Phase II study of savolitinib in patients (pts) with pulmonary sarcomatoid carcinoma (PSC) and other types of non-small cell lung cancer (NSCLC) harboring MET exon 14 skipping mutations (METex14+)

Authors: Shun Lu1, Jian Fang2, Xingya Li3, Lejie Cao4, Jianying Zhou5, Qisen Guo6, Zongan Liang7, Ying Cheng8, Liyan Jiang9, Nong Yang10, Zhigang Han11, Jianhua Shi12, Yuan Chen13, Hua Xu14, Helong Zhang15, Di Zhang16, Jing Li16, Linfang Wang16, Yongxin Ren16, Weiguo Su16

1.Shanghai Lung Cancer Center, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China; 2.Department of Thoracic Oncology II, Peking University Cancer Hospital & Institute, Beijing, China; 3.Department of Oncology, First Affiliated Hospital of Zhengzhou University, Zhengzhou, China;4.Anhui Provincial Hospital, The First Affiliated Hospital of USTC, Hefei, China; 5.the First Affiliated Hospital of Zhejiang University, Hangzhou, China; 6.Shandong Cancer Hospital Affiliated to Shandong University, Jinan, China; 7.West China Hospital of Sichuan University,, Chengdu, China; 8.Jilin Cancer Hospital, Changchun, China; 9.Department of Pulmonary, Shanghai Chest Hospital,

Shanghai Jiaotong University, Shanghai, China; 10.Hunan Cancer Hospital, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China; 11.First Department of Lung Cancer Chemotherapy, The Affiliated Cancer Hospital of Xinjiang Medical University, Urumqi, China; 12.Linyi Cancer Hospital, Linyi, China; 13.Department of Oncology, Tongji hospital, Huazhong University of Science and Technology, Wuhan, China; 14.The Second Affiliated Hospital of Nanchang University, Nanchang, China; 15.Tangdu Hospital, Air Force Medical University, Xi’an, China; 16.Hutchison MediPharma Limited, Shanghai, China

Savolitinib demonstrated promising anti-tumor activity and acceptable tolerability in METex14+ NSCLC patients

Correspondence: Shun Lu at shun_lu@hotmail.com

Background: • Treatment options are limited for pts with METex14+ NSCLC.• PSC is a rare type of NSCLC with more progressive clinical behavior and poorer

diagnosis than other types of NSCLC, and resistant to chemotherapy (historically,PFS<3 months)1,2.

• Savolitinib (AZD6094, HMPL-504, volitinib) is a highly selective oral MET tyrosinekinase inhibitor with an IC50＜10 nM in vitro.

Methods: • A multicenter, multi-cohort, single-arm phase II study in China to evaluate the

efficacy, safety, and pharmacokinetics of savolitinib in pts with unresectable ormetastatic METex14+ PSC and other NSCLC. The cohort 1 was presented here.

• Cohort 1 was designed to reject the null hypothesis that the ORR does not exceed30%, with at least 90% power. Assuming the ORR was at least 55%, the minimumrequired sample size were 50 efficacy evaluable patients. Efficacy

• Robust and durable tumor response with savolitinib among METex14+ NSCLC pts: IRC-assessed ORR 49.2% in efficacy evaluable set and 42.9% in full analysis set, DoR was 9.6 months (maturity 40.0%); observations consistent across subgroups.

• PFS and OS data were both not mature yet; median PFS was 6.9 months (maturity 50.0%) and median OS was 14.0 months (maturity 45.7%) in 70 pts.

• PFS was of clinical significance both among PSC and other NSCLC subgroups.

• Promising PFS was observed among previously treated subgroup.

• In the treatment naïve subgroup, nearly half of pts were with PSC (46.4%, 13/28), which reflected in the PFS of this subgroup.Results:

Patients• A total of 593 Chinese pts were pre-screened/screened, 87 identified with

METex14+ and 70 treated. As of 31 Mar 2020, 50 pts discontinued treatment, 20 were still on treatment, follow-up was ongoing.

• Most of the pts were of senior age, with stage IV disease and previously treated with systemic antitumor treatment.

• The proportion of pts with PSC was 35.7% (25/70); half of pts with PSC were prior treatment naïve.

Safety• Median treatment duration of 70 pts was 6.8 months (range 0.2 to 37.3); 62

pts initially received 600mg QD, 8 received 400 mg QD.

Primary Endpoint:

● IRC-assessed ORR (RECIST v1.1)

Secondary Endpoints:

● DCR, DoR, TTR, PFS, 6-month PFS rate, OS

● Safety and tolerability

Study population:● unresectable/metastatic PSC or other

NSCLC● MET exon 14 skipping+ and

EGFR/ALK/ROS1 WT(local test results acceptable; central

retrospective confirmation required*)

● Failed/or medically unfit for chemotherapy

● Naïve to MET inhibitor

Savolitinib treatment:

600mg (BW≥50kg) or 400mg (BW<50kg)

orally, once daily (QD), 21 days/cycle

Tumor evaluation by IRC and investigators respectively

1st year: every 6 weeks

After 1 year: every 12 weeks

Treatment until disease progression

or

unacceptable toxicity

*Gene status verified by Sanger or NGS (Geneseeq Tetradecan Panel) in central lab.

DemographicsPSC

N=25Other NSCLC

N=45Total N=70

Age, yearsmedian (range)

69.3(54.1-84.8)

68.1(51.7-85.0)

68.7（51.7-85.0）

>75 years, n (%) 6 (24.0) 10 (22.2) 16 (22.9)

Weight, kgmedian (range)

61.0 (44.0, 89.5)

60.0 (41.5, 84.0)

60.0 (41.5, 89.5)

Smokinghistory, n (%)

Former/current smoker

12 (48.0) 16 (35.6) 28 (40.0)

Non-smoker 13 (52.0) 29 (64.4) 42 (60.0)Gender,n (%)

Male 17 (68.0) 24 (53.3) 41 (58.6)Female 8 (32.0) 21 (46.7) 29 (41.4)

Disease characteristicsPSC

N=25Other NSCLC

N=45Total N=70

ECOG performance status,n (%)

0 3 (12.0) 9 (20.0) 12 (17.1)

1 22 (88.0) 35 (77.8) 57 (81.4)

3 0 1 (2.2) 1 (1.4)

TNM stage, n (%)

III 1 (4.0) 4 (8.9) 5 (7.1)

IV 24 (96.0) 41 (91.1) 65 (92.9)

Tumor histology, n (%)

Adenocarcinoma NA 40 (88.9) 40 (57.1)

Others NA 5 (11.1) 5 (7.1)

Brain metastases, n (%) 3 (12.0) 14 (31.1) 17 (24.3)

Prior systemic treatment

Naïve 13 (52.0) 15 (33.3) 28 (40.0)

Treated 12 (48.0) 30 (66.7) 42 (60.0)

Abbreviations in this poster:AE: adverse event; BW: body weight; CI: Confidence interval; CTCAE: Common Terminology Criteria for Adverse Events; DCR: diseasecontrol rate; DoR: duration of response; IRC: independent review committee; NE: non-evaluable; non-CR/non-PD: non-completeresponse/non-progressive disease; NR: not reached; NSCLC: non-small cell lung cancer; ORR: objective response rate; OS: overallsurvival; PFS: progression free survival; PSC: pulmonary sarcomatoid carcinoma; RECIST: response evaluation criteria in solid tumors;TTR: time to response;

Table 1. Demographics and baseline disease characteristics (N=70)

Efficacy evaluable set IRC (N=61) Investigator (N=62)

Confirmed PR 30 (49.2) 32 (51.6)

SD 27 (44.3) 25 (40.3)

PD 4 (6.6) 5 (8.1)

Interim ORR, % (95% CI) 49.2 (36.1, 62.3) 51.6 (38.6, 64.5)

Interim DCR, % (95% CI) 93.4 (84.1, 98.2) 91.9 (82.2, 97.3)

Interim DoR*, months, (95% CI) 9.6 (5.5, NR) 6.9 (5.0, NR)

Full analysis set IRC (N=70) Investigator (N=70)

Confirmed PR 30 (42.9) 32 (45.7)

SD 27 (38.6) 25 (35.7)

Non-CR/non-PD* 1 (1.4) 0

PD# 7 (10.0) 8 (11.4)

NE** 5 (7.1) 5 (7.1)

Interim ORR, % (95% CI) 42.9 (31.1, 55.3) 45.7 (33.7, 58.1)

Interim DCR, % (95% CI) 82.9 (71.2, 90.8) 81.4 (70.3, 89.7)

Interim DoR, months, (95% CI) 9.6 (5.5, NR) 6.9 (5.0, NR)

Table 3. Tumor response in full analysis set

*1 pt without target lesion according to IRC assessment; **NE: 2 pts without post-baseline tumor evaluation & 3 pts with 1 unscheduled tumor assessment within 6 wks.# PD: besides pts with assessment of PD, 3 pts died early without post-baseline tumor evaluation were included.

Pts excluded from efficacy evaluable set as below:• 5 pts without post-baseline tumor assessment.• 3 pts with 1 unscheduled tumor assessment of

PR or SD within 6 wks of starting savolitinib.• 1 pt without target lesion as assessed by IRC.

Table 4. IRC-assessed tumor response in subgroups by pathological types

Efficacy evaluable set PSC (N=20)

Other NSCLC(N=41)

Interim ORR, n (%) [95% CI]

10 (50.0)[27.2, 72.8]

20 (48.8)[32.9, 64.9]

Interim DCR, n (%)[95% CI]

18 (90.0) [68.3, 98.8]

39 (95.1)[83.5, 99.4]

Interim DoR, months (95% CI) NR (4.1, NR) 9.6 (4.2, NR)

Full analysis set PSC (N=25)

Other NSCLC(N=45)

Interim ORR, n (%) [95% CI]

10 (40.0)[21.1, 61.3]

20 (44.4)[29.6, 60.0]

Interim DCR, n (%)[95% CI]

18 (72.0)[50.6, 87.9]

40 (88.9)[76.0, 96.3]

Interim DoR, months (95% CI) NR (4.1, NR) 9.6 (4.2, NR)

Efficacy evaluable set Treatment naïve

(N=24)

Previously treated(N=37)

Interim ORR, n (%) [95% CI]

13 (54.2)[32.8, 74.5]

17 (46.0) [29.5, 63.1]

Interim DCR, n (%)[95% CI]

23 (95.8) [78.9,99.9]

34 (91.9) [78.1, 98.3]

Interim DoR, months (95% CI) 6.8 (3.8, NR) NR (6.9, NR)

Full analysis set Treatment naïve

(N=28)

Previouslytreated(N=42)

Interim ORR, n (%)[95% CI]

13 (46.4)[27.5, 66.1]

17 (40.5) [25.6, 56.7]

Interim DCR, n (%)[95% CI]

23 (82.1)[63.1, 93.9]

35 (83.3)[68.6, 93.0]

Interim DoR, months (95% CI) 6.8 (3.8, NR) NR (6.9, NR)

Median PFS, month (95%CI)Other NSCLC: 9.7 (4.2, NR)PSC: 5.5 (2.8, 9.6)

Figure 3. IRC-assessed progression-free survival of subgroups

Median PFS, month (95%CI)Previously treated: 13.8 (4.1, NR)Treatment naïve: 5.6 (2.8, 9.7)

A: by pathological types B: by prior treatment

Preferred term

Total N=70

Any Graden (%)

Grade ≥3n (%)

Any AE 69 (98.6) 29 (41.4)

Peripheral edema 38 (54.3) 5 (7.1)

Nausea 31 (44.3) 0

Aspartate aminotransferase increased

26 (37.1) 9 (12.9)

Alanine aminotransferase increased

26 (37.1) 7 (10.0)

Vomiting 17 (24.3) 0

Hypoalbuminemia 16 (22.9) 0

Decreased appetite 13 (18.6) 0

Blood bilirubin increased 12 (17.1) 0

Asthenia 11 (15.7) 0

Hypoproteinemia 11 (15.7) 0

• 18 (25.7%) pts reported treatment-related serious adverse events (SAE): Hepatic function abnormal (4.3%), drug

hypersensitivity (2.9%) and pyrexia (2.9%) reported in ≥2 pts.

One patient had treatment-related fatal SAE (tumor lysis syndrome).

• 10 (14.3%) pts reported treatment-related AEs leading to dose discontinuation: Drug-induced liver injury and drug

hypersensitivity each reported 2 pts (2.9%). Others each reported in 1 pt.

Table 6. Summary of related* AEs reported by >15% Patients (N=70)

*Related: probably related and possibly related.Treatment emergent adverse event were presented; graded by CTCAE 4.03.Reference:

1. Vieira T, et al. J Thorac Oncol.2013;8(12):1574-72. Ung M, et al. Clin Lung Cancer. 2016;17(5):391-7

Table 2. Tumor response in efficacy evaluable set

Figure 1. Study design of cohort 1 (NCT02897479)

Table 5. IRC-assessed tumor response in subgroups by prior treatment5A: in efficacy evaluable set 5B: in full analysis set

4A: in efficacy evaluable set 4B: in full analysis set

09-002

11-009

08-021

02-014

02-016

13-030

01-007

29-003

17-053

03-007

03-009

12-003

07-014

01-038

13-027

17-031

01-074

07-025

13-015

17-026

03-049

12-011

01-030

17-091

10-002

13-033

13-019

08-006

01-072

08-002

17-042

13-017

17-012

31-024

19-003

17-032

03-024

10-003

13-023

03-050

07-023

03-053

21-010

18-015

11-010

01-003

17-039

12-022

17-028

17-005

12-002

17-025

11-004

01-067

17-074

01-017

07-027

11-012

23-015

07-017

01-071

17-144

01-069

06-003

Subject

-100

-90

-80

-70

-60

-50

-40

-30

-20

-10

0

10

20

30

40

50

60

Be

st P

erc

ent

ag

e C

hang

e (

%)

PRNESDPD

Figure 2. Tumor shrinkage in full analysis set per IRC

Bes

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han

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f ta

rget

lesi

on

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)

Abstract # 9519

Efficacy evaluable set included pts who hadmeasurable lesions at baseline, received at leastone dose of savolitinib, and had at least oneadequate scheduled ( ≥ 6wks) post-baselinetumor assessment or radiological diseaseprogression at anytime based on RECIST 1.1.

*DoR maturity: 40.0% and 40.6% by IRC and investigator assessment respectively.