UNITED STATES
SECURITIES AND EXCHANGE COMMISSION
Washington, D.C. 20549
Form 6-K
REPORT OF FOREIGN PRIVATE ISSUER PURSUANT TO RULE 13a-16 OR
15d-16
UNDER THE SECURITIES EXCHANGE ACT OF 1934
For the
month of April 2021
Commission
File Number 001-15170
GlaxoSmithKline plc
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Issued: 22 April 2021, London UK - LSE announcement
FDA grants accelerated approval for GSK's JEMPERLI
(dostarlimab-gxly) for women with recurrent or advanced dMMR
endometrial cancer
●
GARNET study
represents the largest dataset of anti-PD-1 monotherapy treatment
of women with endometrial cancer
●
Study results showed
an overall response rate of 42%
●
93% of responders had
a duration of response of ≥6 months
GlaxoSmithKline plc (LSE/NYSE: GSK) today announced that the US
Food and Drug Administration (FDA) has approved JEMPERLI
(dostarlimab-gxly), a programmed death receptor-1 (PD-1) blocking
antibody, based on the company's Biologics License Application.
Dostarlimab is indicated for the treatment of adult patients with
mismatch repair-deficient (dMMR) recurrent or advanced endometrial
cancer, as determined by an FDA-approved test, that have progressed
on or following prior treatment with a platinum-containing regimen.
This indication is approved under accelerated approval based on
tumour response rate and durability of response. Continued approval
for this indication may be contingent upon verification and
description of clinical benefit in a confirmatory
trial(s).
Dr Hal Barron, Chief Scientific Officer and President R&D, GSK,
said: "Unfortunately, as
many as 60,000 women are diagnosed with endometrial cancer in the
US each year and these women currently have limited treatment
options if their disease progresses on or after first-line
therapy. Today's approval of dostarlimab by the FDA has
the potential to transform the treatment landscape for these women
and demonstrates our continued commitment to helping patients with
gynaecologic cancers."
Around 1 in 4 women with endometrial cancer may experience a
recurrence or be diagnosed with advanced
disease.[i],[ii] For
women whose disease recurs after platinum-based chemotherapy, there
is generally no accepted standard of care.[iii],[iv],[v] Additionally,
endometrial cancer has the highest rate of dMMR among tumour
types[vi],[vii] at
approximately 25%,vii and
increased rates of recurrence have been reported for women with
dMMR endometrial cancer.[viii]
Dr Jubilee Brown, Professor and Division Director
of Gynaecologic Oncology at Levine Cancer Institute, Atrium
Health, and investigator on the GARNET study,
noted: "The approval of
dostarlimab has the potential to change the way we've been treating
dMMR advanced or recurrent endometrial cancer after standard
platinum-based chemotherapy, especially given the overall response
rate and durability of response that we saw in the GARNET
trial."
The approval is based on results from the dMMR endometrial cancer
cohort of the ongoing GARNET trial, a large, multicentre,
non-randomised, multiple parallel-cohort, open-label study,
representing the largest dataset to date evaluating an anti-PD-1
antibody as monotherapy treatment in women with endometrial
cancer.v The
approval was granted under
the FDA's Real-Time Oncology Review pilot programme, and
dostarlimab was initially granted breakthrough therapy designation
in May of 2019 for recurrent or advanced dMMR endometrial
cancer.
The primary endpoints in the GARNET trial were overall response
rate (ORR) and duration of response (DOR) as assessed by blinded
independent central review (BICR). Results showed an ORR of 42.3%
(95% CI; 30.6-54.6) with a complete response (CR) rate of 12.7% and
partial response rate (PR) of 29.6% among the 71 evaluable patients
with dMMR advanced or recurrent endometrial cancer who had
progressed on or after treatment with a platinum-containing
regimen. Of those that responded, 93.3% demonstrated a DOR of 6
months or more. After a median follow-up of 14.1 months, the median
duration of response was not reached (2.6-22.4+).
Patients received 500 mg of dostarlimab as an intravenous infusion
once every three weeks for four doses, followed by 1,000 mg once
every six weeks until disease progression or unacceptable toxicity.
Among the 104 patients evaluable for safety, the most commonly
reported adverse reactions (occurring in 20% or more of patients)
were fatigue/asthenia (48%), nausea (30%), diarrhoea (26%), anaemia
(24%) and constipation (20%). The most common Grade 3 or 4 adverse
reactions (≥2%) were anaemia and transaminases
increase. Dostarlimab
was permanently discontinued due to adverse reactions in 5 (4.8%)
patients. No deaths attributed to dostarlimab were reported in the
study.
Dr Sue Friedman, Executive Director of Facing Our Risk of Cancer
Empowered (FORCE), commented: "We applaud GSK and their ongoing efforts to
support women with endometrial cancer, the most common gynaecologic
malignancy in the US and the sixth most common cancer in women
worldwide. For many women whose disease is dMMR and has progressed
after platinum-based chemotherapy, the approval
of dostarlimab brings a new treatment option to an
underserved patient 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 Endometrial Cancer
Endometrial cancer is a main type of uterine cancer that forms in
the inner lining of the uterus, known as the
endometrium.[ix] Endometrial
cancer can be classified as mismatch
repair-deficient/microsatellite instability-high (dMMR/MSI-H) or
mismatch repair-proficient/microsatellite stable. There are limited
treatment options for women whose disease progresses on or after
first-line therapy.ix Nearly
60,000 new cases of endometrial cancer are expected in the US in
2021, making endometrial cancer the most common gynaecologic
malignancy in the US.[x],[xi] Approximately
25% of women with endometrial cancer will be diagnosed with
advanced disease or will experience a
recurrence.i,ii
About GARNET
The ongoing phase I 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 still
enrolling patients.
About JEMPERLI (dostarlimab-gxly)
Dostarlimab is a programmed death receptor-1 (PD-1)-blocking
antibody that binds to the PD-1 receptor and blocks its interaction
with the PD-1 ligands PD-L1 and PD-L2.xiii 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 therapies 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, commercialization, and manufacture of each of these
Products under the Agreement.
Important Safety Information for JEMPERLI
Indication
●
JEMPERLI is indicated
for the treatment of adult patients with mismatch repair deficient
(dMMR) recurrent or advanced endometrial cancer (EC), as determined
by an FDA-approved test, that has progressed on or following prior
treatment
with a platinum-containing
regimen.
●
This indication is
approved under accelerated approval based on tumour response rate
and durability of response. Continued approval for this indication
may be contingent upon verification and description of clinical
benefit in a confirmatory
trial(s).
Important Safety Information
Immune-Mediated Adverse Reactions
●
Immune-mediated adverse
reactions, which can be severe or fatal, can occur in any organ
system or tissue and can occur at any time during or after
treatment with a PD-1/PD-L1-blocking antibody, including
JEMPERLI.
●
Monitor closely for
signs and symptoms of immune-mediated adverse reactions. Evaluate
liver enzymes, creatinine, and thyroid function tests at baseline
and periodically during treatment. For suspected immune-mediated
adverse reactions,
initiate appropriate workup to exclude alternative
etiologies, including infection. Institute medical management
promptly, including specialty consultation as
appropriate.
●
Based on the severity of
the adverse reaction, withhold or permanently discontinue JEMPERLI.
In general, if JEMPERLI requires interruption or discontinuation,
administer systemic corticosteroids (1 to 2 mg/kg/day prednisone or
equivalent)
until improvement to ≤Grade 1. Upon
improvement to ≤Grade 1, initiate corticosteroid taper and
continue to taper over at least 1 month. Consider administration of
other systemic immunosuppressants in patients whose
immune-mediated
adverse reaction is not controlled with
corticosteroids.
Immune-Mediated Pneumonitis
●
JEMPERLI can cause
immune-mediated pneumonitis, which can be fatal. The incidence of
pneumonitis in patients receiving PD-1/PD-L1 inhibitors, including
JEMPERLI, may be increased in patients who have received prior
thoracic
radiation.
●
Immune-mediated
pneumonitis occurred in 1.1% (5/444) of patients, including Grade 2
(0.9%) and Grade 3 (0.2%) pneumonitis. Pneumonitis led to
discontinuation of JEMPERLI in 0.7% of patients. Systemic
corticosteroids were required in
all patients with pneumonitis. Pneumonitis
resolved in 80% of the 5 patients. Three patients reinitiated
JEMPERLI after symptom improvement; of these, 33% had recurrence of
pneumonitis.
Immune-Mediated Colitis
●
JEMPERLI can cause
immune-mediated colitis. Cytomegalovirus infection/reactivation
have occurred in patients with corticosteroid-refractory
immune-mediated colitis treated with PD-1/PD-L1-blocking
antibodies. In cases of corticosteroid-
refractory colitis, consider repeating infectious
workup to exclude alternative
etiologies.
●
Immune-mediated colitis
occurred in 1.4% (6/444) of patients, including Grade 3 (0.7%) and
Grade 2 (0.7%). Colitis did not lead to discontinuation of JEMPERLI
in any patients. Systemic corticosteroids were required in 17%
(1/6) of patients
with colitis. Colitis resolved in 50% of the 6
patients. Of the 2 patients in whom JEMPERLI was withheld for
colitis, both reinitiated JEMPERLI.
Immune-Mediated Hepatitis
●
JEMPERLI can cause
immune-mediated hepatitis, which can be fatal. Immune-mediated
Grade 3 hepatitis occurred in 0.2% (1/444) of patients. Systemic
corticosteroids were required, and the event
resolved.
Immune-Mediated Endocrinopathies
●
Adrenal
Insufficiency
o JEMPERLI
can cause primary or secondary adrenal insufficiency. For Grade 2
or higher adrenal insufficiency, initiate symptomatic treatment per
institutional guidelines, including hormone replacement as
clinically indicated. Withhold
JEMPERLI if not clinically stable. Adrenal
insufficiency occurred in 0.9% (4/444) of patients, including Grade
3 (0.5%) and Grade 2 (0.5%). Adrenal insufficiency resulted in
discontinuation in 1 (0.2%) patient and resolved in 25% of
the
4 patients.
●
Hypophysitis
o JEMPERLI
can cause immune-mediated hypophysitis. Hypophysitis can present
with acute symptoms associated with mass effect such as headache,
photophobia, or visual field cuts. Hypophysitis can cause
hypopituitarism. Initiate
hormone replacement as clinically indicated. Withhold
JEMPERLI if not clinically
stable.
●
Thyroid
Disorders
o JEMPERLI
can cause immune-mediated thyroid disorders. Thyroiditis can
present with or without endocrinopathy. Hypothyroidism can follow
hyperthyroidism. Initiate hormone replacement or medical management
of hyperthyroidism as
clinically indicated. Withhold JEMPERLI if not
clinically stable.
o Thyroiditis
occurred in 0.5% (2/444) of patients; both were Grade 2. Neither
event of thyroiditis resolved; there were no discontinuations of
JEMPERLI due to thyroiditis.
o Hypothyroidism
occurred in 5.6% (25/444) of patients, all of which were Grade 2.
Hypothyroidism did not lead to discontinuation of JEMPERLI and
resolved in 40% of the 25 patients. Systemic corticosteroids were
not required for any
of
the 25 patients with
hypothyroidism.
o Hyperthyroidism
occurred in 1.8% (8/444) of patients, including Grade 2 (1.6%) and
Grade 3 (0.2%). Hyperthyroidism did not lead to discontinuation of
JEMPERLI and resolved in 63% of the 8 patients. Systemic
corticosteroids were not
required for any of the 8 patients with
hyperthyroidism.
●
Type 1 Diabetes
Mellitus, Which Can Present with Diabetic
Ketoacidosis
o JEMPERLI
can cause type 1 diabetes mellitus, which can present with diabetic
ketoacidosis. Monitor patients for hyperglycemia or other signs and
symptoms of diabetes. Initiate treatment with insulin as clinically
indicated. Withhold or
permanently discontinue JEMPERLI depending on
severity.
Immune-Mediated Nephritis with Renal Dysfunction
●
JEMPERLI can cause
immune-mediated nephritis, which can be fatal. Nephritis occurred
in 0.5% (2/444) of patients; both were Grade 2. Nephritis did
not lead to discontinuation of JEMPERLI and resolved in both
patients. Systemic
corticosteroids were required in 1 of the 2
patients experiencing nephritis.
Immune-Mediated Dermatologic Adverse Reactions
●
JEMPERLI can cause
immune-mediated rash or dermatitis. Bullous and exfoliative
dermatitis, including Stevens-Johnson syndrome (SJS), toxic
epidermal necrolysis (TEN), and drug rash with eosinophilia and
systemic symptoms (DRESS), have occurred with PD-1/PD-L1-blocking
antibodies. Topical emollients and/or topical corticosteroids may
be adequate to treat mild to moderate non-bullous/exfoliative
rashes. Withhold or permanently discontinue JEMPERLI depending on
severity.
Other Immune-Mediated Adverse Reactions
●
The following clinically
significant immune-mediated adverse reactions occurred in <1% of
the 444 patients treated with JEMPERLI or were reported with the
use of other PD-1/PD-L1-blocking antibodies. Severe or fatal cases
have been reported for some of these adverse
reactions.
o Nervous
System: Meningitis,
encephalitis, myelitis and demyelination, myasthenic
syndrome/myasthenia gravis, Guillain-Barre syndrome, nerve paresis,
autoimmune neuropathy
o Cardiac/Vascular: Myocarditis,
pericarditis, vasculitis
o Ocular: Uveitis,
iritis, other ocular inflammatory toxicities. Some cases can be
associated with retinal detachment. Various grades of visual
impairment to include blindness can occur.
o Gastrointestinal: Pancreatitis,
including increases in serum amylase and lipase levels, gastritis,
duodenitis
o Musculoskeletal
and Connective Tissue: Myositis/polymyositis, rhabdomyolysis and
associated sequelae including renal failure, arthritis, polymyalgia
rheumatica
o Endocrine: Hypoparathyroidism
o Other
(Hematologic/Immune): Haemolytic anaemia, aplastic anaemia,
hemophagocytic lymphohistiocytosis, systemic inflammatory response
syndrome, histiocytic necrotizing lymphadenitis (Kikuchi
lymphadenitis), sarcoidosis, immune
thrombocytopenia, solid organ transplant
rejection
Infusion-Related Reactions
●
Severe or
life-threatening infusion-related reactions have been reported with
PD-1/PD-L1-blocking antibodies. Severe infusion-related reactions
(Grade 3) occurred in 0.2% (1/444) of patients receiving JEMPERLI.
All patients recovered from the infusion-related
reactions.
●
Monitor patients for
signs and symptoms of infusion-related reactions. Interrupt or slow
the rate of infusion or permanently discontinue JEMPERLI based on
severity of reaction.
Complications of Allogeneic HSCT after PD-1/PD-L1-Blocking
Antibody:
●
Fatal and other serious
complications can occur in patients who receive allogeneic
hematopoietic stem cell transplantation (HSCT) before or after
treatment with a PD-1/PD-L1-blocking antibody. 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.
Embryo-Fetal Toxicity and Lactation:
●
Based on its mechanism
of action, JEMPERLI can cause fetal harm. Advise pregnant women of
the potential risk to a fetus. Advise females of reproductive
potential to use effective contraception during treatment with
JEMPERLI and for 4 months after their last dose. Because of the
potential for serious adverse reactions from JEMPERLI in a
breastfed child, advise women not to breastfeed during treatment
with JEMPERLI and for 4 months after their last
dose.
Common Adverse Reactions
●
The most common adverse
reactions (Grades 1-4) in ≥10% of 104 dMMR endometrial cancer
patients who received JEMPERLI as monotherapy were fatigue (48%),
nausea (30%), diarrhoea (26%), anaemia (24%), constipation (20%),
vomiting (18%), pruritus (14%), cough (14%), decreased appetite
(14%), urinary tract infection (13%), and myalgia
(12%).
●
JEMPERLI was permanently
discontinued due to adverse reactions in 5 (4.8%) patients,
including transaminases increased, sepsis, bronchitis, and
pneumonitis. Dosage interruptions due to an adverse reaction
occurred in 23% of patients who received JEMPERLI. Adverse
reactions that required dosage interruption in ≥1% of
patients who received JEMPERLI were anaemia, diarrhoea, increased
lipase, and pyrexia.
Please see
full Prescribing
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.us.gsk.com/about-us.
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[i] CancerMPact® Patient
Metric, Kantar. Available from www.cancermpact.com. Accessed 18
March 2020.
[ii] NCCN
Clinical Practice Guidelines in Oncology (NCCN
Guidelines®)
for Uterine Neoplasms V1.2020. © National Comprehensive Cancer
Network, Inc. 2020. All rights reserved. Accessed 17 April 2020.
SGO Clinical Practice Endometrial Cancer Working
Group.
[iii] Burke WM, Orr J, Leitao M,
et al. Endometrial Cancer: a review and current management
strategies: part II. Gynecol
Oncol. 2014;134(2):393-402.
[iv] Brooks RA, Flemming GF,
Lastra RR, et al. Current recommendations and recent progress in
endometrial cancer. CA Cancer J
Clin.
2019;69(4):258-279.
[v] Oaknin A, Tinker AV,
Gilbert L, et al. Clinical activity and safety of the
anti-programmed death 1 monoclonal antibody dostarlimab for
patients with recurrent or advanced mismatch repair-deficient
endometrial cancer: a nonrandomized phase 1 clinical
trial. JAMA
Oncol.
2020;6(11):1766-1772.
[vi] Le
DT, Durham JN Smith KN, et al. Mismatch repair deficiency
predicts response of solid tumors to PD-1
blockade. Science. 2017;357(6349):409-413.
[vii] Lorenzi M, Amonkar M, Zhang
J, et al. Epidemiology of microsatellite instability high
(MSI-H) and deficient mismatch repair (dMMR) in solid tumor: a
structured literature review. Journal of
Oncology.
2020; Article ID 18079.
[viii] Backes
FJ, Haag J, Cosgrove CS, et al. Mismatch repair deficiency
identifies patients with high-intermediate risk (HIR) endometrioid
endometrial cancer at the highest risk of recurrence: a prognostic
biomarker. Cancer.
2019;125(3):398-405.
[ix] Endometrial Cancer
Treatment (PDQ®)
- Health Professional Version. National Cancer
Institute. https://www.cancer.gov/types/uterine/hp/endometrial-treatment-pdq.
Accessed May 2020.
[x] Cancer Facts & Figures
2021. American Cancer Society. Accessed 30 March
2021. https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/annual-cancer-facts-and-figures/2021/cancer-facts-and-figures-2021.pdf.
[xi] Fung-Kee-Fung M, Dodge J,
Elit L, et al. Follow-up after primary therapy for endometrial
cancer: a systematic review. Gynecol
Oncol.
2006;101(3):520-529.
SIGNATURES
Pursuant
to the requirements of the Securities Exchange Act of 1934, the
registrant has duly caused this report to be signed on its behalf
by the undersigned, thereunto duly authorised.
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GlaxoSmithKline plc
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(Registrant)
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Date: April
23, 2021
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By:/s/ VICTORIA
WHYTE
--------------------------
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Victoria Whyte
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Authorised
Signatory for and on
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behalf
of GlaxoSmithKline plc
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