A Phase 2 Study of Sitravatinib in Combination With Nivolumab in Patients Undergoing Nephrectomy for Locally Advanced Clear Cell Renal Cell Carcinoma Jose 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.

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.

Author contact: [email protected] 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

Key Eligibility Criteria • Patients with locally advanced ccRCC who are Surgery candidates for partial or complete nephrectomy BIOPSY Sitravatinib BIOPSY Sitravatinib 120 mg QD + BIOPSY • Patients with clinical stage Day -4 120 mg QD Day 14 nivolumab 240 mg Q2Wb cT2-T3b, N0a, and M0 tumors 2 weeks 4-6 weeks • No prior systemic treatment for RCC

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 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.

• 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 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.

PRESENTED BY: Pavlos Msaouel Sitravatinib + Nivolumab in Patients With ccRCC: Patient Characteristics and Efficacy Outcomes

Patient Characteristics Total, n=20 Efficacy Outcome, n(%) Total, n=17

Median age, years (range) 61.5 (37-80) Radiologic response following up to 2b (11.8%) Gender, n (%) 8 weeks of treatmenta Male 16 (80%) Preoperative timepoint response Race, n (%) Partial response (PR) 2 (11.8%) Caucasian 19 (95%) Stable disease (SD) 15 (88.2%) ECOG performance status (PS), n (%) Progressive disease (PD) 0 (0%) 0 19 (95%) 1 1 (5%) Disease recurrence, n (%) 0c (0%) Primary tumor stage, n (%) T2b 1 (5%) Delay in surgery, n (%) 4d (24%) T3 3 (15%) Median delay, days (range) 1 (0-39) T3a 16 (80%)

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.

PRESENTED BY: Pavlos Msaouel Sitravatinib + Nivolumab in Patients With ccRCC: Safety Summary

Sitravatinib (120 mg) Sitravatinib (80 mg) + Nivolumab + Nivolumab a TRAEs (n=7) (n=13) • 4/7 patients treated with sitravatinib 120 mg QD Any Grade Grade 3 Any Grade Grade 3 developed grade 3 hypertension Any TRAE, % 100% 71% 100% 31% – Starting dose was decreased to 80 mg QD and b TRAEs (≥20%), % further dose de-escalation was not required Hypertension 5 (71%) 4 (57%) 7 (54%) 2 (15%) • Median duration of sitravatinib: 7.1 weeks (120 mg) Dysphonia 4 (57%) 0 (0%) 6 (46%) 0 (0%) and 6.3 weeks (80 mg) Oral dysesthesia 3 (43%) 0 (0%) 0 (0%) 0 (0%) Lipase increased 3 (43%) 1 (14%) 3 (23%) 1 (8%) • Median number of doses of nivolumab: 2.5 Diarrhea 2 (29%) 0 (0%) 6 (46%) 0 (0%) Amylase increased 2 (29%) 0 (0%) 1 (8%) 0 (0%) (sitravatinib 120 mg) and 2.0 (sitravatinib 80 mg) TSH increased 2 (29%) 0 (0%) 1 (8%) 0 (0%) • 6 patients (30%) experienced TRAEs leading to Fatigue 2 (29%) 0 (0%) 7 (54%) 0 (0%) Myalgia 2 (29%) 0 (0%) 0 (0%) 0 (0%) treatment discontinuation (either sitravatinib Hypothyroidism 2 (29%) 0 (0%) 0 (0%) 0 (0%) or nivolumab)c ALT increased 1 (14%) 0 (0%) 5 (39%) 0 (0%) Headache 1 (14%) 0 (0%) 3 (23%) 0 (0%) • There were no grade 4 TRAEs nor any grade 5 AEs Pruritis 0 (0%) 0 (0%) 3 (23%) 0 (0%)

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).

PRESENTED BY: Pavlos Msaouel Sitravatinib ± Nivolumab Alters Tumor Inflammation and Hypoxia Signatures

Sitravatinib monotherapy upregulates hypoxia and immunostimulatory gene signatures Angiogenesis biomarker FLT1 (VEGFR1) and KDR (VEGFR2) were among the Combination therapy further enriches these signatures relative to baseline and leads to the top, downregulated transcripts, confirming a key MOA of sitravatinib significant upregulation of the interferon-g response signature

Top Categories for: Post-Combination vs. Baseline A Post-Sitravatinib vs Baseline B Post-Combination vs Baseline Category: h FDR <0.25 = *** 15 10.0 ALLOGRAFT REJECTION *** *** APICAL JUNCTION *** *** 2.0 COMPLEMENT *** *** (NES) Score Enrichment Normalized 7.5 HEDGEHOG SIGNALING *** *** 1.5 10 HYPOXIA *** *** *** IL6 JAK STAT3 SIGNALING *** *** 1.0 5.0 INFLAMMATORY RESPONSE *** *** (P. Value) (P. Value) (P. 0.5

10 10 INTERFERON GAMMA RESPONSE *** -5

log log KRAS SIGNALING UP *** *** - - 0.0 2.5 MYOGENESIS *** *** P53 PATHWAY *** -0.5 PEROXISOME *** *** 0.0 0.0 TNFA SIGNALING VIA NFKB *** *** -1.0 -2 -1 0 1 2 -2 0 2 UV RESPONSE DN *** logFC logFC UV RESPONSE UP *** -1.5 Adjusted pValue (FDR) < 0.05 WNT BETA CATENIN-SIGNALING *** *** XENOBIOTIC METABOLISM *** False -2.0 True Post-Sitravatinib Post-Combination Post-Combination vs Baseline vs Baseline vs Post-Sitravatinib 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 Figure 2: GSEA analysis of significantly altered Hallmark pathways in post-combination vs baseline on the HTG EdgeSeq platform and were analyzed using Limma V. 3.40.6. tumor biopsies

PRESENTED BY: Pavlos Msaouel Sitravatinib ± Nivolumab Increases Immune Cell Tumor Infiltration and Proliferation of CD8+ T-cells

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

Total immune cells CD3T-cell positive frequency cells CD4/CD8CD4/CD8 ratio LAG3 Ki67 A B C D E Total Ki67 Non-Responder Ki67 Responder Ki67

10001000 100 024 p=0.0518 500500 20 80 ) 80 80

+ 30 10 40 100 028 TIL 80 TIL 005 30 015 + 006018 15 + 60 012014001 8 60 004 cells 015

022 cells 019 + 20 60 030013 + 010 6 20 6 CD8 014 CD8 +

10 40 CD8 + (of CD45 (of 40 030 CD8 +

(of Live cells) Live (of 50

015 + 030 40 + 4 012 + CD4/CD8 ratio 10 006 015 10 014

CD4/CD8 ratio CD4/CD8 5 20 010 % CD45+ cells %CD3 028 001028 20 2 %CD3 010 012030 %CD3+ CD8+ cells

% Ki67 % 019 006019018 010014006 013018 018019 015 LAG3% 001028 % CD3% 004013012030001 013018019 0 004022 0 0 024 0 028022005 0 0 005004022 005 0 022 % CD45% Baseline D14 Surgery Baseline D14 Surgery Baseline Post- Post- BaselineBaseline PostD14- SurgeryPost- Baseline Post- Post- Baseline Post- Post- Baseline PostD14- SurgeryPost- Baseline D14 Surgery Sitravatinib Combination Sitravatinib Combination Sitravatinib Combination Sitravatinib Combination Sitravatinib Combination

One-way ANOVA, ***p>0.001, **

PRESENTED BY: Pavlos Msaouel 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