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38108211000001107

New Medicines

Kymriah Relapsed or refractory follicular lymphoma - third line

Information

Kymriah
Licence extension / variation
Novartis
Novartis

Development and Regulatory status

Phase II Clinical Trials
Launched
Approved (Licensed)
Yes
Yes
May 22FDA grants accelerated approval for the treatment of adult patients with relapsed or refractory (r/r) follicular lymphoma (FL) after two or more lines of systemic therapy. In accordance with the Accelerated Approval Program, continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial(s) [18]
May 22Approved in EU for the treatment of adult patients with relapsed or refractory (r/r) follicular lymphoma (FL) after two or more lines of systemic therapy [17].
Mar 22EU positive opinion granted recommending a license change to include use in adult patients with relapsed or refractory follicular lymphoma (FL) after two or more lines of systemic therapy [17].
Oct 21Has been granted orphan drug status in the EU and US for FL [16].
Oct 21FDA and EMA both accept Kymriah for review as a treatment for adult patients with relapsed or refractory (r/r) follicular lymphoma (FL) after two lines of prior treatment. The FDA granted a priority review [15].
Jan 21US and EU filings planned for H2 21 [13].
Aug 20Novartis announces that ELARA trial findings will be included in regulatory submissions, with filing in the US anticipated in 2021, and the EU following [11].
Apr 20FDA grants regenerative medicine advanced therapy (RMAT) designation to tisagenlecleucel in the US for treatment of relapsed or refractory follicular lymphoma. The designation was granted based on preliminary clinical evidence from the ELARA clinical trial [10].
Dec 18US filing planned for 2021 [8].
Dec 17Filings planned for 2020 [6].
May 16Filing for this indication not listed before 2020 [5].
Apr 14Filings planned for 2016 [1].
Apr 14PII in the US [2].

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 lentiviral vector encoding an anti-CD19 CAR protein. Re-infused as a single dose.
The UK incidence of NHL is about 18 per 100,000 people. About 55-60% of people have aggressive disease (10-11 per 100,000). 45% can be cured with combination chemotherapy, alone or with radiotherapy.
Relapsed or refractory follicular lymphoma - third line
Intravenous

Further information

Yes

Trial or other data

Jun 21Data from primary analysis of the PII ELARA trial announced. 97 patients were infused and evaluated for safety, and 94 patients were evaluable for efficacy with a median follow-up of 11 months. 66% achieved a complete response (CR) (95% CI, 56-75). The overall response rate was 86% (95% CI, 78-92). Response rates were consistent across high-risk patient subgroups. The median duration of response (DOR) in all responders (95% CI, NE-NE), progression free survival (PFS) (95% CI, 12.1-NE), and overall survival (OS) (95% CI, NE-NE) were not reached. Estimated DOR in patients with CR and PFS rates at six months were 94% (95% CI, 82-98) and 76% (95% CI, 65-84), respectively. No patients experienced grade 3/4 cytokine release syndrome (CRS). Grade 1 or 2 CRS, as defined by the Lee Scale, occurred in 49% of patients. Grade 1 or 2 neurological events (NEs) (per CTCAE v4.03) occurred in 9% of patients and one patient experienced grade 4 NEs and recovered. 65% patients experienced grade ≥3 adverse events within 8 weeks post-infusion, most commonly neutropenia (28%) and anaemia (13%). Three patients died from progressive disease and no deaths were treatment related [14].
Dec 20Novartis releases more data from ELARA. In the interim analysis in which 52 patients were evaluable for efficacy with a median follow-up of 9.9 months, Kymriah led to a complete response (CR) in 65% of patients and an overall response rate (ORR) of 83% after at least three months of follow-up. These patients continued to relapse or have refractory disease despite exposure to numerous lines of therapy (median four prior lines of therapy [range 2-13]) prior to Kymriah infusion. Safety results suggest there was no emergence of new safety signals for Kymriah in the 97 patients evaluable for safety. No patients experienced grade 3/4 CRS, as defined by the Lee Scale, and any grade CRS occurred in 49% of patients (29% grade 1; 20% grade 2). To treat CRS, 15% of patients required tocilizumab and 3% required steroids. One percent of patients experienced grade 3/4 NEs and any grade NEs occurred in 9% of patients. Median time to CRS and severe NE onset was four and 8.5 days respectively, with respective median time to resolution of four and two days. All neurological and CRS events resolved with appropriate management. Three patients died from progressive disease and no deaths were treatment-related. Kymriah was administered in the outpatient setting for 18% of patients in the ELARA trial [12].
Aug 20Novartis announces the PII ELARA trial met its primary endpoint of complete response rate and no new safety signals were observed [10].
Feb 20PII ELARA is active and has finished recruiting [8].
Nov 18PII ELARA trial to determine the efficacy and safety of tisagenlecleucel in adult patients with relapsed or refractory FL starts (NCT03568461). 113 adults will be recruited in countries including the US, EU & UK. Collection of primary outcome data (complete response rate) is due to complete Feb 21 [8].
Dec 17Results of PII NCT02030834 published in NEJM. In this study, 28 patients with lymphoma were treated with autologous T cells modified by chimeric antigen receptor to target CD19 on B-cells. Complete remission occurred in 6 of 14 patients with diffuse large B cell lymphoma, and 10 of 14 patients with follicular lymphoma [7].
Dec 15Findings from an ongoing PIIa study to evaluate safety and efficacy of CTL019 in certain types of relapsed or refractory (r/r) non-Hodgkin lymphoma will be presented in an oral session at the 57th American Society of Hematology (ASH) annual meeting. The study found an overall response rate (ORR) at three months of 47% in adults with r/r diffuse large B-cell lymphoma (DLBCL) and an ORR of 73% in adults with follicular lymphoma (FL). The study findings include 26 adults (15 with DLBCL and 11 with FL) who were evaluable for response. The study found that three patients with DLBCL who achieved a partial response (PR) to treatment at three months converted to complete response (CR) by six months. In addition, three patients with FL who achieved a PR to treatment at three months converted to CR by six months. One DLBCL patient with a PR to treatment at three months experienced disease progression at six months after treatment. One FL patient with a PR to treatment at three months who remained in PR at nine months experienced disease progression at approximately 12 months after treatment. Median progression-free survival (PFS) was 11.9 months for patients with FL and 3.0 months for patients with DLBCL [4].
Jan 14An open-label PII trial of CTL 019 began at the Abramson Cancer Center of the University of Pennsylvania. It is recruiting approximately 55 patients with chemotherapy-relapsed or refractory CD19-positive non-Hodgkin´s lymphoma (UPCC 13413; NCT02030834) [2].

Evidence based evaluations

Kymriah Acute lymphoblastic leukaemia (ALL) in high-risk children and young adults who are minimal residual disease (MRD)-positive - first-line

Information

Kymriah
Licence extension / variation
Novartis
Novartis

Development and Regulatory status

Phase II Clinical Trials
Phase II Clinical Trials
Phase II Clinical Trials
Yes
Dec 21Filings in high risk ALL (first-line) planned for 2026 or later [8].
Oct 20Data readout from PII CASSIOPEIA anticipated 2025 [4].
May 20Has orphan drug status in US and PRIME status in EU [3].
May 20Filings planned for 2024 at the earliest [2].

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 lentiviral vector encoding an anti-CD19 CAR protein. Re-infused as a single dose.
About 7,600 people are diagnosed with leukaemia each year in the UK. Of these, only about 650 have ALL.
Acute lymphoblastic leukaemia (ALL) in high-risk children and young adults who are minimal residual disease (MRD)-positive - first-line
Intravenous infusion

Trial or other data

Nov 21PII CASSIOPEIA trial is recruiting; completion of outcome data collection delayed to Apr 27 [7].
Apr 21Novartis suspends the PII CASSIOPEIA trial due to unavailability of central lab facilities [6]
Dec 20PII CASSIOPEIA study is recruiting; timescales unchanged [5].
Apr 20PII CASSIOPEIA study (NCT03876769) is recruiting [1].
Jun 19PII trial to evaluate the safety and efficacy of tisagenlecleucel in first-line, high-risk paediatric and young adult patients with B-cell acute lymphoblastic leukemia who are MRD-positive starts (CCTL019G2201J, NCT03876769). 140 patients aged 1 to 25 years will be recruited in the US, Spain, Belgium, Finland, Denmark, France, Germany, Canada, Norway, Italy, Netherlands and the UK. Collection of primary outcome data (disease free survival) is due to complete Nov 26 [1].

Kymriah Relapsed/refractory diffuse large B-cell lymphoma (DLBCL) - second-line

Information

Kymriah
Licence extension / variation
Novartis
Novartis

Development and Regulatory status

Discontinued
Discontinued
Discontinued
Aug 21Development discontinued [11].
Aug 21Following the BELINDA study failing to meet its primary outcome, planned date for filings have been removed from company pipeline [10].
Oct 20Data readout from the PIII BELINDA study expected H2 21 [8].
Dec 18Now PIII [2].
Sep 18PII. Filings planned for 2021 [1].

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 lentiviral 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). Around one third of patients will develop refractory or relapsed disease (Hematology ASH Education Book. 2011; 2011: 498-505).
Relapsed/refractory diffuse large B-cell lymphoma (DLBCL) - second-line
Intravenous

Further information

Yes

Trial or other data

Aug 21Novartis announces that PIII BELINDA study did not meet its primary endpoint of event-free survival compared to treatment with the standard-of-care (SOC, salvage chemotherapy followed in responding patients by high-dose chemotherapy and stem cell transplant). The safety profile was consistent with the established safety profile of Kymriah. Novartis will complete a full evaluation of the BELINDA data and work with investigators on the future presentation of the results [9].
Nov 20PIII BELINDA study is recruiting; collection of primary outcome data now due to complete Dec 25. It was temporarily suspended earlier in the year due to the Covid-19 pandemic [7].
Apr 20PII BIANCA trial to assess the efficacy and safety of tisagenlecleucel in children and adolescents with relapsed/refractory B-cell non-Hodgkin lymphoma (r/r B-NHL) is recruiting (NCT03610724; CCTL019C2202). It started in Feb 19 and intends to enrol approximately 25 patients aged up to 21 years in the US, Australia, & the EU (not UK). Collection of primary outcome (overall response rate) is due to complete Mar 21 [6].
Jan 20NCT03570892 - no UK trial sites [4]
Jan 19PIII BELINDA study (NCT03570892) starts. This is a randomized, open label, multicenter phase III trial comparing the efficacy, safety, and tolerability of tisagenlecleucel to Standard Of Care in adult patients with aggressive B-cell Non-Hodgkin Lymphoma after failure of rituximab and anthracycline containing frontline immunochemotherapy. Aggressive B-cell NHL is heretofore defined by the following list of subtypes (Swerdlow et al 2016): DLBCL, NOS; FL grade 3B; Primary mediastinal B cell lymphoma (PMBCL); T cell rich/histiocyte rich large B cell lymphoma (T/HRBCL); DLBCL associated with chronic inflammation; Intravascular large B-cell lymphoma; ALK+ large B-cell lymphoma; B-cell lymphoma, unclassifiable, (with features intermediate between DLBCL and classical Hodgkin´s Lymphoma (HL)); High grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements; High-grade B-cell lymphoma, NOS; HHV8+ DLBCL, NOS; DLBCL transforming from follicular lymphoma; DLBCL transforming from marginal zone lymphoma; DLBCL, leg type. 318 adults will be recruited. Primary outcome is event-free survival; collection of these data is due to complete May 25 [3].

Evidence based evaluations