European Approval Sought for Cilta-cel in Relapsed and Lenalidomide-Refractory Myeloma

Sen Zhuang, MD, PhD

A Type II variation application seeking the approval of ciltacabtagene autoleucel (Carvykti; cilta-cel) in adult patients with relapsed and lenalidomide (Revlimid)-refractory multiple myeloma has been submitted to the European Medicines Agency (EMA).¹

The application is based on findings from the phase 3 CARTITUDE-4 trial (NCT04181827). Leaked data from an abstract that was slated for presentation at the 2023 EHA Hybrid Congress and have since been taken down indicated that the CAR T-cell therapy reduced the risk of progressive disease or death vs pomalidomide (Pomalyst), bortezomib (Velcade), and dexamethasone (PVd), or daratumumab (Darzalex), pomalidomide, and dexamethasone (DPd) in those with relapsed or refractory disease who received 1 to 3 prior lines of therapy.²

The median progression-free survival (PFS) was not yet reached with cilta-cel vs 12 months with the control regimen. Moreover, the 12-month PFS rates were 76% in the investigative arm and 49% in the control arm. The CAR T-cell therapy elicited an overall response rate of 88% vs 67% with the control. Notably, 73% of patients who received cilta-cel had a complete response to treatment vs 22% who were given the control.

The data will be shared in a special session at the upcoming ASCO Annual Meeting.¹

“This submission is a testament to our relentless commitment to advance science, transform outcomes, challenge what a multiple myeloma diagnosis means for patients, and ultimately, work toward our goal of one day curing this complex disease,” Sen Zhuang, MD, PhD, vice president of clinical research and development at Janssen Research & Development, LLC, stated in a press release. “We look forward to collaborating with EMA to bring this potential new indication for cilta-cel to the multiple myeloma community as soon as possible.”

The trial enrolled patients with multiple myeloma who had measurable disease at screening, previously received 1 to 3 lines of therapy that included a proteasome inhibitor (PI) and an immunomodulatory drug (IMiD) and had evidence of progressive disease on or within 6 months of their last regimen by International Myeloma Working Group.³ They also needed to be refractory to lenalidomide and meet all prespecified clinical laboratory values.

If they previously received CAR T-cell therapy or any BCMA-targeted treatment or are experiencing any ongoing toxicity from prior treatment that has not resolved to baseline or grade 1 or less, they were excluded. Other exclusion criteria included having received a monoclonal antibody treatment in 21 days, cytotoxic therapy within 2 weeks, a PI in 2 weeks, an IMiD in 1 week, or a cumulative dose of corticosteroids equivalent to 70 mg of prednisone in the week before randomization on the trial.

Those randomly assigned to the investigative arm received at least 1 cycle of bridging therapy with PVd or DPd, with additional cycles permitted based on clinical status and availability of cilta-cel. They also received a conditioning regimen comprised of 300 mg/m² of cyclophosphamide and 30 mg/m² of fludarabine for 3 days. The CAR T-cell therapy was then administered via infusion at 0.75 x 10⁶ CAR+ viable T cells/kg.

Those in the control arm received standard treatment with either PVd or DPd. Those who had PVd were given pomalidomide at 4 mg on days 1 to 14 of each 21-day cycle, bortezomib at 1.3 mg/m² on days 1, 4, 8, and 11 of cycles 1 through 8 and on days 1 and 8 of cycle 9 and thereafter, and dexamethasone at 20 mg on days 1, 2, 4, 5, 8, 9, 11, and 12 of cycles 1 through 8 and on days 1, 2, 8, and 9 for cycle 9 and beyond. Those given DPd received daratumumab at a weekly dose of 1800 mg on days 1, 8, 15, and 22 on cycles 1 and 2 and then every 2 weeks on days 1 and 15 for cycles 3 to 6 and then every 4 weeks on day 1 for cycle 7 and beyond; plus 4 mg of pomalidomide on days 1 to 21 for cycle 1 and on; and 40 mg of dexamethasone weekly on days 1, 8, 15, and 22 for cycle 1 and on.

The primary end point of CARTITUDE-4 is PFS, and key secondary end points include overall survival, minimal residual disease negativity rate, overall response rate, and safety.¹

In January 2023, The Janssen Pharmaceutical Companies of Johnson & Johnson announced that the trial met its primary end point at the first prespecified interim analysis.⁴ Due to this, the independent data monitoring committee recommended the unblinding of the trial.

Participants will continue to be followed for primary, secondary, and exploratory end points for the duration of the trial.

Previously, in February 2022, the FDA approved cilta-cel for the treatment of patients with relapsed/refractory multiple myeloma after at least 4 prior lines of therapy, including a PI, an IMiD, and an anti-CD38 monoclonal antibody.⁵ The decision was supported by findings from the phase 1b/2 CARTITUDE-1 trial (NCT03548207), where the CAR T-cell therapy induced a 98% ORR (95% CI, 92.7%-99.7%) in the population.⁶ The stringent complete response rate was 78% (95% CI, 68.8%-86.1%). At a median follow-up of 18 months, the median duration of response was 21.8 months.

References

1. Janssen seeks European Commission approval of a new indication for Carvykti (ciltacabtagene autoleucel; cilta-cel) for the earlier treatment of patients with relapsed and refractory multiple myeloma. News release. The Janssen Pharmaceutical Companies of Johnson & Johnson. May 25, 2023. Accessed May 26, 2023. https://www.globenewswire.com/news-release/2023/05/25/2675919/0/en/Janssen-Seeks-European-Commission-Approval-of-a-New-Indication-for-CARVYKTI-ciltacabtagene-autoleucel-cilta-cel-for-the-Earlier-Treatment-of-Patients-with-Relapsed-and-Refractory-M.html
2. Legend Biotech: leaked EHA abstract shows outstanding CARTITUDE-4 results. Legend Biotech Corporation. April 19, 2023. Accessed May 26, 2023. https://seekingalpha.com/article/
3. A study comparing JNJ-68284528, a CAR-T therapy directed against B-cell maturation antigen (BCMA), versus pomalidomide, bortezomib and dexamethasone (PVd) or daratumumab, pomalidomide and dexamethasone (DPd) in participants with relapsed and lenalidomide refractory multiple myeloma (CARTITUDE-4). ClinicalTrials.gov. Updated April 13, 2023. Accessed May 26, 2023. https://clinicaltrials.gov/ct2/show/NCT04181827
4. Janssen announces unblinding of phase 3 CARTITUDE-4 study of Carvykti (cilta-cel) as primary endpoint met in treatment of patients with relapsed and refractory multiple myeloma. News release. The Janssen Pharmaceutical Companies of Johnson & Johnson. January 27, 2023. Accessed May 26, 2023. https://www.prnewswire.com/news-releases/janssen-announces-unblinding-of-phase-3-cartitude-4-study-of-carvykti-cilta-cel-as-primary-endpoint-met-in-treatment-of-patients-with-relapsed-and-refractory-multiple-myeloma-301732398.html
5. US FDA approves Carvykti (ciltacabtagene autoleucel), Janssen’s first cell therapy, a BCMA-directed CAR-T immunotherapy for the treatment of patients with relapsed or refractory multiple myeloma. News release. Janssen. February 28, 2022. Accessed May 26, 2023. https://www.janssen.com/us-fda-approves-carvykti-ciltacabtagene-autoleucel-janssens-first-cell-therapy-bcma-directed-car-t
6. Carvykti (ciltacabtagene autoleucel) suspension for intravenous infusion. Prescribing information. Janssen Biotech and Legend Biotech Corporation; 2022. Accessed May 26, 2023.