Epkinly, promise new treatment option for follicular lymphoma

Positive early-stage trial results suggest that Epkinly, a dual-acting cancer immunotherapy from AbbVie and Genmab, could soon offer a new treatment option for patients with follicular lymphoma. Following approval for use in diffuse large B-cell lymphoma, these promising results could lead to its expanded use. While the 82% response rate is promising, cytokine release syndrome, a potential side effect, was reported in 66.4% of patients. Despite this, the findings could herald an expansion in the use of bispecific antibody drugs, which present a more convenient alternative to complex CAR-T cell therapies.

The companies plan to engage global regulatory authorities, including the FDA, based on the promising topline results from the EPCORE NHL-1 clinical trial. Positive topline results were announced for the relapsed/refractory follicular lymphoma cohort of the Phase I/II EPCORE NHL-1 trial evaluating Genmab and AbbVie’s Epkinly (Epcoritamab-bysp). 

Epkinly is an IgG1 bispecific antibody that initiates a targeted T-cell mediated immune response by binding to CD20 and CD-3 receptors on the T-cell and B-cells, respectively. 

 This study focused on adult patients who had relapsed or were refractory (R/R) to FL after at least two prior treatments. The study showed an impressive overall response rate of 82%. These promising results could extend Epkinly's use, already approved for diffuse large B-cell lymphoma, to follicular lymphoma patients.

The EPCORE NHL-1 trial could expand treatment options for follicular lymphoma

After gaining initial approval in May for use in diffuse large B-cell lymphoma (DLBCL), AbbVie and Genmab hope to extend the use of Epkinly to follicular lymphoma patients. The study cohort includes 128 adult patients with relapsed or refractory (R/R) FL who received at least two or more lines of systemic therapy. 70.3 percent of patients were double refractory to an anti-CD20 monoclonal antibody and an alkylating agent. 

Epcoritamab is being co-developed by AbbVie and Genmab as part of the companies' oncology collaboration. The EPCORE NHL-1 trial was designed as an open-label, multi-center study to evaluate the safety and preliminary efficacy of Epcoritamab-bysp (Epkinly). 

The topline results showed an overall response rate of 82%, as confirmed by an independent review committee, exceeding the protocol's predefined threshold for efficacy. It is significant to note that Epkinly’s response rate seems to rival Roche’s Lunsumio, which had an 80% response rate in a similar patient population. 

Epkinly and Lunsumio belong to a class of bispecific antibody drugs that have been increasingly gaining prominence for treating blood malignancies. These drugs work by simultaneously binding to cancer cells and T cells to trigger an immune attack against the disease. Epkinly, for instance, is designed to bind to CD3 on T cells and CD20 on B cells, inducing T cell-mediated killing of CD20+ cells. 

The emergence of these bispecific antibody drugs is seen as an important development, especially as they offer a more convenient alternative to complex CAR-T cell therapies for some of the same blood cancers. However, they share a common potentially deadly immune reaction known as cytokine release syndrome (CRS) with CAR-T treatments. This side effect of CRS was also observed in the EPCORE NHL-1 trial. AbbVie and Genmab reported that 66.4 percent of the patients experienced CRS, with 1.6 percent graded as “severe” or higher, necessitating hospital intervention. 

This is a comparable figure to the 39% CRS incidence in Lunsumio patients, where 2.5% were at a grade 3 or higher level. 

Despite the promising results, William Blair analyst Matt Phipps suggested that the FDA may want more data on the dosing study currently underway, which could help control the incidence and severity of CRS before AbbVie and Genmab file their application. In light of the CRS risk, the FDA already mandates that DLBCL patients receiving their third Epkinly shot should remain in the hospital for 24 hours afterward. 

AbbVie and Genmab's announcement marks a significant step forward in providing another potential therapeutic option for patients with follicular lymphoma, particularly in the relapsed/refractory setting. However, the companies must still complete additional testing for an “accelerated” approval. Detailed results from the EPCORE NHL-1 trial will be submitted for presentation at a future medical conference. The success of Epkinly and Lunsumio also opens a new avenue of research in bispecific antibody drugs. As more of these treatments receive approval, researchers will be able to better understand the best ways to leverage this new approach in cancer treatment.

About the Phase 1/2 EPCORE NHL-1 Trial

The EPCORE™ NHL-1 is an open-label, multi-center trial investigating the safety and preliminary efficacy of epcoritamab. The trial consists of three components: a Phase 1 first-in-human, dose escalation study; a Phase 2a expansion study; and a Phase 2a dose optimization study. The trial was devised to examine subcutaneous epcoritamab in adult patients with relapsed, progressive, or refractory CD20+ mature B-cell non-Hodgkin's lymphoma (NHL), which includes follicular lymphoma (FL). 

In the Phase 2a expansion study, additional patients are being enrolled to further assess the safety and efficacy of epcoritamab in three separate patient cohorts with varying types of relapsed or refractory (R/R) B-cell NHLs, all of whom have limited therapeutic alternatives. The dose optimization study evaluates the possibility of alternate step-up dosing schedules to help minimize Grade 2 CRS and mitigate Grade ≥3 cytokine release syndrome. The primary endpoint of the expansion study is the overall response rate, as assessed by an independent review committee. 

Secondary efficacy endpoints include duration of response, complete response rate, duration of complete response, progression-free survival, and time to response, as determined by the Lugano criteria. Other secondary efficacy endpoints under evaluation are overall survival, time to the next therapy, and the rate of minimal residual disease negativity."

About Epcoritamab

Epcoritamab is an investigational IgG1-bispecific antibody created using Genmab's proprietary DuoBody® technology and administered subcutaneously. Genmab's DuoBody-CD3 technology is designed to direct cytotoxic T cells selectively to elicit an immune response toward target cell types. Epcoritamab is designed to simultaneously bind to CD3 on T cells and CD20 on B-cells and induces T cell mediated killing of CD20+ cells. Epcoritamab-bysp (EPKINLY™) was recently approved in the United States (U.S.) and is indicated for the treatment of adult patients with R/R diffuse large B-cell lymphoma (DLBCL), not otherwise specified (NOS), including DLBCL arising from indolent lymphoma, and high-grade B-cell lymphoma (HGBL) after two or more lines of systemic therapy. 

This indication is approved under accelerated approval based on response rate and durability of response. Continued approval for this indication is contingent upon verification and description of clinical benefit in a confirmatory trial(s). Please see U.S. Important Safety Information below. In October 2022, a Marketing Authorization Application was submitted for epcoritamab for the treatment of patients with R/R DLBCL after two or more lines of systemic therapy, which was validated by the European Medicines Agency. Additionally, in December 2022, a Japan new drug application was submitted to the Ministry of Health, Labor and Welfare of Japan for epcoritamab for the treatment of patients with R/R large B-cell lymphoma (LBCL) after two or more lines of systemic therapy. 

Epcoritamab is not approved in the European Union and Japan. The companies will share commercial responsibilities in the United States and Japan, with AbbVie responsible for further global commercialization. AbbVie will continue to pursue regulatory submissions for epcoritamab across international markets excluding the United States and Japan throughout the year. Genmab and AbbVie are continuing to evaluate the use of epcoritamab as a monotherapy, and in combination, across lines of therapy in a range of hematologic malignancies. 

This includes an ongoing Phase 3, open-label, randomized trial evaluating epcoritamab as a monotherapy in patients with R/R DLBCL (NCT: 04628494), an ongoing Phase 3, open-label, randomized trial evaluating epcoritamab in combination in adult participants with newly diagnosed DLBCL (NCT: 05578976), and a Phase 3, open-label clinical trial evaluating epcoritamab in combination in patients with R/R FL (NCT: 05409066). Epcoritamab is not approved to treat newly diagnosed patients with DLBCL or FL. The safety and efficacy of epcoritamab has not been established for these investigational uses. Please visit clinicaltrials.gov for more information.

Important Warnings: EPKINLY can cause serious side effects

Cytokine Release Syndrome (CRS). CRS is common during treatment with EPKINLY and can be serious or life-threatening. Tell your healthcare provider or get medical help right away if you develop symptoms of CRS, including fever of 100.4°F (38°C) or higher, dizziness or lightheadedness, trouble breathing, chills, fast heartbeat, feeling anxious, headache, confusion, shaking (tremors), or problems with balance and movement, such as trouble walking. Due to the risk of CRS, you will receive EPKINLY on a "step-up" dosing schedule. The step-up dosing schedule is when you receive smaller "step-up" doses of EPKINLY on day 1 and day 8 of your first cycle of treatment (cycle 1). 

You will receive your first full dose of EPKINLY on day 15 of cycle 1. If your dose of EPKINLY is delayed for any reason, you may need to repeat the step-up dosing schedule. Before each dose in cycle 1, you will receive medicines to help reduce your risk of CRS. Your healthcare provider will decide if you need to receive medicine to help reduce your risk of CRS with future cycles. Neurologic problems. EPKINLY can cause serious neurologic problems that can be life-threatening and lead to death. Neurologic problems may happen days or weeks after you receive EPKINLY. 

Your healthcare provider may refer you to a healthcare provider who specializes in neurologic problems. Tell your healthcare provider right away if you develop any symptoms of neurologic problems, including trouble speaking or writing, confusion and disorientation, drowsiness, tiredness or lack of energy, muscle weakness, shaking (tremors), seizures, or memory loss. Due to the risk of CRS and neurologic problems, you should be hospitalized for 24 hours after receiving your first full dose of EPKINLY on day 15 of cycle 1. 

Your healthcare provider will monitor you for symptoms of CRS and neurologic problems during treatment with EPKINLY, as well as other side effects, and treat you if needed. Your healthcare provider may temporarily stop or completely stop your treatment with EPKINLY if you develop CRS, neurologic problems, or any other side effects that are severe. Do not drive or use heavy or potentially dangerous machinery if you develop dizziness, confusion, tremors, drowsiness, or any other symptoms that impair consciousness until your symptoms go away. These may be symptoms of CRS or neurologic problems.

Other serious side effects

• Infections. EPKINLY can cause serious infections that may lead to death. Your healthcare provider will check you for symptoms of infection before and during treatment. Tell your healthcare provider right away if you develop any symptoms of infection during treatment, including fever of 100.4°F (38°C) or higher, cough, chest pain, tiredness, shortness of breath, painful rash, sore throat, pain during urination, or feeling weak or generally unwell.
• Low blood cell counts. Low blood cell counts are common during treatment with EPKINLY and can be serious or severe. Your healthcare provider will check your blood cell counts during treatment. EPKINLY may cause low blood cell counts, including low white blood cell counts (neutropenia), which can increase your risk for infection; low red blood cell counts (anemia), which can cause tiredness and shortness of breath; and low platelet counts (thrombocytopenia), which can cause bruising or bleeding problems.