIVO + IPI

(n = 550)

SUN

(n = 546)

NIVO + IPI

(n = 425)

SUN

(n = 422)

NIVO + IPI

(n = 125)

SUN

(n = 124)

DOR ≥18 mo, % 53 39 52 28 57 60

Ongoing CR, n/N (%) 51/58 (88) 6/10 42/48 (88) 4/5 9/10 2/5

50%

40%

30%

20%

10%

0

OR

R,

%

41% 34%

P = .0154

42% 29%

P = .0001 P = .1436

39% 50%

CheckMate -214: Response1,a

a Investigator assessed.


CR

PR

NIVO

+ IPI SUN

21

NIVO + IPI (n = 547) SUN (n = 535) 5

4

3

2

1

0

Pa

tie

nts

Wit

h G

rad

e 3

/4 A

Es

, %

Endocrine Gastrointestinal Hepatobiliary

Renal and urinary Respiratory, thoracic, and mediastinal Skin and subcutaneous tissue

Time, mo

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38

Blood & lymphatic system Gastrointestinal Renal and urinary

Respiratory, thoracic, &

mediastinal Skin and subcutaneous tissue Vascular

Time, mo

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40

5

4

3

2

1

0

Pa

tie

nts

Wit

h G

rad

e 3

/4 A

Es

, %

• In the NIVO + IPI arm, 35% of patients received high-dose glucocorticoids (prednisone ≥40 mg/d or equivalent) for select

treatment-related AE management

• No additional treatment-related deaths occurred

CheckMate -214: Treatment-Related AEs By Organ

System – All Treated Patients1


40

CheckMate -214: TFS in IMDC Intermediate-/Poor-

Risk Patients Who Discontinued Protocol Therapy1

Time From Treatment Discontinuation, mo

0 6

No. at risk NIVO + IPI 352 98 69 46 34 22 5 SUN 383 42 23 13 8 2 0

12 18 24

18 months 24 months

30

100

75

50

25

0

36

NIVO + IPI

SUN

TFS, mo TFS rate (95% CI), %

NIVO + IPI (n = 352)

SUN (n = 383)

18 20 (16-26) 6 (4-9)

24 19 (15-24) 6 (4-9)

Shaded area around curves represents 95% CI.

1. McDermott D et al. Annals of Oncology. 2018;29:viii303-viii331. 2. McDermott D et al. ASCO-GU. Abstract 564.

Pati

en

ts F

ree

Fro

m

Sec

on

d-L

ine T

reatm

en

t, %

The durable TFS

benefit with first-line

nivolumab +

ipilimumab compared

to sunitinib was

noted in patients with

IMDC favorable-risk

patients as well.2

CheckMate -214: TFS in IMDC Intermediate-/Poor-

Risk Patients Achieving CR/PR or SD1

Shaded area around curves represents 95% CI. a Based on investigator assessment of response.

1. McDermott D et al. Annals of Oncology. 2018;29:viii303-viii331.

Time From Treatment Discontinuation, mo 0 6

No. at risk NIVO+IPI, CR/PR 117 59 45 30 23 15 3

NIVO+IPI, SD 104 29 18 11 7 3 1

SUN, CR/PR 104 24 14 7 5 1 0

SUN, SD 162 16 9 6 3 1 0

12 18 24

18 months 24 months

30

100

75

50

25

0

36

NIVO+IPI, CR/PR

NIVO+IPI, SD

SUN, CR/PR

SUN, SD

P value SUN

Median TFS, mo at 18 mo, % at 24 mo, % vs SUN)

Pati

en

ts F

ree F

rom

Se

co

nd

-Lin

e T

reatm

en

t, %

Subgroup NIVO + IPI (TFS) SUN (TFS) P value

(NIVO + IPI vs SUN) 18 mo rate, % 24 mo rate, % Median, mo 18 mo rate, % 24 mo rate, % Median, mo

Responsea

CR/PR

SD

44 (35-55)

14 (8-23)

42 (34-54)

12 (7-21)

9.6 (5.7-NE)

2.8 (1.6-3.9)

12 (6-21)

6 (4-12)

12 (6-21)

6 (4-12)

1.9 (1.5-3.1)

1.4 (1.1-1.6)

< .0001

.0001

Retrospective Analyses in CheckMate -214: Comparing All Randomized and Sarcomatoid Intermediate-/Poor-Risk Patients1

1. McDermott DF et al. 17th International Kidney Cancer Symposium. Poster.

• Baseline characteristics were well balanced between the treatment arms

• A higher percentage of intermediate-/poor-risk patients with sarcomatoid features had ≥1% PD-L1

expression than those without sarcomatoid features

Sarcomatoid

Intermediate/Poor Risk All Intermediate/Poor Risk

NIVO + IPI

N = 60

SUN

N = 52

NIVO + IPI

N = 425

SUN

N = 422

Confirmed ORR, % 56.7 19.2 41.9 29.4

P value < .0001 .0001

CR

PR

18.3

38.3

0

19.2

11.3

30.6

1.2

28.2

Update

McDermott D et al.

Abstract 4513.

Monday, June 3

at 1:15 PM

Poster board 339

PFS

probability,

% (95% CI)

NIVO + IPI

(N = 60)

SUN

(N = 52)

12 mo 40 (27-52) 18 (8-30)

24 mo 40 (27-52) 16 (7-28)

30 mo 36 (23-48) 13 (5-24)

Pro

gre

ss

ion

-Fre

e S

urv

ival,

Pro

bab

ilit

y

Time, mo

0.8

1.0

0.7

0.9

0.6

0.5

0.4

0.3

0.2

0.1

0

0 6 3 9 12 15 18 21 24 27 30 33 36 39 42

60 41 35 28 23 23 21 19 19 17 16 10 4 2 0 52 32 20 11 8 7 6 6 5 4 4 2 1 0 0

No. at risk NIVO + IPI SUN

NIVO + IPI

(N = 60)

SUN

(N = 52)

Events, n (%) 37 (62) 40 (77)

Median PFS (95% CI),

mo 8.4 (5.2-24.0) 4.9 (4.0-7.0)

Hazard ratio (95% CI)

P value

0.61 (0.38-0.97)

.0329

Retrospective Analyses in CheckMate -214: PFS in Intermediate/Poor-Risk Sarcomatoid Patients1


OS

probability,

% (95% CI)

NIVO + IPI

(N = 60)

SUN

(N = 52)

12 mo 80 (67-88) 56 (41-68)

24 mo 58 (45-70) 35 (22-47)

30 mo 53 (39-65) 29 (17-41)

Overa

ll S

urv

iva

l, P

rob

ab

ilit

y

Time, mo

0 6 3 9 12 15 18 21 24 27 30 33 36 39 42 45

60 56 52 49 47 45 43 37 32 30 29 22 10 5 1 0

52 48 36 32 29 23 22 19 18 17 15 15 9 3 1 0

No. at risk

NIVO + IPI

SUN

NIVO + IPI

(N = 60)

SUN

(N = 52)

Events, n (%) 31 (52) 39 (75)

Median OS, (95% CI),

mo 31.2 (23.0-NE) 13.6 (7.7-20.9)

Hazard ratio (95% CI)

P value

0.55 (0.33-0.90)

.0155

Retrospective Analyses in CheckMate -214: OS in Intermediate-/Poor-Risk Sarcomatoid Patients1


0.8

1.0

0.7

0.9

0.6

0.5

0.4

0.3

0.2

0.1

0

<1% PD-L1 Expression

NIVO + IPI

(N = 30)

SUN

(N = 23)

Events, n (%) 16 (53) 19 (83)

Median OS,

(95% CI), mo 23.7 (14.1-NE) 13.8 (4.7-22.9)

Retrospective Analyses in CheckMate -214: OS in PD-L1–Evaluable Sarcomatoid Patients1


≥1% PD-L1 Expression

NIVO + IPI

(N = 27)

SUN

(N = 26)

Events, n (%) 12 (44) 17 (65)

Median OS,

(95% CI), mo NR (29.9-NE) 13.8 (8.9-NE)

Overa

ll S

urv

ival,

Pro

bab

ilit

y

Time, mo

0.8

1.0

0.7

0.9

0.6

0.5

0.4

0.3

0.2

0.1

0.0

0 6 3 9 12 15 18 21 24 27 30 33 36 39 42 6 3 9 12 15 18 21 24 27 30 33 36 39 42 45

30 29 25 24 22 20 19 15 13 12 12 9 2 0 0 0

23 21 13 12 12 10 9 8 7 6 5 5 3 0 0 0

27 25 25 24 24 24 23 21 18 18 17 13 8 5 1 0

26 24 21 18 15 12 12 11 11 11 10 10 6 3 1 0

No. at risk

NIVO + IPI

SUN O

vera

ll S

urv

ival,

Pro

bab

ilit

y

<1% PD-L1

0.8

1.0

0.7

0.9

0.6

0.5

0.4

0.3

0.2

0.1

0.0

0 45

No. at risk

NIVO + IPI

SUN

≥1% PD-L1

Time, mo

Ongoing Phase 3 Trials Assessing Immunotherapy

Combinations in Frontline Advanced RCC1

Treatment Arms Primary Endpoint Trial ClinicalTrials.gov ID

Nivolumab + ipilimumab →

nivolumab vs nivolumab +

cabozantinib (in non-CR/non-PD

patients)

OS PDIGREE NCT03793166

Nivolumab + ipilimumab vs

nivolumab + placebo PFS — NCT03873402

Bempegaldesleukin (NKTR-214) +

nivolumab vs cabozantinib or

sunitinib

ORR and OS PIVOT-09 NCT03729245

1. http://www.clinicaltrials.gov. Accessed May 24, 2019.

My Thoughts on Benefits of IO + IO

• IO + IO is different from IO + anti-VEGF because of the ability of

IO + IO to produce treatment-free survival (TFS) benefit/potential

for cure

• Combinations that improve median PFS or median OS without

producing TFS benefit may sacrifice the potential of IO while

contributing toxicity, inconvenience, and cost

• Not only must A + B be superior to A followed by B (or B followed

by A), but TFS benefit/potential for cure must be maintained for

such therapies to be fully embraced

• Clinical trials with IO agents need to use IO endpoints

• Landmark PFS/OS

• Complete response rate

• Time to initiation of subsequent therapy

• TFS/potential for cure

• Overall quality of life/overall value

Principal IO Endpoints

IO + VEGFR-TKI Is a

Treatment of Choice David F. McDermott, MD










Is VEGF Inhibition Synergistic With Anti–PD-1?1

PD-L1, PD-1 inhibitors

VEGF blockade2-4

1. Chen DS, Mellman I. Immunity. 2013;39:1-10. 2. Shrimali RK et al. Can Res. 2010;70:6171-6180. 3. Manning EA et al. Clin Cancer Res. 2007;13:3951-3959.

4. Motz GT et al. Nat Med. 2014;20:607-615.

Experimental Arm Primary Endpoint Trial ClinicalTrials.gov ID

Bevacizumab + atezolizumab

PFS and OS

in PD-L1–detectable

tumors

IMmotion151 NCT02420821

Axitinib + avelumab PFS JAVELIN Renal 101 NCT02684006

Axitinib + pembrolizumab PFS and OS KEYNOTE-426 NCT02853331

Nivolumab + cabozantinib PFS in intermediate-/

poor-risk patients CheckMate 9ER NCT03141177

Lenvatinib-pembrolizumab

or lenvatinib-everolimus PFS CLEAR NCT02811861

Cabozantinib + nivolumab-

ipilimumab PFS COSMIC-313 NCT03937219

First-Line Phase 3 Combinations of Anti-VEGF

Agents and Immunotherapy in Advanced RCC1

1. http://www.clinicaltrials.gov. Accessed May 24, 2019.

Phase 3 KEYNOTE-426: Pembrolizumab + Axitinib in

Newly Diagnosed Advanced RCC—Study Design1,2

a Axitinib dose could be increased to 7 mg, then 10 mg, twice daily if safety criteria were met; dose could be reduced to 3 mg, then 2 mg, twice daily to manage

toxicity. b Sunitinib dose could be decreased to 37.5 mg, then 25 mg, once daily for the first 4 wk of each 6-wk cycle to manage toxicity.

1. Powles T et al. ASCO-GU 2019. Abstract 543. 2. Rini BI et al. N Engl J Med. 2019;380:1116-1127.


• Newly diagnosed or recurrent

stage IV clear-cell RCC

• No previous systemic tx for

advanced disease

• KPS ≥70

• Measurable disease per

RECIST v1.1

• Provision of a tumor sample for

biomarker assessment

• Adequate organ function

Pembrolizumab (200 mg IV

Q3W for up to 35 cycles)

+

Axitinib (5 mg orally

twice daily)a

Sunitinib 50 mg orally once daily for first 4 wk

of each 6-wk cycleb

Stratification

• IMDC risk group

(favorable vs

intermediate vs

poor)

• Region (North

America vs

Western Europe

vs rest of the

world)

Endpoints

• Dual primary: OS and PFS (RECIST v1.1, BICR) in ITT

• Key secondary: ORR (RECIST v1.1, BICR) in ITT

• Other secondary: DOR (RECIST v1.1), PROs, safety

1:1

R

n = 432

n = 429

KEYNOTE -426: Pembrolizumab + Axitinib

Survival Outcomes1,2


KEYNOTE -426: Pembrolizumab + Axitinib

Survival Outcomes1,2 (Cont’d)


Update on outcomes

in IMDC risk and

sarcomatoid

subgroups

Rini BI et al.

Oral abstract 4500.

Monday, June 3 at

8:00 AM

KEYNOTE-426: Response1,2


Best

Response

Pembrolizumab

+ Axitinib

(n = 432)

Sunitinib

(n = 429)

CR 25 (5.8%) 8 (1.9%)

PR 231 (53.5%) 145 (33.8%)

Response

Duration

Pembrolizumab +

Axitinib

(n = 256)

Sunitinib

(n = 153)

Median

(range), mo

NR

(1.4+ to 18.2+)

15.2

(1.1 to 15.4+)

0

10

20

30

40

50

60

70

80

90

100

Pembro + Axi Sunitinib

59.3

(54.5-63.9)

35.7

(31.1-40.4)

P < .0001

Overa

ll R

esp

on

se R

ate

, %

(95%

CI)

KEYNOTE-426: Treatment-Related

Adverse Events1,2

Data cutoff date: August 24, 2018. a One patient each from myasthenia gravis, myocarditis, necrotizing fasciitis, and pneumonitis. b One patient each from acute myocardial infarction, cardiac arrest,

fulminant hepatitis, GI hemorrhage, intracranial hemorrhage, malignant neoplasm progression, and pneumonia.


All Cause Treatment Related

Pembro +

Axi

(n = 429)

Sunitinib

(n = 425)

Pembro

+ Axi

(n = 429)

Sunitinib

(n = 425)

Any 98.4% 99.5% 96.3% 97.6%

Grade 3-5 75.8% 70.6% 62.9% 58.1%

Led to death 2.6% 3.5% 0.9%a 1.6%b

Led to

discontinuation of

any treatment

30.5% 13.9% 25.9% 10.1%

Led to

discontinuation of

both pembro and

axi

10.7% — 8.2% —

Led to axi or

sunitinib dose

reduction

20.3% 30.1% 20.0% 28.5%

Led to interruption

of any treatment 69.9% 49.9% 62.2% 40.2%

100 90 80 70 60 50 40 30 20 10 0 10 20 30 40 50 60 70 80 90 100

Diarrhea

Hypertension

PPE

Fatigue

Hypothyroidism

Nausea

Decreased appetite

Dysgeusia

ALT increased

AST increased

Stomatitis

Mucosal inflammation

Dysphonia

Thrombocytopenia

Pembro + Axi Sunitinib

Incidence, %

Grade 1-2

Grade 3-5

Phase 3 JAVELIN Renal 101: Axitinib + Avelumab in

Newly Diagnosed Advanced RCC—Study Design1,2

1. Motzer RJ et al. European Society for Medical Oncology Congress 2018 (ESMO 2018). Abstract LBA6_PR. 2. Motzer RJ et al. N Engl J Med. 2019;380:1103-1115.


• Treatment-naïve aRCC

with a clear-cell component

• ≥1 measurable lesion as

defined by RECIST v1.1

• Tumor tissue available for

PD-L1 staining

• ECOG PS 0-1

Avelumab 10 mg/kg IV Q2W

+

Axitinib 5 mg orally BID

(6-wk cycle)

Sunitinib 50 mg orally QD

(4 wk on, 2 wk off)

Stratification

• ECOG PS

(0 vs 1)

• Geographic

region (US vs

Canada/Western

Europe vs rest

of world)

• Coprimary endpoints: PFS and OS in PD-L1–positive patients

1:1

R N= 886

JAVELIN Renal 101: PFS Outcome1,2

a Median follow-up: 9.9 months (avelumab + axitinib) and 8.4 months (sunitinib). b Median follow-up: 10.8 months (avelumab + axitinib) and 8.6 months (sunitinib).

1. Motzer RJ et al. ESMO 2018. Abstract LBA6_PR. 2. Motzer RJ et al. N Engl J Med. 2019;380:1103-1115.

Primary Endpointa

PFS per IRC in the PD-L1+ Group

Secondary Endpointb

PFS per IRC in the Overall Population

Phase 3 JAVELIN Renal 101: PFS

Subgroup Analysis1

PFS per IRC in Key Subgroups

1. Choueiri T et al. ASCO-GU 2019. Abstract 544.

NR

13.8

[VALUE]

NR

13.3

5.6

13.8

8.4

2.9

16.7

7.9

2.8

IMDC

MSKCC

Median PFS, mo

Avelumab + axitinib Sunitinib

0 5 10 15 20

Favorable

Intermediate

Poor

Favorable

Intermediate

Poor

Positive

Negative

Unevaluable

13.8 7.2

16.1 11.1

9.9 8.4

8.4 15.2

9.9 6.9

Yes

No

PD-L1

Status

Prior

Nephrectomy

0.1 1 10

0.539 (0.321-0.907)

0.736 (0.570-0.950)

0.574 (0.375-0.880)

0.652 (0.397-1.072)

0.715 (0.559-0.915)

0.495 (0.296-0.827)

Favors avelumab + axitinib Favors sunitinib

0.626 (0.487-0.805)

0.800 (0.551-1.164)

0.827 (0.403-1.699)

0.673 (0.538-0.842)

0.748 (0.480-1.165)

HR (95% CI)

PD-L1+ Group

(n = 560)

Overall Population

(N = 886)

Per IRC

Avelumab

+ Axitinib

(n = 270)

Sunitinib

(n = 290)

Avelumab

+ Axitinib

(n = 442)

Sunitinib

(n = 444)

ORR, % 55 25.5 51 25.7

Best overall response, %

CR 4 2 3 2

PR 51 23 48 24

SD 27 43 30 46

Patients

with

ongoing

response,

%

73 65 70 71

JAVELIN Renal 101: Response1-3

Confirmed Objective Response

1. Motzer RJ et al. ESMO 2018. Abstract LBA6_PR. 2. Motzer RJ et al. N Engl J Med. 2019;380:1103-1115. 3. Choueiri T et al. ASCO-GU 2019. Abstract 544.

Avelumab + Axitinib (n = 252) Sunitinib (n = 265)

Best percent change in target lesions in the PD-L1+ group

Progressive disease Stable disease Partial response Complete response Not evaluable

Be

st

Ch

an

ge

Fro

m B

as

eli

ne

in T

arg

et

Le

sio

ns

, %

Be

st

Ch

an

ge

Fro

m B

as

eli

ne

in T

arg

et

Le

sio

ns

, %

JAVELIN Renal 101: Safety1,2

a TRAEs of any grade occurring in ≥20% of patients or grades 3-4 in ≥3% of patient are show. b No events occurred in ≥1% of patients.


Avelumab + Axitinib (n = 434) Sunitinib (n = 439)

All Grades Grade 3 (Grade 4) All Grades Grade 3 (Grade 4)

All TRAEs, % 95 51 (4) 96 48 (7)

Diarrhea 54 5 (0) 45 3 (0)

Hypertension 48 24 (0) 32 15 (0)

Fatigue 36 3 (0) 36 4 (0)

Hand-foot syndrome 33 6 (0) 34 4 (0)

Dysphonia 27 1 (0) 3 0 (0)

Nausea 25 1 (0) 34 1 (0)

Hypothyroidism 24 <1 (0) 13 <1 (0)

Stomatitis 22 2 (0) 23 1 (0)

Decreased appetite 20 2 (0) 26 1 (0)

Dysgeusia 13 0 (0) 32 0 (0)

Increased alanine aminotransferase 13 4 (1) 10 2 (0)

Thrombocytopenia 3 <1 (0) 18 5 (1)

Anemia 2 <1 (0) 17 5 (<1)

Neutropenia 1 <1 (0) 18 7 (1)

TRAEs leading to discontinuation of all study drugs, %a 4 8

TRAEs leading to death, %b 1 <1

JAVELIN Renal 101: Safety1,2 (Cont’d)

a Grade 5 events occurred in 3 patients in the avelumab + axitinib arm (myocarditis, necrotizing pancreatitis, sudden death; n = 1 each); in 1 patient in the sunitinib arm

(intestinal perforation). b IrAEs of any grade occurring in ≥5% of patients or grade 3 in ≥1% of patients are shown. ≥40 mg total daily prednisone or equivalent.


AEs of Special Interest in All Treated Patients

Avelumab + Axitinib

(n = 434)

All Grades Grade 3 (Grade 4)

All irAEs, %a 38 8 (1)

Hypothyroidism 21 <1 (0)

Liver function test abnormalities 5 4 (< 1)

Adrenal insufficiency 2 1 (0)

Diarrhea 2 1 (0)

Acute kidney injury 1 1 (0)

Colitis 1 1 (0)

Hepatotoxicity 1 1 (0)

Infusion-related reaction,% 12 1 (0)

High-dose corticosteroidsb were administered to 11% of patients who experienced an irAEs

N = 915

Phase 3 IMmotion151 Trial Design1

1. Motzer RJ et al. J Clin Oncol. 2018;36(suppl 6s). Abstract 578.


• Treatment-naïve advanced

or metastatic RCC

• Clear-cell and/or

sarcomatoid histology

• KPS ≥70

• Tumor tissue available for

PD-L1 staining

Atezolizumab 1,200 mg IV

+

Bevacizumab 15 mg/kg Q3W

Sunitinib 50 mg (4 wk on, 2 wk off)

Stratification

• MSKCC

risk score

• Liver

metastases

• PD-L1 IC

IHC status

(<1% vs ≥1%)

• Coprimary endpoints: Investigator-assessed PFS in patients with PD-L1 expression ≥1

and OS in ITT population

1:1 R

N = 915

Stratification

• MSKCC risk

score

• Liver metastases

• PD-L1 IC

IHC status

(<1% vs ≥1%)

1:1 R

Phase 3 IMmotion151: PFS and ORR

(PD-L1+ and ITT Patients)1

1. Motzer RJ et al. J Clin Oncol. 2018;36(suppl 6s). Abstract 578.

Median Follow-Up, 15 mo

Coprimary Endpoint Secondary Endpoint

PD-L1+ (N = 362) ITT (N = 915)

SUN

(n = 184)

ATEZO + BEV

(n = 178)

SUN

(n = 461)

ATEZO + BEV

(n = 454)

mPFS, mo 7.7 11.2 8.4 11.2

Stratified HR (95% CI) 0.74 (0.57-0.96) 0.83 (0.70-0.97)

P .0217 .0219

ORR, % 35 43 33 37

DOR, mo 12.9 NE 14.2 16.6

OS data immature at first interim analysis

Outcomes in patients with sarcomatoid histology

Rini BI et al.

Abstract 4512.

Monday, June 3 at 1:15 PM

Poster board 338

Atezolizumab + Bevacizumab: Safety

Pooled Analysis of IMmotion150 and IMmotion1511

1. Suarez C et al. ESMO 2018. Abstract 873P.

Atezolizumab + Bevacizumab: Safety

Pooled Analysis of IMmotion150 and IMmotion1511 (Cont’d)

Safety Summary of TRAEs and Serious TRAEs

N, % Sunitinib (n = 546) Atezolizumab + bevacizumab

(n = 552)

Any grade TRAEsa 525 (96%) 502 (91%)

Any serious TRAEsb 52 (10%) 83 (15%)

Grade 5 TRAEs 3 (<1%) 6 (1%)

AEs leading to discontinuation

to treatment regimen 46 (8%) 26 (5%)

Most common grades 3-4

serious TRAEsc

Pneumonitis 0 4 (0.7%)

Pyrexia 0 1 (0.2%)

Diarrhea 3 (0.5%) 3 (0.5%)

Acute kidney injury 3 (0.5%) 2 (0.4%)

Hypothyroidism 1 (0.2%) 0

AEs requiring systemic

corticosteroids:

atezolizumab + bevacizumab, 88

pts (16%); sunitinib, 27 pts (5%)

AEs requiring high-dose

corticosteroids:

atezolizumab + bevacizumab, 49

pts (9%); sunitinib, 5 pts (1%)

1. Suarez C et al. ESMO 2018. Abstract 873P.

a Includes AEs related to any of the 3 treatments. b Serious TRAEs defined as TRAEs that met any of the following criteria: fatal, life threatening, requires or

prolongs inpatient hospitalization, results in significant disability, is a congenital anomaly in an infant born to a mother exposed to study drug, or a significant

medical event per investigator assessment. c Grade 5 serious TRAEs are reported as grade 5 TRAEs.

My Thoughts on Frontline IO + VEGFR-TKI

• The fusion of VEGF (first-line) and PD-1/PD-L1 (second-line)

blockade produces impressive anti-tumor effects

• ORR and PFS meaningfully improved

• Impact of axi/pembro in KEYNOTE 426 on overall survival sets a

high bar for future trials

• VEGF + PD-1/PD-L1 combinations are tolerable and broadly

applicable, although impact on QOL remains to be determined

• Predictive biomarkers are emerging (ASCO 2019)

When Might Single-Agent Therapy

Be Appropriate in This Setting?

Toni K. Choueiri, MD Director, Lank Center for Genitourinary Oncology

Department of Medical Oncology


The Jerome and Nancy Kohlberg Endowed Chair




• What do the analyses from the phase 3 trials show?

– COMPARZ

– CABOSUN/METEOR

– KEYNOTE 427

• Role of PD-L1 IHC and other biomarkers

Single-Agent TKI or PD-1 Inhibitor?

VEGFR-TKI vs VEGFR-TKI: COMPARZ1

1. Motzer RJ et al. N Engl J Med. 2013;369:722-731.

N = 1,110


• Locally advanced RCC or

mRCC with clear-cell

histology

• Measurable disease

• No prior systemic treatment

• KPS ≥70

Pazopanib 800 mg/d

Sunitinib 50 mg/d

(schedule 4/2)

Endpoints

• Primary: PFS for noninferiority (independent review)

• Secondary: OS, ORR, PRO, safety, QOL, and medical resource utilization

1:1 R

n = 557

n = 553

Non-inferiority

study

0

0.2

0.4

0.6

0.8

1

0 4 8 12 16 20 24 28 32 36 40

COMPARZ: Efficacy

Pazopanib vs Sunitinib1,a

COMPARZ: Progression-Free Survival (Independent Review)

a Good/intermediate-risk patients; 9%-12% of patients were poor-risk (MSKCC).

1. Motzer RJ. N Engl J Med. 2013;369:722-731.

Pro

gre

ss

ion

-Fre

e

Su

rviv

al,

Pro

po

rtio

n

Time, mo

n Median PFS, mo (95% CI)

Pazopanib 557 8.4 (8.3-10.9)

Sunitinib 553 9.5 (8.3-11.1)

HR: 1.047 (95% CI, 0.898-1.220)

557 361 245 136 105 61 46 19 13 1

553 351 249 147 111 69 48 18 10 3

No. at Risk

Pazopanib

Sunitinib

Pazopanib

Sunitinib

PD-L1 Expression by H-Score in COMPARZ Trial1

1. Choueiri TK et al. Clin Cancer Res. 2015;21:1071-1077.

0

0.2

0.4

0.6

0.8

1

0 10 20 30 400

0.2

0.4

0.6

0.8

1

0 10 20 30 40

HS: 50 HS: 125

Pazopanib low

Pazopanib high

Sunitinib low

Sunitinib high

Ove

rall S

urv

iva

l, P

rob

ab

ilit

y

Time, mo

Ove

rall S

urv

iva

l, P

rob

ab

ilit

y

Time, mo

H-score: low ≤50, high >50 H-score: low ≤125, high >125

Group (n) Median OS, mo (95% CI)

Pazopanib low (194) 31.6 (26.7-NR)

Pazopanib high (27) 19.7 (9.8-NR)

Sunitinib low (198) 27.7 (23.7-34.5)

Sunitinib high (34) 15.3 (11.2-30.5)

P = .046

Group (n) Median OS, mo (95% CI)

Pazopanib low (213) 31.6 (26.5-NR)

Pazopanib high (8) 5.1 (4.2-NR)

Sunitinib low (225) 27.4 (21.4-30.5)

Sunitinib high (7) 8.9 (2.6-NR)

P = .017

N = 453

Pazopanib low

Pazopanib high

Sunitinib low

Sunitinib high

CABOSUN: Randomized Phase 2 of Frontline

Cabozantinib Versus Sunitinib1

1. Choueiri TK et al. J Clin Oncol. 2016;35:591-597.

N = 157


• Patients with clear-cell

RCC of intermediate or

poor risk

• No prior systemic therapy

Cabozantinib 60 mg/d

(continuous dosing)

Sunitinib 50 mg/d

(4/2 dosing)

Stratification

• IMDC risk

group

(intermediate

vs poor)

• Bone

metastasis

(yes/no)

• Coprimary endpoints: PFS, OS

1:1

R

n = 79

n = 78

• Multicenter, randomized phase 2 study

CABOSUN: PFS per IRC and OS1,a

OS

HR: 0.80 (95% CI, 0.53-1.21)

P = .29 (2-sided)

Median OS: cabozantinib, 26.6 mo; sunitinib, 21.2 mo a Data cutoff: PFS, September 15, 2016; OS, July 1, 2017.

1. Choueiri TK et al. ESMO 2017. Abstract LBA38.

Original Report2,a

Investigator

September 2016 Cutoff

Investigatorb

September 2016 Cutoff

IRCb

Cabozantinib

(n = 79)

Sunitinib

(n = 78)

Cabozantinib

(n = 79)

Sunitinib

(n = 78)

Cabozantinib

(n = 79)

Sunitinib

(n = 78)

PFS

Median PFS, mo 8.2 5.6 8.3 5.4 8.6 5.3

Stratified HR (95% CI) 0.66 (0.46-0.95) 0.56 (0.37-0.83) 0.48 (0.31-0.74)

P .012 (1-sided) .0042 (2-sided) .0008 (2-sided)

Tumor response

Objective response rate

(95% CI), % 46 (34-57) 18 (10-28) 33 (23-44) 12 (5-21) 20 (12-31) 9 (4-18)

Disease control rate,c % 78 54 76 49 75 47

Any reduction in target lesions, % 87 44 85 38 80 50

CABOSUN: PFS Consistent Across Methodologies1

Cabozantinib was associated with improved PFS and ORR

across all patient subgroups3

a Data cutoff: April 11, 2016. b Data cutoff: September 15, 2016. c CR + PR + SD.

1. Choueiri TK et al. ESMO 2017. Abstract LBA38. 2. Choueiri TK et al. J Clin Oncol. 2017;35:591-597. 3. George D. ASCO-GU 2018. Abstract 582.

Impact of PD-L1 Status on Outcomes With TKIs

Analysis of METEOR and CABOSUN1

METEOR (N=306) CABOSUN (N=110)

Combining Two Trials

All Patients

(N = 416)

Cabozantinib

Only

(n = 211)

Total/

No. of

Events

Median Mo

(95% CI)

Total/

No. of

Events

Median Mo

(95% CI)

Adjusted HR

(95% CI) a

Adjusted HR

(95% CI) a

PFS

PD-L1(-) 218/126 7.2

(5.6-7.5) 85/45

8.3

(5.4-12.9) 1(reference) 1(reference)

PD-L1(+) 88/60 5.3

(3.7-5.6) 25/20

5.5

(2.8-10.1)

1.21

(0.92-1.61)

1.28

(0.83-1.99)

P value .027 .051 .173 .265

OS

PD-L1(-) 218/91 21.3

(18.0-NR) 85/44

28.1

(18.9-NR) 1(reference) 1(reference)

PD-L1(+) 88/52 15.1

(10.4-18.8) 25/18

20.8

(12.3-26.6)

1.39

(1.03-1.87)

1.63

(1.03-2.60)

P value .003 .047 .034 .038

a All models were adjusted for treatment, IMDC risk groups, and presence of bone metastases. For METEOR and combined analysis, the models were also adjusted

for number of previous VEGFR-TKI treatment (1 or ≥2 for METEOR; 0, 1, or ≥2 for the combined analysis).

1. Choueiri TK et al. ESMO 2018. Abstract LBA34.

KEYNOTE-427: Pembrolizumab Monotherapy

in Frontline Advanced RCC1

• Single-arm, nonrandomized phase 2 study

1. McDermott D et al. 2018 American Society of Clinical Oncology Annual Meeting (ASCO 2018). Abstract 4500.

Anticipated N = 255


• No prior systemic therapy

• KPS ≥70

• Must provide adequate

tissue for biomarker

analysis

Pembrolizumab 200 mg IV

Q3W (clear-cell RCC)

Pembrolizumab 200 mg IV

Q3W (non–clear-cell RCC)

• Primary endpoint: ORR

R

Cohort A:

n = 110

Cohort B:

n = 164

KEYNOTE-427: Pembrolizumab Monotherapy

Outcomes

ORR

• Overall = 36.4%

(CR = 3%; PR = 34%)

• Favorable risk = 31%

• Intermediate/

poor risk = 39.7%

• Sarcomatoid

histology = 63.6%

• PD-L1 positive = 44.2%

• PD-L1 negative = 29.3%

• Response≥ 6 mo = 76.8%

Median PFS: 7.1 mo

Median OS: NR

Safety

• One grade 5 treatment-

related pneumonitis

ORR

• Overall = 24.8%

(CR = 5%; PR = 20%)

• Papillary = 25.4%

• Chromophobe = 9.5%

• Unclassified

nccRCC = 34.6%

• Sarcomatoid = 44.7%

• CPS ≥1 = 33.3%

• CPS <1 = 10.3%

Safety

• Grade 3-5 TRAE = 11%

• Two grade 5 treatment-

related deaths

(pneumonitis and cardiac

arrest)

1. Tykodi SS et al. J Clin Oncol. 2019. Abstract 4570. 2. Lee JL et al. J Clin Oncol. 2019. Abstract 4569.

At 18-mo Follow-Up

(Cohort A Results)1

N = 110

At 11.1-mo Follow-Up

(Cohort B Results)2

N = 165

KEYNOTE-427: ORR by PD-L1 Expression1-3

Database cutoff: March 12, 2018. a DCR = CR + PR + SD ≥6 mo.

1. McDermott D et al. ASCO 2018. Abstract 4500. 2. Donskov F et al. Annals of Oncol. 2018;29:871P. 3. McDermott D et al. ASCO-GU 2019. Abstract 546.

CPS ≥1

(n = 46)

CPS <1

(n = 53)

Missing

(n = 11)

Confirmed ORR, %

(95% CI) 50.0 (34.9-65.1) 26.4 (15.3-40.3) 45.5 (16.7-76.6)

DCR, % (95% CI)a 67.4 (52.0-80.5) 49.1 (35.1-63.2) 72.7 (39.0-94.0)

Confirmed BOR, %

CR

PR

SD

PD

NA

6.5

43.5

26.1

23.9

0

0

26.4

35.8

34.0

3.8

0

45.5

36.4

18.2

0

Outcomes by PD-L1 Status

Combination Regimens

CheckMate -214: ORR by PD-L1 Expression

IMDC Intermediate-/Poor-Risk Patients1

a Response was assessed according to RECIST v1.1 by an independent radiology review committee. b Per exploratory analysis.


PD-L1 <1% PD-L1 ≥1%

Outcome NIVO + IPI

(n = 284)

SUN

(n = 278)

NIVO + IPI

(n = 100)

SUN

n= 114)

Objective

response

rate,a %

37 28 58 22

P = .0252b P < .001b

Best overall

response,a %

CR

PR

7

30

1

27

16

42

1

21

CheckMate -214: OS by PD-L1 Expression

IMDC Intermediate-/Poor-Risk Patients1

a Response was assessed according to RECIST v1.1 by an independent radiology review committee.


0 . 8

0 . 9

1 . 0

0 . 4

0 . 5

0 . 6

0 . 7

0 6 1 2 1 8 2 7 3 3

0 . 1

0 . 0

0 . 2

0 . 3

3 9 1 5 2 1 2 4 3 0

0 . 8

0 . 9

1 . 0

0 . 4

0 . 5

0 . 6

0 . 7

0 6 1 2 1 8 2 7 3 3

0 . 1

0 . 0

0 . 2

0 . 3

3 9 1 5 2 1 2 4 3 0

OS

Pro

ba

bilit

y

Time, mo Time, mo

284 251 223 200 76 0

278 239 198 157 61 1

100 87 83 76 33 2

114 90 72 55 21 2

NIVO + IPI

SUN

No. at Risk

HR: 0.73 (95% CI, 0.56-0.96)

P = .0249

Median OS (95% CI), mo

NIVO + IPI NR (28.2-NE)

Sunitinib NR (24.0-NE)

HR: 0.45 (95% CI, 0.29-0.71)

P < .001

Median OS (95% CI), mo

NIVO + IPI NR (NE-NE)

Sunitinib 19.6 (14.8-NE)

PD-L1 <1% (n = 562) PD-L1 ≥1% (n = 214)

OS

Pro

ba

bilit

y

KEYNOTE-426: PFS and OS by PD-L1 Status1

1. Powles T et al. ASCO-GU 2019. Abstract 543.

Subgroup

No. of Events/

No. of Patients

Hazard Ratio

(95% CI) PD-L1 CPS

<1 137/325 0.87 (0.62-1.23)

≥1 240/497 0.62 (0.47-0.80)

Progression-Free Survival

Subgroup

No. of Events/

No. of Patients

Hazard Ratio

(95% CI) PD-L1 CPS

<1 54/325 0.59 (0.34-1.03)

≥1 90/497 0.54 (0.35-0.84)

Overall Survival

0.1 0.5 2

Pembro-Axi

better

Suntinib

better

1

Ongoing Phase 3 Studies in the Frontline Setting

Stratification by PD-L1 Status1

Trial Name Treatment Arms

Stratification

by PD-L1

Status

CheckMate 9ER Nivolumab + cabozantinib vs sunitinib Yes

PIVOT-09 Bempegaldesleukin (NKTR-214) +

nivolumab vs cabozantinib or sunitinib Yes

COSMIC-313 Nivolumab/ipilimumab + cabozantinib

vs nivolumab/ipilimumab + placebo

No

PDIGREE

Nivolumab + ipilimumab →

nivolumab vs nivolumab + cabozantinib

(in non-CR/non-PD patients)

No

CLEAR Lenvatinib-pembrolizumab

or lenvatinib-everolimus No

1. https://www.clinicaltrials.gov. Accessed May 26, 2019.

Other Biomarkers

IMmotion 151: Molecular Correlates of Differential Response to

Atezolizumab ± Bevacizumab vs Sunitinib in mKC1

Angiogenesis T-effectorHigh

Myeloid InflammationLow

VEGF TKI

PD-L1 Ab

T-effectorHigh

Myeloid

InflammationHigh

Immune Suppressed

PD-L1 + VEGF Ab

Tumor cells

T-effector cells

Myeloid cells

Vasculature

Clinical

Activity

1. Rini BI et al. ESMO 2018. Abstract LBA31.

IMmotion151: Atezolizumab + Bevacizumab

Improved PFS in Different Subsets1


Atezolizumab + Bevacizumab Improved PFS vs Sunitinib

in the AngiogenesisLow Subset

IMmotion151: Atezolizumab + Bevacizumab

Improved PFS in Different Subsets1 (Cont’d)


Atezolizumab + Bevacizumab Demonstrated Improved PFS vs

Sunitinib in T-EffectorHigh Subset

• T-effector gene signature did not differentiate PFS within the sunitinib or

atezolizumab + bevacizumab treatment arms

Biomarker Analyses from

JAVELIN Renal 101

Findings define molecular

features that differentiate

therapy-specific outcomes

in first-line advanced RCC.

Choueiri T et al.

Abstract 101.

Saturday, June 1 at 8:00 AM

Practicum Optimizing the Application of TKIs and Immune

Checkpoint Inhibitors in the Frontline Setting















Houston, Texas

Tumor Board 1: Treatment and Follow-Up

Tina, a 43-year-old female

• Received 4 cycles of

nivolumab 3 mg/kg IV +

ipilimumab 1 mg/kg IV Q3W

and started nivolumab

maintenance 480 mg IV Q4W

• Resolution of all symptoms at

baseline and no AEs related to

therapy

Post-Tx

Assessment • CT of CAP

• Resolution of bilateral

pulmonary metastases with

marked improvement of liver

metastases

• Primary complex cystic/solid

tumor in the lower pole of the

left kidney slightly enlarged

with expansion of a necrotic

center

• Small lymph nodes in the

retroperitoneum near the left

renal vessels are slightly more

prominent

Further Tx • Left radical

nephrectomy

Pathology: Clear-cell RCC,

Fuhrman nuclear grade 4

• Extensive tx effect and

sarcomatoid and rhabdoid

dedifferentiation, invasive

into the renal sinus and

perinephric adipose tissue

• 0/3 para-aortic and left renal

hilar lymph nodes positive for

tumor

• Extensive necrosis was

identified with ~30% of the

tumor viable

Tumor Board 1: Post-Treatment CT Scans

Images courtesy of Dr. Tannir.

3/18/2019

Checkmate -214 KEYNOTE-426

Nivo/Ipi Sunitinib Delta Axi/Pembro Sunitinib Delta

12 mo, % 44 44 0 60 46 14

18 mo, % 37 33 4 41 33 8

24 mo, % 31 23 8 ? ? ?

30 mo, % 28 18 10 ? ? ?

Landmark PFS Comparisons:

CheckMate -214 vs KEYNOTE-426

Courtesy of Dr. Tannir.

Considerations for Sequencing Multitargeted

TKIs and Immune Checkpoint Inhibitors in the

Management of Pretreated Advanced RCC

Toni K. Choueiri, MD Director, Lank Center for Genitourinary Oncology

Department of Medical Oncology


The Jerome and Nancy Kohlberg Endowed Chair




Tumor Board 2: A Patient With

Previously Treated Metastatic RCC

Peter, a 62-year-old professor

• Found an incidental

10-cm left renal

mass

• Nephrectomy reveals

grade 3 clear-cell

RCC, no

sarcomatoid

elements,

extracapsular

extension, 0/6 nodes

(pT3a, N0, Mx)

Follow-Up

• 2 years later, patient

found to have 1.8-cm

right adrenal nodule

and 2 pancreatic

lesions (2.2 and

1.5 cm)

• Labs WNL except

creatinine = 1.6

First-Line Therapy

• He is started on

sunitinib 50 mg

daily 4 wk on,

2 wk off

Tumor Board 2: Treatment Outcomes

After 3 months on treatment, his

lesions have decreased. The

patient develops increased BP,

grade 2 fatigue, and HFS

• Sunitinib dose is decreased

to 37.5 mg and switched to

2 wk on, 1 wk off

• Anti-hypertensives were

added

• 9 mo later, he has increasing

pancreatic lesions (3 and 2.4 cm)

with new T 10 lytic MET

(asymptomatic)

• KPS 80

• Hb 11.5, WBC 5.7, plts 180, Ca 9.8,

albumin 3.2, creatinine 1.7

What are his options now?

Kidney in place?

Consider cytoreductive nephrectomy ±

metastasectomy if LOW-VOLUME DISEASE/

NED goal

Unresectable disease on imaging?

Axitinib

Cabozantinib

Lenvatinib + everolimus

Nivolumab

Everolimus or sorafenib

• Bevacizumab +

interferon-α

• High-dose IL-2

• Pazopanib

• Sunitinib

• Cabozantinib

• Nivolumab +

ipilimumab

• Temsirolimus

(poor-risk RCC)

Consider metastasectomy

No Yes

Yes

Decision-Making Strategy for Advanced RCC

January 2019

First-line

options

Second-line

or later

options

Other

options

No

Approved

VEGFR-TKIs

Phase 3 METEOR: Cabozantinib Versus Everolimus

Study Design1

1. Choueiri TK et al. N Engl J Med. 2015;373:1814-1823.

N = 658


• mRCC with clear-cell

component

• ≥1 prior VEGFR-TKI

• Progression on or after

prior VEGFR-TKI within

6 mo of study enrollment

• KPS ≥70

Cabozantinib

60 mg/d orally QD

Everolimus

10 mg orally QD

Stratification

• MSKCC risk

criteria

• Number of prior

VEGFR-TKIs

Endpoints

• Primary: PFS

• Secondary: OS, ORR

• Exploratory: Safety, tolerability, tumor MET status, circulating tumor cells, serum bone markers and plasma

biomarkers, skeletal-related events, and HR-QoL

1:1

R

• Treatment until loss of clinical

benefit or intolerable toxicity

• Treatment beyond progression

was permitted if drug was tolerable

and clinical benefit was noted

METEOR: Cabozantinib Versus Everolimus

PFS per IRC1,a

Median

Cabozantinib (n = 330) 7.4 mo

Everolimus (n = 328) 3.9 mo

HR: 0.51 (95% CI, 0.41-0.62)

P < .0001

a Confirmed responses per RECIST version 1.1. All responses were partial responses.

1. Choueiri TK et al. Lancet Oncol. 2016;17:917-927.


Secondary Endpoints1,a

Parameters Cabozantinib, %

(n = 330)

Everolimus, %

(n = 328)

ORR per IRC

(95% CI)

17

(13-22)

3

(2-6)

Median OS,

mo (95% CI)

No. of

Deaths

Cabozantinib (n = 330) 21.4 (18.7-NE) 140

Everolimus (n = 328) 16.5 (14.7-18.8) 180

HR: 0.66 (95% CI, 0.53-0.83)

P = .00026

a Confirmed responses per RECIST version 1.1. All responses were partial responses.

1. Escudier B et al. J Clin Oncol. 2016;34(suppl 2S). Abstract 499.

METEOR: OS and PFS

Based on Subgroups1


METEOR: OS and PFS

Based on Prior Therapies1


Event

Cabozantinib, n (%)

(n = 406)

Everolimus, n (%)

(n = 397)

Grades 1-2 Grade 3 Grades 1-2 Grade 3

Any AEa 70 (21) 210 (63) 103 (32) 167 (52)

Diarrhea 206 (62) 43 (13) 85 (26) 7 (2)

Fatigue 159 (48) 36 (11) 130 (40) 24 (7)

Nausea 158 (48) 15 (5) 92 (29) 1 (<1)

Decreased appetite 146 (44) 10 (3) 111 (35) 3 (1)

PPE syndrome 115 (35) 27 (8) 16 (5) 3 (1)

Hypertension 73 (22) 49 (15) 14 (4) 12 (4)

Vomiting 106 (32) 7 (2) 44 (14) 3 (1)

Weight decreased 105 (32) 9 (3) 42 (13) 0

Constipation 89 (27) 1 (<1) 64 (20) 1 (<1)

Dysgeusia 80 (24) 0 30 (9) 0

Hypothyroidism 76 (23) 0 1 (<1) 1 (<1)


Adverse Events1

Patients requiring dose reduction on study: cabozantinib = 60% vs everolimus = 25%

Patients discontinued because of an AE: cabozantinib = 12% vs everolimus = 11%

a Any grade 4 AE for cabozantinib, n (%): 25 (8). Any grade 4 AE for everolimus, n (%): 26 (8).


Randomized Phase 2 Trial of Lenvatinib Versus

Everolimus Versus Lenvatinib Plus Everolimus1

Eligibility criteria

• Advanced or mRCC

with clear-cell component

• One prior VEGF-targeted

therapy

• ECOG PS 0 or 1 Lenvatinib

24 mg orally QD

Everolimus

10 mg orally QD

N = 153

Lenvatinib + Everolimus

18 mg + 5 mg orally QD

1:1:1

R

Endpoints

• Primary: PFS

• Secondary: OS, ORR, and safety

1. Motzer RJ et al. Lancet Oncol. 2016;17:e4-e5.

Phase 2 Lenvatinib Plus Everolimus: PFS1,a

a As assessed by an independent radiologic review.

1. Motzer RJ et al. Lancet Oncol. 2016;17:e4-e5.

Lenvatinib Plus Everolimus: TEAEs1,a

AE

Lenvatinib + Everolimus, n (%)

(n = 51)

Lenvatinib, n (%)

(n = 52)

Everolimus, n (%)

(n = 50)

Grades 1-2 Grade 3 Grade 4 Grades 1-2 Grade 3 Grade 4 Grades 1-2 Grade 3 Grade 4

Diarrhea 33 (65) 10 (20) 0 31 (60) 6 (12) 0 16 (32) 1 (2) 0

Fatigue or

asthenia 23 (45) 7 (14) 0 22 (42) 4 (8) 0 18 (36) 0 1 (2)

Vomiting 19 (37) 3 (8) 0 18 (35) 2 (4) 0 5 (10) 0 0

Nausea 18 (35) 3 (6) 0 28 (54) 4 (8) 0 8 (16) 0 0

Constipation 6 (12) 19 (37) 0 19 (37) 0 0 9 (18) 0 0

Hypertension 14 (27) 7 (14) 0 16 (31) 9 (17) 0 4 (8) 1 (2) 0

Proteinuria 9 (18) 2 (4) 0 6 (12) 10 (19) 0 6 (2) 1 (2) 0

Hyper-

triglyceridemia 14 (27) 4 (8) 0 5 (10) 2 (4) 0 8 (16) 4 (8) 0

Hyperglycemia 8 (16) 0 0 3 (6) 0 0 6 (12) 4 (8) 1 (2)

Dyspnea 11 (22) 0 1 (2) 10 (19) 1 (2) 0 7 (14) 4 (8) 0

Anemia 4 (8) 4 (8) 0 3 (6) 1 (2) 0 7 (14) 6 (12) 0

a TEAEs leading to death: cerebral hemorrhage (lenvatinib + everolimus, 1 [2%]); myocardial infarction (single-agent lenvatinib, 1 [2%]); intracranial hemorrhage

(single-agent lenvatinib, 1 [2%]).

1. Motzer RJ et al. Lancet Oncol. 2015;16:1473-1482.

Phase 3 TIVO-3: Tivozanib Versus Sorafenib

in Advanced RCC—Study Design1

1. Rini B et al. J Clin Oncol. 2019;37(suppl 7). Abstract 541.

N = 350


• Advanced clear-cell RCC

• Failed 2 or 3 prior regimens

including ≥1 VEGFR-TKI

• ECOG PS 0 or 1

Tivozanib 1.5 mg orally QD

(3 wk on, 1 wk off per cycle)

Sorafenib 400 mg orally BID

(continuously in 4-wk cycles)

Stratification

• Prior regimen

(TKI–PD-1,

TKI-TKI,

TKI-other)

• IMDC

prognostic

score (fav, int,

poor)

1:1

R • Treatment until progression or

unacceptable toxicity

Endpoints

• Primary: PFS

• Secondary: ORR, OS, and duration of response

0

0.2

0.4

0.6

0.8

1

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28

2-y PFS

18%

5%

28%

1-y PFS

11% Sorafenib

Tivozanib

TIVO-3: Progression-Free Survival per IRC1

1. Rini B et al. J Clin Oncol. 2019;37(suppl 7; abstr 541).

Time, mo

170 128 94 69 56 48 37 31 24 20 16 14 6 0 0

159 116 65 42 27 18 11 9 5 3 3 2 2 0 0

No. at Risk

Tivozanib

Sorafenib


Tivozanib 5.6 (5.3- 7.3)

Sorafenib 3.9 (3.7-5.6)

HR: 0.73 (95% CI, 0.56-0.94)

P = .0165

Pro

gre

ssio

n-F

ree

Su

rviv

al,

Pro

bab

ilit

y

1.0

Subgroup Analyses

of PFS

PFS benefit was

observed in most

subgroups except IMDC

poor risk.

Porta C et al.

Abstract 4572.

Monday, June 3

at 1:15 PM

Poster board 398

Tivozanib (n = 173) Sorafenib (n = 170)

Preferred Term, % All Grades Grade 3/4 All Grades Grade 3/4

Treatment-related AEs 84 44 94 55

Hypertension 36 20 25 14

Diarrhea 33 2 50 9

Fatigue 29 4 19 5

Decreased appetite 26 4 21 2

Dysphonia 24 1 8 0

Asthenia 21 5 17 4

Stomatitis 19 2 18 2

Nausea 19 0 14 2

PPE syndrome 16 1 38 10

Hypothyroidism 14 1 6 0

Rash 4 0 24 8

TIVO-3: Treatment-Related Adverse Events

(≥10% Frequency in Either Arm)1

1. Rini B et al. J Clin Oncol. 2019;37(suppl 7). Abstract 541.

Putting the Rest of the

Targeted Agents Into Context

Everolimus, Sorafenib,

Axitinib

Activity of Cabozantinib, Everolimus, and Axitinib

in Patients Who Have Received Prior Sunitinib Only

a Total enrolled population.

1. Choueiri TK et al. Lancet Oncol. 2016;17:917-927. 2. Motzer RJ et al. Cancer. 2010;116:4256-4265. 3. Motzer RJ et al. Lancet Oncol. 2013;14:552-562.

Cabozantinib

(METEOR)1

(N = 76)

40% of Primary

ITT

Everolimus

(METEOR)1

(N = 77)

41% of Primary

ITT

Everolimus

(RECORD-1)2

(N = 124)

45% of ITT

Axitinib

(AXIS)3

(N = 194)

54% of ITT

Sorafenib

(AXIS)3

(N = 195)

54% of ITT

Response rate 22% 3% 1-2% 11% 8%

PFS (mo) 9.1 3.7 3.9 4.8 3.4

Discontinuation

due to AEsa 9% 10% 14% 9% 13%

Selected “Emerging” Experience

With “RCC” Drugs Post IO

Author/Journal/Year Study Agents N ORR PFS/TTF

Albiges. EJC 2015 Retrospective VEGF-TKI/mTOR (axi/eve++) 56 13% 6.6 mo

Nadal. Ann Oncol. 2016 Retrospective VEGF-TKI 70 28% 6.4 mo

Derosa. ESMO 2017 Retrospective VEGF-TKIs (cabo/axi) 56 33% 8 mo

McGregor. ESMO 2018 Retrospective Cabozantinib 86 36% 6.6 mo

Ornstein. ASCO 2018 Phase 2 Axitinib, dose titrated 38 38% 9.2 mo

Auvray. EJC 2019 Retrospective TKIs (post combo nivo/ipi) 33 36% 8 mo

Shah. EJC 2019 Retrospective TKIs 70 41% 13.2 mo

Martini. JITC 2017 Retrospective Nivolumab 3 0 —

Allman. IKCS 2018 Retrospective Nivolumab + ipilimumab 14 33% —

Preliminary safety data show no concerning signals of “amplified” or unusual toxicities

Cabozantinib Activity After Prior

PD-1/PD-L1 Therapy1

• Retrospective data from two institutions; N = 86

• Cabozantinib following immune checkpoint blockade is effective

─ ORR, favorable/intermediate risk: 41%; poor risk: 25%

─ TTF, favorable/intermediate risk: 7.4 mo; poor risk: 3.9 mo

─ Clinical benefit noted independent of duration of prior immune checkpoint

inhibitor therapy

Overall:

ORR: 36%

ORR + SD: 79%

TTF After Cabozantinib Initiation OS After Cabozantinib Initiation

Phase 2 BREAKPOINT (NCT03463681)2

Prospective analysis of cabozantinib post–

immune checkpoint inhibitor therapy

1. McGregor B et al. Annals of Oncology. 2018;29:879P. 2. Verzoni E et al. J Clin Oncol. 2019;7S. Abstract TPS685.

Approved

Immune Checkpoint

Inhibitors

Phase 3 CheckMate 025: Nivolumab Versus

Everolimus – Study Design1

Endpoints

• Primary: OS

• Secondary: Response rate, PFS, effect of PD-L1 expression on OS, and safety


N = 821


• mRCC patients with

clear-cell histology

• Prior antiangiogenic

therapy

Nivolumab

3 mg/kg IV Q2W

Everolimus

10 mg orally daily

R 1:1

CheckMate 025: OS1

No. of Patients


No. of Deaths

Nivolumab 410 25.0 (21.8-NE) 183

Everolimus 411 19.6 (17.6-23.1) 215

HR: 0.73 (98.5% CI, 0.57-0.93); P = .002


OS benefit

noted in

patients with

or without

PD-L1

expression

CheckMate 025: Objective Response Rate1

Nivolumab

N = 410

Everolimus

N = 411

Objective response rate, n (%) 103 (25)

P < .001 22 (5)

Odds ratio (95% CI) 5.98 (3.68-9.72)

Best overall response

CR

PR

SD

PD

NE

4 (1)

99 (24)

141 (34)

143 (35)

23 (6)

2 (<1)

20 (5)

227 (55)

114 (28)

48 (12)

Median time to response, mo (range) 3.5 (1.4-24.8) 3.7 (1.5-11.2)

Median duration of response, mo (range) 12.0 (0-27.6) 12.0 (0-22.2)

Median duration of treatment, mo (range) 5.5 (<1-29.6) 3.7 (0.2-25.7)


Event Nivolumab (n = 406), n (%) Everolimus (n = 397), n (%)

Any Grade Grades 3 or 4 Any Grade Grades 3 or 4

All events 319 (79) 76 (19) 349 (88) 145 (37)

Fatigue 134 (33) 10 (2) 134 (34) 11 (3)

Nausea 57 (14) 1 (<1) 66 (17) 3 (1)

Pruritus 57 (14) 0 39 (10) 0

Diarrhea 50 (12) 5 (1) 84 (21) 5 (1)

Decreased

appetite 48 (12) 2 (<1) 82 (21) 4 (1)

Rash 41 (10) 2 (<1) 79 (20) 3 (1)

CheckMate 025: Comparison of Adverse Events1

Rate of discontinuation because of toxicity:

nivolumab, 8.7% (n = 35); everolimus, 13.4% (n = 53)

TRAEs Reported in ≥10% of Treated Patients in Either Group


Kidney in place?

Consider cytoreductive nephrectomy ±

metastasectomy if LOW-VOLUME DISEASE/

NED goal

Unresectable disease on imaging?

Therapy not used prior

Therapy not used prior

IO + IO or

IO + VEGFR or

IO + IO + VEGFR

Consider metastasectomy

No Yes

Yes

Decision-Making Strategy for Advanced RCC

May 2019

First-line

options

Second-line

options

Later

options

No

• Fewer and fewer patients treated with first-line VEGF-TKIs

– Sunitinib/cabozantinib in IMDC good-risk patients?

– But, IO-VEGF combos are NOW approved

• Second-line landscape will be defined by

– Therapies not received prior

– Probably single agents

• IO post-IO (PD-1/PD-L1) remains experimental, and new trials should focus on

that niche

– Eg, post–nivo-ipi failure: should we give pembro/axi or axi? Nivo/cabo or

cabo, etc…

• New drugs with new MOA are TOTALLY welcome in RCC!

Conclusions: “Second-/Next-Line”

Therapies in RCC

HIF-

2α

HO

HO

HIF-2α pVHL

pVHL

HO

HO

HIF-

2α

Cytosol

Nucleus

HIF-2α

Hypoxia

• EPO

• VEGFA

HIF-1β

HIF-2α

HIF-1β

O2

Nucleus

Hypoxia-Response

Element

Function of HIF-2α Under Hypoxia

PT2977 (HIF-2α Inhibitor)1

1. Choueiri TK et al. 14th European International Kidney Cancer Symposium. Paper.

Function of HIF-2α Under Hypoxia

PT2977 (HIF-2α Inhibitor)1 (Cont’d)


HIF-2α

HIF-2α

HO

HO

HIF-2α

• Proliferation

• Survival

• Metastasis

• Angiogenesis

Prolyl

Hydroxylases

Hypoxia

O2

Cytosol

Nucleus

Normoxia

O2

Hypoxia-Response

Element

Defective

VHL

pVHL HIF-

1β

Pseudohypoxia

O2 PT2977

PT2977 potently

and selectively binds

to HIF-2α and prevents

its heterodimerization

with HIF-1β

Phase 1/2 Trial of PT2977 in Advanced RCC1


Best Change in Tumor Size From Baseline

Best Response N = 55

PR 12 (22%)

SD 31 (56%)

DCR 43 (78%)

Duration of Treatment

Pati

en

ts

Time on Treatment, wk Patients

Best

Ch

an

ge i

n S

um

of

Targ

et

Le

sio

ns

Fro

m B

as

eli

ne

, %

→ Ongoing treatment

Partial response

80

70

60

50

40

30

20

10

0

-10

-20

-30

-40

-50

-60

-70

-80

0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72 76

• Two patients (4%) discontinued treatment for drug-related adverse events

• Three other patients (6%) required dose reductions for drug-related adverse events

PT2977: All-Cause Adverse Events ≥20%1

As of January 1, 2019.


Adverse Event PT2977 (n = 55)

Grade 1/2 (%) Grade 3 (%) Grade 4 (%) All Grades n (%)

Anemia 30 (55) 11 (20) — 41 (75)

Fatigue 32 (58) 3 (5) — 35 (64)

Dyspnea 20 (36) 4 (7) — 24 (44)

Nausea 17 (31) 1 (2) — 18 (33)

Edema peripheral 16 (29) — 16 (29)

Cough 15 (27) — 15 (27)

Headache 13 (24) 1 (2) — 14 (25)

Arthralgia 14 (25) — 14 (25)

Blood creatinine

increased 13 (24) 1 (2) — 14 (25)

Vomiting 13 (24) — 13 (24)

Constipation 12 (22) — 12 (22)

Hypoxia 5 (9) 6 (11) — 11 (20)

Dizziness 11 (20) — 11 (20)

Hyperkalemia 10 (18) 1 (2) — 11 (20)

Practicum Optimizing the Application of TKIs and Immune

Checkpoint Inhibitors in the Pretreated Setting















Houston, Texas

Symposium Summary and

Audience Q&A

Go online to access full [Certification Type] information, including faculty disclosures.











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Thank you and good evening.

Please remember to complete and submit your Post-Test

and Evaluation for CME/MOC credit.

Missed anything?

Ab: antibody

AJCC: American Joint Committee on Cancer

ANC: absolute neutrophil count

aRCC: advanced renal cell carcinoma

ATEZO: atezolizumab

Axi: axitinib

BEV: bevacizumab

BICR: blinded independent central radiologic review

BID: twice daily

Ca: calcium

CAP: chest abdomen pelvis

CPS: combined positive score

CR: complete response

CXCR2: C-X-C chemokine receptor type 4

DCR: disease control rate

DFS: disease-free survival

DOR: duration of response

ECOG PS: Eastern Cooperative Oncology Group

performance status

EPO: erythropoietin

ESMO: European Society for Medical Oncology

HERV-E: human endogenous retrovirus group E

HFS: hand-foot syndrome

HIF-1β: hypoxia-inducible factor 1-beta

HIF-2α: hypoxia-inducible factor 1-alpha

HLA: human leukocyte antigen

Abbreviations

HR: hazard ratio

HR-QoL: health-related quality of life

IC: immune cell

IDO: indoleamine-pyrrole 2,3-dioxygenase

IHC: immunohistochemistry

IL-2: interleukin 2

IMDC: International Metastatic

Renal Cell Carcinoma Database Consortium

IO: immuno-oncology

IPI: ipilimumab

irAE: immune-related adverse event

IRC: independent review committee

ITT: intent-to-treat

KPS: Karnofsky performance status

LDH: lactate dehydrogenase

MET: hepatocyte growth factor receptor

MOA: mechanism of action

mPFS: median progression-free survival

MSKCC: Memorial Sloan Kettering Cancer Center

mTORC: mammalian target of rapamycin complex 1

Mx: distant metastasis cannot be assessed

N0: no regional lymph node metastasis

NA: not applicable

nccRCC: non–clear-cell renal cell carcinoma

NE: not evaluable

Abbreviations (Cont’d)

NED: no evidence of disease

NIVO: nivolumab

NR: not reached

ORR: overall response rate

PD: progressive disease

PD-1: programmed cell death protein 1

PD-L1: programmed cell death ligand 1

Pembro: pembrolizumab

PITT: primary intent-to-treat population

Plts: platelets

PPE: palmar-plantar erythrodysesthesia

PR: partial response

PRO: patient-reported outcomes

Q2W/Q3W/Q4W: every 2/3/4 weeks

QD: every day

RCC: renal cell carcinoma

RECIST: Response Evaluation Criteria in Solid

Tumors

RFS: relapse-free survival

SC: subcutaneous

SD: stable disease

SUN: sunitinib

TCR: T-cell receptor

TFS: treatment-free survival

TNM: tumor, node, metastasis

TRAE: treatment-related adverse event


TTF: time to treatment failure

Tx: treatment

UISS: University of California, Los Angeles Integrated

Staging System

VEGFA: vascular endothelial growth factor A

VEGFR: vascular endothelial growth factor receptor

WNL: within normal limits


redefining the management of advanced rcc

Documents