Abstract #811

ENTRATA: Randomized, double-blind, phase 2 study of telaglenastat (tela; CB-839) + everolimus

(E) vs. placebo (pbo) + E in patients (pts) with advanced/metastatic renal cell carcinoma (mRCC)

Robert J. Motzer1, Chung-Han Lee1, Hamid Emamekhoo2, Marc Matrana3, Ivor Percent4, James J. Hsieh5, Arif Hussain6, Ulka Vaishampayan7, Robert Graham8, Sandy Liu9, Steve McCune10,

Montaser Shaheen11, Hema Parmar12, Yijing Shen12, Sam H. Whiting12, Nizar M. Tannir13

1Memorial Sloan Kettering Cancer Center, New York, NY, USA; 2University of Wisconsin Carbone Cancer Center, Madison, WI, USA; 3Ochsner Clinic Foundation, New Orleans, LA, USA; 4Florida Cancer Specialists – South, Port Charlotte, FL, USA; 5Washington University School of Medicine, St. Louis, MO, USA; 6University of Maryland Greenebaum

Comprehensive Cancer Center, Baltimore, MD, USA; 7Karmanos Cancer Institute, Detroit, MI, USA; 8UT/Erlanger Oncology & Hematology; 9UCLA Department of Medicine, Los Angeles, CA, USA; 10Northwest Georgia Oncology Centers, P.C., Marietta, GA, USA; 11The University of Arizona Cancer Center, Tucson, AZ; 12Calithera Biosciences, Inc.,

South San Francisco, CA, USA; 13The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Disclosures for Dr. Lee

2

• Consultancy for Eisai, Exelixis, Amgen, BMS

• Research funding from Eisai

• Institutional research funding from BMS, Exelixis, Eisai, Calithera, Pfizer

Glucose and Glutamine Metabolism in TumorsIncreased Glutamine and Glucose Metabolism Supports Tumor Cell Growth and Proliferation

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Growth factor signaling drives abnormal glucose metabolism in cancer cells1

Cancer cells compensate for the Warburg effect by increasing glutamine metabolism to sustain the TCA cycle for growth and proliferation1,4

Abnormal glucose metabolism, known as the Warburg effect, deprives the TCA cycle of critical metabolites1-3

TCA, tricarboxylic acid.1Cantor and Sabatini. Cancer Disc. 2012;2(10):881-898; 2Warburg et al. Science. 1956;123:309-314; 3Phan et al. Cancer Biol Med. 2014;11(1):1-19; 4Altman et al. Nature Rev Cancer. 2016;16:619-634.

Growth factor

signal transductionLactate

TelaglenastatSynergistic Antitumor Activity with Signal Transduction Inhibitors

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Dual inhibition of glutamine and glucose metabolism

PFS, progression-free survival; TCA, tricarboxylic acid; TKI, tyrosine kinase inhibitor.1Parlati F, et al. Presented at: AACR Annual Meeting 2015; April 18-22, 2015; Philadelphia, PA (abstr 4711). 2Emberley E, et al. Poster presented at: Keystone Symposia: Tumor Metabolism: Mechanisms and Targets; March 5-9, 2017; Whistler, BC, Canada.; 3Meric-Bernstam F, et al. Poster presented at: ASCO; June 3-7, 2016; Chicago, IL (abstr 4568); 4Meric-Bernstam F, et al. Poster presented at: ASCO GU 2019. February 14-16, 2019; San Francisco, CA (abstr 549); 5Momcilovic M, et al. Cell Rep. 2017;18:601-610; 6Tannir et al. J Clin Oncol. 2018;36(suppl 6S):abstract 603.

• In preclinical studies, the combination of telaglenastat with signal transduction inhibitor everolimus1-5:

- Inhibited both glucose and glutamine metabolic pathways

- Had synergistic antiproliferativeactivity in vitro

- Had enhanced anti-tumor activity in mouse xenograft models

• In Phase 1b study of telaglenastat + everolimus in patients with metastatic renal cell carcinoma (median 2 prior lines of therapy)6

- 92% disease control rate (n=24)

- 5.8-month median PFS

Growth factor

signal transduction

Lactate

ENTRATA – Phase 2 Study Design

• Advanced/metastatic RCC with clear cell component

• At least 2 prior therapies including at least 1 prior VEGFR-targeting TKI

• KPS ≥ 70%

• Treated/stable brain mets allowed

• No prior mTOR inhibitor

2:1

Telaglenastat(800 mg BID)

+Everolimus(10 mg QD)

Placebo+

Everolimus(10 mg QD)

Surv

ival

Fo

llow

-Up

5

Key Inclusion / Exclusion Criteria

BID, twice daily; KPS, Karnofsky Performance Status; PFS, progression-free survival; ORR, overall response rate; OS, overall survival; QD, once daily; QOL, quality of life; RCC, renal cell carcinoma; TKI, tyrosine kinase inhibitor; VEGFR, vascular endothelial growth factor receptor

• Stratification factors:

- MSKCC (Intermediate/poor vs. favorable)

- Prior TKI (1 vs. >1)

Data cut: April 26, 2019

ENDPOINTS

PrimaryPFS per investigator

SecondaryOS

AdditionalSafety, ORR, QOL

ENDPOINTS

Statistical Design

• Primary Endpoint: Investigator-assessed progression-free survival (PFS)

• Primary Comparison

- With 80% power, 1-sided alpha of 0.2, and 2:1 randomization, approximately 48 events (progression or death) required to detect a hazard ratio of 0.6 (minimum detectable hazard ratio = 0.77)

- Assumed 3.7-month median PFS for everolimus control group, based on published data for clear cell mRCC patients after 2 prior lines of therapy1,2

- Estimated sample size: 63 patients

Heng et al. J Clin Oncol. 2015;30(suppl):abstr e15578; 2Motzer et al. Lancet Oncol. 2014;15:286-96 6

Baseline Characteristics Telaglenastat + Everolimus

(n=46)Placebo + Everolimus

(n=23)

Age Median, years (range) 64.5 (47–85) 65.0 (37–76)

Sex Male, n (%) 37 (80) 20 (87)

MSKCC risk, n (%)Favorable 14 (30) 8 (35)

Intermediate or poor 32 (70) 15 (65)

Prior therapies inadvanced/metastatic setting, n (%)

No. prior lines, median (range) 3 (2–7) 3 (2–5)

1 TKI 13 (28) 8 (35)

≥ 2 TKI 33 (72) 15 (65)

PD-(L)1 42 (91) 19 (83)

Sites of metastasis, n (%)

Adrenal 16 (35) 3 (13)

Bone 15 (33) 8 (35)

Brain 1 (2) 0

Liver 17 (37) 8 (35)

Lung 31 (67) 16 (70)

Lymph nodes 34 (74) 14 (61)

Demographics and Patient Characteristics

7MSKCC, Memorial Sloan Kettering Cancer Center; TKI, tyrosine kinase inhibitor

Endpoint Statistical ParameterTelaglenastat + Everolimus

(n=46)Placebo + Everolimus

(n=23)

Progression-free survival (primary)

Median 3.8 months 1.9 months

Hazard ratio (95% CI)a 0.64 (0.34–1.20)

P-value (one-sided) 0.079

Best tumor responseb Partial response, n (%) 1 (2.2%) 0

Stable disease, n (%) 26 (56.5%) 11 (47.8%)

Top-Line Results

CI, confidence interval; mo, month; NR, not reached 8

aStratified analysisbPer RECIST v1.1

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Progression-Free Survival

9*Stratified analysis

Number at risk

CI, confidence interval; PFS, progression-free survival

Telaglenastat + Everolimus: 46 44 28 25 15 13 10 9 7 7 2 2 0Placebo + Everolimus: 23 23 10 8 6 6 5 5 2 1 1 0 0

Follow-up

Minimum: 3 months

Median: 7.5 months

SubgroupNo. Events/ No. Patients Hazard Ratio (95% CI)

Age<65 22/34 1.03 (0.41-2.60)≥65 24/35 0.49 (0.20-1.20)

SexMale 38/57 0.63 (0.32-1.27)Female 8/12 0.90 (0.17-4.83)

RaceWhite 41/62 0.66 (0.34-1.27)Other 5/7 1.92 (0.18-20.38)

KPS score≤80% 16/23 0.65 (0.23-1.85)>80% 30/46 0.72 (0.33-1.57)

Prior TKI1 12/21 0.25 (0.05-1.19)>1 34/48 1.02 (0.48-2.14)

MSKCC riskFavorable 13/22 0.86 (0.27-2.75)Intermediate/poor 33/47 0.56 (0.27-1.18)

Prior anti-PD-(L)1Yes 38/61 0.75 (0.38-1.49)No 8/8 0.32 (0.06-1.82)

0.01 0.1 1 10 100

PFS Subgroup Analysis

10Telaglenastat + Everolimus Better Placebo + Everolimus Better

KPS, Karnofsky performance score; TKI, tyrosine kinase inhibitor

Telaglenastat + Everolimus(n=46)

Placebo + Everolimus(n=23)

n (%)

All Grade AEs, any cause 46 (100) 23 (100)

Grade 3-4 AEs 35 (76.1) 13 (56.5)

Grade 5 AEa 2 (4.3) 1 (4.3)

AE leading to treatment discontinuation of any drug 13 (28.3) 7 (30.4)

Everolimus discontinuation 11 (23.9) 7 (30.4)

Telaglenastat/placebo discontinuation 12 (26.1) 7 (30.4)

AE leading to dose interruption or reduction of any drug 35 (76.1) 14 (60.9)

Everolimus interruption or reduction 35 (76.1) 14 (60.9)

Telaglenastat/placebo interruption or reduction 32 (69.6) 13 (56.5)

AE, adverse event

ENTRATA SafetySummary

aNone were considered treatment-related per investigator

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Adverse events occurring in >20% of patients in either treatment arm

Adverse event, n (%)Telaglenastat + Everolimus

(n=46)Placebo + Everolimus

(n=23)

Any Grade Grade ≥3 Any Grade Grade ≥3

Any event 46 (100) 37 (80) 23 (100) 14 (61)

Fatigue 20 (44) 2 (4) 10 (44) 2 (9)

Anemia 18 (39) 8 (17) 8 (35) 4 (17)

Serum creatinine increased 15 (33) 0 6 (26) 1 (4)

Cough 15 (33) 0 9 (39) 0

Nausea 15 (33) 1 (2) 4 (17) 0

Decreased appetite 14 (30) 0 4 (17) 0

Dyspnea 14 (30) 1 (2) 6 (26) 1 (4)

Peripheral edema 12 (26) 1 (2) 4 (17) 0

Pruritus 11 (24) 1 (2) 7 (30) 1 (4)

Constipation 10 (22) 1 (2) 2 (9) 0

Photophobia 10 (22) 0 2 (9) 0

Stomatitis 10 (22) 1 (2) 6 (26) 1 (4)

Diarrhea 9 (20) 1 (2) 11 (48) 0

Hyperglycemia 6 (13) 2 (4) 6 (26) 1 (4)

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ENTRATA SafetyTreatment-Emergent Adverse Events

Conclusions

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• This randomized phase 2 trial demonstrated improvement in PFS for telaglenastat + everolimus vs placebo + everolimus

• Patients were heavily pretreated (median 4th line therapy) and included those refractory to multiple TKIs and checkpoint inhibitor therapy

• Secondary endpoint of OS is not mature

• Telaglenastat + everolimus had a tolerable safety profile in this study

• ENTRATA supports proof-of-concept for telaglenastat and glutaminase inhibition as a new therapeutic strategy in mRCC

• ENTRATA supports further study of this new MOA in mRCC

MOA, mechanism of action; mRCC, metastatic renal cell carcinoma; OS, overall survival; PFS, progression free survival; TKI, tyrosine kinase inhibitor

CANTATA Pivotal Study Design

• Clear cell RCC• KPS ≥ 70%• 1-2 lines of prior therapy including

at least one antiangiogenic therapy or nivolumab + ipilimumab

1:1

Telaglenastat(800 mg BID PO)

+ Cabozantinib

(60 mg QD PO)

Placebo BID +

Cabozantinib(60 mg QD PO)

Surv

ival

Fo

llow

-Up

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Key Inclusion / Exclusion Criteria

BID, twice daily; IMDC, International Metastatic RCC Database Consortium; IRC, independent review committee; KPS, Karnofsky Performance Status; PFS, progression-free survival; PO, per oral; QD, once daily; QOL, quality of life; RCC, renal cell carcinoma; RECIST, Response Evaluable Criteria in Solid Tumors

• N~416 planned

• Stratification factors:

- Prior PD-(L)1 inhibitor therapy (yes vs. no)

- IMDC Prognostic Risk Group (favorable vs. intermediate vs. poor)

ENDPOINTS

PrimaryIRC-adjudicated PFS

per RECIST v1.1

SecondaryOverall Survival

Investigator-assessed PFS

ENDPOINTS

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Acknowledgments

• Thank you to all of the ENTRATA investigators and site staff and to the patients and their families for their participation in the study

• Ingrid Koo, PhD, provided editorial support on the slides