Breyanzi (lisocabtagene maraleucel) Gets FDA Approval for Relapsed or Refractory LBCL After One Prior Therapy

The new FDA approval gives Breyanzi (lisocabtagene maraleucel) the broadest patient eligibility of any CAR T-cell therapy in relapsed or refractory LBCL. Product logo and product image courtesy of Bristol Myers Squibb.

Lymphoma is one of the most aggressive types of cancer. Lymphoma targets the immune system of the body as it affects the lymphocytes (T cells and B cells), the fighters of the body’s foreign invaders. There are two distinct types of lymphoma, Hodgkin’s lymphoma and non-Hodgkin’s lymphoma. Hodgkin’s lymphoma is one of the highly treatable types of cancer.

Large B-cell lymphoma (LBCL) is a type of non-Hodgkin’s lymphoma. There are around 150,000 new cases of LBCL annually worldwide. The standard of care therapy for LBCL usually includes a combination of chemotherapy and Rituxan (rituximab), with or without radiation therapy.  The five-year relative survival rate for diffuse large B-cell lymphoma (DLBCL), a common type of non-Hodgkin’s lymphoma, is 64 percent based on people diagnosed between 2011 and 2017. According to a 2018 study, the relapse rate of DLBCL is 40 percent in the rituximab era and individuals that relapsed within a year do poorly with salvage treatment.

The latest scientific advancements to treat cancer involve chimeric antigen receptor (CAR) T-cell therapy. Kymriah (tisagenlecleucel) was the first CAR T-cell therapy to be approved by the US Food and Drug Administration (FDA), and since Kymriah’s approval in 2017, the FDA approved a total of six CAR T-cell therapies.

On June 24^th, 2022, Bristol Myers Squibb announced that Breyanzi (lisocabtagene maraleucel), a CD19-directed CAR T-cell therapy has received FDA approval to treat adult patients with LBCL, including DLBCL not otherwise specified (including DLBCL arising from indolent lymphoma), primary mediastinal large B-cell lymphoma, high-grade 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.

These are expanded indications after the FDA’s first approval of Breyanzi back in February 2021. The new approval now gives Breyanzi the widest patient eligibility of any CAR T-cell therapy in relapsed or refractory LBCL. Patients with primary central nervous system lymphoma are not eligible for Breyanzi treatment.

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The Development Technique of Breyanzi (lisocabtagene maraleucel)

Treatment with Breyanzi is a tailored method of treatment which involves the genetic reprogramming of T cells. The T cells of the LBCL patient are collected by a leukapheresis technique which helps to isolate and collect T cells from the blood. The purified CD4-positive and CD8-positive T cells are then separately activated and transduced with a lentiviral vector which has the anti-CD19 CAR transgene and is replication-incompetent. The transduced T cells will then be able to express CARs (chimeric antigen receptors) targeting CD19 and CD19 is a cell surface molecule on B cells and B cell malignancies.

The CAR T cells are then replicated into millions of copies via cell culture and are transported to the lymphoma treatment facility. The LBCL patient undergoes a short span of chemotherapy called lymphodepleting chemotherapy which is usually given two to 14 days before CAR T-cell therapy to reduce the T cell population in the body and make room for new CAR T cells. After the preliminary chemotherapy, the patient receives an intravenous infusion of CAR T cells. Post-infusion, the patient is closely monitored for adverse reactions such as cytokine release syndrome and neurologic toxicities.

WHY CD19?

Immunotherapy techniques use monoclonal antibodies to target malignant cells. Rituximab, a chimeric anti-CD20 monoclonal antibody, became a breakthrough treatment method in 1997 for non-Hodgkin’s lymphoma. While C19 and C20 are both consistently and highly expressed in B-cell lymphomas, CD19 expression is more homogenous and is preserved in small CD20-negative tumor subsets.

Outcomes of Clinical Trials for Breyanzi

Breyanzi was evaluated in a broad second-line patient population for LBCL in two distinct studies, TRANSFORM and PILOT.

TRANSFORM (NCT03575351) is a pivotal, global, randomized, multicenter Phase III trial evaluating Breyanzi (lisocabtagene maraleucel) compared to current standard therapy regimens. This trial involved 184 patients between 18 to 75 years of age with LBCL that was primary refractory or relapsed within 12 months after CD20-antibody and anthracycline containing first-line therapy.

The patients were randomized and grouped into Arm A or Arm B. Arm A underwent a standard of care salvage therapy (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]) followed by high-dose chemotherapy and HSCT. Arm B received a lymphodepleting therapy followed by Breyanzi.

The TRANSFORM trial results showed that most of the patients (66 percent) showed a complete response (CR) with Breyanzi when compared to less than half of the patients (39 percent) with standard therapy. Breyanzi more than quadrupled the median event-free survival (EFS) compared to standard therapy (10.1 months vs. 2.3 months). In addition, Breyanzi more than doubled progression-free survival (PFS) compared to standard therapy (median PFS: 14.8 months vs. 5.7 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, MD, lead investigator of the TRANSFORM study in Bristol Myers Squibb’s press release.

“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,” added Dr. Kamdar.

PILOT (NCT03483103) is a Phase II, open-label, multicenter study evaluating the efficacy and safety of Breyanzi (lisocabtagene maraleucel) in 61 adult patients with primary refractory or relapsed LBCL who were ineligible for HSCT due to age, performance status and/or comorbidities. Breyanzi showed durable and deep responses with an overall response rate of 80 percent and a complete response rate of 54 percent. Complete response was achieved with a median time of one month.

“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 and general manager, US Hematology, Bristol Myers Squibb in the company’s press release. “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.”