SAFFRON-301: SITRAVATINIB PLUS
TISLELIZUMAB IN ADVANCED/METASTATICNSCLC PROGRESSING ON/AFTERCHEMOTHERAPY AND ANTI–PD-(L)1
Q. Zhou1, B. Gao2, J. Hu3, J. Zhao4, M. Wang5, K. He6, W. Zhang7, C. Liu8, J. Fang4, X. Li9,Z. Wang10, M. Matos11, V. Kwatra12, Xin Li13*, Y. Chen13, J. Zhang13, J. Wang13, Y-L. Wu1

1Guangdong Lung Cancer Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern

Medical University, Guangzhou, CN; 2BIacktown Cancer and Haematology Centre, Blacktown, AU; 3Fudan University Affiliated Zhongshan
Hospital; Shanghai, CN, 4Beijing Cancer Hospital, Beijing, CN; 5Peking Union Medical Hospital, Beijing, CN; 6The Ohio State University
College of Medicine, Columbus, OH, USA; 7The First Affiliated Hospital of Nanchang University, Nanchang, CN; 8Xinjiang Cancer
Hospital, Urumqi, CN; 9The First Affiliated Hospital of Zhengzhou University, Zhengzhou, CN; 10Shandong Cancer Hospital, Jinan, CN;
11Pindara
Prof Yi-Long
Wu MD,
PhDHospital,| SAFFRON-301:
Plus
Sitravatinib
in Advanced/Metastatic
Progressing
on/afterChemotherapy
PrivateBenowa, Tislelizumab
AU; 12Cancer
Research
South
Australia, Adelaide,NSCLC
AU;13BeiGene(Beijing)
Co.,Ltd., Beijing,andCN
Anti-PD-(L)1*Affiliation at the time that the study was performed1

Background• Patients with advanced NSCLC who progress following chemotherapy and/or CPI-based immunotherapy
targeting PD-1/PD-L1 have limited efficacious treatment options1• Combining CPIs with agents that target molecular and cellular mechanisms of resistance to CPIs is arational approach to overcoming resistance2• RTK inhibitors can stimulate the immune system and cause synergistic effects that stimulate tumor
shrinkage3• Sitravatinib is an oral spectrum-selective TKI that targets TAM receptors (TYRO3/AXL/MERTK) and splitkinase domain containing receptors (VEGFR2/KIT) and can shift the immunosuppressive tumor
microenvironment toward an immunostimulatory state3-5• In the phase 1b SAFFRON-103 study, combination therapy with sitravatinib and the anti–PD-1 antibody,tislelizumab, had promising efficacy in patients with metastatic NSCLC who were refractory/resistant toanti–PD-(L)16• The phase 3 SAFFRON-301 study was performed to confirm the efficacy signal observed in SAFFRON-103
AXL, AXL receptor tyrosine kinase; CPI, checkpoint inhibitor; KIT, KIT proto-oncogene tyrosine kinase; MERTK, MER proto-oncogene tyrosine kinase; NSCLC, non-small cell lung cancer; PD-1; programmed cell death
protein-1 ; PD-L1, programmed death-ligand 1; RTK, receptor tyrosine kinase; TKI, tyrosine kinase inhibitor; TRYO 3, TYRO3 protein tyrosine kinase; VEGFR2, vascular endothelial growth factor receptor-2.
1. Moliner L, et al. ESMO Open. 2023:8:1-3. 2. Horvath L, et al. Mol Cancer. 2020;19:1411. 3. Du W, et al. JCI Insight. 2018;3: e124184. doi:10.1172/jci.insight.124184. 4. Bauer T, et al. Invest New Drugs. 2022;40:9901000. 5. Patwardhan PP, et al. Oncotarget. 2015; 5: 4093-4109. 6. Zhao J, et al. J Immunother Cancer. 2023;11:e006055. doi:10.1136/jitc-2022-006055.

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SAFFRON-301 Study Design• Open-label, randomized, multicenter phase 3 clinical study (NCT04921358)
Key eligibility criteria• Histologically or cytologicallyconfirmed unresectable locallyadvanced or metastatic NSCLC• No known EGFR- or BRAFsensitizing mutation, or ALK or
ROS1 rearrangement• Previously treated, diseaseprogression on or after
platinum-based chemotherapy
and anti–PD-L(1) Aba

SITRA + TIS (N=187)
SITRA 100 mg PO QD
TIS 200 mg IV Q3W
R
1:1
N=377bTreatment until diseaseprogression, intolerable toxicity,
death, or withdrawal of consent
Chemotherapy (N=190)
Docetaxel 75 mg/m2 IV Q3W

Primary endpoints (alpha splitting)• OS• PFS (IRC by RECIST 1.1)
Secondary endpoints• PFS (investigator)
• ORR
• DoR
• DCR
• Safety
Stratification factors• Histological subtype(non-squamous/squamous)• PD-L1 expression (<1% TC/≥1%)• Race (Asian/non-Asian)

Study was terminated early on September 25, 2023, due to an imbalanced rate of serious/fatal pulmonary hemorrhage
and an unfavorable risk-benefit assessment in the investigational arm
aAnti-PD-(L)1 antibody administered with or sequentially before or after platinum-based chemotherapy.
bActual sample size; planned sample size was N=420.

Ab, antibody; ALK, anaplastic lymphoma kinase; BRAF, B-Raf proto-oncogene; DCR, disease control rate; DoR, duration of response; EGFR, epidermal growth factor receptor; IRC, Independent Review Committee;
IV, intravenous; NSCLC, non-small cell lung cancer; ORR, overall response rate; OS, overall survival; PD-(L)1, programmed cell death protein-1/programmed death-ligand 1; PFS, progression-free survival; PO, oral; QD,once daily; Q3W, every 3 weeks; R, randomized; RECIST, Response Evaluation in Solid Tumors; ROS1, ROS Proto-Oncogene 1; TC, tumor cells; TIS, tislelizumab; SITRA, sitravatinib.

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Screened (n = 606)

Patient Disposition

Excluded (n=229)• Did not meet inclusion/exclusion criteria (n=179)• Adverse event (n=3)• Withdrawal by participant (n=25)• Other (n=22)
Enrolled/Randomized (N=377)

Median study follow-up•

SITRA + TIS: 8.0 months•

Docetaxel: 7.6 months

Not treated (n=1)

Not treated (n=13)

Treated (n=186)
Treatment discontinuation (n=186/186 [SITRA/TIS])• Progressive disease (n=99/97)• Adverse events (n=34/34)• Study terminated by sponsor (n=33/33)• Drug withdrawal by subject (n=13/15)• Investigator decision (n=5/5)• Lost to follow-up (n=1/1)• Other (n=1/1)••••

ITT, intent-to-treat; SITRA, sitravatinib; TIS, tislelizumab.

Docetaxel
N=190

SITRA + TIS
N=187

Study discontinuation (n=187)
Death (n=92)
Study terminated by sponsor (n=86)
Withdrawal by subject (n=6)
Lost to follow-up (n=3)
Analysis sets
ITT (N=187)
Safety (N=186)

Treated (n=177)
Treatment discontinuation ​(n=177)​• Progressive disease (n=113)• Adverse event (n=9)• Study terminated by sponsor (n=18)• Drug withdrawal by subject (n=23)• Investigator decision (n=12)• Lost to follow-up (n=1)• Other (n=1)••••

Study discontinuation (n=190)
Death (n=82)
Study terminated by sponsor (n=89)
Withdrawal by subject (n=13)
Lost to follow-up (n=6)
Analysis sets
ITT (N=190)
Safety (N=177)4Baseline Characteristics (ITT Population)
SITRA + TIS
N=187

DocetaxelN=190

Total
N=377

Age, median (range), years

63.0 (29-76)

63.0 (34-79)

63.0 (29-79)

Gender, n (%)
MaleFemale

153 (81.8)
34 (18.2)

151 (79.5)
39 (20.5)304 (80.6)
73 (19.4)

Race, n (%)
AsianWhite

175 (93.6)
12 (6.4)

177 (93.2)
13 (6.8)352 (93.4)
25 (6.6)

47 (25.1)
140 (74.9)

46 (24.2)
144 (75.8)

93 (24.7)
284 (75.3)

96 (51.3)
91 (48.7)

97 (51.1)
93 (48.9)

193 (51.2)
184 (48.8)

68 (36.4)
106 (56.7)
13 (7.0)70 (36.8)
107 (56.3)
13 (6.8)

138 (36.6)
213 (56.5)
26 (6.9)142 (75.9)
45 (24.1)

140 (73.7)
50 (26.3)

282 (74.8)
95 (25.2)

ECOG performance status, n (%)
01Histology, n (%)
Squamous
Non-squamous
PD-L1 expression status, n (%)≥1%<1%
Not evaluablea
Number of lines of prior systemic therapy, n (%)
12aPatients with unevaluable PD-L1 expression status were included in the <1% TC group during randomization.

ECOG, Eastern Cooperative Oncology Group; ITT, intent-to-treat; PD-L1, programmed death-ligand 1; SITRA, sitravatinib; TC, tumor cells; TIS, tislelizumab.

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PFS by IRC and by INV (ITT Population)• The dual primary endpoint, PFS (IRC), was numerically longer with investigational therapy (median, 4.4 vs 2.9 months; HR, 0.82)• PFS (INV), a secondary endpoint, was comparable with IRC-assessed PFS (median, 4.4 vs 2.9 months; HR, 0.64)

1.0

EventsMedianHazard Ratio(%)(95% CI)(95% CI)
SITRA + TIS 125 (66.8) 4.4 (4.0-5.7) 0.82 (0.62-1.07)
Docetaxel 98 (51.6) 2.9 (2.6-4.2)

0.9
0.8
0.7
0.6
0.50.40.3
0.2

Docetaxel

0.10.0SITRA + TIS
0246810

Number at Risk:
SITRA + TIS
187 118 87
Docetaxel
190 84 53473035
1715712141618202224

105535222222
100

Time (Months)

Events(%)
SITRA + TIS 131 (70.1)
Docetaxel 127 (66.8)

0.9

Survival Probability

1.0

Survival Probability

PFS by INVPFS by IRC

0.8
0.7

MedianHazard Ratio(95% CI)(95% CI)
4.4 (4.0-5.6) 0.64 (0.50-0.83)
2.9 (2.6-4.1)

0.6
0.5
0.4
0.30.2Docetaxel
SITRA + TIS

0.1
0.00246810

Number at Risk:
187 128 90
SITRA + TIS
Docetaxel
190 91 60

5129381718
712141618202224

115737242222100

Time (Months)

aMedian follow-up time was estimated by the reverse Kaplan-Meier method with 95% CIs estimated using the Brookmeyer and Crowley method.

CI, confidence interval; IRC, Independent Review Committee; INV, investigator; ITT, intent-to-treat; PFS, progression-free survival; SITRA, sitravatinib; TIS, tislelizumab.

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OS (Dual Primary Endpoint; ITT Population)• At data cutoff (December 20, 2023), median follow-up time for OS was 11.7 months (SITRA + TIS) versus 11.4 months (docetaxel)a• Median OS was similar in both arms (11.5 vs 11.4 months)

OS

1.0

EventsMedianHazard Ratio(%)(95% CI)(95% CI)
SITRA + TIS 91 (48.7) 11.5 (9.4-14.6) 1.02 (0.75-1.39)
Docetaxel 80 (42.1) 11.4 (9.9-15.0)

Survival Probability

0.9
0.8
0.7
0.60.50.4Docetaxel

0.3

SITRA + TIS

0.2
0.1
0.002468101214161820222426

Number at Risk:
SITRA + TIS
187 161 140 116 91
Docetaxel
190 162 140 117 82

6060

4443332925221512106724100

Time (Months)

aMedian follow-up time was estimated by the reverse Kaplan-Meier method with 95% CIs estimated using the Brookmeyer and Crowley method.

CI, confidence interval; ITT, intent-to-treat; OS, overall survival; SITRA, sitravatinib; TIS, tislelizumab.

7OS Subgroup Analyses (ITT Population)
Subgroup
OverallAge group<65 years≥65 years
SexMaleFemale
RaceAsian
Non-AsianGeographic region
ChinaAustralia
ECOG performance status
01PD-L1 Expression≥1% TC<1% TCNot evaluable
Histological subtype
Non-squamous
Squamous
Smoking Status
Former/current smoker
Non-Smoker
Disease status at study entry
Locally advanced
Metastatic
Number of lines of prior systemic therapy
12

Event/Total
SITRA + TIS
91/187

Event/Total
Docetaxel
80/190

Hazard Ratio for Death(95% CI)

Hazard Radio(95% CI)1.10 (0.82-1.49)

48/106
43/81

51/11229/78

0.87 (0.59-1.29)
1.52 (0.94-2.44)

78/153
13/34

68/15112/39

1.11 (0.80-1.54)
1.13 (0.52-2.49)

82/175
9/12

73/1777/13

1.08 (0.79-1.49)
1.26 (0.47-3.41)

81/174
10/13

72/1758/15

1.07 (0.78-1.47)
1.56 (0.61-3.99)

16/47
75/14013/46
67/1441.27 (0.61-2.64)
1.06 (0.76-1.47)

32/68
52/106
7/13

25/70
50/1075/13

1.30 (0.77-2.20)
0.96 (0.65-1.41)
1.45 (0.46-4.62)

46/91
45/96

39/93
41/97

1.18 (0.77-1.81)
1.01 (0.66-1.54)

71/131
20/56

60/132
20/58

1.17 (0.83-1.66)
0.95 (0.51-1.76)

9/19
82/16810/24
70/1660.91 (0.37-2.25)
1.10 (0.80-1.52)

68/142
23/45

64/14016/50

0.97 (0.69-1.36)
1.68 (0.89-3.19)

0.0 0.5 1.0 1.5 2.0
SITRA + TIS Docetaxel
CI, confidence interval; ECOG, Eastern Cooperative Oncology Group; OS, overall survival; PD-L1, programmed death-ligand 1; ITT, intent-to-treat; SITRA, sitravatinib; TC, tumor cells; TIS, tislelizumab.

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Tumor Response (ITT Population)• IRC-confirmed ORR was similar in both arms (12.3% vs 12.6%)
25

ORR (95% CI)

2012.3%(95% CI, 8.0-17.9)a12.6%(95% CI, 8.3-18.2)aOverall response rate by IRC, n (%)

1595% CI (%)aDisease control rate by IRC, n (%)

1050Category

95% CI (%)an (%)c
CR: 0 (0)PR: 23 (12.3)
SD: 102 (54.5)
PD: 33 (17.6)

n (%)d
CR: 0 (0)PR: 24 (12.6)
SD: 74 (38.9)
PD: 51 (26.8)

SITRA + TIS
N=187

Docetaxel
N=190

Median duration of response by IRC(95% CI), monthsbSITRA + TIS
N=187

Docetaxel
N=190

23 (12.3)

24 (12.6)

8.0-17.9

8.3-18.2

130 (69.5)

102 (53.7)

62.4-76.0

46.3-60.9

6.0 (3.2-8.5)

NR (5.4-NE)

Complete response and partial response were confirmed per RECIST v1.1.
aThe 95% CI was estimated using the Clopper-Pearson method.
bThe 95% CI was estimated using the Brookmeyer and Crowley method with log-log transformation.
c5 (2.7%) and 24 (12.8%) had non-CR/non-PD and could not be determined, respectively.
d4 (2.1%) and 37 (19.5%) had non-CR/non-PD and could not be determined, respectively.
CI, confidence interval; CR, complete response; ITT, intent-to-treat; IRC, Independent Review Committee; NE, not estimable; ORR, overall response rate; PD, progressive disease; PR, partial response;
RECIST, Response Evaluation Criteria in Solid Tumors; SD, stable disease; SITRA, sitravatinib; TIS, tislelizumab.

9Safety (Safety Population)•

Higher incidences of most categories of TEAEs ininvestigational arm•Fatal hemoptysis was more common in investigational arm

Patients with ≥1 TEAE
≥Grade 3Serious
Leading to deatha
Leading to treatment discontinuation
TEAEs leading to death in >1 patienta
DeathbPneumonia
Hemoptysis
Treatment-relatedc

TEAEs (Any Grade)Occurring in >25% in
Any Arm

SITRA + TIS
N=186n (%)

Docetaxel
N=177
n (%)

Any Grade≥Grade 3

Any Grade≥Grade 3

111 (59.7)

6 (3.2)18 (10.2)

3 (1.7)

97 (52.2)

5 (2.7)17 (9.6)

4 (2.3)83 (44.6)

9 (4.8)26 (14.7)

5 (2.8)74 (39.8)

5 (2.7)3 (1.7)0

68 (36.6)

12 (6.5)00Anemia

61 (32.8)

7 (3.8)84 (47.5)5 (2.8)Aspartate aminotransferase
increased
Alanine aminotransferase
increased

SITRA + TIS
N=186n (%)

Docetaxel
N=177n (%)

183 (98.4)
121 (65.1)
83 (44.6)
15 (8.1)
45 (24.2)

162 (91.5)
100 (56.5)
66 (37.3)
5 (2.8)15 (8.5)

4 (2.2)1 (0.6)

Hypoalbuminemia

58 (31.2)

1 (0.5)41 (23.2)

0

3 (1.6)3 (1.6)3 (1.6)d

2 (1.1)00

Hypertension

56 (30.1)

25 (13.4)

6 (3.4)2 (1.1)

Weight decreased54 (29.0)

8 (4.3)15 (8.5)

1 (0.6)

Decreased appetite

53 (28.5)

2 (1.1)29 (16.4)

2 (1.1)Adverse event grades were evaluated based on NCI-CTCAE Version 5.0.

aDeath events due to disease under study are not included as a TEAE leading to death.

bFor all 5 fatal TEAE cases where death was listed as the preferred term, all reported terms were “unexplaineddeath”.

cTEAEs that were considered by the Investigator to be related to study drug or TEAEs with a missing causality.
dIDMC reviewed and concluded the fatal events were confounded by squamous central NSCLC (n=2) andDiarrhea
Blood creatine phosphokinase
MB increased
Palmar-plantar
erythrodysesthesia syndrome

White blood cell countdecreased
Neutrophil count decreased

11 (5.9)066 (37.3)

52 (29.4)

10 (5.4)

1 (0.5)59 (33.3)

51 (28.8)

Alopecia

5 (2.7)059 (33.3)

0pre-existing hemoptysis at baseline (n=1).
NCI-CTCAE, National Cancer Institute-Common Terminology Criteria for Adverse Events;
TEAE, treatment-emergent adverse event; SITRA, sitravatinib; TIS, tislelizumab.

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Conclusions
In patients with locally advanced/metastatic NSCLC whose disease progressed following platinum-based chemotherapy
and anti–PD-(L)1 antibody:• IRC- and investigator-assessed PFS were numerically longer in investigational versus docetaxel arm• No improvements of OS were observed
 Data were immature with limited follow-up and event rates
 Higher number of patients in the docetaxel arm who did not receive treatment may bring biases
 Lack of survival benefit is consistent with other phase 3 studies of anti–PD-(L)1 and TKI combinations (LEAP-008, CONTACT-01,and SAPPHIRE) in NSCLC1-3• There were higher incidences of ≥grade 3 TEAEs, serious TEAEs, and TEAEs leading to discontinuation and death in
the investigation arm versus docetaxel
 Patient population included squamous central NSCLC• The study was terminated early based on unfavorable benefit: risk ratio

Acknowledgments

We would like to thank the investigators, site support staff, and especially the patients for participating in this study. We would like to thank Fan Yu, MD, for contributions
to this presentation. Medical writing support, under the direction of the authors, was provided by Lori Kornberg, PhD and Smitha Reddy, PhD. Thank you for listening!
IRC, Independent Review Committee; NSCLC, non-small cell lung cancer; OS, overall survival; PD-(L)1, programmed cell death protein-1/programmed death-ligand 1; PFS, progression-free survival;
TEAE, treatment-emergent adverse event; TKI, tyrosine kinase inhibitor.
1. Borghaei H, et al. Ann Oncol. 2024;35:66-76. 2. Leighl N, et al. Ann Oncol. 2024;20(suppl_1):100535-100535. doi:101016/iotech/iotech100535. 3. Neal J, et al. J Clin Oncol. 2024; 42:2393-2403.

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