- Jemperli approval now includes MMRp/MSS tumors, which represent
majority of endometrial cancer cases
- Jemperli plus chemotherapy demonstrated a statistically
significant and clinically meaningful 31% reduction in risk of
death versus chemotherapy alone
GSK plc (LSE/NYSE: GSK) today announced the US Food and Drug
Administration (FDA) has approved Jemperli (dostarlimab-gxly) in
combination with carboplatin and paclitaxel (chemotherapy) followed
by Jemperli as a single agent for the treatment of adult patients
with primary advanced or recurrent endometrial cancer. This
approval broadens the previous indication for Jemperli plus
chemotherapy to include patients with mismatch repair proficient
(MMRp)/microsatellite stable (MSS) tumors who represent 70-75% of
patients diagnosed with endometrial cancer and who have limited
treatment options. The supplemental Biologics License Application
(sBLA) supporting this expanded indication received Priority Review
and was approved ahead of the Prescription Drug User Fee Act action
date.
Hesham Abdullah, Senior Vice President, Global Head Oncology,
R&D, GSK, said: “Jemperli plus chemotherapy is the first
and only immuno-oncology regimen to show significant and meaningful
improvement in overall survival for adult patients with primary
advanced or recurrent endometrial cancer regardless of biomarker
status. We are thrilled this option is now available for more
patients in the US, including the 70-75% with MMRp/MSS tumors where
treatment options have been limited.”
Today’s expanded approval is based on results from dual primary
endpoints of investigator-assessed progression-free survival (PFS)
and overall survival (OS) from Part 1 of the RUBY phase III trial.
RUBY Part 1 is the only clinical trial in this setting to show a
statistically significant OS benefit in the full population of
patients with primary advanced or recurrent endometrial cancer,
demonstrating a 31% reduction in risk of death (HR: 0.69; 95% CI:
0.54–0.89) compared to chemotherapy alone.
At the 2.5-year landmark, 61% (95% CI: 54-67) of patients in the
Jemperli plus chemotherapy group compared to 49% (95% CI: 43-55) in
the chemotherapy group were alive. In addition, a 16.4-month
improvement in median OS was observed with Jemperli plus
chemotherapy versus chemotherapy alone (44.6 months [95% CI:
32.6–NR] vs. 28.2 months [95% CI: 22.1–35.6], respectively). The
median duration of follow-up was more than three years.1 The safety
and tolerability analysis from RUBY Part 1 showed a safety profile
for Jemperli and carboplatin-paclitaxel that was generally
consistent with the known safety profiles of the individual agents.
The most common treatment-emergent adverse events (≥ 20%) in
patients receiving Jemperli plus chemotherapy were nausea,
alopecia, fatigue, peripheral neuropathy, anemia, arthralgia,
constipation, diarrhea, myalgia, rash, hypomagnesemia, decreased
appetite, peripheral sensory neuropathy and vomiting.
Matthew Powell, MD, Chief, Division of Gynecologic Oncology,
Washington University School of Medicine, and US principal
investigator of the RUBY trial said: “The initial approval of
Jemperli plus chemotherapy was practice-changing for patients with
dMMR/MSI-H primary advanced or recurrent endometrial cancer and
today’s expanded approval will offer even more patients the
opportunity for improved outcomes. This is the only immuno-oncology
treatment regimen that has shown a statistically significant
overall survival benefit for the full patient population, which is
a meaningful step forward in treating this challenging cancer.”
Adrienne Moore, Survivor, Founding Member and President of
Endometrial Cancer Action Network for African-Americans (ECANA)
said: “With this expanded approval for Jemperli plus
chemotherapy, GSK is bringing a much-needed new treatment regimen
to the endometrial cancer community that may help patients with
primary advanced or recurrent endometrial cancer live longer,
providing hope to patients and their families. Survivors and
advocates should be excited by today’s news and especially
delighted that this approval means that more patients in the US who
are diagnosed with endometrial cancer will have a new treatment
option.”
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 in
developed countries,2 with an estimated 1.6 million people living
with active disease at any stage and 417,000 new cases reported
each year worldwide.3 Incidence rates are expected to rise by
approximately 40% between 2020 and 2040.4 Approximately 15-20% of
patients with endometrial cancer will be diagnosed with advanced
disease at the time of diagnosis.5 Among patients with primary
advanced or recurrent endometrial cancer, approximately 70-75% have
MMRp/MSS tumors.6
About RUBY RUBY is a two-part global, randomized,
double-blind, multi-center phase III trial of patients with primary
advanced or recurrent endometrial cancer. Part 1 is evaluating
dostarlimab-gxly plus carboplatin-paclitaxel followed by
dostarlimab-gxly versus carboplatin-paclitaxel plus placebo
followed by placebo. Part 2 is evaluating dostarlimab-gxly plus
carboplatin-paclitaxel followed by dostarlimab-gxly plus niraparib
versus placebo plus carboplatin-paclitaxel followed by placebo.
In Part 1, the dual-primary endpoints are investigator-assessed
PFS based on the Response Evaluation Criteria in Solid Tumors v1.1
and OS. The statistical analysis plan included pre-specified
analyses of PFS in the mismatch repair deficient
(dMMR)/microsatellite instability-high (MSI-H) and overall
populations and OS in the overall population. Pre-specified
exploratory analyses of PFS and OS in the MMRp/MSS population and
OS in the dMMR/MSI-H populations were also performed. RUBY Part 1
included a broad population, including histologies often excluded
from clinical trials and had approximately 10% of patients with
carcinosarcoma and 20% with serous carcinoma.
In Part 2, the primary endpoint is investigator-assessed PFS in
the overall population, followed by PFS in the MMRp/MSS population,
and OS in the overall population is a key secondary endpoint.
Additional secondary endpoints in Part 1 and Part 2 include PFS per
blinded independent central review, PFS2, overall response rate,
duration of response, disease control rate, patient-reported
outcomes, and safety and tolerability.
RUBY is part of an international collaboration between the
European Network of Gynaecological Oncological Trial groups
(ENGOT), a research network of the European Society of
Gynaecological Oncology (ESGO) that consists of 22 trial groups
from 31 European countries that perform cooperative clinical
trials, and the GOG Foundation, a non-profit organization dedicated
to transforming the standard of care in gynecologic oncology.
About Jemperli (dostarlimab-gxly) Jemperli, a programmed
death receptor-1 (PD-1)-blocking antibody, is the backbone of GSK’s
ongoing immuno-oncology-based research and development program. A
robust clinical trial program includes studies of Jemperli alone
and in combination with other therapies in gynecologic, colorectal
and lung cancers, as well as where there are opportunities for
transformational outcomes.
Jemperli was discovered by AnaptysBio, Inc. and licensed to
TESARO, Inc., under a collaboration and exclusive license agreement
signed in March 2014. Under this agreement, GSK is responsible for
the ongoing research, development, commercialization, and
manufacturing of Jemperli and cobolimab (GSK4069889), a TIM-3
antagonist.
Indications and Important Safety Information for JEMPERLI
(dostarlimab-gxly)
- JEMPERLI, in combination with carboplatin and paclitaxel,
followed by JEMPERLI as a single agent, is indicated for the
treatment of adult patients with primary advanced or recurrent
endometrial cancer (EC).
- JEMPERLI, as a single agent, is indicated for the treatment of
adult patients with mismatch repair deficient (dMMR) recurrent or
advanced:
- 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 3
hypophysitis occurred in 0.4% (1/241) of patients receiving
JEMPERLI in combination with carboplatin and paclitaxel. Grade 2
hypophysitis occurred in 0.2% (1/605) of patients receiving
JEMPERLI as a single agent. 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 12% (30/241) of patients receiving
JEMPERLI in combination with carboplatin and paclitaxel. Grade 2
hypothyroidism occurred in 8% (46/605) of patients receiving
JEMPERLI as a single agent. Hyperthyroidism occurred in 3.3%
(8/241) of patients receiving JEMPERLI in combination with
carboplatin and paclitaxel, including Grade 2 (2.9%) and Grade 3
(0.4%). Hyperthyroidism occurred in 2.3% (14/605) of patients
receiving JEMPERLI as a single agent, including Grade 2 (2.1%) and
Grade 3 (0.2%). Initiate thyroid 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 0.4% (1/241) of patients receiving JEMPERLI in
combination with carboplatin and paclitaxel. Grade 3 type 1
diabetes mellitus occurred in 0.2% (1/605) of patients receiving
JEMPERLI as a single agent. 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-Barré 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, other
transplant (including corneal graft) 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%), including laboratory
abnormalities, in patients with EC who received JEMPERLI in
combination with carboplatin and paclitaxel were decreased
hemoglobin, increased creatinine, peripheral neuropathy, decreased
white blood cell count, fatigue, nausea, alopecia, decreased
platelets, increased glucose, decreased lymphocytes, decreased
magnesium, decreased neutrophils, increased AST, arthralgia, rash,
constipation, diarrhea, increased ALT, decreased potassium,
decreased albumin, decreased sodium, increased alkaline
phosphatase, abdominal pain, dyspnea, decreased appetite, increased
amylase, decreased phosphate, urinary tract infection, and
vomiting.
The most common adverse reactions (≥20%) in patients with dMMR
EC who received JEMPERLI as a single agent were fatigue/asthenia,
anemia, nausea, diarrhea, constipation, vomiting, and rash. 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 who received JEMPERLI as a single agent 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
for JEMPERLI, including Medication Guide.
GSK in oncology Oncology is an emerging therapeutic area
for GSK where we are committed to maximizing patient survival with
a current focus on hematologic malignancies, gynecologic cancers
and other solid tumors through breakthroughs in immuno-oncology and
tumor-cell targeting therapies.
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.
Cautionary statement regarding forward-looking statements
GSK cautions investors that any forward-looking statements or
projections made by GSK, including those made in this announcement,
are subject to risks and uncertainties that may cause actual
results to differ materially from those projected. Such factors
include, but are not limited to, those described under Item 3.D
“Risk factors” in GSK’s Annual Report on Form 20-F for 2023, and
GSK’s Q2 Results for 2024.
Registered in England & Wales: No. 3888792
Registered Office: 980 Great West Road Brentford,
Middlesex TW8 9GS
References
___________________________________
1 Powell MA, Bjørge L, Willmott L, et al. Overall survival in
patients with endometrial cancer treated with dostarlimab plus
carboplatin-paclitaxel in the randomized ENGOT-EN6/GOG-3031/RUBY
trial, Annals of Oncology.2024. doi: https://
doi.org/10.1016/j.annonc.2024.05.546. 2 Faizan U, Muppidi V.
Uterine Cancer. [Updated 2022 Sep 5]. In: StatPearls [Internet].
Treasure Island (FL): StatPearls Publishing; 2022 Jan. Available
at: www.ncbi.nlm.nih.gov/books/NBK562313/. 3 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;71(3):209-249.
doi:10.3322/caac.21660 4 International Research on Cancer. Global
Cancer Observatory. Cancer Tomorrow.
Gco.iarc.fr/tomorrow/en/dataviz/. Accessed 12 Jun 2024. 5 CMP:
CancerMPact Patient Metrics Mar-2023, Cerner Enviza. Available at
www.cancermpact.com. Accessed 12 Jun 2024. 6 Based on
CMP:CancerMPact [Patient Metrics], Cerner Enviza. Available from
www.cancermpact.com. Accessed 12 Jun 2024.
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