Zevorcabtagene Autoleucel Approved in China for R/R Multiple Myeloma, Phase 2 Study in US Ongoing

A version of this article previously appeared on our sister site, OncLive.

Earlier this month, China’s National Medical Products Administration (NMPA) approved CARsgen's autologous CAR T-cell therapy zevorcabtagene autoleucel (zevor-cel; previously known as CT053) for the treatment of adult patients with relapsed/refractory multiple myeloma (r/r MM) whose disease progressed after at least 3 lines of therapy, including treatment with a proteasome inhibitor (PI) and an immunomodulatory drug (IMiD).¹

Zever-cel is currently being investigated in North America in the phase 2 the phase 2 LUMMICAR-2 trial (NCT03915184), led by Shaji Kumar, MD, a consultant and the research chair in the Division of Hematology of the Department of Internal Medicine at Mayo Clinic, across several sites in the United States and a site in Ontario, Canada, and an expected primary completion date of December 31, 2024. Previously reported results showed that 11 evaluable patients experienced an ORR of 100%, with all patients achieving very good partial response or better.²

The NMPA's regulatory decision was supported by data from the phase 1/2 LUMMICAR STUDY 1 trial (NCT03975907), which showed that at a median follow-up of 37.7 months (range, 14.8-44.2), evaluable patients treated with the BCMA-targeted CAR T-cell therapy (n = 14) achieved an overall response rate (ORR) of 100% and a complete response (CR)/stringent CR (sCR) rate of 78.6%.³ Notably, all patients who experienced a CR/sCR achieved minimal residual disease negativity.

Wenming Chen, MD, PhD, principal investigator of LUMMICAR STUDY 1 and director of the Hematology Department at Beijing Chao-Yang Hospital of Capital Medical University in China, said in a statement¹ that, “In the realm of traditional treatments, the prognosis for patients dealing with relapsed or refractory multiple myeloma remains notably grim, given the limitations of available therapeutic alternatives."

“These individuals confront substantial unmet clinical needs, necessitating an expeditious adoption of an effective, safe, and convenient treatment modalities. The approval of zevor-cel not only expands the array of choices available to clinical practitioners but also brings new hope to patients," Chen added.¹

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LUMMICAR STUDY 1 was an open-label, multicenter trial that evaluated zevor-cel in patients who were at least 18 years old, but no older than 75, with r/r MM and who had at least 3 prior lines of treatment exposure, including at least 1 PI and 1 IMiD.³ Additional inclusion criteria were disease relapse within 12 months following the last line of therapy or disease progression within 60 days of the last line of therapy, as well as a life expectancy of more than 12 weeks, an Eastern Cooperative Oncology Group (commonly known as ECOG) performance status of 0 or 1, and adequate organ function.

The study excluded patients who received any prior CAR T-cell therapy, those treated with a prior BCMA-directed therapy, and patients who underwent prior allogeneic stem cell transplant for multiple myeloma. Autologous stem cell transplant less than 12 weeks before leukapheresis was not permitted for inclusion.

Following the completion of lymphodepletion, after 1 to 2 days, patients received a single infusion of zevor-cel. Of the 14 evaluable patients at the most recent data cutoff date of July 17, 2023, 3 had received the CAR T-cell therapy at 1.0 × 10⁸ CAR+ T cells, and 11 patients were administered an infusion of 1.5 × 10⁸ CAR+ T cells.³ Dose-limiting toxicities served as the primary end point in the phase 1 portion, and ORR was the primary end point of the phase 2 portion. Secondary end points included Minimal Residual Disease negativity, time to response, CR/sCR rate, ORR at week 12, clinical benefit rate, safety, and pharmacokinetics.⁴

Patients evaluable for efficacy had a median age of 54 years (range, 34-62), and half had high-risk cytogenetic abnormalities. Notably, 14.3% had extramedullary disease, and 14.3% had stage III disease aas defined by the International Staging System.³

No instances of grade 3 or higher cytokine release syndrome or any-grade immune effector cell–associated neurotoxicity were observed in the safety findings. A total of 3 patients experienced treatment-related grade 3 infections, and serious adverse effects (AEs) occurred in 3 patients, including 2 who experienced serious treatment-related AEs in the form of pulmonary infection and tumor lysis syndrome. There were 2 deaths reported, though neither was deemed related to treatment.

“Based on the published results of the LUMMICAR-1 study, zevor-cel has demonstrated profound and enduring therapeutic efficacy in patients with relapsed or refractory multiple myeloma, exhibiting overall favorable tolerability,” Chengcheng Fu, MD, PhD, principal investigator of LUMMICAR STUDY 1 and director of the Hematology Department at the First Affiliated Hospital of Soochow University, stated in a news release.¹ “We are pleased to witness the regulatory approval and market launch of zevor-cel. We look forward to its potential to benefit a larger number of individuals, aiding them in achieving high-quality, long-term survival.”

In 2022, after data from the LUMMICAR-2 study were presented at the 7th Annual CAR-TCR Summit, in Boston, Massachusetts, held from September 20-22, Raffaele Baffa, MD, PhD, the chief medical officer of CARsgen Therapeutics, said in a statement that the data "indicate a consistent trend of clinical benefit with the data of earlier trials conducted on zevor-cel, such as the investigator-initiated trials and LUMMICAR-1 phase 1 trials in China as reported previously in ASH. We are very encouraged by the competitive efficacy and favorable safety profiles and will continue to dedicate our efforts in successfully developing and launching zevor-cel for multiple myeloma patients worldwide."

Those 2022 data included 17 patients with r/r MM who had been treated with 1.8 × 10⁸ zevor-cel cells in the phase 2 portion of the trial as of August 31, 2022. Patients were followed up for a median of 113 days (range, 9-373). Five patients (29.4%) had extramedullary disease (≥1 plasmacytoma) and 9 (52.9%) had high-risk cytogenic features. Patients were refractory to their last line of therapy and were heavily pretreated, with a median of prior lines of therapy (range, 4-17). They received a lymphodepletion regimen of fludarabine (30 mg/m² for 3 consecutive days) and cyclophosphamide (500 mg/m² for 2 consecutive days) prior to zevor-cel infusion.⁵

REFERENCES
1. NMPA Approves the NDA for CARsgen's BCMA CAR-T therapy zevorcabtagene autoleucel for relapsed or refractory multiple myeloma. News release. CARsgen Therapeutics. March 1, 2024. Accessed March 30, 2024. https://www.carsgen.com/en/news/20240301/
2. CARsgen presents North America phase 2 updates for CT053 BCMA CAR T at the 7th annual CAR-TCR summit. News release. CARsgen Therapeutics. September 21, 2022. Accessed March 30, 2024. https://www.carsgen.com/en/news/20220921/
3. CARsgen presents updated research results on zevor-cel at 2023 ASH Annual Meeting. News release. CARsgen Therapeutics. December 12, 2023. Accessed March 1, 2024. https://www.carsgen.com/en/news/20231212/
4. Clinical trial to evaluate CT053 in patients with relapsed and/or refractory multiple myeloma (LUMMICAR STUDY 1). ClinicalTrials.gov. Updated February 28, 2024. Accessed March 30, 2024. . https://classic.clinicaltrials.gov/ct2/show/NCT03975907
5. CARsgen presents north america phase 2 updates for CT053 BCMA CAR T at the 7th Annual CAR-TCR Summit. News release. CARSgen. September 21, 2022. Accessed March 30, 2024. https://www.businesswire.com/news/home/20220921005429/en/CARsgen-Presents-North-America-Phase-2-Updates-for-CT053-BCMA-CAR-T-at-the-7th-Annual-CAR-TCR-Summit