The FDA issued a complete response letter for linvoseltamab aimed at treating relapsed/refractory multiple myeloma post multiple therapies.
Bone marrow aspirate cytology of multiple myeloma: ©David A Litman - stock.adobe.com
The FDA has issued a complete response letter regarding the BLA for linvoseltamab.1 This application sought approval for the treatment of patients with relapsed/refractory multiple myeloma that has advanced after at least 3 prior therapies.1
According to the developer of the drug, Regeneron Pharmaceuticals, Inc., the only approvability concern came from data found during a preapproval inspection of a third-party fill/finish manufacturer for a different company's product candidate. The manufacturer has indicated that they believe the issue has been resolved.
The FDA is anticipated to conduct a reinspection of the facility in the coming months.
“Regeneron is committed to working closely with the third-party fill/finish manufacturer and the FDA to bring linvoseltamab to appropriate patients with relapsed/refractory multiple myeloma as quickly as possible, which is critical because most patients [with multiple myeloma] relapse and ultimately require additional therapies in late-line settings,” according to the press release.1
The BLA had atarget action date of August 22, 2024, based on results from the phase 1/2 LINKER-MM1 trial . In this trial, the bispecific antibody administered at a 200-mg dose (n = 117) demonstrated an objective response rate (ORR) of 71% as assessed by an independent review committee (IRC), with a complete response (CR) or better rate of 46%.2
Updated findings presented at the 2024 European Hematology Association Congress, with a median follow-up of 14.3 months, maintained the ORR at 71% and showed a CR or better rate of 50%.3 Further analysis revealed a stringent CR rate of 44.4%, a CR rate of 5.1%, a very good partial response (VGPR) rate of 13.7%, and a PR rate of 7.7%.
For safety, adverse events (AEs) were observed in all patients treated with the 200-mg dose. A total of 85% of patients experienced AEs of grade 3 or higher. Cytokine release syndrome (CRS) was the most common AE (46%) and of those with CRS, 35% were grade 1, 10% were grade 2, and 1% were grade 3. Adjudicated immune effector cell-associated neurotoxicity syndrome (ICANS) of any grade was seen in 8% of patients, grade 3 ICANS was seen in 3 patients, and no patients experienced grade 4 or higher ICANS. Infections of any grade were seen in 73% of patients, and 34% were grade 3/4.
The most common grade 3/4 AEs included neutropenia (30.8%), anemia (23.9%), thrombocytopenia (13.7%), and lymphopenia (11.1%). The most common nonhematologic treatment-emergent AEs (TEAEs) in this cohort were CRS (45.3%), cough (33.3%), fatigue (32.5%), and diarrhea (32.5%). Twelve percent of patients died due to their TEAEs during treatment or within 30 days after the last dose, 9% of which were due to infections.
LINKER-MM1 is an open-label, multicenter, dose-escalation, and dose-expansion trial. Enrollment was open to patients aged 18 years or older with relapsed/refractory multiple myeloma. All patients were required to have had an ECOG performance status of 0 or 1 and measurable serum or urine markers per the International Myeloma Working Group (IMWG) criteria.4
In phase 1, patients had to have diseases that were refractory to an immunomodulatory agent (IMiD) and a proteasome inhibitor (PI). In phase 2, patients had to have disease that was refractory to an IMiD, a PI, and an anti-CD38 antibody.
A modified 3+3 (4+3) dose-escalation design was used in the study. This also included an observation period of 28 days where investigators looked for dose-limiting toxicities.
Patients received linvoseltamab at full doses of 50 mg or 200 mg once weekly for weeks 3 to 14 via intravenous infusion in phase 2 of the study. Starting on week 16, patients received the agent once every 2 weeks. Patients treated with the 200-mg dose transitioned to a once-every-4-weeks dosing schedule if they experienced a VGPR or better after at least 24 weeks of treatment.
The primary end point for phase 2 was ORR by IRC assessment and IMWG criteria, and secondary end points included duration of response, progression-free survival, ORR by investigator assessment, overall survival, and safety.
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