BREYANZI Dispersion for infusion Ref.[49783] Active ingredients: Lisocabtagene maraleucel

Pharmacotherapeutic group: Other antineoplastic agents
ATC code: not yet assigned

Mechanism of action

Breyanzi is a CD19-directed genetically modified autologous cellular immunotherapy administered as a defined composition to reduce variability in CD8+ and CD4+ T-cell dose. The CAR is comprised of a murine FMC63 monoclonal antibody-derived single chain variable fragment (scFv), IgG4 hinge region, CD28 transmembrane domain, 4-1BB (CD137) costimulatory domain, and CD3 zeta activation domain. CD3 zeta signalling is critical for initiating T-cell activation and antitumor activity, while 4-1BB (CD137) signalling enhances the expansion and persistence of Breyanzi (see also section 5.2).

CAR binding to CD19 expressed on the cell surface of tumour and normal B cells induces activation and proliferation of CAR T cells, release of pro-inflammatory cytokines, and cytotoxic killing of target cells.

Clinical efficacy and safety

TRANSCEND

The anti-tumour activity and safety of Breyanzi were evaluated in an open-label, multicentre, singlearm study, TRANSCEND (017001), in patients with relapsed or refractory (R/R) aggressive B-cell non-Hodgkin lymphoma (NHL). Eligible patients were ≥18 years with R/R DLBCL not otherwise specified (NOS), per WHO 2008 classification, including DLBCL arising from indolent lymphoma (transformed from follicular lymphoma, marginal zone lymphoma, chronic lymphocytic leukaemia/small lymphocytic leukaemia, Waldenström’s macroglobulinaemia, or other), and highgrade B-cell lymphoma; primary mediastinal large B-cell lymphoma (PMBCL) and follicular lymphoma grade 3B (FL3B), who had received at least 2 lines of therapy or after autologous hematopoietic stem cell transplant. Patients with other subtypes of DLBCL have not been included in the study and benefit-risk have not been established. The study included patients with eastern cooperative group (ECOG) performance status <2, prior autologous and/or allogenic haematopoietic stem cell transplant (HSCT), and secondary CNS lymphoma involvement. Patients who received prior CD19-directed therapy were eligible provided CD19-positivity was confirmed on a tumour biopsy at any time after CD19-directed therapy. The study excluded patients with a creatinine clearance of less than 30 mL/min, alanine aminotransferase >5 times the upper limit of normal or, left ventricular ejection fraction <40%.

There was no minimum requirement for blood counts; patients were eligible to enroll if they were assessed by the investigator to have adequate bone marrow function to receive lymphodepleting chemotherapy. See Table 4 for baseline demographic and disease-related characteristics.

Treatment consisted of lymphodepleting (LD) chemotherapy, fludarabine 30 mg/m² /day and cyclophosphamide 300 mg/m² /day for 3 days, followed by Breyanzi 2 to 7 days later. Among the patients treated within the range of 44-120 × 10⁶ CAR+ viable T cells, the median dose of Breyanzi was 87 × 10⁶ CAR+ viable T cells.

Anticancer therapy for disease control (bridging therapy) was permitted between apheresis and lymphodepletion. Of the 229 patients treated with Breyanzi, 60% received anticancer therapy for disease control; the type and duration of bridging therapy was left to the discretion of the investigator.

The median time from leukapheresis to product availability was 24 days (range: 17 to 51 days). In addition, the median time from leukapheresis to infusion was 38.5 days (range: 27 to 156 days).

Of 298 patients who underwent leukapheresis for whom Breyanzi was manufactured in the dose range of 44-120 × 10⁶ CAR+ viable T cells, 229 patients received Breyanzi and 69 patients did not. Of these 69 patients, there were 27 manufacturing failures including 2 patients who did not receive Breyanzi and 25 patients who received treatment with investigational product that did not meet release specifications. Forty-two other patients were not treated with Breyanzi, the most frequent reasons being death (n=29) or disease complications (n=6).

The number of patients who were evaluable for efficacy was 216 (Efficacy set). Thirteen patients were not evaluable for efficacy, including 10 patients who did not have baseline positron emission tomography-positive (PET+) disease, or confirmation of PET+ disease after anticancer therapy for disease control by Independent Review Committee (IRC), and 3 for other reasons.

Table 4 summarises the baseline patient and disease characteristics in the TRANSCEND study.

Table 4. Baseline demographic and disease-related characteristics for TRANSCEND:

^a MYC and BCL2 and/or BCL6 rearrangements with DLBCL histology.
^b Chemorefractory is defined as experiencing stable disease (SD) or progressive disease (PD) to last chemocontaining regimen or relapsed <12 months after autologous stem cell transplantation.
^c The status was refractory if a patient achieved less than a complete response (CR) to last prior therapy.
^d The status was relapsed if a patient achieved CR to last prior therapy.

Efficacy was assessed on the basis of the primary endpoint, overall response rate (ORR), and secondary endpoints which included complete response (CR) rate, duration of response (DOR) as determined by an independent review committee (Table 5 and Figure 1). The median on-study followup time was 19.9 months (range 0.2 to 45.2 months).

Table 5. TRANSCEND study: Response rate, duration of response (IRC assessment):

CI=confidence interval; CR=complete response; IRC=Independent Review Committee; KM=Kaplan-Meier; NR=not reached
^a Per the Lugano 2014 criteria, as assessed by IRC.
^b Deaths after initiation of anti-cancer treatment were considered as events.
^c KM method was used to obtain 2-sided 95% CIs.
⁺ Ongoing.

The median time to response (CR or partial response [PR]) was 1.0 months (range: 0.7 to 8.9 months). The median time to CR was 1.0 months (range: 0.8 to 12.5 months). Response durations were longer in patients who achieved a CR, as compared to patients with a best response of PR.

Six patients with secondary CNS lymphoma were treated and evaluable for efficacy in the TRANSCEND study. Three of these six patients achieved a CR; 2 of 3 patients had durable remissions of 23 months that remained ongoing at study completion. The safety profile of these patients with secondary CNS lymphoma was consistent with that observed in the overall population.

In the Efficacy set, the ORR results within PMBCL and FL3B were 79% (11/14 patients) and 100% (4/4 patients) respectively. CR rates were 50% for PMBCL and 100% for FL3B. The safety profile was consistent across these subtypes.

In the Efficacy set, the ORR results within patients with DLBCL transformed (t) from prior indolent lymphoma of FL, marginal cell lymphoma (MZL), chronic lymphocytic leukaemia/small lymphocytic lymphoma; (CLL/SLL), and Waldenstrom macroglobulinemia (WM) were 86% (38/44 patients), 43% (3/7 patients), 50% (2/4 patients) and 50% (½ patients), respectively. CR rates were 61.4% for tFL, 29% for tMZL, 25% for tCLL/SLL (Richter’s syndrome), and 0% for WM, respectively. The safety profile was consistent across these subtypes. Durable remissions (i.e. DOR ≥12 months) were observed in patients with tFL and tMZL, however, there is very limited experience for patients with tCLL/SLL (4 patients) and tWM (2 patients) in whom maximal DORs of 2 and 5.3 months, respectively were observed. The safety profile was consistent across these subtypes.

In clinical studies of Breyanzi, 89 (39%) of the 229 patients in TRANSCEND were 65 years of age or older, and 19 (8%) were 75 years of age or older. The safety or efficacy of Breyanzi observed between these patients and younger patients was similar.

Eleven patients received prior CD19-directed therapy and had efficacy and safety outcomes similar to the overall population. All patients had CD19 expression prior to Breyanzi infusion.

There is limited experience of the use of Breyanzi for patients with Eastern Cooperative Oncology Group (ECOG) performance status of 2 prior to apheresis (4 patients), and prior allogeneic HSCT (8 patients).

Amongst 229 Breyanzi-treated patients, the majority of patients (n=209) received Breyanzi within the recommended CD4:CD8 ratio range of 0.8 to 1.2. There is limited experience of the use of Breyanzi outside this CD4:CD8 ratio range (n=19 above 1.2, n=1 below 0.8) which therefore limits the interpretation of the data in this subgroup.

Of the 115 patients who achieved CR, 82 (71%) had remission lasting at least 6 months and 72 (63%) had remission lasting at least 12 months.

Figure 1. Duration of response for responders per IRC assessment, TRANSCEND Efficacy set:

CR = complete response; PR = partial response.
Deaths after initiation of anti-cancer treatment were considered as events.

Eleven patients with a history of hepatitis B or hepatitis C were treated with Breyanzi without hepatitis reactivation, while receiving antiviral suppressive therapy in accordance with clinical guidelines (see section 4.4).

TRANSCEND WORLD

TRANSCEND WORLD is an ongoing single-arm, multicentre, phase 2 study. Its Cohort 1 purpose is to provide clinical experience with Breyanzi in Europe for the treatment of adult patients 3L+ large B-cell lymphoma, defined as R/R DLBCL (DLBCL NOS [de novo], transformed FL), high-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements with DLBCL histology and FL3B per WHO 2016 classification. Patients previously treated with CD19-targeted therapy were excluded. See Table 6 below for baseline demographics and disease-related characteristics.

Table 6. Baseline demographic and disease-related characteristics for TRANSCEND WORLD (Cohort 1):

^a MYC and BCL2 and/or BCL6 rearrangements with DLBCL histology.
^b Chemorefractory is defined as experiencing stable disease (SD) or progressive disease (PD) to last chemocontaining regimen or relapsed <12 months after autologous stem cell transplantation.
^c The status was refractory if a patient achieved less than a complete response (CR) to last prior therapy.
^d The status was relapsed if a patient achieved CR to last prior therapy.

At the time of the most recent data cut-off (04 January 2021), 45 patients in cohort 1 had been leukapheresed and 36 patients treated with Breyanzi, with a median follow-up time of 11.6 months. The median time from leukapheresis to product availability was 29 days (range: 24 to 38 days). In the Breyanzi-treated group, the ORR was 61.1% (95% CI: 43.5-76.9), and the CR rate was 33.3% (95% CI: 18.6-51.0). The disease burden and baseline demographics were indicative of advanced, aggressive disease characteristics. The safety profile of Breyanzi was consistent with the overall pooled safety population. See section 4.8 for adverse drug reactions associated with lisocabtagene maraleucel.

Paediatric population

The European Medicines Agency has deferred the obligation to submit the results of studies with Breyanzi in one or more subsets of the paediatric population in paediatric patients weighing at least 6 kg for the treatment of mature B-cell neoplasms (see section 4.2 for information on paediatric use).