Axi-cel as Frontline Therapy for High-Risk Large B-cell Lymphoma Produces Encouraging Responses

Article

In 37 evaluable patients, the objective response rate in the study was 89% (95% CI, 75%-97%) with complete responses in 78%.

(Adobe Stock)

(Adobe Stock)

This article was originally published on OncLive.com.

Axicabtagene ciloleucel (axi-cel; Yescarta) CAR T-cell therapy as first-line treatment for patients with high-risk large B-cell lymphoma (LBCL) produced encouraging responses, according to updated phase 2 ZUMA-12 (NCT03761056) data presented during the 2022 Transplantation & Cellular Therapy Meetings.

In 37 evaluable patients, the objective response rate (ORR) in the study was 89% (95% CI, 75%-97%) with complete responses (CRs) in 78%. Partial responses (PRs) were observed in 11% of the evaluable population, while 8% has stable disease (SD), and only 3 had progressive disease (PD).

Axi-cel is an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy that already has FDA approval for the treatment of adults with relapsed or refractory LBCL and relapsed/refractory follicular lymphoma following at least 2 prior lines of therapy. ZUMA-12 is the first study to assess treatment with axi-cel in the first-line setting.

“Patients with high-risk large B cell lymphoma have poor outcomes, including lower response rates and poor overall survival. In addition, patients with early disease resistance as assessed by dynamic PET scan, after first-line chemoimmunotherapy have an increased risk of death,” said Sattva Neelapu, MD, professor, Department of Lymphoma/Myeloma, Division of Cancer Medicine, and deputy department chair, Department of Lymphoma/Myeloma, Division of Cancer Medicine, at The University of Texas MD Anderson Cancer Center, Houston, TX during a presentation at the 2022 Transplantation and Cellular Therapy Meetings.

Based on the unmet medical need for therapies to improve outcomes in high-risk LBCL, ZUMA-12 was created. The study is a phase 2, multicenter, open-label, single-arm study. At the 2022 TCT Meetings, Neepalu presented results on efficacy, safety, pharmacokinetics, and pharmacodynamics.

Per the study design, patients included in ZUMA-12 were those with high-grade B-cell lymphoma with MYC and BCL-2 and/or BCL-6 translocations or have an International Prognostic Index (IPI) score of ≥ 3. All patients must be 18 years of age or older with an ECOG performance score of 0 or 1, and their interim PET scan should show a Deauville score of 4 or 5 after 2 cycles of anti-CD20 mAb plus an anthracycline-containing regimen.

“Following enrollment and leukapheresis, patients could receive optional non-chemotherapy bridging, which could have included either corticosteroids or localized radiation. And once the product has been generated, they received standard [fludarabine] conditioning followed by a single infusion of axi-cel,” explained Neelapu about ZUMA-12 treatment.

The fludarabine conditioning was administered at 30 mg/m2 via intravenous (IV) infusion with cyclophosphamide 500 mg/m2 IV on days -5, -4, and -3. Axi-cel was administered at 2 x 106 CAR T cells/kg on day 0.

The primary end point of the ZUMA-12 study is CR rate assessed by investigators per Lugano 2014 classification. Secondary end points of the study include ORR, duration of response (DOR), event-free survival (EFS), progression-free survival (PFS), overall survival (OS), safety, and CAR T cells in blood and cytokine levels in serum.

Of the 42 patients enrolled, 40 were treated with condition chemotherapy and axi-cel. The patients had a median age of 61 years (range, 23-86), and were 68% male. In terms of disease characteristics, 95% of patients in the study has stage III or IV disease, 63% had an ECOG score of 1, and 100% had at least 1 prior systemic therapy. FISH testing assessed by investigator showed that 40% of patients had double- or triple-hit, and 25% were double- or triple-hit per central laboratory assessment. Also, the IPI score was ≥ 3 for 78% of patients, and 48% had a Deauville score of 4, while 53% had a Deauville score of 5.

The median follow-up for response in the evaluable population was 15.9 months (range, 6.0-26.7), with 62% of patients having been followed for ≥ 12 months. As of the data cutoff date, 73% of patients were having an ongoing response to axi-cel. The median time to response was 1.0-month (range, 0.9-6.8). Of the 11% who initially had a PR, 16% eventually converted to a PR. Moreover, 3% of those whose initial response was SD converted to a CR.

In the overall population (n = 40), the ORR was 90% (95% CI, 76%-97%) with a CR rate of 80% (95% CI, 64%-91%. Notably, CRs were consistent across all subgroup populations. The median DOR was not reached, but at month 12, the DOR rate was 80.8% (95% CI, 59.3%-91.6%).

All survival outcomes had not been reached by the time of data cut off. At 12 months, the EFS rate was 72.5% (95% CI, 53.1%-84.9), the PFS rate was 74.6% (95% CI, 54.8%-86.7%, and the OS rate was 90.6% (95% CI, 73.4%-96.9%).

Any-grade treatment-emergent adverse events (TEAEs) occurred in all 40 patients in the study of which, 85% were grade 3 or higher. The most common grade ≥ 3 axi-cel-related TEAEs were neutrophil count decrease (53%), white blood cell count decrease (43%), anemia (30%), encephalopathy (15%), and platelet count decrease (15%).

Serious TEAEs were observed in 45% of patients. In 68% of patients, grade ≥ 3 cytopenias occurred, and 15% experienced grade ≥ 3 infections. Twelve of patients died due to either PD (10%), COVID-19 (3%), or septic shock (3%).

Cytokine release syndrome (CRS) occurred in all patients in the study, but only 8% experienced grade 3 CRS. The most common CRS-related symptoms observed were pyrexia (100%), hypotension (30%), chills (25%), and hypoxia (23%).

“Tocilizumab was administered in 63% of outpatients and corticosteroids in 35% of the patients for management of CRS, only one patient required vasopressors,” noted Neelapu. “The median time to onset of CRS was four days and the median duration was 6 days. There were no grade 4 grade 5 CRS events and all CRS events resolved as of the data cut off.”

Neurologic events of any grade were observed in 73% of patients, and these events were grade 3 for 23% and grade 2 for 38%. The most common symptoms associated with neurologic events in the study were confusional state (28%), encephalopathy (25%), and tremor (25%).

Regarding neurologic events, Neelapu stated: “The median time to onset was 9 days and the median duration was 7 days. There were 2 grade 4 neurological events both due to encephalopathy and both resolved. There were no grade 5 neurological events noted. As of the data cut off, there's 1 patient who has an ongoing grade 1 tremor.”

Finally, ZUMA-12 results were compared with results from ZUMA-1 (NCT02348216), in which axi-cel was evaluated as third-line treatment for patients with LBCL.

“We observed a higher frequency of CCR7-positive, CD45RA-positive T cells in ZUMA-12 versus in ZUMA-1. Within the product, 35% of these T cells were of this phenotype on ZUMA-12 versus only 14% on ZUMA-1. And this was a phenotype that was previously associated with a favorable newer PK profile and better clinical efficacy,” said Neelapu.

The greater frequency of CCR7-positive, CD45RA-positive T cells observed in ZUMA-12 was associated with greater CAR T-cell expansion, which signals improved T-cell fitness in the first-line setting. Based on the collective findings, Neelapu et al., axi-cel may be beneficial to patients exposed to fewer prior therapies as well as those with high-risk LBCL.

Reference:
  1. Neelapu SS, Dickinson M, Munoz JL, et al. Primary analysis (PA) of Zuma-12: A phase 2 study of axicabtagene ciloleucel (Axi-Cel) as first-line therapy in patients (Pts) with high-risk large b-cell lymphoma (lbcl). Presented at. 2022 Transplantation and Cellular Therapy Meetings; April 23-26, 2022; Salt Lake City, UT. Abstract 12.
Recent Videos
Arun Upadhyay, PhD, the chief scientific officer and head of research, development, and Medical at Ocugen
Arun Upadhyay, PhD, the chief scientific officer and head of research, development, and Medical at Ocugen
Barry J. Byrne, MD, PhD, the chief medical advisor of Muscular Dystrophy Association (MDA) and a physician-scientist at the University of Florida
John Brandsema, MD, a pediatric neurologist in the Division of Neurology at Children’s Hospital of Philadelphia
Chun-Yu Chen, PhD, a research scientist at Seattle Children’s Research Institute
Alexandra Collin de l’Hortet, PhD, the head of therapeutics at Epic Bio
David Dimmock, MBBS, on Accelerating Therapy Discovery and Approval With AI David Dimmock, MBBS, on Accelerating Therapy Discovery and Approval With AI
John Finn, PhD, the chief scientific officer of Tome Biosciences
David Dimmock, MBBS, on a Promising Case Study of Ultra-Rare, AI-Guided, ASO Development
Scott Jeffers, PhD, on The Importance of Precise Reproducibility of AAVs
Related Content
© 2024 MJH Life Sciences

All rights reserved.