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FDA has approved CAR T cell therapy Breyanzi for relapsed or refractory large B-cell lymphoma after one prior therapy


Thr U.S. Food and Drug Administration ( FDA ) has approved Breyanzi ( Lisocabtagene maraleucel ), a CD19-directed chimeric antigen receptor ( CAR ) T cell therapy, for the treatment of adult patients with large B-cell lymphoma ( LBCL ), including diffuse large B-cell lymphoma ( DLBCL ) not otherwise specified ( including DLBCL arising from indolent lymphoma ), high-grade B-cell lymphoma, primary mediastinal large B-cell lymphoma, and follicular lymphoma grade 3B, who have:

Refractory disease to first-line chemoimmunotherapy or relapse within 12 months of first-line chemoimmunotherapy; or

Refractory disease to first-line chemoimmunotherapy or relapse after first-line chemoimmunotherapy and are not eligible for hematopoietic stem cell transplant ( HSCT ) due to comorbidities or age.

With these two new indications, Breyanzi now has the broadest patient eligibility of any CAR T cell therapy in relapsed or refractory large B-cell lymphoma.
Breyanzi is not indicated for the treatment of patients with primary central nervous system lymphoma.

Breyanzi has demonstrated clinically meaningful and statistically significant improvements in event-free survival ( EFS ), complete responses ( CR ) and progression-free survival ( PFS ) compared to standard therapy in patients with large B-cell lymphoma that is primary refractory or relapsed within 12 months after first-line therapy.

Breyanzi, a differentiated CAR T cell therapy, is made from a patient’s T cells, which are collected and genetically reengineered to become CAR T cells that are thendelivered via infusion as a one-time treatment.
Breyanzi can be administered in the inpatient or outpatient setting at a certified treatment center.

Large B-cell lymphoma is a difficult-to-treat and aggressive blood cancer, and up to 40% of patients have disease that is refractory to or relapses after initial therapy.
Historically, the only potential cure for these patients is the current standard of care consisting of intensive hospital-based salvage immunochemotherapy followed by high-dose chemotherapy and HSCT in those whose disease responds to the salvage therapy. However, half of patients are not considered candidates for a stem cell transplant due to age and/or comorbidities, and only an estimated 25% of those who are candidates are able to receive a stem cell transplant and experience long-term clinical benefit.
For patients who are not considered candidates for stem cell transplant, treatment options are limited. If left untreated, relapsed or refractory large B-cell lymphoma has a life expectancy of just three to four months.

The approval of the expanded indications for Breyanzi is based on results from the pivotal phase 3 TRANSFORM study in which adults with large B-cell lymphoma that was primary refractory or relapsed within 12 months of front-line therapy were randomized to receive Breyanzi or standard therapy consisting of salvage immunochemotherapy, and if responsive, high-dose chemotherapy and HSCT.
The trial has included patients with diverse histologic subtypes and high-risk features, and offered a patient-centric design, allowing for bridging immunochemotherapy in the Breyanzi arm for disease control, which reflects real-world clinical practice and allowed for inclusion of patients with more aggressive and fast-progressing disease.
Due to the high rate of patients whose disease does not respond to salvage immunochemotherapy, the trial has also allowed for crossover from the standard therapy arm to the Breyanzi arm if patients did not derive a response after three cycles of salvage chemotherapy or had disease progression at any time.

Results from the TRANSFORM study have shown: Breyanzi ( n=92 ) has more than quadrupled median EFS compared to standard therapy ( n=92 ) ( 10.1 months vs. 2.3 months [ hazard ratio, HR: 0.34; 95% CI ( 0.22-0.52 ) p less than 0.0001 ] ).
The majority of patients has achieved a colplete response ( CR ) with Breyanzi compared to less than half with standard therapy ( 66% [ 95% CI: 56-76% ] versus 39% [ 95% CI: 29- 50% ]; p less than 0.0001 ), with median duration of complete response not-reached in the Breyanzi arm ( 95% CI: 7.9-NR ).
Results have also shown Breyanzi more than doubled PFS versus standard therapy ( median PFS: 14.8 months vs. 5.7 months [ HR: 0.41; 95% CI: 0.25-0.66; p=0.0001 ] ).
In the study, nearly all patients ( 97% ) in the Breyanzi arm have received treatment versus less than half ( 47% ) of patients who completed high-dose chemotherapy and autologous HSCT in the standard therapy arm.

The efficacy of Breyanzi in the second-line setting was also based on data from the phase 2 PILOT study, in which 61 adults with primary refractory or relapsed large B-cell lymphoma who were not considered candidates for stem cell transplant were treated with Breyanzi.
The PILOT study enrolled a broad patient population based on age, performance status and/or organ function and comorbidities, and regardless of time to relapse following first-line treatment.
Breyanzi has shown deep and durable responses, with an overall response rate of 80%, the study’s primary endpoint, and a CR rate of 54%, with median time to complete response of one month ( range: 0.8 – 6.9 months ).
Median duration of response was 11.2 months, with the median duration of response not reached for those patients who achieved a complete response.

Breyanzi has a well-established safety profile and based on results from the TRANSFORM and PILOT studies, occurrences of CRS and neurologic events were generally low grade and mostly resolved quickly with standard protocols, and without the use of prophylactic steroids.

Any-grade CRS was reported in less than half of patients ( 45%; 68/150 ), with grade 3 CRS reported in 1.3% of patients.
Median time to onset of CRS was four days ( range: 1 to 63 days ) and median duration of CRS was four days ( range: 1 to 16 days ).

Any-grade neurologic events were reported in 27% ( 41/150 ) of patients treated with Breyanzi, with grade 3 neurologic events reported in 7% of patients.
The median time to onset of neurologic events was eight days ( range: 1 to 63 days ).
The median duration of neurologic toxicities was six days ( range: 1 to 119 days ).

The delayed onset of CRS and neurologic events allowed for the option of outpatient treatment and management of patients.

Breyanzi is a CD-19 directed CAR T cell therapy, administered as a defined composition to reduce variability of the CD8 and CD4 component dose.
Breyanzi has a 4-1BB costimulatory domain which enhances the expansion and persistence of the CAR T cells.

Breyanzi was previously approved by the U.S. Food and Drug Administration for the treatment of adult patients with relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy, including diffuse large B-cell lymphoma ( DLBCL ) not otherwise specified ( including DLBCL arising from indolent lymphoma ), high-grade B-cell lymphoma, primary mediastinal large B-cell lymphoma, and follicular lymphoma grade 3B.

Clinical trial

A) TRANSFORM is a pivotal, global, randomized, multicenter phase 3 trial evaluating Breyanzi compared to current standard therapy regimens ( Platinum-based salvage chemotherapy followed by high-dose chemotherapy and HSCT in patients responding to salvage chemotherapy ) in patients with large B-cell lymphoma that was primary refractory or relapsed within 12 months after CD20-antibody and anthracycline containing first-line therapy.
Patients were randomized to receive Breyanzi or standard of care salvage therapy, including Rituximab plus Dexamethasone, high-dose Cytarabine, and Cisplatin ( R-DHAP ), Rituximab plus Ifosfamide, Carboplatin and Etoposide ( R-ICE ), or Rituximab plus Gemcitabine, Dexamethasone and Cisplatin ( R-GDP ) per the investigators’ choice before proceeding to high-dose chemotherapy ( HDCT ) and hematopoietic stem cell transplant ( HSCT ).
The primary endpoint of the study was event-free survival, defined as time from randomization to death from any cause, progressive disease, failure to achieve complete response or partial response, or start of new antineoplastic therapy due to efficacy concerns, whichever occurs first.
Complete response rate was a key secondary endpoint. Other efficacy endpoints have included progression-free survival, overall survival, overall response rate and duration of response.

B) PILOT is a multicenter phase 2 trial evaluating Breyanzi as a second-line therapy in adults with relapsed or refractory large B-cell lymphoma after front-line therapy who are not considered candidates for hematopoietic stem cell transplant ( HSCT ).
All enrolled patients have relapsed or refractory large B-cell lymphoma after treatment with a single line of chemoimmunotherapy containing an anthracycline and a CD20-targeted agent.
The primary endpoint of the study is overall response rate. Other efficacy endpoints include complete response rate, duration of response, progression-free survival, event-free survival and overall survival. ( Xagena )

Source: BMS, 2022

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