TIDMHCM
Hutchmed (China) Limited
26 August 2021
Press Release
HUTCHMED Initiates a Phase Ib/II Trial of Fruquintinib in
Combination with Tislelizumab in Advanced Triple Negative Breast
Cancer or Advanced Endometrial Cancer
Hong Kong, Shanghai & Florham Park, NJ - Thursday, August
26, 2021: HUTCHMED (China) Limited ("HUTCHMED") (Nasdaq/AIM: HCM;
HKEX:13) has initiated a Phase Ib/II study of fruquintinib in
combination with BeiGene's tislelizumab in patients with advanced
triple negative breast cancer ("TNBC") or advanced endometrial
cancer ("EC") in the U.S. The first patient was dosed on August 24,
2021. This trial is to explore the potential for the addition of a
highly selective vascular endothelial growth factor receptor
("VEGFR") inhibitor, fruquintinib, to anti-programmed death-1
("PD-1") antibody tislelizumab in inducing activity to immune
checkpoint inhibitors.
This is an open-label, multi-center, non-randomized study to
assess the safety and efficacy of fruquintinib in combination with
tislelizumab in patients with locally advanced or metastatic TNBC
or advanced EC. This study will be conducted in two parts; a safety
lead-in phase (Part 1) and a dose expansion phase (Part 2). The
safety lead-in phase will determine safety and tolerability and the
recommended Phase II dose ("RP2D") of the combination. In the dose
expansion phase, the RP2D will be administered to two cohorts of
patients: Cohort A - Patients with TNBC who have received prior
therapy with an immune checkpoint inhibitor; and Cohort B -
Patients with TNBC who have not received prior therapy with an
immune checkpoint inhibitor. A cohort evaluating the combination in
second line advanced EC is anticipated to open in 3Q2021.
Additional details may be found at clinicaltrials.gov, using
identifier NCT04577963.
About TNBC and EC
Breast cancer is a common type of cancer in the U.S., estimated
to be diagnosed in over 281,000 women during 2021.[1] TNBC is one
of several subtypes of breast cancer, accounting for approximately
10% of newly diagnosed breast cancer cases.[2] The number of women
living with TNBC in the U.S. was estimated to be over 150,000 in
2018.[3] PD-L1 expression is estimated to be present in
approximately 20% of TNBC.[4] TNBC is distinguished from the other
subtypes of breast cancer in that the cancer cells do not have
receptors for the hormones estrogen or progesterone (hormone
receptor negative) and do not make excessive amount of the protein
human epidermal growth factor receptor 2 (HER2). TNBC is more
aggressive and has a worse prognosis compared to other types of
breast cancer.
EC is the fourth most common type of cancer among women in the
U.S., estimated to be diagnosed in over 66,000 women during
2021.[5] The number of women living with EC in the U.S. was
estimated to be over 800,000 in 2018. Options are limited beyond
front line chemotherapy treatment for the 20-30% of women who are
diagnosed at an advanced stage of the disease, as well as those who
develop advanced disease that are not curable with surgery. Among
patients with EC, an estimated 14% of advanced stage tumors express
PD-L1, and approximately 20-30% of EC are microsatellite
instability-high (MSI-H).[6](,[7],[8],[9])
Immune checkpoint inhibitors ("ICIs") have improved clinical
outcomes in TNBC and EC, but a large proportion of patients do not
respond to ICIs and initial responders eventually develop
resistance. Combination therapy including VEGFR inhibition may
improve the clinical efficacy of ICIs by promoting inhibition of
angiogenesis in the tumor region, which can suppress tumor growth
and reduce metastasis.
About Fruquintinib
Fruquintinib is a highly selective and potent oral inhibitor of
VEGFR-1, -2 and -3. VEGFR inhibitors play a pivotal role in
blocking tumor angiogenesis. Fruquintinib was designed to improve
kinase selectivity to minimize off-target toxicities, improve
tolerability and provide more consistent target coverage. The
generally good tolerability in patients to date, along with
fruquintinib's low potential for drug-drug interaction based on
preclinical assessment, suggests that it may also be highly
suitable for combinations with other anti-cancer therapies.
HUTCHMED retains all rights to fruquintinib outside of China. In
China, HUTCHMED is partnered with Eli Lilly and Company and is
responsible for development and execution of all on-the-ground
medical detailing, promotion and local and regional marketing.
About Fruquintinib Development
Metastatic colorectal cancer in China: Fruquintinib was approved
for marketing by the China National Medical Products Administration
("NMPA") in September 2018 and commercially launched in China in
late November 2018 under the brand name Elunate(R) . It was
included in the China National Reimbursement Drug List (NRDL) in
January 2020. Elunate(R) is for the treatment of patients with
metastatic colorectal cancer ("CRC") who have been previously
treated with fluoropyrimidine, oxaliplatin and irinotecan,
including those who have previously received anti-VEGF therapy
and/or anti-EGFR therapy (RAS wild type). Results of the FRESCO
study, a Phase III pivotal registration trial of fruquintinib in
416 patients with metastatic CRC in China, were published in The
Journal of the American Medical Association, JAMA, in June 2018
(clinicaltrials.gov identifier: NCT02314819).
Metastatic CRC in the U.S., Europe, and Japan: The U.S. Food and
Drug Administration ("FDA") granted Fast Track Designation for the
development of fruquintinib for the treatment of patients with
metastatic CRC in June 2020. A Phase III registration study of
fruquintinib for the treatment of patients with metastatic CRC,
FRESCO-2, is currently underway in the U.S., Europe, Japan and
Australia. Additional details of the study may be found at
clinicaltrials.gov, using identifier NCT04322539. The U.S. FDA has
acknowledged that the totality of the fruquintinib clinical data,
including the FRESCO-2 study (if positive), the prior positive
Phase III FRESCO study demonstrating improvement in overall
survival that led to fruquintinib approval for metastatic CRC in
China in 2018, and additional completed and ongoing supporting
studies in metastatic CRC, could potentially support a New Drug
Application (NDA) for the treatment of patients with advanced
metastatic CRC (third-line and above). The FRESCO-2 study design
was also reviewed and endorsed by The European Medicines Agency
(EMA) and Japanese Pharmaceuticals and Medical Devices Agency
(PMDA).
Gastric Cancer in China : In October 2017, HUTCHMED initiated
the FRUTIGA study, a randomized, double-blind, Phase III trial
evaluating the efficacy and safety of fru quintinib combined with
paclitaxel for second-line treatment of advanced g astric or
esophagogastric junction ("GEJ") a denocarcinoma. The trial is
designed to enroll patients who did not respond to first-line
standard chemotherapy. Subjects receive either fruquintinib
combined with paclitaxel or placebo combined with paclitaxel.
Patients are randomized at a 1:1 ratio and stratified according to
factors such as stomach vs. GEJ tumor type and performance status.
The primary efficacy endpoint is overall survival. Secondary
efficacy endpoints include progression-free survival (as defined by
RECIST 1.1), objective response rate, disease control rate,
duration of response, and quality-of-life score (EORTC QLQ-C30,
version 3.0). Biomarkers related to the antitumor activity of
fruquintinib will also be explored (clinicaltrials.gov identifier:
NCT03223376). In June 2020, HUTCHMED completed a planned interim
data review. Based on the preset criteria, the Independent Data
Monitoring Committee (IDMC) recommended that the trial
continue.
Metastatic breast cancer: HUTCHMED initiated this open-label,
multi-center, non-randomized, Phase Ib/II study in the U.S. to
assess the safety and efficacy of fruquintinib in combination with
tislelizumab in patients with advanced, refractory TNBC. This study
is being conducted to investigate if the addition of fruquintinib
can potentially induce activity to ICIs therapy in TNBC. Additional
details of the study may be found at clinicaltrials.gov, using
identifier NCT04577963. Safety and preliminary efficacy of
fruquintinib were demonstrated in advanced solid tumors, including
TNBC, in a phase I study conducted in China (NCT01645215) and a
phase 1/1b study is ongoing in the United States (NCT03251378).
Other Immunotherapy combinations: HUTCHMED has entered into
other collaboration agreements to evaluate the safety, tolerability
and efficacy of fruquintinib in combination with PD-1 monoclonal
antibodies, including with Tyvyt (R) (sintilimab, IBI308, developed
by Innovent Biologics, Inc.).
About Tislelizumab
Tislelizumab (BGB-A317) is a humanized IgG4 anti-PD-1 monoclonal
antibody specifically designed to minimize binding to
Fc<GAMMA>R on macrophages. In pre-clinical studies, binding
to Fc<GAMMA>R on macrophages has been shown to compromise the
anti-tumor activity of PD-1 antibodies through activation of
antibody-dependent macrophage-mediated killing of T effector cells.
Tislelizumab is the first drug from BeiGene's immuno-oncology
biologics program and is being developed internationally as a
monotherapy and in combination with other therapies for the
treatment of a broad array of both solid tumor and hematologic
cancers.
The NMPA has granted tislelizumab approval in five indications,
including full approval for first-line treatment of patients with
advanced squamous non-small cell lung cancer ("NSCLC") in
combination with chemotherapy and for first-line treatment of
patients with advanced non-squamous NSCLC in combination with
chemotherapy; and conditional approval for the treatment of
patients with classical Hodgkin's lymphoma (cHL) who received at
least two prior therapies, for the treatment of patients with
locally advanced or metastatic urothelial carcinoma (UC) with PD-L1
high expression whose disease progressed during or following
platinum-containing chemotherapy or within 12 months of neoadjuvant
or adjuvant treatment with platinum-containing chemotherapy, and
for the treatment of patients with hepatocellular carcinoma (HCC)
who have received at least one systemic therapy. Full approval for
these indications is contingent upon results from ongoing
randomized, controlled confirmatory clinical trials.
In addition, four supplemental Biologics License Applications
for tislelizumab have been accepted by the Center for Drug
Evaluation (CDE) of the NMPA and are under review for second- or
third-line treatment of patients with locally advanced or
metastatic NSCLC who progressed on prior platinum-based
chemotherapy, for patients with previously treated, locally
advanced unresectable or metastatic microsatellite instability-high
(MSI-H) or mismatch repair-deficient (dMMR) solid tumors, for the
treatment of patients with locally advanced or metastatic
esophageal squamous cell carcinoma (ESCC) who have disease
progression following or are intolerant to first-line standard
chemotherapy, and for first-line treatment of patients with
recurrent or metastatic nasopharyngeal cancer (NPC).
BeiGene has initiated or completed 17 potentially
registration-enabling clinical trials in China and globally,
including 13 Phase III trials and four pivotal Phase II trials.
In January 2021, BeiGene and Novartis entered into a
collaboration and license agreement granting Novartis rights to
develop, manufacture, and commercialize tislelizumab in North
America, Europe, and Japan.
Tislelizumab is not approved for use outside of China.
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. A dedicated organization of over 1,400
personnel 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 and other federal
securities laws, including statements regarding the clinical
development of fruquintinib in combination with tislelizumab,
HUTCHMED's and BeiGene's roles and responsibilities in the
collaboration, the opportunity and potential benefits of their
product candidates both as monotherapies and in combination, and
other information that is not historical information. Actual
results may differ materially from those indicated in the
forward-looking statements as a result of various important
factors, including the ability of HUTCHMED and BeiGene to develop
and receive regulatory approvals for the combination therapies in
the collaboration; the risk that the potential benefits of the
collaboration do not materialize or do not outweigh the costs; the
ability of HUTCHMED and BeiGene to demonstrate the efficacy and
safety of their respective drug candidates as monotherapies or in
combination; the clinical results for such drug candidates, which
may not support further development or marketing approval; actions
of regulatory agencies, which may affect the initiation, timing and
progress of clinical trials and marketing approval; HUTCHMED's and
BeiGene's ability to achieve commercial success for their marketed
products and drug candidates, if approved; HUTCHMED's and BeiGene's
ability to obtain and maintain protection of intellectual property
for their respective technology and drugs; HUTCHMED's and BeiGene's
reliance on third parties to conduct drug development,
manufacturing and other services; HUTCHMED's and BeiGene's limited
experience in obtaining regulatory approvals and commercializing
pharmaceutical products and HUTCHMED's and BeiGene's ability to
obtain additional funding for operations and to complete the
development and commercialization of their drug candidates; and the
impact of the COVID-19 pandemic on general economic regulatory and
political conditions and on HUTCHMED's and BeiGene's clinical
development, regulatory, commercial and other operations. 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 or BeiGene's filings with the U.S. Securities and
Exchange Commission, The Stock Exchange of Hong Kong Limited and,
in the case of HUTCHMED, on AIM. All information in this press
release is as of the date of this press release, and neither
HUTCHMED nor BeiGene undertakes a duty to update such information
unless required by law.
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
FTI Consulting 545 055 (Mobile)
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
[1] SEER. Cancer Stat Facts: Female Breast Cancer. National
Cancer Institute.
https://seer.cancer.gov/statfacts/html/breast.html
[2] SEER. Cancer Stat Facts: Female Breast Cancer Subtypes.
National Cancer Institute.
https://seer.cancer.gov/statfacts/html/breast-subtypes.html
[3] SEER*Explorer. HR-/HER2- (Triple Negative) Breast Cancer
(Female only). National Cancer Institute.
https://seer.cancer.gov/explorer/application.html?site=623&data_type=5&graph_type=12&compareBy=prev_duration&chk_prev_duration_3=3&series=9&hdn_sex=3&race=1&age_range=1&advopt_limprev_y_axis_var=0
[4] Mittendorf, E., Philips, A., Funda, M., et al. PD-L1
Expression in Triple-Negative Breast Cancer. Cancer Immunol Res
April 1 2014 (2) (4) 361-370; DOI:
10.1158/2326-6066.CIR-13-0127.
[5] SEER. Cancer Stat Facts: Uterine Cancer. National Cancer
Institute. https://seer.cancer.gov/statfacts/html/common.html
[6] Pasanen A, Ahvenainen T, Pellinen T, Vahteristo P,
Loukovaara M, Bützow R. PD-L1 Expression in Endometrial Carcinoma
Cells and Intratumoral Immune Cells: Differences Across Histologic
and TCGA-based Molecular Subgroups. Am J Surg Pathol.
2020;44(2):174-181. doi:10.1097/PAS.0000000000001395.
[7] Bonneville R, Krook MA, Kautto EA, et al. Landscape of
Microsatellite Instability Across 39 Cancer Types. JCO Precis
Oncol. 2017;2017:PO.17.00073. doi:10.1200/PO.17.00073
[8] Cancer Genome Atlas Research Network, Kandoth C, Schultz N,
et al. Integrated genomic characterization of endometrial carcinoma
[published correction appears in Nature. 2013 Aug 8;500(7461):242].
Nature. 2013;497(7447):67-73. doi:10.1038/nature12113
[9] Setiawan VW, Yang HP, Pike MC, et al. Type I and II
endometrial cancers: have they different risk factors?. J Clin
Oncol. 2013;31(20):2607-2618. doi:10.1200/JCO.2012.48.2596
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