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36461111000001102

New Medicines

YescartaRelapsed or refractory follicular lymphoma - fourth-line

Information

Yescarta
Licence extension / variation
Gilead Sciences
Kite

Development and Regulatory status

None
Launched
Launched
Yes
Yes
Jun 22Approved in EU for treatment of adults with relapsed or refractory follicular lymphoma after three or more lines of systemic therapy [17].
Apr 22Recommended for EU approval by CHMP – the extension to the existing indication is for “the treatment of adult patients with relapsed or refractory follicular lymphoma (FL) after three or more lines of systemic therapy” [16].
Dec 21Currently under review in the EU for treatment of adults with relapsed or refractory FL. Was filed in Oct 21 [14,15].
Jul 21Has breakthrough therapy status in US for r/r FL [11].
Mar 21Approved in US for treatment of adults with relapsed or refractory follicular lymphoma [10].
Dec 20FDA has accepted sBLA and granted Priority Review designation, with a target action date of 5/3/21. Application is based on data from PII ZUMA-5 trial [9].
Sep 20Kite has submitted a supplemental Biologics License Application (sBLA) to the U.S. FDA for axicabtagene ciloleucel for the treatment of relapsed or refractory follicular lymphoma and marginal zone lymphoma after two or more prior lines of systemic therapy [6].
Apr 19Has orphan drug status in EU and US for follicular lymphoma [3].

Category

Autologous chimeric antigen receptor (CAR)-T cell therapy. T-lymphocytes are collected from the patient by leukapheresis and modified genetically ex vivo using a retroviral vector encoding an anti-CD19 CAR protein. Re-infused as a single dose.
NHL can be divided into two prognostic groups: low-grade (indolent) or high-grade (aggressive). Follicular lymphoma is an indolent form of NHL and accounts for 20-25% of all NHL. The annual incidence of follicular lymphomas has increased from 2-3 per 100,000 during the 1950s to 5-7 per 100,000 recently [1].
Relapsed or refractory follicular lymphoma - fourth-line
Intravenous infusion

Further information

Yes

Trial or other data

Dec 21Follow-up data from PII ZUMA-5 shows long-term survival benefit with axi-cel in pts with R/R indolent NHL who have failed > 2 lines of therapy. The analysis includes 110 pts (86 with FL, 24 with MZL). After a median follow-up of 30.9 months for FL and 23.8 months for MZL, 94% with FL had an OR including 79% with a CR. The estimated DOR and PFS medians were 38.6 months and 39.6 months in patients with FL, respectively. Median OS was not reached, but estimated OS rate was 81% at 24 months. Among pts with MZL, 83% had an OR, with 63% achieving a CR. Median DOR and OS were not reached, but pts had an estimated 70% OS rate at 24 months. Median PFS was 17.3 months. The treatment was well tolerated, as reported in previous studies with this therapy. [13]
Aug 21PII ZUMA-5 trial is no longer recruiting and now due to complete collection of primary outcome data in Feb 22 [12].
Dec 20Primary analysis of PII ZUMA-5 trial shows high response rates in indolent non-Hodgkin lymphoma. In study (n=104), 92% of patients responded after a single infusion, including 76% achieving a complete response at a median follow-up of 17.5 months [9].
Nov 20PII ZUMA-5 trial is still recruiting; collection of primary outcome data now anticipated to finish in Feb 22 [8].
May 20Data from PII ZUMA-5 trial presented at the annual ASCO meeting. After a single infusion of Yescarta, 93% of patients (n=96 evaluable for efficacy) responded, with 80% patients achieving a complete response (CR) as assessed by an independent review committee. With a median follow-up of 15.3 months in all patients, median duration of response (DOR) was 20.8 months, median PFS was 23.5 months and median OS was not reached [7].
Apr 20Axicabtagene has been prioritised for potential TA guidance production. Topic has been passed to scoping team to prepare for a consultation exercise [5].
Dec 19No UK trial sites [4].
Mar 19PII ZUMA-5 trial (NCT03105336) is recruiting [2].
Jun 17PII ZUMA-5 trial to evaluate safety and efficacy of axicabtagene ciloleucel in patients with relapsed or refractory indolent non-Hodgkins lymphoma starts (KTE-C19-105; NCT03105336). The single-group assignment trial intends to enrol approximately 160 patients in the US & France. Primary outcome is objective response rate; collection of these data is due to complete Mar 20 [2].

Evidence based evaluations

YescartaDiffuse large B-cell lymphoma - second-line

Information

Yescarta
Licence extension / variation
Gilead Sciences
Kite

Development and Regulatory status

None
Pre-registration (Filed)
Launched
Yes
Apr 22Approved in the US for treating patients with large B-cell lymphoma that is refractory to one prior therapy or that relapses within 12 months of first-line chemoimmunotherapy [16].
Nov 21Filed in the EU [14].
Sep 21Filed in the US [11].
Jun 21Following positive PIII trial results (ZUMA-7), Kite plan to initiate discussions later this year with the FDA, EMA and other global health authorities for a licence extension to the second-line setting for Yescarta [10].
May 20Has orphan drug status in EU [6].

Category

Autologous chimeric antigen receptor (CAR)-T cell therapy. T-lymphocytes are collected from the patient by leukapheresis and modified genetically ex vivo using a retroviral vector encoding an anti-CD19 CAR protein. Re-infused as a single dose.
12,294 people were diagnosed with non-Hodgkin’s lymphoma in the UK in 2009 (info.cancerresearchuk.org); DLBCL accounts for ~ 40% of all cases (www.macmillan.org.uk).
Diffuse large B-cell lymphoma - second-line
Intravenous infusion

Further information

Yes

Trial or other data

Dec 21PIII ZUMA-7 trial (n=359) found axicabtagene ciloleucel therapy was superior to standard care for event-free survival (median 8.3 v 2.0 months; HR for event or death: 0.40; 95% CI, 0.31 to 0.51; P<0.001) [15].
Dec 21Results of interim analysis of PIII ZUMA-3 study (n=359) are published in NEJM [13].
Oct 21ZUMA-7 now on course to complete collection of all primary outcome data in Jan 23 [12].
Jun 21Kite announced top-line results from the primary analysis of the randomised PIII global, multicentre study ZUMA-7 (n=359) showing superiority of axicabtagene ciloleucel (Yescarta) vs standard of care (SOC) in second-line relapsed or refractory large B-cell lymphoma (LBCL). With a median follow-up of two years, the study met the primary endpoint of event-free survival (EFS; hazard ratio 0.398, p <0.0001). The study also met the key secondary endpoint of objective response rate (ORR). The interim analysis of overall survival (OS) showed a trend favouring Yescarta; however, the data are immature at this time, and further analyses are planned for the future. Safety results from the study were consistent with or lower than the known safety profile of Yescarta for the treatment of LBCL in the third-line setting. 6% of patients experienced cytokine release syndrome (CRS) Grade 3 or higher, with a median onset of 3 days, and 21% experienced neurological events Grade 3 or higher. No new safety concerns were identified [10].
Oct 20PIII ZUMA-7 study has finished recruiting [7].
Apr 20Axicabtagene has been prioritised for potential TA guidance production. Topic has been passed to scoping team to prepare for a consultation exercise [5].
Dec 19UK Trial sites: Birmingham, Barts, UCL, Christie, Marsden [4]
Sep 18PIII ZUMA-7 study (NCT03391466) is still recruiting; timescales unchanged [3].
Dec 17PIII ZUMA-7 study (NCT03391466) to evaluate whether axicabtagene ciloleucel therapy improves the clinical outcome compared with standard of care second-line therapy in patients with relapsed/refractory DLBCL starts. 350 adults will be recruited in the US, Canada & the Netherlands. Primary outcome is event-free survival; collection of these data is due to complete Jan 22 [1].

Evidence based evaluations

YescartaDiffuse large B-cell lymphoma (DLBCL) - first-line

Information

Yescarta
Licence extension / variation
Gilead
Kite

Development and Regulatory status

None
Phase II Clinical Trials
Phase II Clinical Trials
Yes
Dec 14Granted orphan drug status in EU for DLBCL [3].

Category

Autologous chimeric antigen receptor (CAR)-T cell therapy. T-lymphocytes are collected from the patient by leukapheresis and modified genetically ex vivo using a retroviral vector encoding an anti-CD19 CAR protein. Re-infused as a single dose
There were around 12,065 people diagnosed with NHL in England in 2017. It is estimated that about 40% of people with NHL have DLBCL, which would equate to 4,826 registrations of DLBCL per year [1].
Diffuse large B-cell lymphoma (DLBCL) - first-line
Intravenous infusion

Trial or other data

Dec 21Kite presents results from the ZUMA-12 trial at the 63rd American Society of Hematology Annual Meeting & Exposition (ASH-Hem-2021). Data (n=42) showed complete response rate (CR) in 78% (n=29; 95% CI, 62–90) patients as part of first-line treatment in newly diagnosed high-risk large B-cell lymphoma. Objective response was observed in 89% of patients and median time to initial response was one month. Among all 40 treated patients, 90% had an objective response (80% CR rate). At data cutoff, 73% of response-evaluable patients had ongoing responses. Medians for duration of response (DOR), event-free survival (EFS), and progression-free survival (PFS) were not yet reached, with 12-month estimates of 81%, 73%, and 75%, respectively, and an estimated 12-month OS rate of 91%. Levels of CCR7+CD45RA+ T cells in pre-infused product have been associated with a favorable pharmacokinetic (PK) profile. CAR T-cell expansion also appeared greater in ZUMA-12 compared with ZUMA-1. Grade 3 cytokine release syndrome (CRS) occurred in (8%) of patients and Grade =3 neurologic events occurred in (23%) of patients. No Grade 5 CRS or neurological events occurred. There was one Grade 5 adverse event due to COVID-19. All CRS cases and most neurologic events (28/29) of any grade resolved by the time of data cut-off [3].
May 21ZUMA-12 completes collection of primary outcome data [2].
Jan 19Single-arm PII ZUMA-12 study to evaluate the efficacy and safety of axicabtagene ciloleucel as first-line therapy in subjects with high-risk large B-cell lymphoma starts (NCT03761056). 40 adults will be recruited in the US, Canada and France. Participants will receive cyclophosphamide and fludarabine conditioning chemotherapy followed by a single dose of axicabtagene ciloleucel. Primary outcome is complete response rate; collection of these data is due to complete May 21 [2].

YescartaRelapsed or refractory follicular lymphoma - second-line high risk and third-line

Information

Yescarta
Licence extension / variation
Gilead
Kite

Development and Regulatory status

None
None
None
Yes
Yes
Jun 22Has orphan drug status in EU and US for follicular lymphoma [3].

Category

Autologous chimeric antigen receptor (CAR)-T cell therapy. T-lymphocytes are collected from the patient by leukapheresis and modified genetically ex vivo using a retroviral vector encoding an anti-CD19 CAR protein. Re-infused as a single dose.
NHL can be divided into two prognostic groups: low-grade (indolent) or high-grade (aggressive). Follicular lymphoma is an indolent form of NHL and accounts for 20-25% of all NHL. The annual incidence of follicular lymphomas has increased from 2-3 per 100,000 during the 1950s to 5-7 per 100,000 recently [1].
Relapsed or refractory follicular lymphoma - second-line high risk and third-line
Intravenous infusion

Trial or other data

Jul 22PIII ZUMA-22 trial to determine if axicabtagene ciloleucel is superior to standard of care therapy (SOCT), as measured by progression-free survival (PFS) in participants with relapsed/refractory follicular lymphoma is due to start (NCT05371093). 230 adults with relapsed/refractory (R/r) disease after first-line chemoimmunotherapy and high-risk disease with relapse or progression within 24 months of the initial course of chemoimmunotherapy (ie, POD24), Or r/r disease after ≥ 2 prior systemic lines of therapy will be recruited (sites not stated yet). Participants will receive cyclophosphamide 500 mg/m^2/day intravenously (IV) and fludarabine 30 mg/m^2/day IV lymphodepletion chemotherapy for 3 days followed by axicabtagene ciloleucel administered as a single IV infusion at a target dose of 2 x 10^6 anti-cluster of differentiation (CD)19 chimeric antigen receptor (CAR) transduced autologous T cells/kg on Day 0. For participants weighing ≥ 100 kg, a maximum flat dose of axicabtagene ciloleucel at 2 x 10^8 anti-CD19 CAR T cells will be administered. Or they will receive investigator choice of one of the following therapies/dosing schedules Rituximab plus lenalidomide (R^2) for 12 cycles, 28-day cycle; Rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) for 6 cycles, 21-day cycle; Rituximab plus bendamustine (BR) for 6 cycles, 28-day cycle. Primary outcome is progression-free survival; collection of these data is due to complete Apr 2027 [2].