REG - GSK PLC - New Phase III Jemperli data in endometrial cancer

GSKAnnouncement

18/03/2024 09:30

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RNS Number : 1138H  GSK PLC  18 March 2024

Issued: 16 March 2024, London UK

 

Positive RUBY phase III data show potential for Jemperli (dostarlimab)
combinations in more patients with primary advanced or recurrent endometrial
cancer

·   Dostarlimab plus chemotherapy is the only immuno-oncology combination
to show statistically significant and clinically meaningful overall survival
(OS) in the overall population

 

·   31% reduction in risk of death and 16.4-month improvement in median OS
observed with dostarlimab plus chemotherapy versus chemotherapy in the overall
population

 

·   37% reduction in risk of disease progression or death and 6-month
improvement in median progression-free survival observed with the addition of
Zejula (niraparib) to dostarlimab maintenance following dostarlimab plus
chemotherapy versus chemotherapy in MMRp/MSS population where treatment
options are still needed

 

 

GSK plc (LSE/NYSE: GSK) today announced statistically significant and
clinically meaningful overall survival (OS) results from Part 1 and
progression-free survival (PFS) results from Part 2 of the
RUBY/ENGOT-EN6/GOG3031/NSGO phase III trial in adult patients with primary
advanced or recurrent endometrial cancer. These data were presented today in a
late-breaking plenary session at the Society of Gynecologic Oncology 2024
Annual Meeting on Women's Cancer (16-18 March).

 

The goal of the RUBY phase III trial programme is to evaluate which patients
with primary advanced or recurrent endometrial cancer could potentially
benefit from treatment with Jemperli (dostarlimab) plus chemotherapy, with or
without the addition of Zejula (niraparib) maintenance. Part 1 of the RUBY
phase III trial is investigating dostarlimab plus standard-of-care
chemotherapy (carboplatin-paclitaxel) followed by dostarlimab compared to
chemotherapy plus placebo followed by placebo. Part 2 of the RUBY phase III
trial is evaluating dostarlimab plus standard-of-care chemotherapy, followed
by dostarlimab plus niraparib as maintenance therapy compared to chemotherapy
plus placebo followed by placebo. The safety and tolerability profiles of
dostarlimab plus carboplatin-paclitaxel and dostarlimab plus
carboplatin-paclitaxel followed by dostarlimab plus niraparib were generally
consistent with the known safety profiles of the individual medicines.

 

Previous data showed a statistically significant and clinically meaningful
improvement in PFS with Jemperli plus chemotherapy versus chemotherapy alone
in frontline mismatch repair deficient (dMMR)/microsatellite instability-high
(MSI-H) primary advanced or recurrent endometrial cancer. These data led to
regulatory approvals for this patient population in the US, EU and certain
other countries. Data presented today show additional potential benefit of
dostarlimab plus chemotherapy, with or without the addition of niraparib, in
the overall population of patients with primary advanced or recurrent
endometrial cancer, including patients with mismatch repair proficient
(MMRp)/microsatellite stable (MSS) tumours, for which there are currently no
approved immuno-therapy-based regimens.

Hesham Abdullah, Senior Vice President, Global Head Oncology, R&D, GSK
said: "The positive data presented today further show how dostarlimab-based
regimens could benefit a broader set of patients with endometrial cancer. The
results we've seen to date comprise the growing body of evidence supporting
the role of dostarlimab as the backbone of our immuno-oncology development
programme. Our goal is to continue to identify ways to use dostarlimab alone
and in combination with other therapies to help improve outcomes for patients
with limited treatment options."

 

RUBY Part 1: a statistically significant and clinically meaningful improvement
in OS was observed for dostarlimab plus chemotherapy versus placebo plus
chemotherapy, meeting a primary endpoint of the study.

Dostarlimab plus chemotherapy versus chemotherapy alone showed:

In the overall population:

·      a statistically significant reduction in the risk of death by 31%
(Hazard Ratio  HR : 0.69; [95% CI: 0.539-0.890])

·      a clinically meaningful improvement of 16.4 months in median OS
(44.6 months vs 28.2 months)

 

In a prespecified exploratory analysis of the MMRp/MSS population:

·      a clinically meaningful trend in reduced risk of death by 21%
(HR: 0.79; [95% CI: 0.602-1.044])

·      a clinically meaningful improvement of seven months in median OS
(34.0 months vs 27.0 months)

 

Full OS summaries are shown below.

                                 dostarlimab +              placebo +

 carboplatin-paclitaxel
 carboplatin-paclitaxel
 Overall population, Number (N)  245                        249
 OS, HR (95% CI)                 0.69 (0.539-0.890)
 P-value 1                       0.002
 OS, median (95% CI), mo.        44.6 (32.6-NR)             28.2 (22.1-35.6)
 dMMR/MSI-H population2, N       53                         65
 OS, HR (95% CI)                 0.32 (0.166-0.629)
 OS, median3 (95% CI), mo.       NR (NR-NR)                 31.4 (20.3-NR)
 MMRp/MSS2, N                    192                        184
 OS, HR (95% CI)                 0.79 (0.602-1.044)
 OS, median (95% CI), mo.        34.0 (28.6-NR)             27.0 (21.5-35.6)

1 One-sided p-value based on stratified log-rank test.
2 Exploratory analyses of OS in dMMR/MSI-H and OS in MMRp/MSS populations were
pre-specified with no planned hypothesis testing.
3 Although the median OS was not reached, at 30 months the estimated reduction
in the risk of death was 82.8% for patients who received dostarlimab plus
chemotherapy vs. 54.1% for patients who received chemotherapy alone.

Matthew Powell, MD, Division of Gynecologic Oncology, Washington University
School of Medicine,
and US principal investigator of the RUBY trial said: "RUBY Part 1 is the
first clinical trial to show a statistically significant and clinically
meaningful improvement in overall survival for an immuno-oncology therapy in
combination with chemotherapy in the overall population of patients with
primary advanced or recurrent endometrial cancer. As a clinician, I celebrate
the results of the RUBY Part 1 trial presented today, which show how
dostarlimab added to chemotherapy could potentially benefit a broader set of
patients with this type of cancer."

 

In RUBY Part 1, grade 3 or higher and serious treatment-emergent adverse
events (AEs) were approximately 12% higher in the dostarlimab plus
carboplatin-paclitaxel arm (treatment arm) compared with the placebo plus
carboplatin-paclitaxel arm (control arm). The nature and types of
immune-related AEs in the dostarlimab plus chemotherapy safety profile were
consistent with the mechanism of action of dostarlimab and similar to those
reported for other PD-(L)1 inhibitors. In the trial, 40.7% of participants in
the treatment arm and 16.3% of participants in the control arm had
immune-related AEs assessed by the investigator as related to dostarlimab or
placebo, respectively. Discontinuation of dostarlimab or placebo due to a
treatment-emergent AE occurred in 19.1% of patients in the treatment arm and
8.1% of patients in the control arm.

 

GSK expects US Food and Drug Administration regulatory submission acceptance
based on RUBY Part 1 data for an expanded indication in the overall population
in the first half of this year.

 

RUBY Part 2: addition of niraparib to dostarlimab in maintenance setting
significantly improved PFS in first-line primary advanced or recurrent
endometrial cancer compared to chemotherapy alone, meeting the primary
endpoint of the trial.

Dostarlimab plus chemotherapy followed by dostarlimab plus niraparib compared
to placebo plus chemotherapy followed by placebo showed:

In the overall population:

·      a statistically significant reduction in the risk of disease
progression or death by 40% (HR: 0.60 [95% CI: 0.43-0.82])

·      a clinically meaningful improvement of 6.2 months in median PFS
(14.5 months vs 8.3 months)

 

In the MMRp/MSS population:

·      a statistically significant reduction in the risk of disease
progression or death by 37% (HR: 0.63 [95% CI: 0.44-0.91])

·      a clinically meaningful improvement of 6.0 months in median PFS
(14.3 months vs 8.3 months)

 

Dr Mansoor Raza Mirza, Chief Oncologist, Copenhagen University Hospital,
Denmark, and RUBY principal investigator said: "In RUBY Part 2, we observed
that the use of dostarlimab in combination with niraparib in the maintenance
therapy setting further improved progression-free survival versus placebo for
patients with primary advanced or recurrent endometrial cancer. These findings
are particularly important for patients who have MMRp/MSS tumours as the data
help build on the initial benefit observed with an immuno-oncology plus
chemotherapy regimen, reflecting the potential for the addition of niraparib
maintenance to address unmet medical need for these patients."

 

In RUBY Part 2, grade 3 or higher and serious treatment-emergent AEs were
approximately 36% and 24% higher, respectively, in the dostarlimab plus
chemotherapy followed by dostarlimab plus niraparib arm (treatment arm)
compared with the placebo plus chemotherapy followed by placebo arm (control
arm). In the trial, 36.6% of participants in the treatment arm and 6.3% of
participants in the control arm had immune-related AEs assessed by the
investigator as related to dostarlimab or placebo, respectively. No cases of
myelodysplastic syndrome/acute myeloid leukaemia were reported; other
secondary primary malignancies occurred in 1 patient each in both treatment
arms. Discontinuation of dostarlimab or placebo due to a TEAE occurred in
24.1% of patients in the treatment arm and 5.2% of patients in the control
arm. Discontinuation of niraparib or placebo due to a treatment-emergent AE
occurred in 15.7% of patients in the treatment arm and 4.2% of patients in the
control arm.

 

About endometrial cancer

Endometrial cancer is found in the inner lining of the uterus, known as the
endometrium. Endometrial cancer is the most common gynaecologic cancer in
developed countries, with approximately 417,000 new cases reported each year
worldwide(1), and incidence rates are expected to rise by almost 40% between
2020 and 2040.(2)(,)(3) Approximately 15-20% of patients with endometrial
cancer will be diagnosed with advanced disease at the time of diagnosis.(4)

 

About RUBY

RUBY is a two-part global, randomised, double-blind, multicentre phase III
trial of patients with primary advanced or recurrent endometrial cancer. Part
1 is evaluating dostarlimab plus carboplatin-paclitaxel followed by
dostarlimab versus carboplatin-paclitaxel plus placebo followed by placebo.
Part 2 is evaluating dostarlimab plus carboplatin-paclitaxel followed by
dostarlimab 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 Tumours v1.1 and OS. The statistical
analysis plan included pre-specified analyses of PFS in the dMMR/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 organisation dedicated to transforming
the standard of care in gynaecologic oncology.

 

About Jemperli (dostarlimab)

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)

 

In the US, Jemperli is indicated in combination with carboplatin and
paclitaxel, followed by Jemperli as a single agent for the treatment of adult
patients with primary advanced or recurrent endometrial cancer that is dMMR,
as determined by a US FDA-approved test, or MSI-H, and as a single agent for
adult patients with 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. The supplemental Biologics License Application
supporting the newly approved indication in combination with carboplatin and
paclitaxel for dMMR/MSI-H primary advanced or recurrent endometrial cancer
received Breakthrough Therapy designation and Priority Review from the US FDA.

 

Jemperli is also indicated in the US for patients with dMMR recurrent or
advanced solid tumours, as determined by a US FDA-approved test, that have
progressed on or following prior treatment and who have no satisfactory
alternative treatment options. The latter indication is approved in the US
under accelerated approval based on tumour response rate and durability of
response. Continued approval for this indication in solid tumours may be
contingent upon verification and description of clinical benefit in a
confirmatory trial(s).

 

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, commercialisation, and manufacturing of Jemperli, and cobolimab
(GSK4069889), a TIM-3 antagonist.

 

Important Information for Jemperli in the EU

 

Indication 

Jemperli is indicated:

·      in combination with carboplatin-paclitaxel, for the treatment of
adult patients with mismatch repair deficient (dMMR)/microsatellite
instability-high (MSI-H) primary advanced or recurrent endometrial cancer and
who are candidates for systemic therapy;

·      as monotherapy for treating adult patients with mismatch repair
deficient (dMMR)/microsatellite instability-high (MSI-H) recurrent or advanced
endometrial cancer that has progressed on or following prior treatment with a
platinum-containing regimen.

Refer to the Jemperli EMA Reference Information
(https://www.ema.europa.eu/en/medicines/human/EPAR/jemperli) for a full list
of adverse events and the complete important safety information in the EU.

About Zejula (niraparib)

Zejula is an oral, once-daily poly(ADP-ribose) polymerase (PARP) inhibitor
indicated in the US for the maintenance treatment of adult patients with
advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer who
are in complete or partial response to first-line platinum-based chemotherapy;
and for the maintenance treatment of adult patients with deleterious or
suspected deleterious germline BRCA-mutated recurrent epithelial ovarian,
fallopian tube, or primary peritoneal cancer who are in a complete or partial
response to platinum-based chemotherapy and who have been selected based on a
US FDA-approved companion diagnostic for Zejula.

 

Important Information for Zejula in the EU 

 

Indication  

Zejula is indicated:

·      as monotherapy for the maintenance treatment of adult patients
with advanced epithelial (FIGO Stages III and IV) high-grade ovarian,
fallopian tube or primary peritoneal cancer who are in response (complete or
partial) following completion of first-line platinum-based chemotherapy.

·      as monotherapy for the maintenance treatment of adult patients
with platinum-sensitive relapsed high-grade serous epithelial ovarian,
fallopian tube, or primary peritoneal cancer who are in response (complete or
partial) to platinum-based chemotherapy.

 

Refer to the Zejula (http://Zejula) (http://Zejula) EMA Reference Information
(http://Zejula) (https://www.ema.europa.eu/en/medicines/human/EPAR/zejula) for
a full list of adverse events and the complete important safety information in
the EU.

 

GSK in oncology

Oncology is an emerging therapeutic area for GSK where we are committed to
maximising patient survival with a current focus on haematologic malignancies,
gynaecologic cancers and other solid tumours through breakthroughs in
immuno-oncology and tumour-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 gsk.com.

 

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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 the company's Annual Report on Form 20-F for 2023.

 

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References

1.     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/.

2.     Braun MM, et al. Am Fam Physician. 2016;93(6):468-474.

3.     International Research on Cancer. Global Cancer Observatory. Cancer
Tomorrow. gco.iarc.fr/tomorrow/en/dataviz/. Accessed 13 July 2022.

4.     CMP: CancerMPact® Patient Metrics Mar-2023, Cerner Enviza.
Available at www.cancermpact.com. Accessed 29 Feb 2024.

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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