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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: [email protected]
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