Bristol Myers Squibb bags USFDA nod for CAR T Cell Therapy Breyanzi

• 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 LBCL," the company stated in its recent release.

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 LBCL that is primary refractory or relapsed within 12 months after first-line therapy. An improvement in EFS represents an increase in the length of time in which patients are alive and without disease progression or in need of further treatment.

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

"As part of our commitment to developing innovative cancer treatments for patients with critical unmet need, Breyanzi offers a potentially curative option for more patients," said Ester Banque, senior vice president & general manager, U.S. Hematology, Bristol Myers Squibb. "Based on the demonstrated clinical benefit, this approval of Breyanzi underscores the significant advances we are making to deliver on the promise of cell therapy."

LBCL 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 LBCL has a life expectancy of just three to four months.

"Breyanzi represents a remarkable advance over a nearly 30-year standard of care, providing significantly improved efficacy with a well-established safety profile," said Manali Kamdar, M.D., lead investigator of the TRANSFORM study and Associate Professor, Clinical Director of Lymphoma Services, Division of Hematology, Hematologic Malignancies and Stem Cell Transplantation, University of Colorado Cancer Center. "This important milestone reinforces the benefit of offering a CAR T cell therapy option to patients earlier in their treatment journey and it's critical that we begin the work to implement this therapy into standard practice as a second-line treatment in order to help improve outcomes for more patients."

"Patients with large B-cell lymphoma whose disease does not respond to or relapses after first-line therapy often face lengthy and intensive cycles of chemotherapy with the goal of proceeding to stem cell transplant," said Lee Greenberger, Ph.D., Chief Scientific Officer of the Leukemia & Lymphoma Society (LLS). "As one of the earliest supporters of CAR T since the 1990's, LLS is excited to see the FDA approval of a CD19 CAR T cell therapy that has moved from later lines of therapy to a second-line option, which offers patients with relapsed or refractory large B-cell lymphoma the potential for long-term remission and the hope of a cure."

Breyanzi is the CAR T cell therapy that has been evaluated in a broad second-line patient population for LBCL in two distinct company-sponsored studies, including in patients whose disease relapsed within or later than 12 months following first-line treatment and regardless of transplant candidacy.

The approval of the expanded indications for Breyanzi is based on results from the pivotal Phase 3 TRANSFORM study in which adults with LBCL 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 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 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 showed, Breyanzi (n=92) more than quadrupled median EFS compared to standard therapy (n=92) (10.1 months vs. 2.3 months [HR: 0.34; 95% CI (0.22-0.52) p<0.0001]). The majority of patients achieved a CR with Breyanzi compared to less than half with standard therapy (66% [95% CI: 56% - 76%] vs. 39% [95% CI: 29% - 50%]; p<0.0001), with median duration of CR not reached in the Breyanzi arm (95% CI: 7.9-NR). Results also showed 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 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 LBCL 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 showed 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 CR 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 CR.

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. 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. 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). 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. In addition, the clinical profile of Breyanzi supported its use in a broad range of relapsed or refractory LBCL patients.

Breyanzi is broadly covered by commercial and government insurance programs in the U.S.