GSK provides an update on Blenrep (belantamab mafodotin-blmf) US marketing authorization
Issued: London, UK
For media and investors only
GSK plc (LSE/NYSE: GSK) today announced it has initiated the process for withdrawal of the US marketing authorization for Blenrep following the request of the US Food and Drug Administration (FDA). This request was based on the previously announced outcome of the DREAMM-3 phase III confirmatory trial, which did not meet the requirements of the US FDA Accelerated Approval regulations. Blenrep is a monotherapy treatment for adult patients with relapsed or refractory multiple myeloma (RRMM) who have received at least four prior therapies, including an anti-CD38 monoclonal antibody, a proteasome inhibitor, and an immunomodulatory agent.
As part of the Company’s efforts to ensure physicians and patients are supported during this important time, patients already enrolled in the Blenrep Risk Evaluation and Mitigation Strategy (REMS) program will have the option to enroll in a compassionate use program to continue to access treatment. Further information on enrolling patients into the compassionate use program will be provided directly to REMS-enrolled prescribers. Patients currently being treated with Blenrep should consult their healthcare provider.
GSK continues to believe, based on the totality of data available from the DREAMM (DRiving Excellence in Approaches to Multiple Myeloma) development program, that the benefit-risk profile of belantamab mafodotin remains favorable in this hard-to-treat RRMM patient population. Patients responding to belantamab mafodotin experienced durable clinical benefit, and safety remains consistent with the known safety profile.
Sabine Luik, Chief Medical Officer, said, “We respect the Agency’s approach to the accelerated approval regulations and associated process. Multiple myeloma is a challenging disease, with poor outcomes for patients whose disease has become resistant to standard-of-care treatments. We will continue the DREAMM clinical trial program and work with the US FDA on a path forward for this important treatment option for patients with multiple myeloma.”
Additional trials within the DREAMM clinical trial program are designed to determine the benefit of belantamab mafodotin in combination treatment with novel therapies and standard-of-care treatments in earlier lines of therapy and dosing optimization to maintain efficacy while reducing corneal events. Data from the DREAMM-7 and DREAMM-8 phase III trials are event-driven, and results are anticipated in the first half of 2023. The results of these trials will be shared with health authorities and inform future regulatory pathways.
About DREAMM-3
The DREAMM-3 phase III trial is an open-label, randomized head-to-head superiority trial evaluating the efficacy and safety of single-agent belantamab mafodotin compared to pomalidomide in combination with low-dose dexamethasone (PomDex) in patients with RRMM. A total of 325 participants were randomized in a 2:1 ratio to receive either single-agent belantamab mafodotin administered as a 2.5 mg/kg dose every three weeks or PomDex. Pomalidomide was administered daily on days 1 to 21 of each 28-day cycle, with dexamethasone administered once weekly (days 1, 8, 15, and 22 of each cycle). The primary endpoint was PFS. Secondary endpoints include overall survival, safety, ORR, duration of response and assessment of minimal residual disease.
About DREAMM-7
DREAMM-7 is evaluating the safety and efficacy of belantamab mafodotin in combination with bortezomib and dexamethasone versus daratumumab in combination with bortezomib and dexamethasone.
About DREAMM-8
DREAMM-8 is assessing the efficacy and safety of belantamab mafodotin in combination with pomalidomide and dexamethasone compared with that of a combination of pomalidomide, bortezomib and dexamethasone in participants with relapsed/refractory multiple myeloma.
About multiple myeloma
Multiple myeloma is the second most common blood cancer in the US and is generally considered treatable but not curable.1,2 In the US, more than 32,000 people are estimated to be diagnosed with multiple myeloma this year, and nearly 13,000 people will die from the disease.3 Research into new therapies is needed as multiple myeloma commonly becomes refractory to available treatments.4
About B-cell maturation antigen (BCMA)
The normal function of BCMA is to promote plasma cell survival by transduction of signals from two known ligands, BAFF (B-cell activating factor) and APRIL (a proliferation-inducing ligand). This pathway has been shown to be important for myeloma cell growth and survival. BCMA expression is limited to B cells at later stages of development. BCMA is expressed at varying levels in myeloma patients and BCMA membrane expression is universally detected in myeloma cell lines.5
About Blenrep
Blenrep is an antibody-drug conjugate comprising a humanized BCMA monoclonal antibody conjugated to the cytotoxic agent auristatin F via a non-cleavable linker. The drug linker technology is licensed from Seagen Inc.; the monoclonal antibody is produced using POTELLIGENT Technology licensed from BioWa Inc., a member of the Kyowa Kirin Group.
Indication and Important Safety Information for BLENREP (belantamab mafodotin-blmf)
BLENREP is indicated for the treatment of adults with relapsed or refractory multiple myeloma who have received at least 4 prior therapies, including an anti-CD38 monoclonal antibody, a proteasome inhibitor, and an immunomodulatory agent.
This indication is approved under accelerated approval based on response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).
IMPORTANT SAFETY INFORMATION
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WARNING: OCULAR TOXICITY BLENREP caused changes in the corneal epithelium resulting in changes in vision, including severe vision loss and corneal ulcer, and symptoms such as blurred vision and dry eyes. Conduct ophthalmic exams at baseline, prior to each dose, and promptly for worsening symptoms. Withhold BLENREP until improvement and resume, or permanently discontinue, based on severity. Because of the risk of ocular toxicity, BLENREP is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the BLENREP REMS. |
WARNINGS AND PRECAUTIONS
Ocular Toxicity: Ocular adverse reactions occurred in 77% of the 218 patients in the pooled safety population. Ocular adverse reactions included keratopathy (76%), changes in visual acuity (55%), blurred vision (27%), and dry eye (19%). Among patients with keratopathy (n = 165), 49% had ocular symptoms, 65% had clinically relevant visual acuity changes (decline of 2 or more lines on Snellen Visual Acuity in any eye), and 34% had both ocular symptoms and visual acuity changes.
Keratopathy: Keratopathy was reported as Grade 1 in 7% of patients, Grade 2 in 22%, Grade 3 in 45%, and Grade 4 in 0.5% per the KVA scale. Cases of corneal ulcer (ulcerative and infective keratitis) have been reported. Most keratopathy events developed within the first 2 treatment cycles (cumulative incidence of 65% by Cycle 2). Of the patients with Grade 2 to 4 keratopathy (n = 149), 39% recovered to Grade 1 or lower after median follow-up of 6.2 months. Of the 61% who had ongoing keratopathy, 28% were still on treatment, 9% were in follow-up, and in 24% the follow-up ended due to death, study withdrawal, or lost to follow-up. For patients in whom events resolved, the median time to resolution was 2 months (range: 11 days to 8.3 months).
Visual Acuity Changes: A clinically significant decrease in visual acuity of worse than 20/40 in the better-seeing eye was observed in 19% of the 218 patients and of 20/200 or worse in the better-seeing eye in 1.4%. Of the patients with decreased visual acuity of worse than 20/40, 88% resolved and the median time to resolution was 22 days (range: 7 days to 4.2 months). Of the patients with decreased visual acuity of 20/200 or worse, all resolved and the median duration was 22 days (range: 15 to 22 days).
Monitoring and Patient Instruction: Conduct ophthalmic examinations (visual acuity and slit lamp) at baseline, prior to each dose, and promptly for worsening symptoms. Perform baseline examinations within 3 weeks prior to the first dose. Perform each follow-up examination at least 1 week after the previous dose and within 2 weeks prior to the next dose. Withhold BLENREP until improvement and resume at same or reduced dose, or consider permanently discontinuing based on severity. Advise patients to use preservative-free lubricant eye drops at least 4 times a day starting with the first infusion and continuing until end of treatment. Avoid use of contact lenses unless directed by an ophthalmologist. Changes in visual acuity may be associated with difficulty for driving and reading. Advise patients to use caution when driving or operating machinery. BLENREP is only available through a restricted program under a REMS.
Thrombocytopenia: Thrombocytopenia occurred in 69% of 218 patients in the pooled safety population, including Grade 2 in 13%, Grade 3 in 10%, and Grade 4 in 17%. The median time to onset of the first thrombocytopenic event was 26.5 days. Thrombocytopenia resulted in dose reduction, dose interruption, or discontinuation in 9%, 2.8%, and 0.5% of patients, respectively. Grade 3 to 4 bleeding events occurred in 6% of patients, including Grade 4 in 1 patient. Fatal adverse reactions included cerebral hemorrhage in 2 patients. Perform complete blood cell counts at baseline and during treatment as clinically indicated. Consider withholding and/or reducing the dose based on severity.
Infusion-Related Reactions: Infusion-related reactions occurred in 18% of 218 patients in the pooled safety population, including Grade 3 in 1.8%. Monitor patients for infusion-related reactions. For Grade 2 or 3 reactions, interrupt the infusion and provide supportive treatment. Once symptoms resolve, resume at a lower infusion rate. Administer premedication for all subsequent infusions. Discontinue BLENREP for life-threatening infusion-related reactions and provide appropriate emergency care.
Embryo-Fetal Toxicity: Based on its mechanism of action, BLENREP can cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with BLENREP and for 4 months after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with BLENREP and for 6 months after the last dose. Pregnancy testing is recommended for females of reproductive potential prior to initiating BLENREP.
ADVERSE REACTIONS
The pooled safety population described in Warnings and Precautions reflects exposure to BLENREP at a dosage of 2.5 mg/kg or 3.4 mg/kg (1.4 times the recommended dose) administered intravenously once every 3 weeks in 218 patients in DREAMM-2. Of these patients, 194 received a liquid formulation (not the approved dosage form) rather than the lyophilized powder.
Patients received BLENREP at the recommended dosage of 2.5 mg/kg administered intravenously once every 3 weeks (n = 95). Permanent discontinuation due to an adverse reaction occurred in 8% of patients who received BLENREP; keratopathy (2.1%) was the most frequent adverse reaction resulting in permanent discontinuation. Dosage interruptions due to an adverse reaction occurred in 54% of patients who received BLENREP. Adverse reactions which required a dosage interruption in >3% of patients included keratopathy (47%), blurred vision (5%), dry eye (3.2%), and pneumonia (3.2%). Dose reductions due to an adverse reaction occurred in 29% of patients. Adverse reactions which required a dose reduction in >3% of patients included keratopathy (23%) and thrombocytopenia (5%).
The most common adverse reactions (≥20%) were keratopathy (71%), decreased visual acuity (53%), nausea (24%), blurred vision (22%), pyrexia (22%), infusion-related reactions (21%), and fatigue (20%). The most common Grade 3 or 4 (≥5%) laboratory abnormalities were lymphocytes decreased (22%), platelets decreased (21%), hemoglobin decreased (18%), neutrophils decreased (9%), creatinine increased (5%), and gamma-glutamyl transferase increased (5%).
Serious adverse reactions occurred in 40% of patients who received BLENREP. Serious adverse reactions in >3% of patients included pneumonia (7%), pyrexia (6%), renal impairment (4.2%), sepsis (4.2%), hypercalcemia (4.2%), and infusion-related reactions (3.2%). Fatal adverse reactions occurred in 3.2% of patients, including sepsis (1%), cardiac arrest (1%), and lung infection (1%).
Clinically relevant adverse reactions from expanded access programs include: pneumonitis including fatal cases.
USE IN SPECIFIC POPULATIONS
Lactation: Because of the potential for serious adverse reactions in the breastfed child, advise women not to breastfeed during treatment with BLENREP and for 3 months after the last dose.
Females and Males of Reproductive Potential: Based on findings in animal studies, BLENREP may impair fertility in females and males.
Geriatric Use: Of the 218 patients who received BLENREP in DREAMM-2, 43% were aged 65 to less than 75 years and 17% were aged 75 years and older. Keratopathy occurred in 80% of patients aged less than 65 years and 73% of patients aged 65 years and older. Among the 95 patients who received BLENREP at the 2.5-mg/kg dose, keratopathy occurred in 67% of patients aged less than 65 years and 73% of patients aged 65 years and older.
Renal or Hepatic Impairment: The recommended dosage has not been established in patients with severe renal impairment (eGFR 15 to 29 mL/min/1.73 m2) or end-stage renal disease (ESRD) with eGFR <15 mL/min/1.73 m2 not on dialysis or requiring dialysis. The recommended dosage has not been established in patients with moderate or severe hepatic impairment (total bilirubin >1.5 × ULN and any AST).
Please see full Prescribing Information, including boxed warning.
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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 in the Company's Annual Report on Form 20-F for 2021, GSK’s Q3 Results for 2022 and any impacts of the COVID-19 pandemic.
References
[1] CA: A Cancer Journal for Clinicians, Vol. 70, Issue 1, Jan/Feb 2020 Pages 7-30.
[2] Kazandjian D. Multiple myeloma epidemiology and survival: A unique malignancy. Semin Oncol. 2016;43(6):676–681. doi:10.1053/j.seminoncol.2016.11.004.
[3] SEER Cancer Facts & Figures 2019. Available at: https://seer.cancer.gov/statfacts/html/mulmy.html. Accessed October 2021.
[4] Nooka AK, Kastritis E, Dimopoulos MA. Treatment options for relapsed and refractory multiple myeloma. Blood. 2015;125(20).
[5] Lonial, S, et al. Belantamab mafodotin for relapsed or refractory multiple myeloma (DREAMM-2): a two-arm, randomised, open-label, phase 2 study. Lancet Oncol. 2020; 21(2):207–21.
