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23rd October 2023
The injectable bispecific antibody epcoritamab (brand name Tepkinly) has been granted conditional marketing authorisation by the Medicines and Healthcare products Regulatory Agency (MHRA), its manufacturer Abbvie has announced.
This follows its conditional marketing authorisation by the European Commission in late September 2023.
The conditional marketing authorisations recommend epcoritamab as a monotherapy for adult patients with relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL) after two or more systemic therapies.
Epcoritamab is the first and only off-the-shelf, subcutaneously administered CD3xCD20 T-cell-engaging bispecific antibody. It is designed to simultaneously bind to both the cluster of differentiation (CD)3 proteins on immune T cells and the CD20 proteins on cancerous B cells and activate the T cell to destroy the B cell.
Unlike existing therapeutic options for DLBCL, epcoritamab does not require cell collection and engineering before eligible patients can start treatment and it can be delivered in broader settings. It therefore has the potential for greater geographical accessibility and more timely administration.
Professor Chris Fox, professor of haematology at the University of Nottingham’s School of Medicine, and honorary consultant haematologist at Nottingham University Hospitals NHS Trust, UK, said: ‘Despite recent therapeutic advances, treatment options for patients with R/R DLBCL after two previous therapies are limited. For such patients living with this type of aggressive blood cancer, many experience disease progression and have poor prognosis.
‘As a novel bispecific antibody, given as a subcutaneous injection, epcoritamab offers a new treatment option for this difficult-to-treat patient group.’
Anna Sureda, head of clinical hematology department, Institut Català d’Oncologia – L’Hospitalet in Barcelona, Spain, said: ‘R/R DLBCL is an aggressive cancer and patients can face a difficult and emotional treatment journey. At this point in the journey, a patient may have had multiple lines of therapy and will already have experienced relapse.
‘This European Commission approval represents an important moment for the DLBCL patient community and brings with it a potential opportunity for effective disease management for a condition with limited available treatment options.’
The conditional marketing authorisations are based on the results of the single-arm Phase 1/2 EPCORE NHL-1 trial, which investigated epcoritamab as monotherapy for 139 patients with R/R DLBCL after two or more lines of systemic therapy.
Phase 1 of the study looked at dose escalation, which determined the recommended phase 2 dose, and the phase 2 expansion treated additional patients to explore safety and efficacy. The primary endpoint was overall response rate determined by the 2014 Lugano criteria as assessed by an independent review committee.
Secondary endpoints included duration of response, complete response rate, progression-free survival, overall survival, time to response, time to next therapy and rate of minimal residual disease negativity.
Patients achieved an overall response rate of 61.9% (n=86/139) and a complete response rate of 39.6% (n=54/139).
The researchers also found that epcoritamab prevented the growth or spread of the cancer for an average of 15.6 months, and the patients lived for an average of 19.4 months from the start of epcoritamab therapy.
The trial results demonstrated a manageable safety profile, with cytokine release syndrome being the most common serious adverse event (31.1%), followed by pneumonia (7.2%), upper respiratory tract infections (2.4%), febrile neutropenia, immune effector cell-associated neurotoxicity syndrome (ICANS) (2.4%) and pyrexia (2.4%).
Four patients (2.4%) experienced a fatal adverse reaction – ICANS in one patient (0.6%) and pneumonia in three patients (1.8%).
Further data from the trial are expected in due course.
Commenting on the MHRA conditional marketing authorisation, Belinda Byrne, medical director at AbbVie UK, said: ‘AbbVie is committed to advancing care for people living with blood cancer. Today’s news is an important step forward in enabling us to provide this hard-to-treat patient group with an innovative subcutaneous treatment.
‘We are working with the NHS and relevant authorities to bring access to eligible patients and clinicians throughout the UK as quickly as possible.’
Epcoritamab is delivered to eligible patients by clinicians as a weekly subcutaneous injection for 12 weeks, then moves to every other week for 24 weeks (12 injections), before continuing as one injection every four weeks until treatment is discontinued due to cancer progression or side effects.
Epcoritamab is the first injectable bispecific antibody to be approved for use in DLBCL. It follows the recent MHRA approval and National Institute for Health and Care Excellence recommendation of glofitamab (brand name Columvi), a bispecific antibody administered via infusion.
Glofitamab also gained conditional marketing authorisation in the EU in July 2023.
19th October 2023
The NHS will fast-track the bispecific antibody glofitamab (brand name Columvi) for treating relapsed or refractory (R/R) diffuse large B‑cell lymphoma (DLBCL) in adults after two or more systemic treatments following its recommendation by the National Institute for Health and Care Excellence (NICE).
Set to be made available in England ‘within weeks‘, glofitamab is the first off-the-shelf CD20xCD3 T-cell engaging bispecific antibody. Administered as an intravenous infusion, it works by encouraging healthy immune cells in the body to destroy the cancer cells.
While current DLBCL treatments such as CAR T therapies are provided in specialist centres across England, glofitamab can be offered at more cancer treatment sites across the country, improving timely access. It is thought that more than 700 people in England could benefit from the treatment.
NHS England’s Cancer Drug’s Fund Lead, Professor Peter Clark, said: ’The approval of this drug is great news for people living with an advanced and aggressive form of blood cancer, who are set to benefit from this new treatment.
’Not only does it provide a potentially life-saving option for patients who may have not responded to CAR T therapy, it is also an alternative for some CAR T eligible patients who choose instead to have glofitamab closer to home.
’This is the latest in a long list of cutting-edge drugs available on the NHS to help people with cancer live a longer and better-quality life.’
Helen Knight, director of medicines evaluation at NICE, added: ‘We are committed to getting the best care to patients fast while ensuring good value for the taxpayer.
‘Advanced B-cell lymphoma is an aggressive form of blood cancer and can progress quickly. The sooner people can access the best treatment for them, the better chance they have of living for longer and improving their quality of life.
‘This is why it is such good news that our independent committee has found that glofitamab is clinically and cost effective for treating people with this advanced form of cancer, and we welcome the news that NHS England will make this available to patients quickly.‘
The NICE recommendation coincides with glofitamab receiving its license by the Medicines and Healthcare products Regulatory Agency and is based on the positive results obtained from the Phase 1/2 NP30179 study.
Of the 154 participants who received treatment, 39% (95% confidence interval [CI], 32 to 48) had a complete response at a median follow-up of 12.6 months.
The majority (78%) of complete responses were ongoing at 12 months. The 12-month progression-free survival was 37% (95% CI, 28 to 46).
The most common adverse event was cytokine release syndrome (CRS) (63%). Adverse events of grade 3 or higher occurred in 62% of the patients, with grade 3 or higher CRS in 4% and grade 3 or higher neurologic events in 3%. Discontinuation of glofitamab due to adverse events occurred in 9% of the patients.
Referring to the rollout of bispecific antibodies as a breakthrough for patients with lymphoma, Dr Wendy Osborne, an NHS consultant haematologist specialising in lymphoma at the Freeman Hospital in Newcastle, said: ‘Bispecific antibodies use the patient’s own white blood cells to attack and kill the lymphoma, a form of blood cancer. The antibody has two arms: one arm attaches to the cancer cell and the other to the patient’s own white blood cell, a T-cell.
‘By bringing these cells together, the patient’s own immune system is activated and kills the cancer cell and so chemotherapy is not required. Patients don’t have the side effects of chemotherapy and often feel well on this outpatient-based treatment.‘
Glofitamab gained conditional marketing authorisation in the EU in July 2023.
Earlier in 2023, glofitamab was found to induce a fast and durable complete response rate in patients with refractory mantle cell lymphoma.
27th January 2023
A T cell biomarker, represented by low levels of differentiated CD3+CD27–CD28– T cells before leukapheresis could serve as a novel marker to predict an individual’s response to CAR T cell therapy in those with relapsed/refractory diffuse large B cell lymphoma (DLBCL), according to a study by researchers from the Medical University of Vienna, Austria.
Chimeric antigen receptor (CAR) T cell therapy produces a durable response in patients with either relapsed or refractory DLBCL. However, trying to identify which groups of patients are likely to respond to therapy is difficult and currently based on lactate dehydrogenase after lymphodepletion, tumour volume and Eastern Cooperative Oncology Group performance status. Nevertheless, each of these three measures does not relate to the immune system. In the current study, the Austrian team looked at a particular T cell biomarker and made use of a matched group of healthy control patients for comparative purposes.
T cell biomarker and CAR T treatment response
A total of 33 patients (mean age = 61.8 years, 42.4% female) with either relapsed or refractory DLBCL were matched with a health control group of 24 patients (median age = 60, 41.7% female).
When compared to healthy controls, DLBCL patients had significant lymphopenia and a higher frequency of differentiated CD3+CD27–CD28– T cells (28.7% vs 6.6%, p < 0.001). There were 26 patients infused with CAR T cell therapy and the overall response (OR) 3 months after the infusion was 57.7%, with a complete response (CR) seen in 42.3% of patients.
In regression analysis, the Austrian team found that low levels of differentiated CD3+CD27–CD28– T cells (23.3% vs 35.1%) were independently associated with an overall response. In fact, the association was even more evident when patients were stratified by either complete remission or non-complete remission (13.7% vs 37.7%, p = 0.001). Using a cut-off value of below 18% of CD3+CD27–CD28– T cells was highly predictive of a complete response at 12 months (67% vs 13%, p = 0.009).
The authors concluded that a low number of CD3+CD27–CD28– T cells at leukapheresis represented a novel, pre-infusion T cell biomarker that enabled prediction of a CAR T cell response in patients with relapsed or refractory DLBCL.
Worel N et al. The frequency of differentiated CD3+CD27–CD28– T cells predicts response to CART cell therapy in diffuse large B-cell lymphoma. Front Immunol 2023
21st December 2022
According the findings of a systematic review and meta-analysis undertaken by Korean researchers and presented at the American Society of Haematology conference, 2022, tafasitamab showed a trend for best efficacy among failed autologous stem cell transplantation (ASCT) or ineligible relapsed/refractory diffuse large B-cell lymphoma (DLBCL) patients.
Diffuse large B cell lymphoma is the most common lymphoma, accounting for about 25% to 30% of all the non-Hodgkin lymphomas and which presents as a rapidly growing mass or enlarging lymph nodes in a nodal or extra-nodal site. Non-Hodgkin lymphomas account for about 80% of all lymphomas and while there are more than 30 subtypes, the common ones are diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma. Although 5-year survival rates range from 60% to 70%, up to 50% of patients become refractory to or relapse after treatment. Moreover, outcomes for refractory or relapsed patients are poor, with one study of 861 patients, 636 of whom had refractory disease, finding that the median overall survival was 6.3 months and that only 20% of patients were alive at 2 years. For patients with relapsed/refractory disease, there are several combination chemotherapy regimens available including tafasitamab-cxix, polatuzumab vedotin-piiq, bendamustine as well as CAR T cell therapies. Nevertheless, the most effective treatment remains to be determined.
In the present study, the Korean researchers performed a systematic review and meta‐analysis to identify prospective phase II or III clinical studies evaluating the efficacy of treatments for ASCT-failed or ineligible relapse/refractory DLBCL patients. They used random effects models to estimate one-year progression-free survival rate, complete remission rate, and subgroup differences. In addition, meta-regression models were performed with adjustment for relevant covariates, particularly the median number of previous lines of systemic therapy and CAR T cell therapy was used as a reference treatment in the meta-regression analysis.
Tafasitamab and one-year progression-free survival
The researchers identified 56 cohorts in 50 studies with 3,544 relapsed/refractory DLBCL patients. For the analysis, treatment regimens were divided into nine groups: CAR T cell therapy, chemotherapy, lenalidomide-based therapy, ibrutinib-based therapy, tafasitamab-based therapy, polatuzumab plus bendamustine and rituximab (pola-BR), loncastuximab, selinexor, and others.
The pooled one-year progression-free survival rate was 0.40 (95% CI 0.35 – 0.46) for CAR T cell therapy, 0.23 (95% CI 0.16 – 0.30) for chemotherapy, 0.28 (95% CI 0.19 – 0.37) for lenalidomide and 0.46 (95% CI 0.37 – 0.56) for tafasitamab.
Although CAR T cell treatment was significantly better than many of the others, in fact, loncastuximab, pola-BR, and tafasitamab were all shown to have no significant difference in efficacy to CAR T cell therapy after adjustment for the median number of prior lines of treatment in the meta-regression analysis.
The authors concluded that tafasitamab showed a trend of best efficacy and that CAR T cell therapy was no more effective than tafasitamab, loncastuximab or pola-BR. However, because of the high level of heterogeneity, the authors called for randomised controlled trials to confirm their findings.
Kim J et al. Comparison of Several Salvage Treatments of Relapsed/Refractory Large B-Cell Lymphoma Including Chimeric Antigen Receptor T-Cell Therapy: A Systematic Review and Meta‐Analysis. Abstract 2986 ASH conference 2022