- Conversion from accelerated to regular (full) approval based on
long-term outcomes from the GARNET phase I trial, which
demonstrated an overall response rate of 45.4%
- 85.9% of patients had duration of response ≥12 months and 54.7%
of patients had duration of response ≥24 months
LONDON, Feb. 10,
2023 /PRNewswire/ -- GSK plc (LSE/NYSE: GSK) today
reports that the US Food and Drug Administration (FDA) granted full
approval for Jemperli (dostarlimab-gxly) for the treatment
of adult patients with mismatch repair-deficient (dMMR) recurrent
or advanced endometrial cancer, as determined by a US FDA-approved
test, that has progressed on or following a prior
platinum-containing regimen in any setting and are not candidates
for curative surgery or radiation.
Hesham Abdullah, Senior Vice
President, Global Head of Oncology Development, GSK,
said: "This US regulatory action confirms our confidence
in Jemperli as an important treatment option for patients
with dMMR recurrent or advanced endometrial cancer. We continue to
unlock the potential of Jemperli as the backbone for our
immuno-oncology development programs to address the unmet needs of
patients, including earlier lines of endometrial cancer and
other solid tumors."
In April 2021, Jemperli
received accelerated approval for the treatment of adult patients
with dMMR recurrent or advanced endometrial cancer that had
progressed on or following prior treatment with a
platinum-containing regimen.
This approval is based on additional data collected from the A1
expansion cohort of the ongoing GARNET trial, a phase I,
multicenter, open-label, single-arm study of Jemperli
monotherapy in patients with advanced or recurrent solid tumors.
Cohort A1 evaluated the efficacy of Jemperli in 141 patients
with dMMR advanced or recurrent endometrial cancer that has
progressed on or following prior treatment with a
platinum-containing regimen. The major efficacy outcome measures
were overall response rate (ORR) and duration of response (DOR) as
assessed by a blinded independent central review according to
RECIST v1.1. Confirmed ORR was 45.4% (95% CI: 37.0, 54.0), with a
15.6% complete response rate and a 29.8% partial response rate.
Median DOR was not reached (range: 1.2+, 52.8+
months), measured from the time of first response, with 85.9%
of patients having duration ≥12 months and 54.7% of patients having
duration ≥24 months. Median follow-up for duration of response
was 27.9 months.
Treatment-related adverse events were consistent with previous
analyses for cohort A1. The most common adverse reactions (≥20%)
were fatigue/asthenia, anemia, rash, nausea, diarrhea,
constipation, and vomiting. The most common Grade 3 or 4 adverse
reactions (≥2%) were anemia, increased transaminases, urinary tract
infection, fatigue/asthenia, and diarrhea.
About endometrial cancer
Endometrial cancer is found
in the inner lining of the uterus, known as the endometrium.
Endometrial cancer is the most common gynecologic cancer globally,
with approximately 417,000 new cases reported each year
worldwide[1], and incidence rates are expected to rise
by almost 40% by 2040.[2][3] Approximately 15-20%
of patients with endometrial cancer will be diagnosed with advanced
disease at the time of diagnosis.[4]
About GARNET
The ongoing GARNET phase I trial is
evaluating Jemperli as monotherapy in patients with advanced
solid tumors. 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
tumor basket cohort (cohort F), and platinum-resistant ovarian
cancer without BRCA mutations (cohort G). GARNET continues
to enroll patients.
In cohort A1, patients received 500mg of Jemperli as an
intravenous infusion once every three weeks (Q3W) for four doses,
followed by 1,000mg once every six weeks until disease progression,
discontinuation or withdrawal.
About Jemperli
(dostarlimab-gxly)
Jemperli 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.[5] GSK's ambition is for
Jemperli to become the backbone of the Company's
ongoing immuno-oncology-based research and development program when
used alone and in combination with standard of care and future
novel cancer therapies, particularly for patients who currently
have limited treatment options. Jemperli is being
investigated in registrational enabling studies as monotherapy and
as part of combination regimens, including in patients with
recurrent or primary advanced endometrial cancer, patients with
Stage III or IV non-mucinous epithelial ovarian cancer, and
patients with other advanced solid tumors or metastatic
cancers.
Jemperli was discovered by AnaptysBio, Inc. 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:
Jemperli (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 manufacturing of each of these
medicines under the agreement.
Indications and Important Safety Information for JEMPERLI
(dostarlimab-gxly)
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 in any setting and are not candidates
for curative surgery or radiation, or
- solid tumors, as determined by an FDA-approved test, that have
progressed on or following prior treatment and who have no
satisfactory alternative treatment options. This indication is
approved under accelerated approval based on tumor 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
Severe and Fatal 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. In patients treated with other PD-1/PD-L1–blocking
antibodies, the incidence of pneumonitis is higher in patients who
have received prior thoracic radiation. Pneumonitis occurred in
2.3% (14/605) of patients, including Grade 2 (1.3%), Grade 3
(0.8%), and Grade 4 (0.2%) pneumonitis.
Immune-Mediated Colitis
- Colitis occurred in 1.3% (8/605) of patients, including Grade 2
(0.7%) and Grade 3 (0.7%) adverse reactions. Cytomegalovirus
infection/reactivation have occurred in patients with
corticosteroid-refractory immune-mediated colitis. In such cases,
consider repeating infectious workup to exclude alternative
etiologies.
Immune-Mediated Hepatitis
- JEMPERLI can cause immune-mediated hepatitis, which can be
fatal. Grade 3 hepatitis occurred in 0.5% (3/605) of patients.
Immune-Mediated Endocrinopathies
- Adrenal Insufficiency
-
- Adrenal insufficiency occurred in 1.2% (7/605) of patients,
including Grade 2 (0.5%) and Grade 3 (0.7%). For Grade 2 or higher
adrenal insufficiency, initiate symptomatic treatment per
institutional guidelines, including hormone replacement as
clinically indicated. Withhold or permanently discontinue JEMPERLI
depending on severity.
- Hypophysitis
-
- JEMPERLI can cause immune-mediated hypophysitis. Grade 2
hypophysitis occurred in 0.2% (1/605) of patients. Initiate hormone
replacement as clinically indicated. Withhold or permanently
discontinue JEMPERLI depending on severity.
- Thyroid Disorders
-
- Grade 2 thyroiditis occurred in 0.5% (3/605) of patients. Grade
2 hypothyroidism occurred in 7.6% (46/605) of patients.
Hyperthyroidism occurred in 2.3% (14/605) of patients, including
Grade 2 (2.1%) and Grade 3 (0.2%). Initiate hormone replacement or
medical management of hyperthyroidism as clinically indicated.
Withhold or permanently discontinue JEMPERLI depending on
severity.
- Type 1 Diabetes Mellitus, Which Can Present with Diabetic
Ketoacidosis
-
- JEMPERLI can cause type 1 diabetes mellitus, which can present
with diabetic ketoacidosis. Grade 3 type 1 diabetes mellitus
occurred in 0.2% (1/605) of patients. 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. Grade 2 nephritis, including tubulointerstitial nephritis,
occurred in 0.5% (3/605) of patients.
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 605 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.
-
- Nervous System: Meningitis, encephalitis, myelitis and
demyelination, myasthenic syndrome/myasthenia gravis,
Guillain-Barre syndrome, nerve paresis, autoimmune neuropathy
- Cardiac/Vascular: Myocarditis, pericarditis,
vasculitis
- 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
- Gastrointestinal: Pancreatitis, including increases in
serum amylase and lipase levels, gastritis, duodenitis
- Musculoskeletal and Connective Tissue:
Myositis/polymyositis, rhabdomyolysis and associated sequelae
including renal failure, arthritis, polymyalgia rheumatica
- Endocrine: Hypoparathyroidism
- Other (Hematologic/Immune): Autoimmune hemolytic anemia,
aplastic anemia, 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% (1/605) of
patients receiving JEMPERLI. 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
- 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,
which may occur despite intervening therapy. Monitor patients
closely for transplant-related complications and intervene
promptly.
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 (≥20%) in patients with dMMR
EC were fatigue/asthenia, anemia, rash, nausea, diarrhea,
constipation, and vomiting. The most common Grade 3 or 4 laboratory
abnormalities (>2%) were decreased lymphocytes, decreased
sodium, increased alanine aminotransferase, increased creatinine,
decreased neutrophils, decreased albumin, and increased alkaline
phosphatase.
The most common adverse reactions (≥20%) in patients with dMMR
solid tumors were fatigue/asthenia, anemia, diarrhea, and nausea.
The most common Grade 3 or 4 laboratory abnormalities (≥2%) were
decreased lymphocytes, decreased sodium, increased alkaline
phosphatase, and decreased albumin.
Please see the full US Prescribing
Information.
GSK in oncology
GSK is committed to maximizing patient
survival through transformational medicines. GSK's pipeline is
focused on immuno-oncology, tumor cell targeting therapies and
synthetic lethality. Our goal is to achieve a sustainable flow of
new treatments based on a diversified portfolio of investigational
medicines utilizing modalities such as small molecules, antibodies,
and antibody-drug conjugates, either alone or in combination.
About GSK
GSK is a global biopharma company with a
purpose to unite science, technology, and talent to get ahead of
disease together. Find out more at us.gsk.com/en-us/company.
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References
1 Sung H, Ferlay J, Siegel R et al. Global cancer
statistics 2020: GLOBOCAN estimates of incidence and mortality
worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021.
doi:10.3322/caac.21660.
2 Braun MM, et al. Am Fam Physician.
2016;93(6):468-474.
3 International Research on Cancer. Global Cancer
Observatory. Cancer Tomorrow.
https://gco.iarc.fr/tomorrow/en/dataviz/. Accessed 13 July 2022.
4 Kantar Health, Cust
Study (2018).
5 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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