TIDMHCM
Hutchmed (China) Limited
24 November 2021
Press Release
HUTCHMED and AstraZeneca Initiate SACHI Phase III Trial of
ORPATHYS(R) and TAGRISSO(R) Combination in Certain Lung Cancer
Patients in China After Progression on EGFR Inhibitor Therapy
- Follows important findings from the TATTON [1] study of the
combination in EGFR inhibitor refractory lung cancer patients whose
tumors harbor aberrations of MET -
Hong Kong, Shanghai & Florham Park, NJ - Wednesday, November
24, 2021: HUTCHMED (China) Limited ("HUTCHMED") (Nasdaq/ AIM: HCM;
HKEX: 13) and AstraZeneca PLC ("AstraZeneca") (LSE/ STO/ Nasdaq:
AZN) have initiated SACHI, a China Phase III study of ORPATHYS(R)
(savolitinib), an oral, potent, and highly selective MET tyrosine
kinase inhibitor ("TKI"), in combination with AstraZeneca's
third-generation, irreversible epidermal growth factor receptor
("EGFR") TKI, TAGRISSO(R) (osimertinib). The first patient received
their first dose on November 22, 2021.
The Phase III trial is a multi-center, open-label, randomized,
controlled study in patients with locally advanced or metastatic
EGFR mutation-positive non-small cell lung cancer ("NSCLC") with
MET amplification after disease progression on EGFR inhibitor
therapy. The study will evaluate the efficacy and safety of
ORPATHYS(R) in combination with TAGRISSO(R) , compared to
platinum-based doublet-chemotherapy (pemetrexed plus cisplatin or
carboplatin), the standard-of-care treatment option in this
setting. The primary endpoint of the study is median progression
free survival ("PFS") as assessed by investigators. Other endpoints
include median PFS assessed by an independent review committee,
median overall survival ("OS"), objective response rate ("ORR"),
duration of response ("DoR"), disease control rate ("DCR"), time to
response (TTR), and safety. Additional details may be found at
clinicaltrials.gov, using identifier NCT 05015608 .
About NSCLC, EGFR and MET Aberrations
Lung cancer is the leading cause of cancer death among men and
women, accounting for about one-fifth of all cancer deaths. [2]
More than a third of the world's lung cancer patients are in China.
[3] Lung cancer is broadly split into NSCLC and small cell lung
cancer, with 80-85% classified as NSCLC. [4] The majority of NSCLC
patients are diagnosed with advanced disease while approximately
25-30% present with resectable disease at diagnosis. [5](,) [6] For
patients with resectable tumors, the majority of patients
eventually develop recurrence despite complete tumor resection and
adjuvant chemotherapy. [7]
Approximately 10-25% of NSCLC patients in the US and Europe, and
30-40% of patients in Asia have EGFR-mutated NSCLC. [8](,) [9] ,
[10] These patients are particularly sensitive to treatment with an
EGFR TKI which blocks the cell-signaling pathways that drive the
growth of tumor cells. [11]
MET is a tyrosine kinase receptor. [12] Aberration of MET
(amplification or overexpression) is present in both treatment
naïve patients as well as being one of the primary mechanisms of
acquired resistance to EGFR TKIs for metastatic EGFR-mutated NSCLC.
[13](,) [14]
About Savolitinib (ORPATHYS(R) in China)
Savolitinib is an oral, potent, and highly selective MET TKI
that has demonstrated clinical activity in advanced solid tumors.
It blocks atypical activation of the MET receptor tyrosine kinase
pathway that occurs because of mutations (such as exon 14 skipping
alterations or other point mutations) or gene amplification.
Savolitinib is marketed in China under the brand name
ORPATHYS(R) for the treatment of patients with NSCLC with MET exon
14 skipping alterations who have progressed following prior
systemic therapy or are unable to receive chemotherapy. It is
currently under clinical development for multiple tumor types,
including lung, kidney, and gastric cancers, as a single treatment
and in combination with other medicines.
In 2011, following its discovery and initial development by
HUTCHMED, AstraZeneca and HUTCHMED entered a global licensing
agreement to jointly develop and commercialize savolitinib. Joint
development in China is led by HUTCHMED, while AstraZeneca leads
development outside of China. HUTCHMED is responsible for the
marketing authorization, manufacturing and supply of savolitinib in
China. AstraZeneca is responsible for the commercialization of
savolitinib in China and worldwide. Sales of savolitinib are
recognized by AstraZeneca.
Savolitinib development in NSCLC
Phase II study of savolitinib monotherapy in MET Exon 14
skipping alteration NSCLC ( NCT02897479) - In June 2021,
savolitinib was granted drug registration conditional approval by
the National Medical Products Administration of China (NMPA) for
MET Exon 14 skipping alteration NSCLC. The approval was based on
the results of a Phase II study in China; results of this study
were published in The Lancet Respiratory Medicine [15] . At a
median follow up of 17.6 months, savolitinib demonstrated an ORR of
42.9% (95% confidence interval [CI] 31.1-55.3) and median PFS of
6.8 months (95% CI 4.2-9.6) in the overall trial population. DCR in
the overall trial population was 82.9% (95% CI 72.0-90.8). The
safety and tolerability profile of savolitinib was consistent with
previous trials, and no new safety signals were identified.
Continued approval is contingent upon the successful completion of
a confirmatory trial in this patient population (NCT04923945).
TATTON Phase Ib/II expansion studies of savolitinib in
combination with TAGRISSO(R) in patients who have )progressed
following EGFR TKI treatment due to MET amplification (
NCT02143466) - This global exploratory study in over 220 EGFR
mutation positive NSCLC patients with MET amplified tumors
following progression after treatment with any EGFR TKI. Results
were published in Lancet Oncology ([16]) and final analysis was
presented at the World Conference on Lung Cancer(1) . Three cohorts
with patients treated following progression on first- or
second-generation EGFR TKI demonstrated an ORR of 64.7-66.7% and a
median PFS of 9.0-11.1 months. The cohort of patients treated
following progression on a third-generation EGFR TKI demonstrated
an ORR of 33.3% (95% CI 22.4-45.7), with a median PFS of 5.5 months
(95% CI 4.1-7.7). The combination demonstrated encouraging
anti-tumor activity and an acceptable risk-benefit profile.
SAVANNAH Phase II study of savolitinib in combination with
TAGRISSO(R) in patients who have progressed following TAGRISSO(R)
due to MET amplification or overexpression ( NCT03778229 ) - This
is a single-arm, open-label, global study in epidermal growth
factor receptor ("EGFR") mutation positive NSCLC patients with MET
amplified/overexpressed tumors following progression after
treatment with TAGRISSO(R) , an EGFR TKI owned by AstraZeneca.
SACHI Phase III study of savolitinib in combination with
TAGRISSO(R) in patients who have progressed following EGFR TKI
treatment due to MET amplification ( NCT05015608 ) - This is a
randomized, open-label study in China in EGFR mutation positive
NSCLC patients with MET amplified tumors following progression
after treatment with any EGFR TKI.
SANOVO Phase III study of savolitinib in combination with
TAGRISSO(R) in treatment-naïve patients with EGFR mutant positive
NSCLC with MET overexpression ( NCT05009836 ) - This is a
randomized, blinded study in China in untreated, unresectable or
metastatic patients with EGFR mutation positive NSCLC with MET
positive tumors.
Savolitinib development in kidney cancer
SAVOIR randomized, controlled study of savolitinib monotherapy
in MET-driven papillary renal cell carcinoma ("RCC") ( NCT03091192
) - In May 2020, data from 60 patients in this global study of
savolitinib monotherapy compared with sunitinib monotherapy in
MET-driven papillary RCC was presented at the ASCO 2020 Program and
published simultaneously in JAMA Oncology ([17]) . Savolitinib
demonstrated encouraging activity, including an ORR of 27% versus
7% for sunitinib, with no savolitinib responding patients
experiencing disease progression at data cut-off, and an
encouraging OS hazard ratio of 0.51 (95% CI: 0.21-1.17; p=0.110)
with median not reached at data cut-off.
CALYPSO Phase I/II study of savolitinib in combination with
IMFINZI(R) PD-L1 inhibitor in RCC ( NCT02819596 ) - The CALYPSO
study is an investigator initiated open-label Phase I/II study of
savolitinib in combination with IMFINZI(R) , a PD-L1 antibody owned
by AstraZeneca. The study is evaluating the safety and efficacy of
the savolitinib/IMFINZI(R) combination in patients with papillary
RCC and clear cell RCC. An analysis of 41 patients enrolled in the
papillary RCC cohort of in this study was presented at the 2021
ASCO Annual Meeting ([18]) , showing a confirmed response rate in 8
out of the 14 MET-driven patients, or 57%, with a median DoR of 9.4
months, median PFS of 10.5 months and median OS of 27.4 months. No
new safety signals were seen.
SAMETA Phase III study in combination with IMFINZI(R) PD-L1
inhibitor in MET-driven, unresectable and locally advanced or
metastatic papillary RCC ( NCT05043090 ) - Based on the encouraging
results of the SAVOIR and CALYPSO studies, we have initiated
SAMETA, a global Phase III, open-label, randomized, controlled
study of savolitinib plus IMFINZI(R) versus sunitinib monotherapy
versus IMFINZI(R) monotherapy in patients with MET-driven,
unresectable and locally advanced or metastatic papillary RCC.
Savolitinib development in gastric cancer
Phase II study of savolitinib monotherapy in advanced or
metastatic MET amplified gastric cancer ("GC") or adenocarcinoma of
the gastroesophageal junction ("GEJ") ( NCT04923932 ) - This is an
open-label, two-cohort, multi-center study to evaluate the
efficacy, safety and pharmacokinetics (PK) of savolitinib in
locally advanced or metastatic GC or GEJ patients whose disease
progressed after at least one line of standard therapy.
This trial follows multiple Phase II studies that have been
conducted in Asia to study savolitinib in MET-driven GC patients,
including VIKTORY. [19] VIKTORY is an investigator-initiated Phase
II umbrella study in GC in South Korea in which a total of 715
patients were successfully sequenced into molecular-driven patient
groups, including those with MET amplified GC. Patients whose
tumors harbor MET amplification were treated with savolitinib
monotherapy, reporting an ORR of 50% (10/20, 95% CI: 28.0,
71.9).
Savolitinib development in other cancer indications
Savolitinib opportunities are also continuing to be explored in
multiple other MET-driven tumor settings via investigator-initiated
studies including colorectal cancer.
About TAGRISSO(R)
TAGRISSO(R) (osimertinib) is a third-generation, irreversible
EGFR TKI with clinical activity against central nervous system
metastases. TAGRISSO(R) (40mg and 80mg once-daily oral tablets) has
been used to treat more than 485,000 patients across indications
worldwide and AstraZeneca continues to explore TAGRISSO(R) as a
treatment for patients across multiple stages of EGFR-mutated
NSCLC.
In Phase III trials, TAGRISSO(R) is being tested in the
neoadjuvant resectable setting (NeoADAURA), in the Stage III
locally advanced unresectable setting (LAURA) and, in combination
with chemotherapy, in the Stage III locally advanced or Stage IV
metastatic settings (FLAURA2). AstraZeneca is also researching ways
to address tumor mechanisms of resistance through the SACHI and
SANOVO Phase III trials, as well as the SAVANNAH and ORCHARD Phase
II trials, which test TAGRISSO(R) given concomitantly with
savolitinib, (ORPATHYS(R) in China), as well as other potential new
medicines.
About HUTCHMED
HUTCHMED (Nasdaq/AIM:HCM; HKEX:13) is an innovative,
commercial-stage, biopharmaceutical company. It is committed to the
discovery and global development and commercialization of targeted
therapies and immunotherapies for the treatment of cancer and
immunological diseases. It has more than 4,500 personnel across all
its companies, at the center of which is a team of over 1,400 in
oncology/immunology. Since inception it has advanced eleven cancer
drug candidates from in-house discovery into clinical studies
around the world, with its first three oncology drugs now approved
and marketed. For more information, please visit: www.hutch-med.com
or follow us on LinkedIn.
Forward-Looking Statements
This press release contains forward-looking statements within
the meaning of the "safe harbor" provisions of the U.S. Private
Securities Litigation Reform Act of 1995. These forward-looking
statements reflect HUTCHMED's current expectations regarding future
events, including its expectations regarding the therapeutic
potential of savolitinib for the treatment of patients with NSCLC,
the further clinical development of savolitinib in this and other
indications, its expectations as to whether clinical studies of
savolitinib would meet their primary or secondary endpoints, and
its expectations as to the timing of the completion and the release
of results from such studies. Forward-looking statements involve
risks and uncertainties. Such risks and uncertainties include,
among other things, assumptions regarding the sufficiency of its
data to support New Drug Application approval of savolitinib for
the treatment of patients with NSCLC in China, its potential to
gain expeditious approvals for savolitinib in other jurisdictions
such as E.U. or Japan, the safety profile of savolitinib the
potential for savolitinib to become a new standard of care for
NSCLC patients, its ability to implement and complete its further
clinical development plans for savolitinib its potential commercial
launch in the U.S., E.U., Japan, China and other jurisdictions, the
timing of these events, and the impact of the COVID-19 pandemic on
general economic, regulatory and political conditions. In addition,
as certain studies rely on the use of TAGRISSO(R) and IMFINZI(R) as
combination therapeutics with savolitinib, such risks and
uncertainties include assumptions regarding the safety, efficacy,
supply and continued regulatory approval of TAGRISSO(R) and
IMFINZI(R) . Existing and prospective investors are cautioned not
to place undue reliance on these forward-looking statements, which
speak only as of the date hereof. For further discussion of these
and other risks, see HUTCHMED's filings with the U.S. Securities
and Exchange Commission, on AIM and with The Stock Exchange of Hong
Kong Limited. HUTCHMED undertakes no obligation to update or revise
the information contained in this press release, whether as a
result of new information, future events or circumstances or
otherwise.
CONTACTS
Investor Enquiries
Mark Lee, Senior Vice President +852 2121 8200
Annie Cheng, Vice President +1 (973) 567 3786
Media Enquiries
Americas - Brad Miles, +1 (917) 570 7340 (Mobile)
Solebury Trout bmiles@troutgroup.com
Europe - Ben Atwell / Alex Shaw, +44 20 3727 1030 / +44 7771 913 902 (Mobile) / +44 7779 545 055 (Mobile)
FTI Consulting HUTCHMED@fticonsulting.com
Asia - Zhou Yi, +852 97 83 6894 (Mobile)
Brunswick HUTCHMED@brunswickgroup.com
Nominated Advisor
Atholl Tweedie / Freddy Crossley,
Panmure Gordon (UK) Limited +44 (20) 7886 2500
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EGFRm MET-amplified/overexpressed NSCLC: Phase Ib TATTON Parts B
and D final analysis. WCLC January 2021 #FP14.03. doi:
10.1016/j.jtho.2021.01.146.
[2] World Health Organization. International Agency for Research
on Cancer. Lung Fact Sheet. Available at gco.iarc.fr/ today/ data/
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2021.
[3] World Health Organization. International Agency for Research
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gco.iarc.fr/ today/ data/ factsheets/
populations/160-china-fact-sheets.pdf. Accessed June 2021.
[4] LUNGevity Foundation. Types of Lung Cancer. Available at lungevity.org/for-patients-caregivers/lung-cancer-101/types-of-lung-cancer. Accessed June 2021.
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[6] Le Chevalier T, et al. Adjuvant Chemotherapy for Resectable
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[8] Zhang YL, et al. The prevalence of EGFR mutation in patients
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[9] Keedy V.L., et al. American Society of Clinical Oncology
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[11] Cross DA, et al. AZD9291, an Irreversible EGFR TKI,
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[12] Organ SL, Tsao MS. An overview of the c-MET signaling
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[13] Ramalingham SS, et al. Mechanisms of acquired resistance to
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[14] Sterlacci W, et al. MET overexpression and gene
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[15] Lu S, et al. Once-daily savolitinib in Chinese patients
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[16] Sequist LV, et al. Osimertinib plus savolitinib in patients
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10.1158/2159-8290.CD-19-0442.
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