FDA Issues Complete Response Letter to Linvoseltamab BLA in R/R Multiple Myeloma

The FDA has issued a complete response letter to the biologics license application (BLA) seeking the approval of linvoseltamab (REGN5458) for the treatment of patients with relapsed or refractory multiple myeloma that has progressed following 3 or more prior therapies.¹

Regeneron Pharmaceuticals, Inc., the drug developer, stated that the sole approvability issue was associated with findings from a pre-approval inspection at a third-party fill/finish manufacturer for another company’s product candidate. The manufacturer has informed the pharmaceutical company that they believe the issue has since been resolved. The FDA is expected to reinspect the facility in the coming months.

The BLA, which had a target action date of August 22, 2024,² was based on earlier data from the phase 1/2 LINKER-MM1 trial (NCT03761108). At a median follow-up of 11 months, the bispecific antibody given at a dose of 200 mg (n = 117) elicited an objective response rate (ORR) of 71% per independent review committee (IRC) assessment, which included a complete response (CR) rate or better rate of 46%.³ Updated data presented during the 2024 EHA Congress showed that with longer follow-up, a median of 14.3 months, the ORR reported with the agent at this dose continued to be 71%, with a CR or better rate of 50%.⁴ When broken down further, the stringent CR rate was 44.4%, the CR rate was 5.1%, the very good partial response (VGPR) rate was 13.7%, and the partial response (PR) rate was 7.7%.

Looking Into LINKER-MM1: Population, Treatment, and Key Objectives

The open-label, multicenter, dose-escalation and -expansion trial enrolled patients with relapsed or refractory multiple myeloma who were at least 18 years of age, had an ECOG performance status of 0 or 1, and measurable serum or urine markers per the International Myeloma Working Group (IMWG) criteria.⁵ For the first phase of the research, patients needed to have diseases that proved refractory to an immunomodulatory agent (IMiD) and a proteasome inhibitor (PI). For phase 2, patients needed to have disease that was refractory to an IMiD, a PI, and an anti-CD38 antibody.

The trial utilized a modified 3+3 (4+3) dose-escalation design, which also included an observation period of 28 days in which investigators assessed for dose-limiting toxicities. For phase 2, participants received intravenous linvoseltamab at full doses of 50 mg or 200 mg once weekly for weeks 3 to 14. Starting on week 16, patients received the agent once every 2 weeks. Those who were given 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 phase 2 primary end point was ORR by IRC assessment and IMWG criteria, and secondary end points comprised duration of response (DOR), progression-free survival (PFS), ORR by investigator assessment, overall survival (OS), and safety.

Additional Efficacy Data

In those who received the full dose of the agent, at 200 mg, responses were reported early, and they proved to be durable.⁵ The median time to response was 1 month (range, 0.5-6.3); the median time to a VGPR or better and a CR or better was 2.6 months (range, 0.7-15.7) and 8.5 months (range, 1.6-14.1). The Kaplan Meier (KM)–estimated DOR was 29.4 months (95% CI, 19.2-not evaluable [NE]); 80.9% (95% CI, 70.3%-88.0%) were estimated to maintain response at 1 year.

Moreover, the KM-estimated median PFS was NR (95% CI, 17.3-NE) and the probability of being free of disease progression at 1 year was 70% (95% CI, 60.1%-78.0%). The KM-estimated OS was 31.4 months (95% CI, 21.6-NE) and the probability of survival at 1 year was 75.3% (95% CI, 66.0%-82.3%).

Notably, a subgroup analysis of responses in the 200-mg group showed that linvoseltamab had high efficacy across all high-risk and high disease burden populations.

A Snapshot of Safety Findings

Any-grade treatment-emergent adverse effects (TEAEs) occurred in 98.1% of those in the 50-mg group (n = 104) and all patients in the 200-mg group (n = 117); grade 3 or higher TEAEs occurred in 72.1% and 73.5% of patients, respectively.

In the 200-mg group, the most common TEAEs reported in 20% or more of patients included cytokine release syndrome (any grade, 46.2%; grade 3/4, 0.9%), neutropenia (42.7%; 41.9%), anemia (38.5%; 30.8%), diarrhea (37.6%; 1.7%), cough (36.8%; 0%), fatigue (33.3%; 0%), arthralgia (29.9%; 0%), hypokalemia (24.8%; 3.4%), nausea (23.1%; 0%), headache (23.1%; 0.9%), COVID-19 (22.2%; 9.4%), back pain (20.5%; 2.6%), dyspnea (20.5%; 0.9%), constipation (17.1%; 0%), and pain in the extremity (12.0%; 0.9%).

TEAEs resulted in treatment discontinuation for 18.8% of patients who received the agent at the 200-mg dose; 7.7% were related to the study drug. Six patients in those dose group had TEAEs that proved fatal; 5 were due to infection. Three treatment-related deaths occurred: Pneumocystis jirovecii pneumonia, progressive multifocal leukoencephalopathy, and pseudomonal sepsis.

Next Steps

“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

References

1. Regeneron provides update on biologics license application for linvoseltamab. News release. Regeneron Pharmaceuticals, Inc. August 20, 2024. Accessed August 21, 2024. https://investor.regeneron.com/news-releases/news-release-details/regeneron-provides-update-biologics-license-application-0
2. Linvoseltamab BLA for treatment of relapsed/refractory multiple myeloma accepted for FDA priority review. News Release. Regeneron. February 21, 2024. Accessed August 21, 2024. https://investor.regeneron.com/news-releases/news-release-details/linvoseltamab-bla-treatment-relapsedrefractory-multiple-myeloma
3. Updated linvoseltamab pivotal data demonstrated strong rates and depth of response in patients with heavily pre-treated multiple myeloma. News Release. Regeneron. December 7, 2023. Accessed August 21, 2024. https://investor.regeneron.com/news-releases/news-release-details/updated-linvoseltamab-pivotal-data-demonstrated-strong-rates-and
4. Lentzsch S, Bumma N, Lee HC, et al. Linvoseltamab in patients with relapsed/refractory multiple myeloma in the LINKER-MM1 study: depth and durability of response at 14-month median follow-up. Presented at: 2024 EHA Congress; June 13-16, 2024; Madrid, Spain. Abstract S212.
5. Bumma N, Richter J, Jagannath S, et al. Linvoseltamab for treatment of relapsed/refractory multiple myeloma. J Clin Oncol. 2024;42(22):2702-2712. doi:10.1200/JCO.24.01008