Emerging Novel Therapies in Renal Cell Carcinoma

Nizar M. Tannir, MD, FACP

Ransom Horne, Jr. Professor for Cancer Research

Professor and Chair ad interim

Department of Genitourinary Medical Oncology

Disclosures

2

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., Calithera Biosciences, 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: various combination strategies with targeted agents and immunotherapies for renal cell carcinoma.

Disclaimer

3

The data presented during the followingsession may include information aboutmolecules and/or indications not approved inyour country, therefore you need to verifylocally.

Outline

• Novel immune agents

• Novel targeted agents

4

Bempegaldesleukin/NKTR-214: Mechanism of Action and Pre-Clinical Data

Bempegaldesleukin (NKTR-214)

1. Charych D, et al. PLoS One 2017; 12: e0179431 2. Bentebibel SE, et al. Cancer Discov May 8 2019 DOI: 10.1158/2159-8290.CD-18-1495 3. Diab A, et al. Oral presentation at SITC; November 7-11, 2018; Washington, D.C., USA. Abstract #O4

4. Siefker-Radtke, et al. Poster presentation at ASCO GU; February 13-16, 2019, San Francisco, CA, USA. Abstract #388 5. Opdivo (nivolumab) [package insert]. Princeton, NJ: Bristol-Myers Squibb; 20196. Daud AI, et al. J Clin Oncol 2016; 34:4102-09. 7. Daud AI, et al. J Clin Invest 2016;126:3447-52. 8. Tumeh PC, et al. Nature 2014;515:568-71. 9. Ayers, https://doi.org/10.1172/JCI91190

• Bempegaldesleukin (BEMPEG; NKTR-214) is a CD122-preferential IL-2 pathway agonist that has been shown to increase tumor-infiltrating lymphocytes, T cell clonality and PD-1 expression1,2

• BEMPEG combined with checkpoint inhibitor nivolumab (NIVO) has been shown to convert baseline tumors from PD-L1 negative (<1%) to PD-L1 positive (≥1%)3-5

• Low levels of baseline tumor-infiltrating lymphocytes (TILs)6-8 and T cell–inflammation9 are predictive of a poor response to checkpoint inhibitors (CPIs)

Differences Between NKTR-214 and HD IL-2

Parameter NKTR-214 High Dose IL-2

Modality Biologic Biologic

Dosing q3w or q2w q8 hrs

Receptor Bias βγ αβγ

Half-life ~20 hrs ~20 min

Safety Profile Outpatient regimen ICU regimen

Prodrug Design Yes No

Graded and Sustained Signaling on the IL-2 Pathway

Yes No

7

Activity of NKTR-214 cannot be replicated with any dose administration schedule or regimen of IL-2 in many different in vitro and in vivo test systems

Rapid Activation of the Immune System was Observed with Bempeg and NIVO

Lymphocyte effects of the bempeg + NIVO combination are driven by bempeg, as a similar pattern is observed with monotherapy2

Bempeg + NIVO

Administration

*Lymphocyte levels were obtained from standard hematology analysis. All efficacy evaluable melanoma (n=38) and mUC (n=27) in the bempeg + NIVO combination enrolled in PIVOT-02 (n=65, Mean+SD) were included in the analyses.

Increase in Lymphocytes with Every

Treatment Cycle* On-Treatment Increase in TIL and PD-L1

B a s e lin e W e e k 3

0

5 0 0

1 0 0 0

1 5 0 0

2 0 0 0

CD

8 (

ce

lls

/mm

2)

203

Change in CD8 Infiltrate

in MEL3,^

B a s e lin e W e e k 3

0

2

4

6

2 0

4 0

6 0

8 0

1 0 0

PD

L1

+ (

% T

um

or C

ell

s)

1

3 p ts (0 -> 0 )

2 p ts (0 -> 5 )

PD-L1 Conversion in

UC4,#

^IHC for CD8 was obtained by standard methods. All patients with first-line melanoma (1L MEL) with matched Baseline and Week 3 biopsy (n=8) were included in the analysis.#All patients with 1L urothelial carcinoma (UC) with matched Baseline and Week 3 biopsy (n=13) at time of data cut were included and assessed for PD-L1 expression (28-8 PharmDx).

M. Hurwitz, et al. Poster presentation at ASCO; May 31-June 4, 2019; Chicago, IL, USA

PIVOT-02 Efficacy and Safety Data

• RP2D established

• NKTR-214 0.006 mg/kg q3w + nivolumab 360 mg q3w

• Favorable safety profile and well tolerated combination

• Grade 1/2 AEs are predictable, manageable and of short duration

• Few Grade 3/4 TRAEs

• Few immune-related AEs were observed to date (e.g., 2 pts w/ pneumonitis, 1 pt w/ myocarditis)

• Clinical benefit observed with NKTR-214 and nivolumab as 1L Rx in mRCC (most patients had intermediate- or poor-risk disease)

• CR/PR: 22/51 pts (43%)

• Phase 1 trial with the triplet of NKTR-214 + nivo/ipi is ongoing

9

Phase 3 1L Advanced Renal Cell Carcinoma Trial PIVOT-09 Study Design

clinicaltrials.gov/ct2/show/NCT03729245

Pegilodecakin (Pegylated IL-10)

Mechanism of Action of Pegilodecakin• Pegilodecakin is a pegylated recombinant interleukin-101

• In preclinical tumor models, pegilodecakin induced tumor rejection via specific activation and expansion of tumor-specific CD8+ T cells and established anti-tumor immune memory2,3

• Pegilodecakin induces phosphorylation of STAT1 and STAT3 in CD8+ T cells, resulting in increased antigen-activated intra-tumoral CD8+ T cells4

• N-terminal pegylation provides increased half-life of pegilodecakin, allowing for once daily dosing, ultimately resulting in sustained systemic exposure1

Adapted from poster for J Clin Oncol 36, 2018 (suppl; abstr 9018)

1. Naing A et al., JCO. 2016 Oct 10;34(29):3562-3569.

2. Emmerich J et al., Cancer Res. 2012 72:3570-3581.

3. Mumm JB et al., Cancer Cell. 2011 20:781-796.

4. Oft M. Cancer Immunol Res. 2014 Mar; 2(3):194-9.

Granzymes /

FasL

IFNγ / IL-4

P-STAT1

P-STAT3

TCR

MHC

Proliferation

Survival

Tumor Cell

Pegilodecakin

CD8+ T Cell

Pegilodecakin: Phase I trials• Pegilodecakin promotes immunosurveillance through memory T cell expansion and reduces

metastatic dissemination1

• Pegilodecakin increases PD-1+ Lag-3+ CD8+ T cells in the tumor and blood2

• Pegilodecakin is the 1st pegylated cytokine which targets the immune system with single-agent activity in renal cell cancer (RCC), cutaneous T-cell lymphoma, and uveal melanoma3

• Preliminary results in a Phase I clinical trial in advanced treatment-refractory tumors revealed pegilodecakin selectively induced durable Th1 and Th2 immune responses (i.e. increased INF-gand IL-18) and reduced immune-suppressive TGF-beta3

• IL-18 induction correlates with therapeutic activity in patients treated with pegilodecakin3

• Pegilodecakin causes thrombocytopenia and anemia, but does not cause the immune-related adverse events (irAEs) typically observed with other immune checkpoint inhibitors3

1. Oft M. Cancer Immunol Res. 2014 Mar; 2(3):194-9.

2. Naing A et al., Cancer Cell, 2018

3. Naing A et al., JCO. 2016 Oct 10;34(29):3562-3569.

RCC

(N = 34)

n (%)

ORR (irCR + irPR)* 14 (41.2)

DCR (irCR + irPR + irSD)* 29 (85.3)

irCR 0

irPR 14 (41.2)

irSD 15 (44.1)

irPD 5 (14.7)

DoR (median, in weeks) 64.9

Range (25th percentile, 75th percentile) (52.6, NE)

Abbreviations: irCR, immune-related complete response; irPD, immune-related progressive disease; irPR,

immune-related partial response; irSD, immune-related stable disease; DoR, duration of response; OS, overall

survival; PFS, progression-free survival; ORR, overall response rate; and DCR, disease control rate.*ORR

and DCR evaluated by irRC

Efficacy of pegilodecakin + anti-PD-1 inhibitors in RCC

N Median

OS 37 NA

PFS 37 14.1

Pro

gre

ssio

n F

ree

an

d O

vera

ll S

urv

ival

(%)

Targeting Tumor Metabolism with Telaglenastat/CB-839 (Glutaminase-1 Inhibitor)

Dysregulated Metabolism is a Hallmark of Cancer

Genetic mutations cause unique metabolic adaptations that are specific to cancer cells1,2

1. Hanahan D, Weinberg RA. Cell. 2011;144:646-674. 2. Wong CC, et al. Oncogene. 2017;36:3359-3374.

Specific genetic alterations can cause cancer cells to increase metabolism

of glutamine and glucose1-7

181. Wong CC, et al. Oncogene. 2017;36:3359-3374. 2. Wettersten HI, et al. Nat Rev Nephrol. 2017;13:410-419. 3. Hutton JE, et al. Mol Cell Proteomics.

2016;15:2924-2938. 4. Romero R, et al. Nature Med. 2017;23:1362-1368. 5. Makinoshima H, et al. J Biol Chem. 2014;289:20813-20823. 6. Ma Y, et al.

Oncogene. 2016;35:6132-6142. 7. Rothschild SI. Cancers (Basel). 2015;7:930-949.

Alterations in Glucose and Glutamine Metabolism in Cancer

Increased Glutamine and Glucose Metabolism Supports Tumor Cell Growth and Proliferation

Growth factor signaling

drives abnormal glucose

metabolism in cancer cells

Cancer cells compensate for the

Warburg effect by increasing

glutamine metabolism to sustain

the TCA cycle for growth and

proliferation

Cancer cellNormal cell

Abnormal glucose metabolism,

known as the Warburg effect,

deprives the TCA cycle of

critical metabolites

TCA=tricarboxylic acid.

1. Parlati F, et al. Presented at: AACR Annual Meeting 2015; April 18-22, 2015; Philadelphia, PA (abstr 4711). 2. Emberley E, et al. Poster presented at: Keystone Symposia:

Tumor Metabolism: Mechanisms and Targets; March 5-9, 2017; Whistler, BC, Canada. 3. Meric-Bernstam F, et al. Poster presented at: ASCO; June 3-7, 2016; Chicago, IL (abstr

4568). 4. Meric-Bernstam F, et al. Poster presented at: ASCO GU 2019. February 14-16, 2019; San Francisco, CA (abstr 549). 5. Momcilovic M, et al. Cell Rep. 2017;18:601-610.

Glutaminase Expression in Clinical Samples mRNA and Protein

mRNA levels were obtained from Compendia Bioscience™ Translational Bioinformatics Services (Life Technologies, Ann Arbor, MI)

NSCLC (KRAS mutant)

TNBC SDH-deficient GIST

Mesothelioma

RCC (chromophobe)

RCC (clear cell)

No

rmal

No

rmal

No

rmal

No

rmal

Tum

or

Tum

or

Tum

or

Tum

or

Telaglenastat has Synergistic Antitumor Activity With Signal Transduction Inhibitors

Dual inhibition of glutamine and glucose metabolism results in synergistic antitumor activity in preclinical models1-5

Treated cancer cellUntreated cancer cellTCA=tricarboxylic acid; TKI=tyrosine kinase inhibitor.

1. Parlati F, et al. Presented at: AACR Annual Meeting 2015; April 18-22, 2015; Philadelphia, PA (abstr 4711). 2. Emberley E, et al. Poster presented at: Keystone Symposia:

Tumor Metabolism: Mechanisms and Targets; March 5-9, 2017; Whistler, BC, Canada. 3. Meric-Bernstam F, et al. Poster presented at: ASCO; June 3-7, 2016; Chicago, IL (abstr

4568). 4. Meric-Bernstam F, et al. Poster presented at: ASCO GU 2019. February 14-16, 2019; San Francisco, CA (abstr 549). 5. Momcilovic M, et al. Cell Rep. 2017;18:601-610.

Telaglenastat (CB-839) Phase 1 Monotherapy and Combinations in RCC

22

CX-839-001: Phase I Study of CB-839 Monotherapy or Combined with Either Cabozantinib (Cabo) or Everolimus (E) in Patients

with Clear Cell and Papillary mRCC• Objective: To evaluate safety/tolerability, anti-tumor activity, and RP2D of CB-839 as a monotherapy and in combination with everolimus

or cabozantinib in patients with mRCC

Monotherapy: Meric-Bernstam et al., ASCO. 2016 Combinations: Tannir et al., ASCO GU. 2018

Key Eligibility Criteria:

• Age ≥18 years• ECOG PS 0-1• Measurable disease (RECIST

v1.1)• cc/pap mRCC• Monotherapy: No available

active therapies, prior mTORi allowed

• CBE: ≤4 prior lines of therapy, prior mTORi allowed

• CB-Cabo: ≥1 prior anti-VEGF therapy

CBECB-839 (400-800 mg BID PO) +

Everolimus (10 mg QD PO) 28-day cycle

CB-CaboCB-839 (600-800 mg BID PO) + Cabozantinib (60 mg QD PO)

28-day cycle

RP2D

RP2D

Dose Escalation (3+3)

cc mRCC

cc/pap mRCC

Dose Expansion

pap mRCC

CB-839 Monotherapy100 – 1000 mg PO BID

TID without food orBID with food (selected for Phase II)

RP2D

CB-839 Monotherapy600 – 1000 mg PO BID

TID without food orBID with food (selected for Phase II)

• Well tolerated at active doses

– MTD not reached

– 800 mg PO BID selected as RP2D

– Better exposure with food and low pH

– Half-life ~4 hours

• Clear PK/PD relationship

– Maximum glutaminase inhibition (>90%) in patient platelets at 800 mg BID

• Target inhibition achieved in patient tumors

• CB-839 monotherapy active in RCC patients

– RCC pts (n=21)

– 1 PR (on study 356 days)

– 52% SD (on study 876 days)

Approximately 3 weeks on study drug

[ C B - 8 3 9 @ 4 h ] ( n g / m L )

% G

lu

ta

min

as

e A

ct

iv

it

y

1 1 0 1 0 0 1 0 0 0

0

2 0

4 0

6 0

8 0

1 0 01 0 0 T I D

1 5 0 T I D

2 5 0 T I D

4 0 0 T I D

6 0 0 T I D

8 0 0 T I D

e x v i v o p l a t e l e t

d o s e r e s p o n s e

8 0 0 B I D

6 0 0 B I D

L L O Q

Glu

ta

min

as

e A

ct

iv

it

y

(n

mo

l/

min

/m

g p

ro

te

in

)

5

1 0

1 5

2 0

2 5

3 0

3 5

- 8 6 %

- 7 5 %

- 8 4 %- 5 7 %

U n i n h i b i t e d

I n h i b i t e d

- 9 6 %

Pharmacodynamic Glutaminase Inhibition

Tumor GIST NSCLC colon Meso RCC

662 1384 1945 2352 11530

C1D15 AUC (0-8h) (ng*hr/mL)

Telaglenastat (CB-839) Phase 1 Monotherapy Conclusions

Harding, et al, J Clin Oncol. 2015; 33 (suppl 15S; abstr 2512) – Presented at ASCO 2015

CX-839-001: Telaglenastat (CB-839) Phase 1 Safety Data

Drug-related AEs in ≥10% of patients

CB-839 MonotherapyAll Solid Tumor Pts (N=88)

Adverse Event, n (%) All Grades Grade ≥3

Any 60 (68) 3 (3)Fatigue 21 (24) 0Nausea 19 (22) 0ALT increased 13 (15) 2 (2)Photophobia 12 (14) 0AST increased 10 (11) 1 (1)

Meric-Bernstam et al., NCI AACR EORTC 2016

• Well tolerated at active doses

– 600 – 1000 mg BID

• Majority AEs mild (Grade 1/2)

• Most common AEs:

– fatigue

– GI (nausea, vomiting, decreased appetite)

– Grade 3 AEs < 5%

– transaminase elevation ~ 2%

Dose Expansion

CB-839 + CabozantinibCB-839 (600–800 mg BID PO) +

Cabozantinib (60 mg QD PO)28-day cycle

Key Eligibility Criteria

• Age ≥18 years

• ECOG PS 0-1

• Measurable disease (RECIST v1.1)

• Clear cell or papillary mRCC

• ≥1 prior anti-VEGF therapy

Objective: To evaluate safety/tolerability, anti-tumor activity, and RP2D of CB-839 in combination with cabozantinib in patients with mRCC

Dose Escalation (3+3)

Tumor response (RECIST 1.1) assessed every 8 weeks

Efficacy data cutoff: Dec. 24, 2018

Safety data cutoff: Oct. 23, 2018

RP2D Clear cell or papillary

mRCC

CB-Cabo Combination Cohort Study Design

Meric-Bernstam et al., ASCO GU 2019

CB-Cabo Combination Cohort Patient DemographicsParameters CB-839 + Cabozantinib

N=13

Age, y, median (range) 59 (27-71)

Sex, n (%) Female 4 (31)

Male 9 (69)

Histology, n (%) Clear cell 11 (85)

Papillary 2 (15)

Other 0

ECOG PS, n (%) 0 3 (23)

1 10 (77)

MSKCC risk, n (%) Favorable 3 (23)

Intermediate 10 (77)

Poor 0

Prior therapies by type, n (%) Median no. (range) 3 (0-7)

mTOR inhibitor 3 (23)

Anti-VEGF 12 (92)

≥2 anti-VEGF 4 (31)

Checkpoint inhibitor 7 (54)

CB-839BID dose 400 mg 0

600 mg 6 (46)

800 mg 7 (54)

1000 mg --

Meric-Bernstam et al., ASCO GU 2019; Tannir et al., ASCO GU 2018

• No maximum tolerated dose reached*

• RP2D of CB-839 800 mg BID for combination (same as monotherapy)

• Frequency and severity of treatment-related adverse events (AEs) comparable to that of cabozantinib alone1,2

CB-839 + Cabozantinib (N = 13)

Adverse Event, n (%) All Grades Grade ≥3d

Any 13 (100) 5 (38)Diarrhea 8 (62) 1 (8)Decreased appetite 6 (46) 0ALT increased 6 (42) 0Fatigue 5 (38) 0AST increased 5 (38) 0Nausea 4 (31) 0Rashb 4 (31) 0Mucosal inflammation 3 (23) 0Proteinuria 3 (23) 0Vomiting 3 (23) 0Weight decreased 3 (23) 0Dehydration 2 (15) 0Dysgeusia 2 (15) 0Hypertension 2 (15) 1 (8)Muscle spasms 2 (15) 0Platelet count decreasedc 2 (15) 1 (8)Pruritus 2 (15) 0Stomatitis 2 (15) 0

1. Choueiri TK, et al. N Engl J Med. 2015;373:1814-232. Choueiri TK, et al. Lancet Oncol. 2016;17(7):917-927

aRelated to either CB-839 or cabozantinib; bCombined terms: rash, rash pruritic, rash macular, rash maculo-papular; cCombined terms: thrombocytopenia, platelet count decreased; dOther: hallucination*1 Dose-limiting toxicity of thrombocytopenia at 600 mg dose

CB-Cabo Combination Cohort Safety

Meric-Bernstam et al., ASCO GU 2019; Tannir et al., ASCO GU 2018

Phase 1 Clinical Activity of CB-Cabo in Advanced/Metastatic RCC (N = 12)

• Promising early response rates (50% ORR, 100% DCR) in ccRCC• Cabozantinib monotherapy: 17% ORR (Meteor Study) 1

Efficacy data cutoff: Dec 24, 2018 Meric-Bernstam et al, J Clin Oncol. 2019; 37:7_suuppl, 549 (presented at ASCO GU)

1Choueiri et al. Lancet Oncol. 2016;17(7):917-927

1 1 0 4 3 2 3 1 1 7 3 6

Prior Lines of Advanced/Metastatic Therapy

Papillary

Clear Cell

Phase 1 Demonstrated Efficacy of CB-Cabo in Advanced/Metastatic RCC (N = 12)

• Promising early response rates (50% ORR, 100% DCR) in ccRCC• Cabozantinib monotherapy: 17% ORR (Meteor Study) 1

Efficacy data cutoff: Dec 24, 2018 Meric-Bernstam et al, J Clin Oncol. 2019; 37:7_suuppl, 549 (presented at ASCO GU)

1Choueiri et al. Lancet Oncol. 2016;17(7):917-927

30

Pri

or

Lin

es o

f A

dva

nce

d/

Met

asta

tic

Ther

apy

3

6

7

1

4

0

1

3

1

2

1

3

6

*Discontinued for reason other than radiological disease progression

ENTRATA: Topline Results

• ENTRATA: Randomized, double-blind phase 2 study of telaglenastat with everolimus in 3L + renal cell carcinoma patients

• Telaglenastat, when added to everolimus, doubled the median PFS to 3.8 months compared to 1.9 months for everolimus plus placebo and reduced the risk of disease progression or death by 36% (HR=0.64, p=0.079 one-sided)

• The combination had a tolerable safety profile• Patients enrolled were heavily pre-treated with a median of three prior

lines of therapy for advanced metastatic disease including 70% with two or more prior tyrosine kinase inhibitors (TKI), and 68% with intermediate/poor MSKCC prognostic score

• The secondary endpoint of overall survival is not yet mature• The data will be presented at a future medical conference

CANTATA: A Randomized Trial in 2L/3L Advanced/Metastatic Clear Cell RCC

FDA Fast Track Status

HIF-2 Alpha Inhibitors, PT2385, PT2977/MK6482

pVHL Deficiency Results in HIF-2α Activation

ccRCC, clear cell renal cell carcinoma; HIF-2α, hypoxia-inducible factor 2α; pVHL, protein product of the Von Hippel-Lindau tumor suppressor gene; VHL, Von Hippel-Lindau tumor suppressor

• 90% of patients with sporadic ccRCC have defective pVHL

• Loss of pVHL function results in constitutive activation of HIF-2α

A First-in-Human Phase 1/2 Trial of the Oral HIF-2α Inhibitor PT2977 (MK-6482) in Patients with Advanced RCC

1The MD Anderson Cancer Center, Houston, TX, USA; 2Fox Chase Cancer Center, Philadelphia, PA, USA; 3Sarah Cannon Research

Institute/Tennessee Oncology, PLLC, Nashville, TN, USA; 4University of Miami, Miami, FL, USA; 5South Texas Accelerated Research

Therapeutics (START), San Antonio, TX, USA; 6 Beth Israel Deaconess Medical Center, Boston, MA, USA; 7Massachusetts General

Hospital, Boston, MA, USA; 8University of Pittsburgh Medical Center, Pittsburgh, PA, USA; 9Peloton Therapeutics Inc., Dallas, TX,

USA, a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA; 10Dana-Farber Cancer Institute, Boston, MA, USA

E. Jonasch1, E. R. Plimack2, T. M. Bauer3, J. R. Merchan4, K. P. Papadopoulos5, D. F. McDermott6, M. Dror Michaelson7, L. J. Appleman8, S. Thamake9, N. J. Zojwalla9, T. K. Choueiri10

Best Objective Response

Efficacy Parameter, n (%) [95% CI] PatientsN = 55

ORR 13 (24) [13-37]

PR 13 (24)

SD 31 (56)

Disease control rate (CR+PR+SD) 44 (80)

PD 9 (16)

Nonevaluable 2 (4)

CR, complete response; ORR, objective response rate; PR, partial response; SD, stable disease.Data cutoff: May 15, 2019.

Maximum Change From Baseline in Target Lesionsa

aIncludes patients who had a baseline and an evaluable postbaseline assessment (n = 52).Data cutoff: May 15, 2019.

• 69% of patients experienced any tumor shrinkage

+20%

–30%

Pe

rce

nta

ge C

ha

nge

Fro

m B

ase

lin

e

–100

–80

–60

–40

–20

0

20

40

60

80

100

Duration of Treatment

DOR, duration of response. Data cutoff: May 15, 2019.Weeks

• 16 patients (29%) continued treatment beyond 12 months

• Median DOR was not reached

• 81% of patients experienced response that lasted ≥6 months per Kaplan-Meier estimate

→→

→→

→→

→→→

→→→→→

→→

1009080706050403020100

Partial response

Ongoing treatment→

Progression-Free Survivala

aPer Kaplan-Meier estimates.PFS, progression-free survival. Data cutoff: May 15, 2019.

• Median (95% CI): PFS: 11 (6-17) months

Pro

gre

ssio

n-F

ree

Su

rviv

al,

%

MonthsNo. at Risk

55 41 33 29 24 20 14 7 4 2 0

0 2 4 6 8 10 12 14 16 18 200

20

40

60

80

100

49%

All-Cause Adverse Events ≥20% (CTCAE v4.03)

AE, adverse event; CTCAE v4.03, Common Terminology Criteria for Adverse Events, version 4.03. Data cutoff: May 15, 2019.

Adverse Event, n (%)PT2977 (MK-6482)

N = 55

Grade 1/2 Grade 3 Grade 4 All Grades

Anemia 27 (49) 14 (26) 0 (0) 41 (75)

Fatigue 34 (62) 3 (6) ― 37 (67)

Dyspnea 23 (42) 3 (6) ― 26 (47)

Nausea 17 (31) 1 (2) ― 18 (33)

Cough 17 (31) 0 (0) ― 17 (31)

Edema peripheral 16 (29) 0 (0) ― 16 (29)

Vomiting 16 (29) 0 (0) ― 16 (29)

Headache 13 (24) 1 (2) ― 14 (26)

Hypoxia 6 (11) 8 (15) ― 14 (26)

Arthralgia 13 (24) 0 (0) ― 13 (24)

Dizziness 13 (24) 0 (0) ― 13 (24)

Blood creatinine increased 11 (20) 1 (2) ― 12 (22)

Diarrhea 12 (22) 0 (0) ― 12 (22)

Constipation 11 (20) 0 (0) ― 11 (20)

Hyperkalemia 10 (18) 1 (2) ― 11 (20)

• 2 patients (4%) discontinued treatment for drug-related AEs (hypoxia)

• 5 patients (10%) required dose reductions for drug-related AEs

Sitravatinib (MGCD-516): VEGFR/MET/AXL Inhibitor

HGF

Angiogenesis

Role of MET, VEGF, and AXL in RCC

AXL

MET

Gas6

Tumor cell

Tumor progression

• Growth, invasion, metastasis

• Resistance to VEGFR inhibition

Cabozantinib/

MGCD516

VHL inactivation

• Upregulation of

MET, VEGF, and AXL

Shen C, Kaelin WG Jr. et al. Semin Cancer Biol. 2013;23:18-25.

Zhou L et al. Oncogene. 2016;35:2687-2697.

VHL

inactivation

VEGF

In vitro kinase inhibition profile of MGCD516

RTK target Biochemical Specificity (IC50 nmol/L)

Axl 1.5

MER 2

MET 20

VEGFR2 (KDR) 5

VEGFR1 (FLT1) 6

VEGFR3 (FLT4) 2

FLT3 8

c-KIT 6

PDGFRA 30

DDR1 29

DDR2 0.5

RET 44

TRKA (NTRK1) 5

TRKB (NTRK2) 9

EPHA2 44

EPHA3 1

EPHA4 76

EPHB2 10

EPHB4 12

RON 43

ROS 59

Sunitinib

259

12

34

24

3

Pazopanib

15

7

2

Cabozantinib

7

1.3

0.035

Preclinical data of MGCD516 + PD1 inhibition

Immunocompetent mice bearing subcutaneous CT26 murine colon carcinomas were treated with single-agent MGCD516, an antibody against mouse PD1 (RMP1-14), or their combination. The combination therapy produced higher antitumor efficacy.

Effect of MGCD516 on CD8+ Cells and MDSCs in CT26-bearing mice

0

2

4

6

8

%M

DSC

+ C

D1

1b

/Gr1

+

MDSC CD11b/Gr1+ (Systemic)

Control MGCD516 Control MGCD516Day 3 Day 6

• Depletion of systemic myeloid-derived suppressor cells (MDSC) by Day 3

• Increased CD8+ T effector cell proliferation (Ki67) observed by Day 3

Phase I/II trial of MGCD516 combined with nivolumab in patients with advanced clear-cell renal cell carcinoma that

progressed on prior VEGF-targeted therapy

Study Design

Tumors Included:Clear-cell RCC with

PD after VEGF directed Rx

Four MGCD516 dose levels: 60, 80, 120 and 150 mg/day

1st cohort: 80 mg PO daily

2 weeks to achieveMGCD516 steady state

Week 2 (Day 14)Peripheral blood and

optional tissue sample for correlative studies

Week 6 (day 42):Peripheral blood and

optional tissue sample for correlative studies

Continue Rx and

evaluate Q12 wks

until PD or toxicity

Peripheral blood and optional tissue sample for correlative studies

MGCD516 orally daily at pre-specified dose per EffTox

Nivolumab 240 mg Q2wks starting on day 15

Week 4 (day 29): Peripheral blood

Acknowledgements

OUR

PATIENTS

GU Medical Oncology

Jianjun Gao

Matthew Campbell

Amishi Shah

Amado Zurita

Eric Jonasch

Pavlos Msaouel

Giannicola Genovese

Urology

Christopher Wood

Jose Karam

Immunotherapy (IMT) Platform

James Allison

Padmanee Sharma

France

Gabriel Malouf

University of Strasbourg

Baylor College of Medicine

Cheryl Walker

Pathology

Pheroze Tamboli

Priya Rao

Kanishka Sircar