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International Association for the Study of Lung Cancer
WWW.IASLC.ORG
DECEMBER 4–7, 2016 VIENNA, AUSTRIA
A Randomized, Multi-Center, Double-Blind Phase II
Study of Fruquintinib in Patients with Advanced
Non-Small Cell Lung Cancer (NCT02590965)
Shun Lu1, Jianhua Chang2, XiaoQing Liu3, Jianhua Shi4, You Lu5, Wei Li6, Jinji Yang7, Jianying Zhou8, Jie Wang9, Lei Yang10,
Zhiwei Chen1, Xiangdong Zhou11, Zhe Liu12, Ye Hua13, Weiguo Su13
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Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai/China
Fudan University Shanghai Cancer Center, Shanghai/China
307 Hospital of the Academy of Military Medical Sciences, Beijing/China
Linyi Tumor Hospital, Linyi/China
West China Hospital, Chengdu/China
The First Hospital of Jilin University, Changchun/China
Guangdong General Hospital, Guangzhou/China
The First Affiliated Hospital, Hangzhou/China
Beijing Cancer Hospital and Institute, Beijing/China
Nantong Tumor Hospital, Nantong/China
Xi’nan Hospital, Chongqing/China
Beijing Chest Hospital, Beijing/China
Hutchison MediPharma Limited, Shanghai/China
Corresponding Author/Presenter: Prof. Shun Lu, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai/China
Abstract 4571: A Randomized, Multi-Center, Double-Blind Phase II Study of Fruquintinib in Patients with
Advanced Non-Small Cell Lung Cancer – Shun Lu
International Association for the Study of Lung Cancer
WWW.IASLC.ORG
DECEMBER 4–7, 2016 VIENNA, AUSTRIA
Disclosure
• Leading principal investigator (PI) of fruquintinib phase II clinical trial in lung
cancer sponsored by Hutchison MediPharma (NCT02590965);
• Received research support from AstraZeneca, Boehringer Ingelheim,
Hutchison MediPharma and Roche;
• Received speaker fees from AstraZeneca, Eli Lilly, Roche, and Sanofi;
• An advisor of AstraZeneca, Boehringer Ingelheim, Hutchison MediPharma,
and Roche.
Abstract 4571: A Randomized, Multi-Center, Double-Blind Phase II Study of Fruquintinib in Patients with
Advanced Non-Small Cell Lung Cancer – Shun Lu
International Association for the Study of Lung Cancer
WWW.IASLC.ORG
DECEMBER 4–7, 2016 VIENNA, AUSTRIA
Background
O
• Lung cancer is the leading cause of cancer-related deaths globally
with a poor survival rate.1
• Few targeted therapies are available for patients who fail two lines of
standard chemotherapy.
MeO
MeO
• Fruquintinib is a potent and highly selective oral VEGFR inhibitor and
demonstrated good anti-tumor activity against NSCLC.2
• In Phase I clinical studies, fruquintinib demonstrated encouraging antitumor activity including NSCLC. The RP2D was determined to be 5
mg once daily for 3 weeks on and 1 week off.3
O
O
N
N
Molecular formula:
C21H19N3O5
Molecular weight:
393.40
NSCLC: non-small cell lung cancer; RP2D: recommended Phase 2 dose; VEGFR: vascular endothelial growth factor receptor
1. Torre, LA, et al., Global cancer statistics, 2012; 2. Sun Q, et al., Cancer Biol. & Therapy, 15:12, 1635-1645, 2014; Cao J, et al., Cancer Chemther Pharmacol.,
78:259-269, 2016
Abstract 4571: A Randomized, Multi-Center, Double-Blind Phase II Study of Fruquintinib in Patients with
Advanced Non-Small Cell Lung Cancer – Shun Lu
NHMe
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International Association for the Study of Lung Cancer
DECEMBER 4–7, 2016 VIENNA, AUSTRIA
Study Design
Fruquintinib + BSC
(5 mg QD po)
•Stage IIIB/IV histologically or
cytologically confirmed
non-squamous NSCLC
•Failed 2 prior chemotherapy
regimens
•Age 18-75
•ECOG PS 0-1
N=91
3 weeks on/1 week off
N=61
PD
Primary Endpoint
• PFS
Secondary Endpoints
R
2:1
• ORR
• DCR
Placebo + BSC
3 weeks on/1 week off
N=30
PD
• OS
• Safety
Stratification by EGFR status: mutant vs. wild type vs. unknow
Tumor assessment: 4 week, 8 week, then every 8 weeks thereafter
BSC (best support care); DCR (Disease control rate); EGFR (epidermal growth factor receptor)
ORR (Objective response rate); OS (overall survival); PD (progressive disease); PFS (progression free survival)
Abstract 4571: A Randomized, Multi-Center, Double-Blind Phase II Study of Fruquintinib in Patients with
Advanced Non-Small Cell Lung Cancer – Shun Lu
WWW.IASLC.ORG
International Association for the Study of Lung Cancer
DECEMBER 4–7, 2016 VIENNA, AUSTRIA
Patient Baseline Characteristics
Baseline Characteristics (ITT, N=91)
Age in years, median (range)
Fruquintinib (N=61)
n (%)
Placebo (N=30)
n (%)
55 (36,68)
56.5 (34,73)
Age
<65 years
≥65 years
54 (88.5)
7 (11.5)
24 (80.0)
6 (20.0)
Gender
Male
Female
34 (55.7)
27 (44.3)
12 (40.0)
18 (60.0)
ECOG PS
0
1
4 (6.6)
57 (93.4)
1 (3.3)
29 (96.7)
EGFR status
Mutant
Wild type
Unknown
30 (49.2)
27 (44.3)
4 (6.6)
15 (50.0)
13 (43.3)
2 (6.7)
Prior EGFR inhibitor treatment
Yes
No
23 (37.7)
38 (62.3)
13 (43.3)
17 (56.7)
ITT (intent to treat)
Abstract 4571: A Randomized, Multi-Center, Double-Blind Phase II Study of Fruquintinib in Patients with
Advanced Non-Small Cell Lung Cancer – Shun Lu
Data cut-off: 27Oct2016
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International Association for the Study of Lung Cancer
DECEMBER 4–7, 2016 VIENNA, AUSTRIA
Progression Free Survival
Investigator Evaluation
100
90
80
Censoring Times: Fruquintinib
Censoring Times: Placebo
Fruquintinib
Placebo
90
80
Probability (%) of survival
Probability (%) of survival
Independent Review Committee
100
Censoring Times: Fruquintinib
Censoring Times: Placebo
Fruquintinib
Placebo
mPFS: Fruquintinib vs. placebo
3.81m vs. 1.15m
70
60
HR=0.275 (0.159, 0.476)
50
Log-rank p<0.001
40
30
20
60
30
20
0
0
2
3
Number of subjects at risk
Fruquintinib 61 55 47 37
Placebo
30 16 6
3
4
5
6
7
8
9
10
11
12
13
14
Log-rank p<0.001
40
10
1
HR=0.338 (0.199, 0.572)
50
10
0
mPFS: Fruquintinib vs. placebo
3.78m vs. 1.12m
70
0
1
2
3
4
5
Time (months)
30
3
17
0
15
0
10
0
9
0
8
0
7
0
3
0
1
0
1
0
0
0
Number of subjects at risk
Fruquintinib 61 55 42 33
30 14 4
3
Placebo
6
7
8
9
10
11
12
13
14
5
1
5
1
2
0
0
0
0
0
0
0
Time (months)
26
3
12
1
11
1
Abstract 4571: A Randomized, Multi-Center, Double-Blind Phase II Study of Fruquintinib in Patients with
Advanced Non-Small Cell Lung Cancer – Shun Lu
6
1
6
1
Data cut-off: 7Aug2015
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International Association for the Study of Lung Cancer
DECEMBER 4–7, 2016 VIENNA, AUSTRIA
PFS Subgroup Analysis
Subgroup
Age
<65 years
>=65 years
Gender
Male
Female
ST
Duration from 1 metastatic
Diagnosis to randomization
<18 months
>=18 months
Baseline ECOG PS
0
1
Metastatic tumor site
Single
Multiple
EGFR Status
Mutant
Wild type
Unknown
Brain metastasis
Yes
No
N
HR (95% CI)
78
13
0.39 (0.23-0.65)
0.67 (0.21-2.15)
46
45
0.12 (0.05-0.29)
0.57 (0.30-1.09)
55
35
0.40 (0.21-0.75)
0.31 (0.15-0.67)
5
86
0.29 (0.02-4.65)
0.46 (0.28-0.74)
18
72
0.79 (0.22-2.88)
0.33 (0.19-0.56)
45
40
6
0.17 (0.07-0.37)
0.61 (0.29-1.28)
2.33 (0.25-21.39)
11
80
0.16 (0.03-0.90)
0.47 (0.29-0.77)
0.0
1.0
HR (95%CI)
Favors Fruquintinib
2.0
3.0
29.12
Favors Placebo
Subgroup
EGFR & EGFR-TKI status
EGFR+ & EGFR-TKI+
EGFR+ & EGFR-TKIEGFR- & EGFR-TKI+
EGFR- & EGFR-TKIEGFR Unknown & EGFR-TKI+
EGFR Unknown & EGFR-TKITime from start of 1st-regimen
Treatment to randomization
<9 months
>=9 months
Best response to 1st-regimen
treatment
CR/PR/SD
PD
Sum of target lesion at baseline
<5 cm
>=5 cm
N
HR (95% CI)
32
13
2
38
3
3
0.16 (0.06-0.42)
0.16 (0.03-0.90)
0.00 (0.00-0.00)
0.66 (0.30-1.43)
1.41 (0.08-23.57)
NA
21
68
0.22 (0.07-0.74)
0.45 (0.27-0.76)
47
29
0.65 (0.34-1.23)
0.11 (0.04-0.36)
41
50
0.53 (0.27-1.08)
0.28 (0.14-0.64)
0.0
1.0
2.0
HR (95%CI)
Favors Fruquintinib
Abstract 4571: A Randomized, Multi-Center, Double-Blind Phase II Study of Fruquintinib in Patients with
Advanced Non-Small Cell Lung Cancer – Shun Lu
3.0
29.12
Favors Placebo
NA(not assessable)
Data cut-off: 27Oct2016
WWW.IASLC.ORG
International Association for the Study of Lung Cancer
DECEMBER 4–7, 2016 VIENNA, AUSTRIA
Placebo
(N=30)
n (%)
0
0
Partial response (PR)
10 (16.4)
0
Stable disease (SD)
33 (54.1)
5 (16.7)
Progressive disease (PD)
14 (23.0)
20 (66.7)
Overall response rate (ORR)*
10 (16.4)
0
Disease control rate (DCR)**
43 (70.5)
5 (16.7)
Response Rate
Complete response (CR)
* p=0.021; **p<0.001.
% Change in Target Lesions
Fruquintinib
(N=61)
n (%)
100
90
80
70
60
50
40
30
20
10
0
-10
-20
-30
-40
-50
-60
-70
-80
-90
-100
% Change in Target Lesions
Best Tumor Response by Treatment
100
90
80
70
60
50
40
30
20
10
0
-10
-20
-30
-40
-50
-60
-70
-80
-90
-100
PR, n=10
SD, n=33
PD, n=14
NE, n=3
Fruquintinib
SD, n=5
PD, n=20
NE, n=1
Placebo
Abstract 4571: A Randomized, Multi-Center, Double-Blind Phase II Study of Fruquintinib in Patients with
Advanced Non-Small Cell Lung Cancer – Shun Lu
NE (not evaluated)
Data cut-off: 27Oct2016
WWW.IASLC.ORG
International Association for the Study of Lung Cancer
DECEMBER 4–7, 2016 VIENNA, AUSTRIA
Overall Survival
EGFR Mutant (N=45)
80
70
60
50
100
Censoring Times: Fruquintinib
Censoring Times: Placebo
Fruquintinib
Placebo
mOS: Fruquintinib vs. placebo
8.44m vs. 5.49m
HR= 0.615 (0.298,1.268)
Log-rank p=0.184
40
30
20
90
Probability (%) of survival
Probability (%) of survival
90
EGFR Wild Type (N=40)
80
60
Log-rank p=0.274
40
30
20
0
0
Number of subjects at risk
Fruquintinib 30 30 30 27 24 21 21 18 15 15 13 12 12 12 12 12 12 12 12 10 8 8 4 3 1 1 1 1 0
15 14 11 10 9 8 7 7 7 6 6 5 5 5 5 4 4 3 3 3 2 2 1 0 0 0 0 0 0
Placebo
HR= 0.651 (0.298,1.420)
50
10
Time (months)
mOS: Fruquintinib vs. placebo
7.52m vs. 9.69m
70
10
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28
Censoring Times: Fruquintinib
Censoring Times: Placebo
Fruquintinib
Placebo
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28
Time (months)
Number of subjects at risk
27 26 25 24 22 21 19 16 13 13 13 13 12 12 12 12 10 10 10 10 8 6 6 5 3 2 1 0 0
Fruquintinib
13 12 10 9 8 7 7 6 6 6 5 5 5 5 5 5 4 3 1 1 0 0 0 0 0 0 0 0 0
Placebo
Abstract 4571: A Randomized, Multi-Center, Double-Blind Phase II Study of Fruquintinib in Patients with
Advanced Non-Small Cell Lung Cancer – Shun Lu
Data cut-off: 27Oct2016
International Association for the Study of Lung Cancer
WWW.IASLC.ORG
DECEMBER 4–7, 2016 VIENNA, AUSTRIA
Treatment-Emergent Adverse Event Summary
Overview of TEAE
Fruquintinib (N=61)
n (%)
Placebo (N=30)
n (%)
at least one TEAE
61 (100)
27 (90.0)
8 (13.1)
4 (13.3)
at least one Grade3 TEAE
23 (37.7)
6 (20.0)
at least one Grade4 TEAE
4 (6.6)
2 (6.7)
at least one Grade5 TEAE
3 (4.9)
2 (6.7)
at least one related TEAE
59 (96.7)
22 (73.3)
at least one SAE
at least one TEAE leading to dose interruption
9 (14.8)
0
at least one TEAE leading to dose reduction
8 (13.1)
0
at least one TEAE leading to treatment discontinuation
6 (9.8)
1 (3.3)
Abstract 4571: A Randomized, Multi-Center, Double-Blind Phase II Study of Fruquintinib in Patients with
Advanced Non-Small Cell Lung Cancer – Shun Lu
Data cut-off: 27Oct2016
WWW.IASLC.ORG
International Association for the Study of Lung Cancer
DECEMBER 4–7, 2016 VIENNA, AUSTRIA
Treatment-Emergent Adverse Event
Fruquintinib (N=61)
n (%)
TEAEs (overall rate > 10%)
At least one TEAE
Palmar-plantar erythrodysaesthesia syndrome
Proteinuria
Hypertension
Blood pressure increased
Fatigue
Blood thyroid stimulating hormone increased
Vomiting
Dysphonia
Cough
Nausea
Diarrhoea
Constipation
Mouth ulceration
Aspartate aminotransferase increased
Decreased appetite
Weight decreased
Back pain
Placebo (N=30)
n (%)
Grade 1-2
Grade 3-4
Total *
Grade 1-2
Grade 3-4
Total*
38 (62.3)
26 (42.6)
19 (31.1)
9 (14.8)
4 (6.6)
11 (18.0)
17 (27.9)
8 (13.1)
15 (24.6)
11 (18.0)
10 (16.4)
13 (21.3)
9 (14.8)
12 (19.7)
12 (19.7)
7 (11.5)
9 (14.8)
8 (13.1)
20 (32.8)
3 (4.9)
1 (1.6)
5 (8.2)
2 (3.3)
2 (3.3)
0
0
0
1 (1.6)
0
1 (1.6)
0
1 (1.6)
0
0
1 (1.6)
0
61 (100)
29 (47.5)
20 (32.8)
14 (23.0)
6 (9.8)
13 (21.3)
17 (27.9)
8 (13.1)
15 (24.6)
12 (19.7)
10 (16.4)
14 (23.0)
9 (14.8)
13 (21.3)
12 (19.7)
7 (11.5)
10 (16.4)
8 (13.1)
19 (63.3)
0
5 (16.7)
0
0
5 (16.7)
0
8 (26.7)
1 (3.3)
4 (13.3)
5 (16.7)
1 (3.3)
5 (16.7)
0
1 (3.3)
5 (16.7)
2 (6.7)
2 (6.7)
6 (20.0)
0
0
1 (3.3)
0
0
0
0
0
0
0
0
0
0
0
0
0
0
27 (90.0)
0
5 (16.7)
1 (3.3)
0
5 (16.7)
0
8 (26.7)
1 (3.3)
4 (13.3)
5 (16.7)
1 (3.3)
5 (16.7)
0
1 (3.3)
5 (16.7)
2 (6.7)
2 (6.7)
*Grade 5 TEAEs: 3 in Fruquintinib and 2 in placebo.
Abstract 4571: A Randomized, Multi-Center, Double-Blind Phase II Study of Fruquintinib in Patients with
Advanced Non-Small Cell Lung Cancer – Shun Lu
Data cut-off: 27Oct2016
International Association for the Study of Lung Cancer
WWW.IASLC.ORG
DECEMBER 4–7, 2016 VIENNA, AUSTRIA
Conclusion
• Fruquintinib met the primary endpoint and significantly improved
progression free survival compared with placebo in 3rd line advanced
non‐squamous NSCLC.
• Fruquintinib demonstrated a favorable trend in improving overall survival in
this study.
• Fruquintinib was well tolerated with an acceptable safety profile in
this study
• A Phase III study is ongoing to confirm the survival benefit in 3rd line
advanced non-squamous NSCLC.
Abstract 4571: A Randomized, Multi-Center, Double-Blind Phase II Study of Fruquintinib in Patients with
Advanced Non-Small Cell Lung Cancer – Shun Lu
International Association for the Study of Lung Cancer
WWW.IASLC.ORG
DECEMBER 4–7, 2016 VIENNA, AUSTRIA
Acknowledgment
• We would like to thank all patients and their families who participated in
this trial.
• We would like to thank all investigators, study coordinators and the entire
project team.
• We would like to acknowledge the sponsor for this trial:
Hutchison MediPharma Limited.
Abstract 4571: A Randomized, Multi-Center, Double-Blind Phase II Study of Fruquintinib in Patients with
Advanced Non-Small Cell Lung Cancer – Shun Lu