In the world where medical breakthroughs seem to be happening at an unprecedented pace, one recent development stands out as a beacon of hope for people suffering from relapsed or refractory large B-cell lymphomas. A significant step forward in the battle against this fatal condition is marked by the FDA’s accelerated approval of Glofitamab. In this blog, we will delve into detail about Glofitamab and why is its accelerated approval revolutionary.
Unraveling large B-Cell lymphomas
Large B-cell lymphomas are a type of non-Hodgkin's lymphoma (NHL), a cancer that affects the lymphatic system, a vital component of our immune system. Large B-cell lymphoma is the most frequent type of lymphoma and accounts for about 25-30% of all NHLs. These lymphomas are distinguished by aberrant B-cell development, a type of white blood cell responsible for protecting the body from infections. When these B-cells become malignant and uncontrollable, they can form tumors in lymph nodes or other body organs. Large B-cell lymphomas are often aggressive, and necessitate rapid and efficient treatment .
B-cell lymphomas are treated differently depending on their molecular subtype, type of the disease (aggressive or indolent), and the staging. Chemotherapy, radiation therapy, stem cell transplants, and immunotherapy are examples of traditional therapeutic approaches. Despite being aggressive, they respond well when treated with R-CHOP, which consists of six cycles of rituximab in addition to cyclophosphamide, doxorubicin, vincristine, and prednisone. Further, allogeneic transplants have been used to treat some patients with aggressive low-grade disease .
The quest for effective treatment
Over the years, researchers and clinicians have made significant strides in the treatment of lymphomas, especially large B-cell lymphomas. However, not all patients respond equally to these treatments, and relapse or refractory cases present a formidable challenge. The prognosis for patients with diffuse large B-cell lymphoma who have received several lines of therapy is dismal, and they are in utmost need of new therapeutic options .
This is where Glofitamab comes into the picture, and Glofitamab could change the way this aggressive condition is treated. Glofitamab is a bispecific antibody developed by Roche and Genentech and is intended to target and eliminate malignant B-cells in people with large B-cell lymphomas. It represents a promising addition to the arsenal of treatments available for these patients .
Glofitamab is a T-cell-engaging CD20 × CD3 bispecific monoclonal antibody. Glofitamab binds CD20 on the surface of B-cells and CD3 on the T-cell receptor complex on the surface of T-cells at the same time. This dual mechanism of action makes Glofitamab a viable treatment option for patients with large B-cell lymphomas, especially those who have not responded to conventional therapies.
Glofitamab works to treat large B-cell lymphomas by encouraging T-cell-mediated lysis of B-cells that express CD20. Glofitamab is unique in the newly emerging class of CD20×CD3 bispecific monoclonal antibodies because it has a novel 2:1 tumor–T-cell binding configuration which provides bivalency for CD20 (B-cells) and monovalency for CD3 (T-cells). It forms an immunological synapse between CD3-expressing T-cells and CD20-expressing B-cells, which leads to T-cell activation and proliferation [2,3].
Glofitamab treatment has been shown to induce the expansion of pre-existing intra-tumor resident T-cell populations as well as the recruitment of peripheral blood T-cells. Glofitamab treatment has also been shown to result in a dose-dependent and transient induction of proinflammatory cytokines (inclusive of interferon-, IL-2, IL-6, IL-8, IL-10, IL-15, and IL-17) .
Black box warning with glofitamab use
Glofitamab has a boxed warning for cytokine release syndrome, which may be dangerous or life-threatening. Patients receiving glofitamab should be adequately hydrated before infusion in addition to pretreatment with obinutuzumab and the use of a step-up dosing regimen to lower the risk of cytokine release syndrome.
Glofitamab should be avoided until the cytokine release syndrome is under control. Alternatively, depending on the severity of the cytokine release syndrome, glofitamab may need to be permanently stopped .
The accelerated approval
Glofitamab (Columvi, Genentech, Inc.) received accelerated approval from the U.S. Food and Drug Administration on June 15, 2023. This approval is intended to treat patients with relapsed or refractory diffuse large B-cell lymphoma, not otherwise specified (DLBCL), or large B-cell lymphoma resulting from follicular lymphoma following two or more lines of systemic therapy .
Glofitamab accelerated approval is based on the outcomes of the Phase I/II NP30179 study, which confirmed significant and durable responses in patients with relapsed or refractory large B-cell lymphomas. Glofitamab is still being developed clinically as an NHL treatment, both alone and in combination with other drugs .
Glofitamab's approval is a big step forward even though the fight against cancer is far from ending. It gives people hope and opens the door to a time when the disease will not only be treatable but also curable. As we celebrate this milestone, we look forward to the continued progress and breakthroughs that will transform the landscape of cancer treatment for years to come.
1. Padala, S.A. et al. 'Diffuse Large B-Cell Lymphoma' [https://www.ncbi.nlm.nih.gov/books/NBK557796/]. In: StatPearls [https://www.ncbi.nlm.nih.gov/books/NBK557796/], StatPearls Publishing (2023) [cited 2023 Oct 4].
2. Shirley, M. 'Glofitamab: First Approval'. Drugs. 1. DOI: 10.1007/s40265-023-01894-5.
3. Dickinson, M.J. et al. 'Glofitamab for Relapsed or Refractory Diffuse Large B-Cell Lymphoma'. New England Journal of Medicine. (2022) 387(24), 2220–2231. DOI: 10.1056/NEJMoa2206913.
4. Research, C. for D.E. and. 'FDA grants accelerated approval to glofitamab-gxbm for selected relapsed or refractory large B-cell lymphomas'. FDA. (2023).