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New Medicines

Breyanzi (US) Relapsed or refractory large B cell lymphoma - third-line plus including diffuse large B-cell lymphoma (DLBCL), primary mediastinal B-cell lymphoma (PMBCL), and follicular lymphoma grade 3B (FL3B)

Information

Breyanzi (US)
New molecular entity
Bristol-Myers Squibb
Juno

Development and Regulatory status

None
Pre-registration (Filed)
Launched
Yes
Yes
May 21Launched in US [23].
Feb 21BMS are preparing for launch of Breyanzi in the US by setting up certified treatment centres. The aim is that patients won´t have to stay for prolonged periods in hospitals. They can be treated as outpatients, with close follow-up by the clinics for a week, and must remain close by for at least 4 weeks. The company has also set up digital temperature-tracking for patients via a smartphone app and disposable body-temperature sensing patch, and will provide 24/7 on-call support for patients and healthcare professionals via their website [22].
Feb 21Approved in the US to treat adults with some forms of non-Hodgkins lymphoma, including diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL), after at least two other types of systemic treatment have been tried [21].
Nov 20FDA decision delayed as it was unable to conduct an inspection of a third-party manufacturing facility in Texas during the current review cycle due to travel restrictions related to the COVID-19 pandemic [18].
Jul 20The EU MAA is based on results from TRANSCEND NHL 001 and additional data from the TRANSCEND WORLD study. The studies evaluated patients with R/R DLBCL and included patients with a broad range of histologies and high-risk disease as well as those who received liso-cel in the outpatient setting [17].
Jul 20Filed in the EU. Lisocabtagene is being reviewed under the EMA accelerated assessment programme which reduces the maximum time frame to 150 days for the CHMP to review the application [16,17].
May 20US FDA delays decision on approval of lisocabtagene maraleucel (liso-cel) for relapsed or refractory (R/R) large B-cell lymphoma after at least 2 prior therapies. Bristol Myers attributed the delay to its submission of additional information upon the request of the FDA. The new Prescription Drug User Fee Act (PDUFA) action date set by the FDA is November 16, 2020.[15]
Dec 19Filed in US [13]
Nov 19Bristol-Myers Squibb completes acquisition of Celgene
Aug 19PRIME status in EU
Apr 19Also has orphan drug status in EU [7].
Apr 19Lisocabtagene maraleucel has Regenerative Medicine Advanced Therapy (RMAT) designation for treatment of relapsed or refractory aggressive large B cell NHL, including DLBCL, in the US [7].
Dec 17US FDA grants orphan drug designation to lisocabtagene maraleucel for treatment of patients with DLBCL, chronic lymphocytic leukaemia and acute lymphoblastic leukaemia (precursor cell lymphoblastic leukaemia lymphoma) [7].
Nov 17EU filing will be via the centralised procedure [4].
Dec 16Granted breakthrough therapy status in the US for treatment of patients with relapsed/refractory aggressive large B-cell NHL, including diffuse large B-cell lymphoma (DLBCL), not otherwise specified (de novo or transformed from indolent lymphoma), primary mediastinal B-cell lymphoma (PMBCL) or grade 3B follicular lymphoma. Also granted PRIME designation in the EU for treatment of relapsed/refractory DLBCL [2].
Dec 16Juno Therapeutics plans to initiate a pivotal trial in patients with diffused large B cell lymphoma in the US in 2017 [2].

Category

Autologous CAR-T cell therapy. CD8 and CD4 T-lymphocytes are collected from the patient and modified genetically ex vivo with a lentiviral vector encoding an anti-CD19 CAR protein. Equal numbers of CD8 and then CD4 cells are re-infused as a one-off dose.
The two most common types of NHL are DLBCL and follicular lymphomas. The overall annual incidence of DLBCL in Europe is 3.8/100,000 but the incidence increases with age and varies considerably across Europe [1].
Relapsed or refractory large B cell lymphoma - third-line plus including diffuse large B-cell lymphoma (DLBCL), primary mediastinal B-cell lymphoma (PMBCL), and follicular lymphoma grade 3B (FL3B)
Intravenous infusion

Further information

Yes

Trial or other data

Dec 20PII TRANSCENDWORLD study (NCT03484702) is recruiting and due to complete collection of primary outcome data in Aug 21. PI TRANSCEND-NHL-001 study (NCT02631044) is now due to complete collection of primary outcome data in Dec 22 [20].
Oct 20A major difference in the manufacturing process to that of the other CAR-T therapies (axicabtagene and tisagenlecleucel) is that to produce liso-cel, the patient ’s CD4 and CD8 T cells are separately transduced and expanded and then administered back to the patient in equal target doses, which produces a consistent product for each patient [19].
Dec 19No UK trial sites [14]
Nov 19Pivotal Safety and Efficacy Results from Transcend NHL 001, a Multicenter Phase 1 Study of Lisocabtagene Maraleucel announced. A total of 342 pts with heavily pretreated and aggressive disease were leukapheresed; 268 pts received liso-cel (DL1, n=51; DL2, n=176; DL3, n=41). Liso-cel demonstrated durable clinical activity with a favorable safety profile with low incidence and late onset of CRS and NE which allowed for outpatient administration. Among pts evaluable for efficacy (n=255), ORR was 73% (95% CI, 67‒78); the CR rate was 53% (95% CI, 47‒59). Responses were similar across all pt subgroups. Median PFS was 6.8 mo (95% CI, 3.3‒11.8). Median OS was 19.9 mo (95% CI, 10.9‒NR). Overall, PFS after liso-cel infusion was substantially longer than PFS from the immediate prior therapy. Safety analysis showed 79% of pts had grade ≥3 TEAEs, primarily cytopenias (neutropenia, 60%; anemia, 37%; thrombocytopenia, 27%). CRS or NE occurred in 47% of pts. Any grade CRS occurred in 42% of pts at a median onset of 5 days; only 2% had grade ≥3 CRS.[9]
Aug 19PI (NCT02631044) study is expected to complete collection of primary outcome data in Dec 20. PII (NCT03484702) study is expected to complete primary outcome data collection in Aug 22 [6].
Apr 19Two studies (NCT02631044 and NCT03484702) will provide data in support of the EU licence application [8].
Jun 18PII PILOT trial to determine the efficacy and safety of lisocabtagene maraleucel in adult subjects with aggressive B-NHL (diffuse DLBCL, de novo or transformed follicular lymphoma, double/triple-hit lymphoma, follicular lymphoma grade 3B, primary central nervous system lymphoma and Richter´s transformation) starts (NCT03484702). 124 patients will be recruited in the EU (not UK) [6].
Nov 17PI TRANSCEND-NHL-001 study = NCT02631044 [5].
Jun 17Juno presents updated data at ASCO from its Transcend trial in relapsed and refractory (r/r) aggressive B cell non-Hodgkin lymphoma (NHL). Juno states that JCAR 017 targets CD19, a protein expressed on the surface of almost all B cell malignancies, and uses a defined composition of CD4 to CD8 T cells and a 4-1BB costimulatory domain, which differentiates it from other current CD19-directed CAR T product candidates. The PI study has treated 71 patients with r/r aggressive B cell NHL, including those with diffuse large B cell lymphoma (DLBCL), follicular lymphoma grade 3B or mantle cell lymphoma (MCL). This was a dose-finding study, following preconditioning agents fludarabine/cyclophosphamide lymphodepletion. In total, two analysis groups were presented for the DLBCL cohort: core and full. The core analysis, of 44 patients, includes those that represent the population that will move forward into the biotech’s upcoming pivotal trial, which will begin in H2 2017. This includes patients with DLBCL (de novo and transformed from follicular lymphoma). The full analysis represents all r/r patients in the DLBCL cohort, 55 patients in all, including the 11 patients with poor performance status or niche subtypes of aggressive NHL. When combining data across dose levels, the full data set shows the best ORR was 76% (41/54 patients) and CR 52%. And when using the core group, again combining data across dose levels, ORR hit 86% (38/44 patients) and the CR was 59%. 97% (37/38) of responding patients are alive and in follow up as of May 4, its cut-off date. But there was one death, in what Juno described as a Grade 5 adverse event of diffuse alveolar damage, which the investigator assessed as related to fludarabine, cyclophosphamide, and JCAR017 treatment, occurring on day 23. The 82-year-old patients was said to have refused mechanical ventilation for progressive respiratory failure, while neutropenic on growth factors and broad-spectrum antibiotics and antifungals. It also registered 18% (8/44 patients) having severe neurotoxicity. It was the fatal rates of neurotoxicity, notably cerebral oedema, that killed 5 patients on its other CAR-T med last year, leading to its discontinuation [3].
Dec 16Juno Therapeutics starts the PII portion of a PI/II trial of JCAR 017, in paediatric and young adult patients with relapsed/refractory CD19+ leukaemia (PLAT-02; NCT02028455). The study is designed to determine the maximum tolerated dose and preliminary efficacy and safety of JCAR 017. In the PI part, enrolment is restricted to patients who have received an allogeneic haematopoietic stem cell transplant (HSCT), and the PII part will recruit 70 patients (aged one to 26 years) irrespective of HSCT history, in the US [2].

Evidence based evaluations

Breyanzi (US) Non-Hodgkin lymphoma (NHL) - second-line in transplant eligible patients with relapsed/refractory diffuse large B-cell lymphoma NOS, high grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements with DLBCL histology, primary mediastinal large B-cell lymphoma, T cell/histiocyte-rich large B-cell lymphoma or follicular lymphoma grade 3B.

Information

Breyanzi (US)
Licence extension / variation
Bristol-Myers Squibb
Juno

Development and Regulatory status

Phase III Clinical Trials
Phase III Clinical Trials
Phase III Clinical Trials
Yes
Yes
Feb 21Data readout for TRANSFORM still anticipated 2021 [6].
Mar 20Has orphan drug status in US & EU [3].
Mar 20Lisocabtagene maraleucel has Regenerative Medicine Advanced Therapy (RMAT) designation for treatment of relapsed or refractory aggressive large B cell NHL, including DLBCL, in the US. It also has breakthrough therapy status in US and PRIME status in EU for relapsed/refractory DCBCL [3].
Feb 20Data readout from PIII TRANSFORM study expected in 2021; it is assumed filings will follow should results be positive [4].

Category

Autologous CAR-T cell therapy. CD8 and CD4 T-lymphocytes are collected from the patient and modified genetically ex vivo with a lentiviral vector encoding an anti-CD19 CAR protein. Equal numbers of CD8 and then CD4 cells are re-infused as a one-off dose.
The two most common types of NHL are DLBCL and follicular lymphomas. The overall annual incidence of DLBCL in Europe is 3.8/100,000 but the incidence increases with age and varies considerably across Europe [1].
Non-Hodgkin lymphoma (NHL) - second-line in transplant eligible patients with relapsed/refractory diffuse large B-cell lymphoma NOS, high grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements with DLBCL histology, primary mediastinal large B-cell lymphoma, T cell/histiocyte-rich large B-cell lymphoma or follicular lymphoma grade 3B.
Intravenous infusion

Further information

Yes

Trial or other data

Sep 20PIII TRANSFORM study continues to recruit; collection of primary outcome data now due to complete Jan 24 [5].
Feb 20PIII TRANSFORM study is still recruiting; collection of primary outcome data now expected to complete Oct 23 [2].
Mar 19PIII TRANSFORM study is recruiting [2].
Oct 18PIII TRANSFORM trial to compare the safety and efficacy of lisocabtagene maraleucel to standard of care in adult patients with high-risk, transplant-eligible relapsed or refractory aggressive B-cell NHLs starts (NCT03575351). 182 patients will be recruited in the US, Canada, EU & the UK. Collection of primary outcome data is expected to complete May 23 [2].

Evidence based evaluations

Breyanzi (US) Non-Hodgkin lymphoma (NHL) - second-line in transplant-ineligible patients in relapsed/refractory aggressive B-cell NHL (including diffuse large B-cell lymphoma, high-grade B-cell lymphoma, follicular lymphoma)

Information

Breyanzi (US)
Licence extension / variation
Bristol-Myers Squibb
Juno

Development and Regulatory status

Phase II Clinical Trials
Phase II Clinical Trials
Phase II Clinical Trials
Yes
Yes
Feb 21Data readout from TRANSCEND PILOT study (transplant-ineligible) expected in 2021; presume filings will follow [8].
Mar 20Has orphan drug status in US & EU [3].
Mar 20Lisocabtagene maraleucel has Regenerative Medicine Advanced Therapy (RMAT) designation for treatment of relapsed or refractory aggressive large B cell NHL, including DLBCL, in the US. It also has breakthrough therapy status in US and PRIME status in EU for relapsed/refractory DCBCL [3].

Category

Autologous CAR-T cell therapy. CD8 and CD4 T-lymphocytes are collected from the patient and modified genetically ex vivo with a lentiviral vector encoding an anti-CD19 CAR protein. Equal numbers of CD8 and then CD4 cells are re-infused as a one-off dose.
The two most common types of NHL are DLBCL and follicular lymphomas. The overall annual incidence of DLBCL in Europe is 3.8/100,000 but the incidence increases with age and varies considerably across Europe [1].
Non-Hodgkin lymphoma (NHL) - second-line in transplant-ineligible patients in relapsed/refractory aggressive B-cell NHL (including diffuse large B-cell lymphoma, high-grade B-cell lymphoma, follicular lymphoma)
Intravenous infusion

Further information

Yes

Trial or other data

Feb 21PII TRANSCEND-PILOT-017006 study (NCT03483103) is no longer recruiting; collection of primary outcome data now expected to complete Dec 2022. 61 patients have been recruited [7].
Dec 20PII TRANSCENDWORLD PILOT study (NCT03484702) is also recruiting; collection of primary outcome data due to complete Aug 21 [6].
Aug 20PII TRANSCEND-PILOT-017006 study (NCT03483103) is recruiting; collection of primary outcome data expected to complete early than previously planned in April 21 [6].
May 20In an interim analysis of 29 pts from the PII PILOT trial (NCT03483103) , ORR was 89%, CRR was 56% and PR was 33% at median follow up of 5 months. [5]
Feb 20PII TRANSCENDWORLD PILOT study (NCT03484702) is recruiting; collection of primary outcome data due to complete May 20. PII TRANSCEND-PILOT-017006 study(NCT03483103) is also recruiting and due to complete collection of primary outcome data in Dec 21 [2].
Dec 19Positive data from PII TRANSCENDWORLD PILOT study (NCT03484702) from 12 second-line pts with relapsed or refractory large B-cell NHL who were ineligible for high-dose chemotherapy and hematopoietic stem cell transplant (HSCT). These pts received liso-cel at a target dose of 100 × 106 CAR+ T cells following lymphodepletion and could be treated in the outpatient setting. At the time of data cutoff, 13 pts had undergone lymphodepletion followed by liso-cel and of the 12 pts eligible for evaluation, all achieved a response with 50% achieving a complte response and 58% maintaining response levels at 3 months following liso-cel. Of these, 61% had at least one grade 3 or higher TEAE (primarily cytopenias) and 31% had prolonged grade 3 or higher cytopenias at day 29. No pts had grade 3 or higher CRS and no none experienced NE of any grade. Grade 1-2 CRS occurred in 23% of pts. There were no grade 5 TEAEs. Of the 6 pts treated in the outpatient setting, none were admitted to the hospital in the first 29 days following liso-cel infusion [4].
Jul 18PII TRANSCEND-PILOT-017006 study to determine the efficacy and safety of lisocabtagene maraleucel (JCAR017) in adult subjects who have relapsed from, or are refractory to, a single line of immunochemotherapy for aggressive B-cell non-Hodgkin lymphoma (NHL) and are ineligible for hematopoietic stem cell transplant (based on age, performance status, and/or comorbidities) starts (NCT03483103). 56 subjects will receive treatment with lisocabtagene maraleucel and will be followed for 2 years for safety, pharmacokinetics and biomarkers, disease status, quality of life, and survival. Lisocabtagene maraleucel will be given at a dose of 100×10^6 CAR+ T cells (50×10^6 CD8+ CAR+ T cells and 50×10^6 CD4+ CAR+ T cells), will be given IV in a single-dose schedule on Day 1 (between 2 and 7 days following the completion of lymphodepleting chemotherapy). Patients will be recruited in the US. Collection of primary outcome data due to complete Dec 21 [2].
Jun 18Celgene initiated the PII TRANSCENDWORLD pilot trial to determine the efficacy and safety of lisocabtagene maraleucel in adult patients with aggressive B-NHL (diffuse large B-cell lymphoma (DLBCL) NOS [de novo or transformed follicular lymphoma (tFL)], double/triple-hit lymphoma [DHL/THL], follicular lymphoma Grade 3B [FL3B], primary central nervous system lymphoma and Richter´s transformation (EudraCT2017-000106-38; JCAR017BCM001; U1111-1209-4055; NCT03484702). The open-label trial is enrolling approximately 116 patients in Austria, Belgium, Finland, France, Italy, Japan, Netherlands, Spain, Switzerland and United Kingdom [3].

Evidence based evaluations

Breyanzi (US) Relapsed or refractory chronic lymphocytic leukaemia (CLL) or small lymphocytic lymphoma (SLL) - in combination with ibrutinib

Information

Breyanzi (US)
Licence extension / variation
Bristol-Myers Squibb
Juno

Development and Regulatory status

None
None
Phase II Clinical Trials
Yes
Mar 20Has orphan drug status in US for CLL [4].

Category

Autologous CAR-T cell therapy. CD8 and CD4 T-lymphocytes are collected from the patient and modified genetically ex vivo with a lentiviral vector encoding an anti-CD19 CAR protein. Equal numbers of CD8 and then CD4 cells are re-infused as a one-off dose.
CLL is the most common leukaemia in the Western world with an incidence of 4.2 per 100,000/year. The incidence increases to >30 per 100,000/year at an age of >80 years [1].
Relapsed or refractory chronic lymphocytic leukaemia (CLL) or small lymphocytic lymphoma (SLL) - in combination with ibrutinib
Intravenous infusion

Trial or other data

Aug 20PI/II TRANSCEND-CLL-004 (NCT03331198) study is still recruiting; collection of primary outcome data now due to complete Oct 21 [5].
Feb 20PI/II TRANSCEND-CLL-004 (NCT03331198) study is recruiting. Collection of primary outcome data due to complete Dec 20 [2].
Dec 19Positive data from PI/II TRANSCEND CLL 004 study show that, 23 treatment experienced pts with CLL/SLL who had received liso-cel target doses of 50 × 106 (n=9) or 100 × 106 (n=14) CAR+ T cells following lymphodepletion acheived an overall response rate (ORR) with liso-cel of 81.5% (18/22, 95% CI: 59.7 – 94.8) with 45.5% achieving a complete response (CR) at median follow-up of 11 months. In pts that had failed a BTK inhibitor and venetoclax, the ORR was 89% (8/9, 95% CI: 51.8 – 99.7) with 67% (6/9) achieving a CR. By day 30 following treatment, 68% had achieved an early objective response with 10 of 12 responders at 6 months remaining progression-free after at least 9 months, and 8 pts in response for >12 months. Adverse events (TEAE) of any grade occurred in all pts with 96% experiencing > grade 3 TEAE. The most common adverse effects were anemia (78%), thrombocytopenia (70%), neutropenia (56.5%), leukopenia (43.5%), febrile neutropenia (26%), lymphopenia (26%) and 9% had cytokine release syndrome (CRS). Overall, 74% of pts had CRS of any grade and 39% had neurological events (NE) of any grade and 74% were treated with tocilizumab or steroids, while 22% had grade 3 or higher NE. Median time to onset of CRS was 4 days (range 1-10) and of NE was 4 days (range 2-21). Incidence and severity of CRS and NEs were similar for patients who failed a BTK inhibitor and venetoclax [3].
Dec 17PI/II TRANSCEND-CLL-004 trial to evaluate safety, efficacy, and pharmacokinetics of JCAR 017 in combination with ibrutinib in patients with relapsed or refractory chronic lymphocytic leukaemia (CLL) or small lymphocytic lymphoma (SLL) starts (NCT03331198). The randomised, open-label trial intends to enrol approximately 205 patients in the US [2].

Breyanzi (US) Relapsed/refractory indolent B-cell non-Hodgkin lymphoma (NHL)

Information

Breyanzi (US)
Licence extension / variation
Bristol-Myers Squibb
Juno

Development and Regulatory status

Phase II Clinical Trials
Phase II Clinical Trials
Phase II Clinical Trials

Category

Autologous CAR-T cell therapy. CD8 and CD4 T-lymphocytes are collected from the patient and modified genetically ex vivo with a lentiviral vector encoding an anti-CD19 CAR protein. Equal numbers of CD8 and then CD4 cells are re-infused as a one-off dose.
The most common B-cell lymphomas are follicular lymphoma (FL), which is usually a slow growing, low grade (indolent) form of NHL, and diffuse large B-cell lymphoma, (DLBCL), a fast-growing, high-grade (aggressive) form of NHL. 2,168 people were diagnosed with FL in England in 2017. Most people (80%) with FL present with advanced disease [1].
Relapsed/refractory indolent B-cell non-Hodgkin lymphoma (NHL)
Intravenous infusion

Trial or other data

Feb 21PII TRANSCEND FL trial is recruiting [2].
May 20May 20: PII TRANSCEND FL trial to evaluate the safety and efficacy of lisocabtagene maraleucel in adult patients with high-risk, relapsed or refractory indolent B-cell NHL starts (NCT04245839; EudraCT2019-004081-18; JCAR017-FOL-001; U1111-1244-9768). The study is divided into three periods: Pretreatment, which consists of screening assessments, leukapheresis and the Pretreatment evaluation; Treatment, which starts with the administration of lymphodepleting (LD) chemotherapy and continues through JCAR017 administration at Day 1 with follow-up through Day 29; Posttreatment, which includes follow-up assessments for disease status and safety for 2 years. The open-label, single arm, multicenter trial intends to enrol 188 adults in countries including the UK (at UCL in London and The Chrisie in Manchester), US and Europe. Subjects will be treated with fludarabine IV (30 mg/m2/day for 3 days) and cyclophosphamide IV (300 mg/m2/day for 3 days) prior to JCAR017 infusion. JCAR017 will be infused on Day 1 at a dose of 100 × 10^6 CAR-positive viable T cells (CAR+ T cells), 2 to 7 days after completion of LD chemotherapy. Each JCAR017 dose includes CD4+ CAR+ T cells and CD8+ CAR+ T cells. Primary outcome is complete response rate; collection of these data is due to complete Apr 24 [2].