TIDMGSK
RNS Number : 4889W
GlaxoSmithKline PLC
23 April 2021
Issued: 23 April 2021, London UK
European Commission approves GSK's JEMPERLI (dostarlimab), the
first anti-PD-1 therapy approved for recurrent or advanced
endometrial cancer
GlaxoSmithKline (LSE/NYSE: GSK) plc today announced the European
Commission has granted conditional marketing authorisation for
JEMPERLI (dostarlimab), a programmed death receptor-1
(PD-1)-blocking antibody, for use in women with mismatch
repair-deficient (dMMR)/microsatellite instability-high (MSI-H)
recurrent or advanced endometrial cancer who have progressed on or
following prior treatment with a platinum containing regimen. The
approval makes dostarlimab the first anti-PD-1 therapy available
for endometrial cancer in Europe.
Dr Hal Barron, Chief Scientific Officer and President R&D,
GSK, said: "Women with recurrent endometrial cancer, or advanced
disease that has progressed on or after chemotherapy, currently
have limited treatment options and a poor prognosis. Today's
approval of dostarlimab means that for the first time in Europe,
these women will have access to a new, innovative and much-needed
therapy."
Dr Ana Oaknin, Head of the Gynaecologic Cancer Program at Vall
d'Hebron Institute of Oncology ( VHIO), Vall d'Hebron University
Hospital, Barcelona, Spain, and primary investigator for the GARNET
Trial, said: "As we saw in the pivotal GARNET trial that supported
this approval, treatment with dostarlimab has the potential to
provide clinically significant and durable responses in patients
who formerly had few treatment options. This approval represents a
step forward, providing a new treatment for women with recurrent or
advanced dMMR/MSI-H endometrial cancer who have previously failed a
platinum-based chemotherapy."
Icó Tóth, Co-Chair of European Network of Gynaecological Cancer
Advocacy Groups (ENGAGe), Council member for European Society of
Gynaecological Oncology (ESGO), President, Mallow Flower
Foundation, Hungary, said : "Today's approval of dostarlimab offers
a new treatment option for women with recurrent or advanced
dMMR/MSI-H endometrial cancer. We're inspired by the efforts of
companies like GSK who are continuing to innovate for patients in
dire need of new options."
Endometrial cancer is found in the inner lining of the uterus,
known as the endometrium. It is the most common type of cancer that
affects the female reproductive organs and is the sixth most
prevalent cancer in women worldwide. ([i]) Endometrial cancer has
the highest rate of the MSI-H phenotype of all tumours. ([ii])
The European Medicine Agency's approval of dostarlimab is based
on results from the multi-cohort GARNET study, which included women
with recurrent or advanced dMMR/MSI-H endometrial cancer who
progressed on or after a platinum-based chemotherapy regimen in
cohort A1 (n=108 evaluable for efficacy). Treatment with
dostarlimab resulted in an objective response rate (ORR) of 43.5%
(95% CI; 34-53.4) and a disease control rate of 55.6% (95% CI;
45.7-65.1). The median duration of response (DoR) had not been
reached (2.6 to 28.1+ months) in these patients, and the
probability of maintaining a response at six months and 12 months
was 97.9% (95% CI; 85.8, 99.7) and 90.9% (95% CI; 73.7, 97.1),
respectively.
In the 515 patients with advanced or recurrent solid tumours who
participated in the GARNET study, including 129 patients evaluable
for safety from cohort A1, the most common adverse reactions
(occurring in more than 10% of patients) were anaemia (25.6%),
nausea (25.0%), diarrhoea (22.5%), vomiting (18.4 %), arthralgia
(13.8 %), pruritus (11.5%), rash (11.1%), pyrexia (10.5%) and
hypothyroidism (10.1%). Dostarlimab was permanently discontinued
due to adverse reactions in 17 patients (3.3%); most were
immune-related events. Serious adverse reactions occurred in 8.7%
of patients; most were immune-related adverse reactions. The safety
profile for patients in cohort A1 was comparable with the overall
study population.
GSK is also studying dostarlimab for endometrial cancer in
earlier treatment lines and in combination with other therapeutic
agents for patients with advanced solid tumours or metastatic
cancer as we work to expand our oncology pipeline and reinforce our
portfolio of cancer treatments.
###
About GARNET
The ongoing phase 1 GARNET trial is evaluating dostarlimab as
monotherapy in patients with advanced solid tumours . Part 2B of
the study includes five expansion cohorts: dMMR/MSI-H endometrial
cancer (cohort A1), mismatch repair proficient/microsatellite
stable (MMRp/MSS) endometrial cancer (cohort A2), non-small cell
lung cancer (cohort E), dMMR/MSI-H non-endometrial or POLE-mut
solid tumour basket cohort (cohort F), and platinum-resistant
ovarian cancer without BRCA mutations (cohort G). GARNET is ongoing
and enrolling patients in certain cohorts.
About JEMPERLI (dostarlimab)
Dostarlimab is a programmed death receptor-1 (PD-1)-blocking
antibody that binds with high affinity to the PD-1 receptor and
blocks its interaction with the ligands PD-L1 and PD-L2.[iii] In
addition to GARNET, dostarlimab is being investigated in other
registrational-enabling studies, as monotherapy and as part of
combination regimens for women with recurrent or primary advanced
endometrial cancer stage III or IV non-mucinous epithelial ovarian
cancer for patients with advanced solid tumours or metastatic
cancer.
Dostarlimab was discovered by AnaptysBio and licensed to TESARO,
Inc., under a Collaboration and Exclusive License Agreement signed
in March 2014. The collaboration has resulted in three monospecific
antibody drugs that have progressed into the clinic. These are:
dostarlimab (GSK4057190), a PD-1 antagonist; cobolimab,
(GSK4069889), a TIM-3 antagonist; and GSK4074386, a LAG-3
antagonist. GSK is responsible for the ongoing research,
development, commercialisation, and manufacture of each of these
products under the Agreement.
Important Information for JEMPERLI in the EU
Indication
JEMPERLI is indicated as monotherapy for the treatment of adult
patients with mismatch repair deficient (dMMR)/microsatellite
instability--high (MSI--H) recurrent or advanced endometrial cancer
(EC) that has progressed on or following prior treatment with a
platinum--containing regimen.
Immune-Mediated Adverse Reactions
Immune--related adverse reactions, which may be severe or fatal,
can occur in patients treated with antibodies blocking the
programmed cell death protein--1 / programmed death--ligand 1
(PD--1/PD--L1) pathway, including JEMPERLI . While immune--related
adverse reactions usually occur during treatment with PD--1/PD--L1
blocking antibodies, symptoms can also manifest after
discontinuation of treatment. Immune--related adverse reactions may
occur in any organ or tissue and may affect more than one body
system simultaneously. Important immune--related adverse reactions
listed in this section are not inclusive of all possible severe and
fatal immune--related reactions.
Early identification and management of immune--related adverse
reactions are essential to ensure safe use of PD--1/PD--L1 blocking
antibodies. Patients should be monitored for symptoms and signs of
immune--related adverse reactions. Clinical chemistries, including
liver tests and thyroid function tests, should be evaluated at
baseline and periodically during treatment. For suspected
immune--related adverse reactions, adequate evaluation including
specialty consultation should be ensured.
Based on the severity of the adverse reaction, treatment with
JEMPERLI should be withheld or permanently discontinued and
corticosteroids (1 to 2 mg/kg/day prednisone or equivalent) or
other appropriate therapy administered. Upon improvement to Grade
<=1, corticosteroid taper should be initiated and continued for
1 month or longer. Based on limited data from clinical studies in
patients whose immune--related adverse reactions could not be
controlled with corticosteroid use, administration of other
systemic immunosuppressants can be considered. Hormone replacement
therapy for endocrinopathies should be instituted as warranted.
Treatment with JEMPERLI should be permanently discontinued for
any Grade 3 immune--related adverse reaction that recurs and for
any Grade 4 immune--related adverse reaction toxicity, except for
endocrinopathies that are controlled with replacement hormones and
unless otherwise specified in the Summary of Product
Characteristics (SmPC).
Immune-Related Pneumonitis
Pneumonitis has been reported in patients receiving JEMPERLI.
Patients should be monitored for signs and symptoms of pneumonitis.
Suspected pneumonitis should be confirmed with radiographic imaging
and other causes
excluded. Patients should be managed with JEMPERLI treatment modifications and corticosteroids.
Immune--related pneumonitis occurred in 7 (1.4%) of 515
patients, including Grade 2 (1.2%) and Grade 3 (0.2%) pneumonitis.
Pneumonitis led to discontinuation of JEMPERLI in 3 (0.6%)
patients. Systemic corticosteroids (prednisone >= 40 mg per day
or equivalent) were required in all 7 patients experiencing
pneumonitis. Pneumonitis resolved in 6 (85.7%) patients.
Immune-Related Colitis
JEMPERLI can cause immune--related colitis. Patients should be
monitored for signs and symptoms of colitis and managed with
treatment modifications, anti--diarrhoeal agents and
corticosteroids.
Colitis occurred in 8 (1.6%) patients, including Grade 2 (1.0%)
and Grade 3 (0.6%) colitis. Colitis did not lead to discontinuation
of JEMPERLI in any patients. Systemic corticosteroids (prednisone
>= 40 mg per day or equivalent) were required in 2 (28.6%)
patients. Colitis resolved in 6 (75.0%) patients experiencing
colitis.
Immune--Related Hepatitis
JEMPERLI can cause immune--related hepatitis. Patients should be
monitored for changes in liver function periodically as indicated,
based on clinical evaluation and managed with JEMPERLI treatment
modifications and corticosteroids.
Hepatitis occurred in 1 (0.2%) patient, which was Grade 3.
Systemic corticosteroids (prednisone >= 40 mg per day
or equivalent) were required. Hepatitis did not lead to discontinuation of JEMPERLI and resolved.
Immune-Mediated Endocrinopathies
Hypothyroidism occurred in 37 (7.2%) patients, all of which were
Grade 2. Hypothyroidism did not lead to discontinuation of JEMPERLI
and resolved in 13 (35.1%) patients.
Hyperthyroidism occurred in 10 (1.9%) patients, including Grade
2 (1.7%) and Grade 3 (0.2%). Hyperthyroidism did
not lead to discontinuation of JEMPERLI and resolved in 8 (80%) patients.
Thyroiditis occurred in 2 (0.4%) patients; both were Grade 2.
Neither event of thyroiditis resolved; there were
no discontinuations of JEMPERLI due to thyroiditis.
Adrenal insufficiency occurred in 7 (1.4%) patients, including
Grade 2 (0.8%), and Grade 3 (0.6%). Adrenal insufficiency resulted
in discontinuation of JEMPERLI in 1 (0.2%) patient and resolved in
2 (28.6%) patients.
Immune-Mediated Nephritis
Nephritis, including tubulointerstitial nephritis, occurred in 3
(0.6%) patients; all were Grade 2. Systemic corticosteroids
(prednisone >= 40 mg per day or equivalent) were required in 2
(66.7%) patients experiencing nephritis. Nephritis led to
discontinuation of JEMPERLI in 1 (0.2%) patient and resolved in 2
of 3 (66.7%) patients.
Immune--Related Rash
Immune-related rash occurred in 17 (3.3%) patients, including
Grade 3 in 6 (1.2%) patients receiving JEMPERLI. The median time to
onset of rash was 41 days (range 2 days to 407 days). Systemic
corticosteroids (prednisone >= 40 mg per day or equivalent) were
required in 5 (29%) patients experiencing rash. Rash did not lead
to
discontinuation of JEMPERLI and resolved in 13 (76.5%) patients.
Immune--Related Arthralgia
Immune--related arthralgia occurred in 21 (4.1%) patients. Grade
3 immune--related arthralgia was reported in 3 (0.6%) patients
receiving JEMPERLI. The median time to onset of arthralgia was 87
days (range 1 day to 783 days). Systemic corticosteroids
(prednisone >= 40 mg per day or equivalent) were required in 2
(9.5%) patients experiencing arthralgia. Arthralgia did not lead to
discontinuation of JEMPERLI and resolved in 8 (38%) patients
experiencing arthralgia.
Other Immune--Related Adverse Reactions
Given the mechanism of action of JEMPERLI other potential
immune--related adverse reactions may occur, including potentially
serious events [e.g. myositis, myocarditis, encephalitis,
demyelinating neuropathy (including Guillain Barré syndrome),
sarcoidosis].
Clinically significant immune--related adverse reactions
reported in less than 1% of patients treated with JEMPERLI as
monotherapy in clinical studies include autoimmune haemolytic
anaemia, pancreatitis, iridocyclitis, uveitis and diabetic
ketoacidosis. Patients should be monitored for signs and symptoms
of immune--related adverse reactions and managed as described in
the SmPC.
Solid organ transplant rejection has been reported in the
post-marketing setting in patients treated with PD-1 inhibitors.
Treatment with JEMPERLI may increase the risk of rejection in solid
organ transplant recipients. The benefit of treatment with JEMPERLI
versus the risk of possible organ rejection should be considered in
these patients.
Fatal and other serious complications can occur in patients who
receive allogeneic haematopoietic stem cell transplantation (HSCT)
before or after being treated with a PD--1/PD-L1-blocking antibody.
Transplant-related complications include hyperacute
graft-versus-host disease (GvHD), acute GvHD, chronic GvHD, hepatic
veno-occlusive disease after reduced intensity conditioning, and
steroid-requiring febrile syndrome (without an identified
infectious cause). These complications may occur despite
intervening therapy between PD-1/PD-L1 blockade and allogeneic
HSCT. Follow patients closely for evidence of transplant-related
complications and intervene promptly. Consider the benefit versus
risks of treatment with a PD-1/PD-L1-blocking antibody prior to or
after an allogeneic HSCT.
Infusion--Related Reactions
Infusion--related reactions including hypersensitivity occurred
in 7 (1.4%) patients, including Grade 2 (1.2%) and Grade 3 (0.2%)
infusion--related reactions. All patients recovered from the
infusion--related reaction.
Immunogenicity
Anti--drug antibodies (ADA) were tested in 315 patients who
received JEMPERLI and the incidence of JEMPERLI treatment--emergent
ADAs was 2.5%. Neutralising antibodies were detected in 1.3% of
patients. In the patients who developed anti--JEMPERLI antibodies,
there was no evidence of altered efficacy or safety of
JEMPERLI.
Elderly population
Of the 515 patients treated with JEMPERLI monotherapy, 50.7 %
were under 65 years, 37.9 % were 65--75 years, and 11.5 % were 75
years or older. No overall differences in safety were reported
between elderly (>= 65 years) and younger patients (< 65
years).
P regnancy, Lactation and Fertility
JEMPERLI is not recommended during pregnancy and in women of
childbearing potential not using contraception. JEMPERLI should not
be used during breast--feeding and breast--feeding should be
avoided for at least 4 months after the last dose of JEMPERLI.
Fertility studies have not been conducted with JEMPERLI.
COMMON ADVERSE REACTIONS
JEMPERLI is most commonly associated with immune-related adverse
reactions. Most of these, including severe reactions, resolved
following initiation of appropriate medical therapy or withdrawal
of JEMPERLI .
In patients with advanced or recurrent solid tumours (N = 515),
the most common adverse reactions (> 10%) were anaemia (25.6%),
nausea (25.0%), diarrhoea (22.5%), vomiting (18.4%), arthralgia
(13.8 %), pruritus (11.5%), rash (11.1%), pyrexia (10.5%) and
hypothyroidism (10.1%). JEMPERLI was permanently discontinued due
to adverse reactions in 17 (3.3%) patients; most of them were
immune--related events. Adverse reactions were serious in 8.7% of
patients; most serious adverse reactions were immune-related
adverse reactions.
Refer to the JEMPERLI Prescribing Information for a full list of
adverse events and the complete important safety information .
GSK in Oncology
GSK is focused on maximising patient survival through
transformational medicines. GSK's pipeline is focused on
immuno-oncology, cell therapy, cancer epigenetics and synthetic
lethality. Our goal is to achieve a sustainable flow of new
treatments based on a diversified portfolio of investigational
medicines utilising modalities such as small molecules, antibodies,
antibody drug conjugates and cells, either alone or in
combination.
About GSK
GSK is a science-led global healthcare company with a special
purpose: to help people do more, feel better, live longer. For
further information please visit www.gsk.com/about-us .
GSK enquiries:
Media enquiries: Simon Steel +44 (0) 20 8047 (London)
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GSK cautions investors that any forward-looking statements or
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are subject to risks and uncertainties that may cause actual
results to differ materially from those projected. Such factors
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Annual Report on Form 20-F for 2020 and any impacts of the COVID-19
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[i] Endometrial cancer statistics. World Cancer Research Fund.
https://www.wcrf.org/dietandcancer/cancer-trends/worldwide-cancer-data
. Published 2018. Accessed January 2021.
[ii] Bonneville R, Krook MA, Kautto EA, et al. Landscape of
Microsatellite Instability Across 39 Cancer Types. JCO Precis
Oncol. 2017;1-15.
[iii] Laken H, Kehry M, Mcneeley P, et al. Identification and
characterization of TSR-042, a novel anti-human PD-1 therapeutic
antibody. European Journal of Cancer. 2016;69,S102.
doi:10.1016/s0959-8049(16)32902-1.
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