FDA Approves Lisocabtagene Maraleucel for Relapsed or Refractory CLL or SLL

FDA

The FDA has granted accelerated approval to lisocabtagene maraleucel (liso-cel; Breyanzi) for the treatment of adult patients with relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) who have previously received at least 2 prior lines of therapy, including a BTK inhibitor and a BCL-2 inhibitor.^1,2

The regulatory decision was based on response rate and duration of response (DOR) data from the phase 1/2 TRANSCEND CLL 004 study (NCT03331198) in which the CAR T-cell therapy (n = 65) elicited a complete response rate of 20% (95% CI, 11.1%-31.8%). At the time of the data cutoff date, those who achieved the CR experienced a median DOR that was not yet reached (NR;95% CI, 15 months-NR). The 12-month DOR rate was 100% in these patients, and the 18-month rate was 87.5% (95% CI, 38.7%-98.1%).

The objective response rate experienced with liso-cel was 45% (95% CI, 32.3%-57.5%), and the median DOR was 35.3 months (95% CI, 12.4-NR). The median time to first response was 1.1 months (range, 0.8-17.4), and the median time to first CR was 3.0 months (range, 1.1-17.9).

“CAR T cell therapies represent a transformative treatment option for patients with certain types of blood cancers,” Bryan Campbell, senior vice president and head of Commercial, Cell Therapy at Bristol Myers Squibb, stated in a press release. “For years, attempts to bring other CAR T cell therapies to patients with relapsed or refractory CLL or SLL met challenges and found little success. With the approval of Breyanzi as the first CAR T for relapsed or refractory CLL or SLL, we are now able to offer these patients a personalized option, while further expanding access across the broadest array of B-cell malignancies, to address this critical unmet need.”

About TRANSCEND CLL

The open-label, multicenter, single-arm trial enrolled adult patients with relapsed or refractory CLL or SLL who had previously received at least 2 lines of treatment, including a BTK inhibitor and a BCL-2 inhibitor. The trial included patients with del(17p), complex karyotype, and unmutated IGHV, and they were required to have an ECOG performance status of 0 or 1.

Those with a creatinine clearance of less than 30 mL/min, alanine aminotransferase greater than 5 times the upper limit of normal, or left ventricular ejection fraction less than 40%, were excluded.

The planned dose of the CAR T-cell therapy was 100 × 10⁶ CAR+ viable T cells. Between apheresis and the initiation of lymphodepleting chemotherapy, bridging therapy was permitted.

Of the 89 patients, liso-cel was given 2 to 11 days after lymphodepleting chemotherapy was completed. Chemotherapy comprised 30 mg/m² of fludarabine daily and 300 mg/m² cyclophosphamide daily given concurrently for 3 days. The CAR T-cell therapy was then administered in the inpatient and outpatient settings, for 88% and 12% of patients, respectively.

Of the patients who underwent leukapheresis (n = 113), 94 received liso-cel. Of the 94, 84 patients received the therapy at a dose ranging from 90 to 111 × 10⁶ CAR+ T cells, and 10 patients received a dose outside of this range. Three patients received experienced manufacturing failure and 16 others did not receive liso-cel due to other reasons.

Of the 84 patients, 19 were not efficacy evaluable; 13 did not have baseline disease assessments done after bridging therapy, 1 did not have measurable disease, and 5 had Richter transformation.

In the 65 patients evaluable for efficacy, the median age was 66 years (range, 49-82). Most patients were male (68%), White (80%), and non-Hispanic (89%. The majority of patients (83%) had at least one high-risk genetic attribute; 43% had del(17p), 45% had TP53 mutation, 45% unmutated IGHV, and 62% had complex karyotype. Moreover, 51% of patients had bulky disease. The median number of prior therapies was 5 (range, 2-12).

All patients had previously received a BTK inhibitor; 88% were refractory, 1.5% were relapsed, and 11% were intolerant. All patients had previously received a BCL-2 inhibitor; 92% were refractory and 6% were intolerant. Eighty-three percent of patients had disease that was refractory to their last therapy.

Key efficacy outcome measures included ORR, including CR and partial response (PR) rates, and DOR per independent review committee assessment utilizing 2018 International Workshop CLL criteria.

Additional Efficacy Data

In the 65 patients who received liso-cel, the PR rate was 25% (95% CI, 14.8%-36.9%). The DOR rate at 12 months in those who achieved a PR as a best response was 60.3% (95% CI, 32.0%-79.8%); the 18-month DOR rate was 46.9% (95% CI, 21.4%-68.9%).

Although there was no statistical testing of minimal residual disease (MRD) negativity rate, in patients who achieved CR (n = 13) with liso-cel, the MRD negativity rate was 100% (95% CI, 75.3%-100%) and 92.3% (95%CI, 64%-99.8%) in the peripheral blood and bone marrow, respectively.

Safety Findings

The safety of the CAR T-cell therapy was evaluated in 89 patients enrolled in the study. Sixty percent of patients experienced serious toxicities and 1.1% experienced adverse effects (AEs) that proved to be fatal.

The most common AEs experienced by at least 10% of patients who received liso-cel in the study included febrile neutropenia (any grade, 12%; grade ≥3, 12%), tachycardia (21%; 0%), nausea (35%; 0%), diarrhea (30%; 1.1%), constipation (24%; 0%), abdominal pain (18%; 0%), vomiting (15%; 0%), fatigue (40; 4.5%), edema (30%; 4.5%), fever (27%; 1.1%), chills (17%; 1.1%), cytokine release syndrome (83%; 9%), infection with an unspecified pathogen (23%; 10%), upper respiratory tract infection (19%; 1.1%), viral infection (10%; 1.1%), reduced appetite (27%; 4.5%), tumor lysis syndrome (11%; 11%), musculoskeletal pain (42%; 1.1%), encephalopathy (44%; 18%), headache (28%; 1.1%), tremor (24%; 2.2%), dizziness (21%; 1.1%), motor dysfunction (14%; 2.2%), peripheral neuropathy (12%; 0%), taste disorder (10%; 0%), delirium (20%; 3.4%), insomnia (16%; 1.1%), anxiety (12%; 1.1%), renal failure (15%; 3.4%), dyspnea (27%; 8%), cough (20%; 0%), rash (23%; 2.2%), hypotension (17%; 0%), hemorrhage (16%; 1.1%), and hypertension (10%; 4.5%).

The grade 3 or 4 laboratory abnormalities reported in at least 10% of patients who received liso-cel on the study included decreases in neutrophil count (94%), lymphocyte count (87%), white blood cells (85%), platelet counts (53%), and hemoglobin (49%). Other grade 3 or 4 laboratory abnormalities included hypophosphatemia (24%), hyponatremia (18%), and hypocalcemia (11%).

References

1. US FDA approves Bristol Myers Squibb’s Breyanzi ® as the first and only CAR T cell therapy for adults with relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). News release. Bristol Myers Squibb. March 14, 2024. Accessed March 14, 2024.
2. Breyanzi. Prescribing information. Bristol Myers Squibb; 2024. Accessed March 14, 2024. https://packageinserts.bms.com/pi/pi_breyanzi.pdf