A Phase 2 Study of Sitravatinib in Combination With Nivolumab in Patients Undergoing Nephrectomy for Locally Advanced Clear Cell Renal Cell CarcinomaJose A. Karam1,3, Pavlos Msaouel2,3, Surena F. Matin1, Matthew T. Campbell2, Amado J. Zurita2, Amishi Y. Shah2, Ignacio I. Wistuba3, Cara L. Haymaker3, Enrica Marmonti3, Dzifa Duose3, Edwin R. Parra3, Luisa Maren Solis Soto3, Caddie Laberiano3, Marisa Lozano1, Alice Abraham1, Max Hallin4, Peter D. Olson4, Hirak Der-Torossian4, Nizar M. Tannir2, Christopher G. Wood1

1Department of Urology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; 2Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; 3Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX; 4Mirati Therapeutics, Inc., San Diego, CA, USA.

Author contact: PMsaouel@mdanderson.org

Pavlos Msaouel disclosures: honoraria for service on a Scientific Advisory Board for Mirati Therapeutics BMS, and Exelixis; consulting for Axiom Healthcare Strategies; non-branded educational programs supported by Exelixis and Pfizer; and research funding for clinical trials from Takeda, BMS, Mirati Therapeutics, Gateway for Cancer Research, and UT MD Anderson Cancer Center.

Sitravatinib Mechanism of Action (MOA) and Background

• Sitravatinib is a spectrum-selective TKI targeting TAM receptors (Tyro3/Axl/MerTK) and VEGFR1-5

• Sitravatinib may augment antitumor immune responses by reversing an immunosuppressive tumor microenvironment (TME)

– Reduces myeloid-derived suppressor cells (MDSCs) and regulatory T-cells (Tregs)

– Increases the ratio of M1/M2-polarized macrophages6,7

• Sitravatinib has demonstrated clinical activity as a monotherapy and with nivolumab in accRCC8,9

• Currently, no neoadjuvant therapies are approved in ccRCC leaving an unmet need10

• 516-002 is a Phase 2 window of opportunity neoadjuvant study evaluating the activity and correlative immune effects of sitravatinib + nivolumab in ccRCC

PRESENTED BY: Pavlos Msaouel

Sitravatinib Monotherapy Lead-in, Followed by Combination With Nivolumab, in Patients With ccRCC Prior to Nephrectomy

• Here we report data for 20 patients evaluable for safety treated with sitravatinib 120 mg QD (n=7) and 80 mg QD (n=13) and nivolumab

– 17 patients were evaluable for clinical activityd

PRESENTED BY: Pavlos Msaouel

ccRCC, clear cell renal cell carcinoma; Q2W, every 2 weeks; QD, once daily. Data cut-off date: 2 July 2020, median follow-up was 9.4 months. aRetroperitoneal lymph nodes ≤ 1cm in size each are considered N0. bNivolumab treatment 240 mg Q2W (Day 15, Day 29, and potentially Day 43); patients received nivolumab on Day 43 only if their surgery was expected to occur more than a week from that date; last dose of any drug is administered a minimum of 72 hours prior to surgery. cObjective response was measured as percentage of patients achieving a response at disease assessment within 1 week prior to surgery (CR or PR). d2 patients were found to have had metastatic disease at study entry on retrospective review and a 1 patient only received sitravatinib on study.

A plan for potential dose de-escalation was implemented using a modified toxicity probability interval method with a maximum toxicity of 20% at the tolerated dose.

Primary Endpoint: Percentage of patients achieving a radiographic response (either CR or PR per RECIST v1.1) prior to surgeryc

Secondary Endpoints: Safety, pharmacokinetics (PK), and correlative immune effects

Surgery

Sitravatinib 120 mg QD + nivolumab 240 mg Q2Wb BIOPSYBIOPSY

Day 14Sitravatinib120 mg QD

BIOPSYDay -4

2 weeks 4-6 weeks

Key Eligibility Criteria• Patients with locally

advanced ccRCC who are candidates for partial or complete nephrectomy

• Patients with clinical stage cT2-T3b, N0a, and M0 tumors

• No prior systemic treatment for RCC

PRESENTED BY: Pavlos Msaouel

Sitravatinib + Nivolumab in Patients With ccRCC: Patient Characteristics and Efficacy Outcomes

ECOG, Eastern Cooperative Oncology Group. Data cut-off date: 2 July 2020, median follow-up was 9.4 months. aBased on RECIST v1.1. bBoth patients received sitravatinib 120 mg QD starting dose. cAs of 13 January 2021, with a median follow-up of 15.3 months, 1 patient has recurred since surgery. d1 surgery delayed > 1 week with a 38-day delay due to nivolumab-related thyroiditis that resolved.

Efficacy Outcome, n(%) Total, n=17

Radiologic response following up to 8 weeks of treatmenta 2b (11.8%)

Preoperative timepoint responsePartial response (PR)Stable disease (SD)Progressive disease (PD)

2 (11.8%)15 (88.2%)

0 (0%)

Disease recurrence, n (%) 0c (0%)

Delay in surgery, n (%)Median delay, days (range)

4d (24%)1 (0-39)

Patient Characteristics Total, n=20

Median age, years (range) 61.5 (37-80)

Gender, n (%)Male 16 (80%)

Race, n (%)Caucasian 19 (95%)

ECOG performance status (PS), n (%)01

19 (95%)1 (5%)

Primary tumor stage, n (%)T2bT3T3a

1 (5%)3 (15%)16 (80%)

• 4/7 patients treated with sitravatinib 120 mg QD developed grade 3 hypertension

– Starting dose was decreased to 80 mg QD and further dose de-escalation was not requiredb

• Median duration of sitravatinib: 7.1 weeks (120 mg) and 6.3 weeks (80 mg)

• Median number of doses of nivolumab: 2.5 (sitravatinib 120 mg) and 2.0 (sitravatinib 80 mg)

• 6 patients (30%) experienced TRAEs leading to treatment discontinuation (either sitravatinib or nivolumab)c

• There were no grade 4 TRAEs nor any grade 5 AEs

PRESENTED BY: Pavlos Msaouel

Sitravatinib + Nivolumab in Patients With ccRCC: Safety Summary

AEs, adverse events; ALT, alanine transferase; QD, once daily, TRAEs, treatment-related adverse events. ALT, alanine aminotransferase; TSH, thyroid stimulating hormone. aNo patients experienced wound healing adverse events or surgical complications.bPer the protocol-defined dose de-escalation plan. cIncluded: grade 3 bilateral pulmonary embolisms, grade 3 increased lipase, grade 2 thyroiditis, grade 2 pneumonitis, grade 2 pancreatitis, and grade 1 pancreatitis (n=1 each).

TRAEsa

Sitravatinib (120 mg)+ Nivolumab

(n=7)

Sitravatinib (80 mg)+ Nivolumab

(n=13)Any Grade Grade 3 Any Grade Grade 3

Any TRAE, % 100% 71% 100% 31%

TRAEs (≥20%), %

HypertensionDysphoniaOral dysesthesiaLipase increasedDiarrheaAmylase increasedTSH increasedFatigueMyalgiaHypothyroidismALT increasedHeadachePruritis

5 (71%) 4 (57%)3 (43%) 3 (43%)2 (29%)2 (29%)2 (29%)2 (29%)2 (29%)2 (29%)1 (14%)1 (14%)0 (0%)

4 (57%)0 (0%)0 (0%)1 (14%)0 (0%)0 (0%)0 (0%)0 (0%)0 (0%)0 (0%)0 (0%)0 (0%)0 (0%)

7 (54%)6 (46%)0 (0%)3 (23%)6 (46%)1 (8%)1 (8%)7 (54%)0 (0%)0 (0%)5 (39%)3 (23%)3 (23%)

2 (15%)0 (0%)0 (0%)1 (8%)0 (0%)0 (0%)0 (0%)0 (0%)0 (0%)0 (0%)0 (0%)0 (0%)0 (0%)

Sitravatinib ± Nivolumab Alters Tumor Inflammation and Hypoxia Gene Signatures

PRESENTED BY: Pavlos Msaouel

Figure 1: Volcano plots of post-sitravatinib vs baseline (A) and post-combination vs baseline (B). 42 samples passed QC using the Precision Immuno-Oncology panel on the HTG EdgeSeq platform and were analyzed using Limma V. 3.40.6.

Figure 2: GSEA analysis of significantly altered Hallmark pathways in post-combination vs baseline tumor biopsies

Angiogenesis biomarker FLT1 (VEGFR1) and KDR (VEGFR2) were among the top, downregulated transcripts, confirming a key MOA of sitravatinib

Sitravatinib monotherapy upregulates hypoxia and immunostimulatory gene signaturesCombination therapy further enriches these signatures relative to baseline and leads to the significant upregulation of the interferon-g response signature

Post-Sitravatinib vs Baseline Post-Combination vs BaselineA B

Adjusted pValue (FDR) < 0.05FalseTrue

7.5

10.0

5.0

2.5

0.0

-2 -1 0 1 2logFC

-log 10

(P. V

alue

)

0.0

10

15

-5

0 2logFC

-log 10

(P. V

alue

)

-2

Top Categories for: Post-Combination vs. BaselineCategory: h FDR <0.25 = ***

ALLOGRAFT REJECTION *** ***APICAL JUNCTION *** ***

COMPLEMENT *** ***HEDGEHOG SIGNALING *** ***

HYPOXIA *** *** ***IL6 JAK STAT3 SIGNALING *** ***

INFLAMMATORY RESPONSE *** ***INTERFERON GAMMA RESPONSE ***

KRAS SIGNALING UP *** ***MYOGENESIS *** ***P53 PATHWAY ***PEROXISOME *** ***

TNFA SIGNALING VIA NFKB *** ***UV RESPONSE DN ***UV RESPONSE UP ***

WNT BETA CATENIN-SIGNALING *** ***XENOBIOTIC METABOLISM ***

2.0

1.5

1.0

0.5

0.0

-0.5

-1.0

-1.5

-2.0

Norm

alized Enrichment Score (N

ES)

Post-Sitravatinib vs Baseline

Post-Combination vs Baseline

Post-Combination vs Post-Sitravatinib

Sitravatinib ± Nivolumab Increases Immune Cell Tumor Infiltration and Proliferation of CD8+ T-cells

PRESENTED BY: Pavlos Msaouel

One-way ANOVA, ***p>0.001, **<p 0.01, *p< 0.05 Tukey multicomparison test

Tumors analyzed after treatment with either sitravatinib alone or sitravatinib + nivolumab showed:• An influx of total immune cells, but T-cell frequency and CD4/CD8 ratio remained constant• Increased T-cell proliferation and LAG3 were observed in CD8+ TILs at time of surgery

100

80

60

40

20

0% C

D45

+(o

f Liv

e ce

lls)

Baseline Post-Sitravatinib

Post-Combination

Total immune cellsA

Baseline D14 Surgery0

50

100

% C

D45

+ ce

lls

CD3 positive cells

001004005006

010012013014

015

018019022

024

028

030

100

50

0% C

D3+

(of C

D45

+ )

T-cell frequencyB

Baseline D14 Surgery0

2

4

6

8

105001000

CD

4/C

D8

ratio

CD4/CD8 ratio

001004005006010012013

014

015018019022

024

028030

CD4/CD8 ratio

1000

8

6

4

2

0

50010

CD

4/C

D8

ratio

C20

15

10

5

0

LAG3

% L

AG

3+C

D8+

TIL

D

Baseline D14 Surgery0

10

20

30

%C

D3+

CD

8+ c

ells

Responder Ki67

001006010014

015

018019022

028

030

p=0.0518

Baseline D14 Surgery0

10

20

304080

%C

D3+

CD

8+ ce

lls

Non-Responder Ki67

004005

012

013

015

018019022

028

030

Baseline D14 Surgery0

20

40

60

80

%C

D3+

CD

8+ ce

lls

Total Ki67

001004005006010012013014

015

018019022028030

80

60

40

20

0

Ki67

% K

i67+

CD

8+TI

L

E

Baseline Post-Sitravatinib

Post-Combination

Baseline Post-Sitravatinib

Post-Combination

Baseline Post-Sitravatinib

Post-Combination

Baseline Post-Sitravatinib

Post-Combination

Conclusions

• Sitravatinib + nivolumab demonstrated preliminary activity and an acceptable safety profile in this Phase 2 window of opportunity study– Radiologic responses were noted, and no patients experienced disease progression

while on therapy• Tissue and correlative findings were consistent with the mechanism of action

of sitravatinib• Hypoxia and immunomodulation were key pathways that were altered with sitravatinib

and further enriched with the combination of sitravatinib and nivolumab• Overall, these data demonstrate an immune response with sitravatinib and the

combination of sitravatinib + nivolumab in locally-advanced ccRCC

PRESENTED BY: Pavlos Msaouel

References

1. Pircher A et al. Synergies of Targeting Tumor Angiogenesis and Immune Checkpoints. Int J Mol Sci. 2017;18(11).

2. Garton AJ et al. Anti-KIT Monoclonal Antibody Treatment Enhances the Antitumor Activity of Immune Checkpoint Inhibitors by Reversing Tumor-Induced Immunosuppression. Mol Cancer Ther. 2017;16(4).

3. Akalu YT et al. TAM receptor tyrosine kinases as emerging targets of innate immune checkpoint blockade for cancer therapy. Immunol Rev. 2017;276(1).

4. Graham DK et al. The TAM family. Nat Rev Cancer. 2014;14(12).

5. Du W et al. Sitravatinib potentiates immune checkpoint blockade in refractory cancer models. JCI Insight. 2018;3(21).

6. Wenting D et al. Sitravatinib potentiates immune checkpoint blockade in refractory cancer models. JCI Insight. 2018;3(21):e124184.

7. Oliva M et al. SNOW: Sitravatinib and Nivolumab in Oral Cavity Cancer (OCC) Window of Opportunity Study. Poster presented at: 2020 American Society of Clinical Oncology (ASCO) Annual Meeting; May 29-31, 2020.

8. Pant S et al. Evaluation of the Spectrum Selective RTK Inhibitor Sitravatinib in Clear Cell Renal Cell Carcinoma (ccRCC) Refractory to Anti-Angiogenic Therapy. Presented at: 2018 American Society of Clinical Oncology (ASCO) Annual Meeting; June 1-5, 2018.

9. Msaouel P et al. A phase I/II trial of sitravatinib (sitra) combined with nivolumab (nivo) in patients (pts) with advanced clear cell renal cell cancer (aCCRCC) that progressed on prior VEGF-targeted therapy. Presented at: 2020 Genitourinary Cancers Symposium; February 13-15 2020; San Francisco, CA.

10. National Comprehensive Cancer Network. Kidney Cancer (Version 1.2021). http://www.nccn.org/professionals/physician_gls/pdf/kidney.pdf Accessed January 18, 2021.

PRESENTED BY: Pavlos Msaouel