On March 19, 2021 GlaxoSmithKline (GSK) plc reported that it will present new data across its growing women’s oncology portfolio at the upcoming Society of Gynecologic Oncology (SGO) 2021 Annual Meeting on Women’s Cancer to be held 19-25 March 2021 (Press release, GlaxoSmithKline, MAR 19, 2021, View Source [SID1234576911]).
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GSK, a leader in synthetic lethality and immuno-oncology research, will present seven abstracts at SGO that reflect the increasing depth and breadth of the company’s oncology portfolio in these research areas. There will be a plenary presentation of the results from the phase III NOVA trial that highlight the long-term follow up of secondary endpoints, including safety and survival results of ZEJULA (niraparib) in women with recurrent ovarian cancer. This research builds on the body of evidence supporting poly (ADP-ribose) polymerase (PARP) inhibitor use for maintenance treatment. GSK will also share data from the phase II OVARIO trial underscoring the potential of niraparib maintenance in combination with bevacizumab in first-line ovarian cancer.
In endometrial cancer, updated results from cohorts A1 and A2 of the phase I GARNET trial will be presented that showcase the potential of dostarlimab in women with recurrent or advanced mismatch repair deficient (dMMR)/microsatellite instability-high (MSI-H) endometrial cancer.
Dr Axel Hoos, Senior Vice President and Head of Oncology R&D, GSK said: "For women with gynaecologic cancers, our priority is to continue to evaluate niraparib and dostarlimab in conditions where new treatment options are needed most. Over the last few years, data supporting the use of PARP inhibitors for ovarian cancer has grown, and data presented at SGO demonstrate the potential benefits of niraparib combination therapies and sequencing. We also believe there is significant treatment potential for dostarlimab, which may enhance the anti-cancer immune response in women with endometrial cancer and patients with other types of cancer."
Leadership in advanced ovarian cancer
Niraparib is the only oral, once-daily PARPi approved as a monotherapy maintenance treatment for women with first-line platinum-responsive advanced ovarian cancer regardless of biomarker status in both the US and EU. GSK is committed to fully exploring and maximising the potential of niraparib through a robust clinical development programme evaluating it both as a monotherapy and in combination with other therapies to further improve outcomes for women with ovarian cancer.
GSK will present updated data from three trials at SGO that demonstrates niraparib’s potential regardless of biomarker status as a monotherapy, doublet-therapy and triplet-therapy. In addition to the OVARIO and NOVA trial results, data from cohort A of the phase II OPAL trial, evaluating the triple combination therapy of niraparib (PARPi) and dostarlimab (anti-PD-1) in combination with bevacizumab (anti-VEGF) for women with platinum-resistant ovarian cancer, including several patients with primary platinum resistant disease, will be presented.
GSK also will share a post-hoc analysis from the phase III PRIMA trial on the efficacy of timing of surgery and residual disease, along with results of another study on the factors affecting PARPi use as maintenance treatment in platinum-sensitive recurrent ovarian cancer.
Transforming treatment for patients with endometrial cancer
GSK will present new data from the GARNET trial at SGO, demonstrating clinically meaningful results that reinforce the potential of dostarlimab in endometrial cancer. GARNET represents the largest dataset of an anti-PD-1 monotherapy treatment in this disease.
The Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency adopted a positive opinion last month recommending dostarlimab for use as monotherapy for women with dMMR/MSI-H recurrent or advanced endometrial cancer who have progressed on or after platinum-based chemotherapy. The application is based on data from the GARNET study, which was originally presented at SGO in 2019.
Dostarlimab is also being evaluated in combination with other therapeutic agents for people with advanced solid tumours or metastatic cancer, including combinations with niraparib, and other immuno-oncology agents. It is currently under review with the US Food and Drug Administration (FDA) for the treatment of women with recurrent or advanced endometrial cancer who have progressed on or following platinum-based chemotherapy and whose tumours are dMMR. The FDA is also currently reviewing dostarlimab for the treatment of adult patients with dMMR recurrent or advanced solid tumours. Dostarlimab is not currently approved for use anywhere in the world.
Key GSK presentations during the SGO Annual Meeting on Women’s Cancer include:
Niraparib
Abstract Name
Presenter
Presentation Details
Long-term safety and secondary efficacy endpoints in the ENGOT-OV16/NOVA phase III trial of niraparib in recurrent ovarian cancer
Matulonis, U.
Oral Presentation #11139
Phase 2 OVARIO Study of Niraparib + Bevacizumab Therapy in Advanced Ovarian Cancer Following Front-Line Platinum-Based Chemotherapy With Bevacizumab
Hardesty, M.
Oral Featured Poster #10408
Efficacy of Niraparib by Timing of Surgery and Residual Disease: A Post-Hoc Analysis of Patients in the PRIMA/ENGOT-OV26/GOG-3012 Study
O’Cearbhaill, R.
Featured Poster #10381
Factors Affecting PARP Inhibitor Use as Maintenance Treatment in Platinum-Sensitive Recurrent Ovarian Cancer
Valentine, M.
Poster #10410
An Open-Label Phase 2 Study of Dostarlimab (TSR-042), Bevacizumab (bev), and Niraparib Combination in Patients (pts) with Platinum-Resistant Ovarian Cancer (PROC): Cohort A of the OPAL Trial
Liu, J.
Oral Featured Poster #10415
Dostarlimab
Abstract Name
Presenter
Presentation Details
Interim Analysis of the Immune-Related Endpoints of the Mismatch Repair Deficient (dMMR) and Proficient (MMRp) Endometrial Cancer Cohorts From the GARNET Study
Oaknin, A.
Oral Featured Poster #10417
ENGOT-EN6/GOG-3031/NSGO-RUBY: A phase 3, randomized, double-blind, multicenter study of dostarlimab + carboplatin-paclitaxel versus placebo + carboplatin-paclitaxel in recurrent or primary advanced endometrial cancer (EC)
Mirza, M.
Trial in Progress Poster #10418
About ZEJULA (niraparib)
Niraparib is an oral, once-daily PARP inhibitor that is currently being evaluated in multiple pivotal trials. GSK is building a robust niraparib clinical development programme by assessing activity across multiple tumour types and by evaluating several potential combinations of niraparib with other therapeutics. The ongoing development programme for niraparib includes several combination studies.
Indication and Important Safety Information for ZEJULA
ZEJULA is indicated:
for the maintenance treatment of adult patients with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a complete or partial response to first-line platinum-based chemotherapy
for the maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a complete or partial response to platinum-based chemotherapy
for the treatment of adult patients with advanced ovarian, fallopian tube, or primary peritoneal cancer who have been treated with three or more prior chemotherapy regimens and whose cancer is associated with homologous recombination deficiency (HRD) positive status defined by either:
a deleterious or suspected deleterious BRCA mutation, or
genomic instability and who have progressed more than six months after response to the last platinum-based chemotherapy
Select patients for therapy based on an FDA-approved companion diagnostic for ZEJULA.
Important Safety Information
Myelodysplastic syndrome/acute myeloid leukemia (MDS/AML), including some fatal cases, was reported in 15 patients (0.8%) out of 1785 patients treated with ZEJULA monotherapy in clinical trials. The duration of therapy in patients who developed secondary MDS/cancer therapy-related AML varied from 0.5 months to 4.9 years. These patients had received prior chemotherapy with platinum agents and/or other DNA-damaging agents including radiotherapy. Discontinue ZEJULA if MDS/AML is confirmed.
Hematologic adverse reactions (thrombocytopenia, anemia, neutropenia, and/or pancytopenia) have been reported in patients receiving ZEJULA. The overall incidence of Grade ≥3 thrombocytopenia, anemia, and neutropenia were reported, respectively, in 39%, 31%, and 21% of patients receiving ZEJULA in PRIMA; 29%, 25%, and 20% of patients receiving ZEJULA in NOVA; and 28%, 27%, and 13% of patients receiving ZEJULA in QUADRA. Discontinuation due to thrombocytopenia, anemia, and neutropenia occurred, respectively, in 4%, 2%, and 2% of patients in PRIMA; 3%, 1%, and 2% of patients in NOVA; and 4%, 2%, and 1% of patients in QUADRA. In patients who were administered a starting dose of ZEJULA based on baseline weight or platelet count in PRIMA, Grade ≥3 thrombocytopenia, anemia, and neutropenia were reported, respectively, in 22%, 23%, and 15% of patients receiving ZEJULA. Discontinuation due to thrombocytopenia, anemia, and neutropenia occurred, respectively, in 3%, 3%, and 2% of patients. Do not start ZEJULA until patients have recovered from hematological toxicity caused by prior chemotherapy (≤Grade 1). Monitor complete blood counts weekly for the first month, monthly for the next 11 months, and periodically thereafter. If hematological toxicities do not resolve within 28 days following interruption, discontinue ZEJULA, and refer the patient to a hematologist for further investigations.
Hypertension and hypertensive crisis have been reported in patients receiving ZEJULA. Grade 3-4 hypertension occurred in 6% of patients receiving ZEJULA vs 1% of patients receiving placebo in PRIMA, with no reported discontinuations. Grade 3-4 hypertension occurred in 9% of patients receiving ZEJULA vs 2% of patients receiving placebo in NOVA, with discontinuation occurring in <1% of patients. Grade 3-4 hypertension occurred in 5% of ZEJULA-treated patients in QUADRA, with discontinuation occurring in <0.2% of patients. Monitor blood pressure and heart rate at least weekly for the first two months, then monthly for the first year, and periodically thereafter during treatment with ZEJULA. Closely monitor patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension. Manage hypertension with antihypertensive medications and adjustment of the ZEJULA dose if necessary.
Posterior reversible encephalopathy syndrome (PRES) occurred in 0.1% of 2,165 patients treated with ZEJULA in clinical trials and has also been described in postmarketing reports. Monitor all patients for signs and symptoms of PRES, which include seizure, headache, altered mental status, visual disturbance, or cortical blindness, with or without associated hypertension. Diagnosis requires confirmation by brain imaging. If suspected, promptly discontinue ZEJULA and administer appropriate treatment. The safety of reinitiating ZEJULA is unknown.
Embryo-fetal toxicity and lactation: Based on its mechanism of action, ZEJULA can cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus and to use effective contraception during treatment and for 6 months after receiving their final dose of ZEJULA. Because of the potential for serious adverse reactions from ZEJULA in breastfed infants, advise lactating women to not breastfeed during treatment with ZEJULA and for 1 month after receiving the final dose.
Allergic reactions to FD&C Yellow No. 5 (tartrazine): ZEJULA capsules contain FD&C Yellow No. 5 (tartrazine), which may cause allergic-type reactions (including bronchial asthma) in certain susceptible persons. Although the overall incidence in the general population is low, it is frequently seen in patients who also have aspirin hypersensitivity.
First-line Maintenance Advanced Ovarian Cancer
Most common adverse reactions (Grades 1-4) in ≥10% of all patients who received ZEJULA in PRIMA were thrombocytopenia (66%), anemia (64%), nausea (57%), fatigue (51%), neutropenia (42%), constipation (40%), musculoskeletal pain (39%), leukopenia (28%), headache (26%), insomnia (25%), vomiting (22%), dyspnea (22%), decreased appetite (19%), dizziness (19%), cough (18%), hypertension (18%), AST/ALT elevation (14%), and acute kidney injury (12%).
Common lab abnormalities (Grades 1-4) in ≥25% of all patients who received ZEJULA in PRIMA included: decreased hemoglobin (87%), decreased platelets (74%), decreased leukocytes (71%), increased glucose (66%), decreased neutrophils (66%), decreased lymphocytes (51%), increased alkaline phosphatase (46%), increased creatinine (40%), decreased magnesium (36%), increased AST (35%) and increased ALT (29%).
Maintenance Recurrent Ovarian Cancer
Most common adverse reactions (Grades 1-4) in ≥10% of patients who received ZEJULA in NOVA were nausea (74%), thrombocytopenia (61%), fatigue/asthenia (57%), anemia (50%), constipation (40%), vomiting (34%), neutropenia (30%), insomnia (27%), headache (26%), decreased appetite (25%), nasopharyngitis (23%), rash (21%), hypertension (20%), dyspnea (20%), mucositis/stomatitis (20%), dizziness (18%), back pain (18%), dyspepsia (18%), leukopenia (17%), cough (16%), urinary tract infection (13%), anxiety (11%), dry mouth (10%), AST/ALT elevation (10%), dysgeusia (10%), palpitations (10%).
Common lab abnormalities (Grades 1-4) in ≥25% of patients who received ZEJULA in NOVA included: decrease in hemoglobin (85%), decrease in platelet count (72%), decrease in white blood cell count (66%), decrease in absolute neutrophil count (53%), increase in AST (36%), and increase in ALT (28%).
Treatment of Advanced HRD+ Ovarian Cancer
Most common adverse reactions (Grades 1-4) in ≥10% of patients who received ZEJULA in QUADRA were nausea (67%), fatigue (56%), thrombocytopenia (52%), anemia (51%), vomiting (44%), constipation (36%), abdominal pain (34%), musculoskeletal pain (29%), decreased appetite (27%), dyspnea (22%), insomnia (21%), neutropenia (20%), headache (19%), diarrhea (17%), acute kidney injury (17%), urinary tract infection (15%), hypertension (14%), cough (13%), dizziness (11%), AST/ALT elevation (11%), blood alkaline phosphatase increased (11%).
Common lab abnormalities (Grades 1-4) in ≥25% of patients who received ZEJULA in QUADRA included: decreased hemoglobin (83%), increased glucose (66%), decreased platelets (60%), decreased lymphocytes (57%), decreased leukocytes (53%), decreased magnesium (46%), increased alkaline phosphatase (40%), increased gamma glutamyl transferase (40%), increased creatinine (36%), decreased sodium (34%), decreased neutrophils (34%), increased aspartate aminotransferase (29%), and decreased albumin (27%).
Please see Prescribing Information for ZEJULA.
About Dostarlimab
Dostarlimab is a humanised PD-1 monoclonal antibody that binds with high affinity to the PD-1 receptor and blocks its interaction with the ligands PD-L1 and PD-L2.[1] In addition to GARNET, dostarlimab is being investigated in other registrational enabling studies, including the phase 3 RUBY study for patients with recurrent or primary advanced endometrial cancer in combination with standard of care (SOC) chemotherapy [2] and the phase 3 FIRST study of platinum-based therapy with dostarlimab and ZEJULA versus SOC platinum-based therapy as first-line treatment of stage III or IV non-mucinous epithelial ovarian cancer. It is also being evaluated in combination with other therapeutic agents 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.
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 cell therapy, either alone or in combination.