Epkinly Receives Accelerated Approval for Treatment of Follicular Lymphoma After ≥2 Lines of Systemic Therapy

Follicular lymphoma (FL) is the second most prevalent form of non-Hodgkin lymphoma and makes up approximately 30% of all lymphomas.¹ Currently in the United States, patients are diagnosed at a median age of 64 years, with 2.5 new cases per 100,000 men and women per year.² Comparatively to other lymphomas, FL is an indolent disease.¹

Patients with FL have an 89.9% 5-year survival rate, with survival rates varying little as the severity of the disease increases. Many factors may increase the risk of a patient developing FL, but exposure to certain herbicides and pesticides is one of the most prominent risk factors. The disease can present with a variety of nonspecific symptoms, including painless lymphadenopathy, night sweats, fever, and weight loss. Diagnosis of FL relies on morphological assessment of a lymph node biopsy and can be graded from 1 to 3 based on histology.

Treatment of FL depends on the disease stage as well as physician and patient preferences.¹ Radiation therapy is preferred in earlier stages (I, II, and IIIA) of FL. Systemic therapies, common to hematological malignancies, are preferred in the later stages.¹ Initial systemic therapies may include a combination of immunotherapies and chemotherapy agents such as R-CHOP, or may include single-agent regimens.¹ Resistant disease will often utilize immunotherapies such as mosunetuzumab-axgb or CAR T-cell therapies such as tisagenlecleucel.³ Systemic therapies like those mentioned above are often administered in an outpatient setting, although they can be administered to an inpatient if needed. Although all systemic therapies will require some level of monitoring, the exact degree that is required during and after systemic therapy administration varies on the agent or combination of agents.

The unmet need in the FL population remains high. Efficacy of standard of care is lacking, with approximately 20% of patients with FL experiencing progression of disease within 2 years of first-line treatment.⁴ Furthermore, only 33.5% of patients receiving third-line therapy for relapsed or refractory (R/R) FL are progression-free at 18 months, with the percentage decreasing as lines of therapy increase.⁵

Outcomes in the FL population also have a great deal of heterogeneity, likely due to the underlying biological differences in patients with FL and their disease.⁴ Both of these reasons highlight the need for more effective therapies in the R/R setting, as well as a need for well-defined prognostic methods to help determine the risk level of a patient with FL.

FDA Approval of Epcoritamab-bysp for R/R FL

On June 26, 2024, the FDA granted accelerated approval to epcoritamab-bysp (Epkinly, Abbvie, Genmab) for the treatment of adult patients with R/R FL after ≥2 lines of systemic therapy.³ Epcoritamab-bysp is also currently approved for the treatment of R/R diffuse large B-cell lymphoma after ≥2 lines of systemic therapy.⁶ Epcoritamab-bysp was granted approval based on overall response rate (82.2; 95% confidence interval [CI], 74.3-88.3) and durability of response, following priority review and breakthrough designation status.^3,7

Mechanism of Action

Epcoritamab-bysp is a bispecific T-cell engaging antibody that binds to the CD3 receptor expressed on the surfaces of T cells and the CD20 receptor expressed on the surface of lymphoma cells.⁷ By binding to these receptors, epcoritamab-bysp activates T cells leading to induced lysis of B cells.⁷

Dosing and Administration

Epcoritamab-bysp is dosed subcutaneously, and certain dosages of the drug require a dilution to be performed.⁷ Both the 0.8- and 0.16-mg doses require dilution, which can be performed utilizing an empty syringe or an empty vial, while the 3- and 48-mg doses require no dilution.⁷

To reduce the risk of cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), the manufacturer recommends utilizing a step-up dosing procedure in combination with pre-medication and hydration for cycle 1.⁷ Pre-medication that is often used in combination with step-up dosing includes dexamethasone, prednisolone, diphenhydramine, and acetaminophen.⁷ After receiving epcoritamab-bysp, patients receive steroids such as dexamethasone or prednisolone for 3 consecutive days.⁷ Pre- and post-medication may continue past cycle 1 depending on the adverse events experienced by the patient.⁷ Although not mandatory for epcoritamab-bysp use in FL, due to the severity of CRS and ICANS and the possible need for closer monitoring, some healthcare centers may opt for a short-term hospitalization during the initial step-up period.

Pivotal Clinical Trial

The FDA approval of epcoritamab-bysp for the treatment of FL is based on findings from the EPCORE NHL-1 (NCT03625037) study.⁸ EPCORE NHL-1 was an open-label, multicohort, multicenter, single-arm trial utilizing patients with R/R FL after ≥2 lines of systemic therapy.⁸ Patients were included in the study if they had grade 1-3A R/R CD20+ FL, an ECOG Performance Status of up to 2, and had received at least 2 previous lines of therapy.⁸ Patients were excluded if they had central nervous system involvement of lymphoma, hematopoietic stem-cell transplantation, ongoing active infection, impaired T-cell immunity, creatinine clearance <45 mL/min, alanine aminotransferase >3 times the upper limit of normal, and a cardiac ejection fraction <45%.⁸

Researchers followed 127 patients with FL who were on a 2 step-up dosing procedure where patients received 0.16 mg on day 1, 0.8 mg on day 8, and 48 mg on days 15 and 22 for cycle 1.⁸ Post step-up, for cycles 2 and 3, patients received 48 mg on days 1, 8, 15, and 22.⁸ For cycles 4 to 9, patients received 48 mg on days 1 and 15, and for cycles 10 and beyond, patients received 48 mg on day 1.⁸ Patients continued to receive epcoritamab-bysp until disease progression or unacceptable toxicity.⁸

For the FL patients enrolled in this study, the overall response rate was 82.0% (95% CI, 74.3-88.3) with complete response and partial response rates of 62.5% (95% CI, 53.5-70.9) and 22.0% (95% CI, 15.2-30.3), respectively.^7,8 Duration of response endpoints were not reached.⁷

Adverse Events

The most common adverse events (>20%) of all grades were injection-site reactions (58%), CRS (49%), and COVID-19 (40%).⁷ The most common grade 3 or 4 adverse events were COVID-19 (19%) and pneumonia (13%).⁷ Laboratory anomalies including hematology counts and basic chemistry were commonplace. However, most serious lab abnormalities were hematology related, with the most common grade 3 or 4 laboratory anomalies including decreased lymphocytes (82%) and decreased neutrophils (30%).⁷

Use in Specific Populations

There are no data indicating safe use of epcoritamab-bysp in pregnant patients. Based on the mechanism of action and animal data, epcoritamab-bysp may cause fetal harm to pregnant women.⁷ The background risk of major birth defects and miscarriage in recognized pregnancies is 2% to 4% and 15% to 20%, respectively.⁷ Therefore, before initiating epcoritamab-bysp, female patients are recommended to verify their pregnancy status and utilize effective contraception during and for 4 months after receiving epcoritamab-bysp.⁷

Epcoritamab-bysp has no information on its presence in human milk, the effect on a child who is breastfeeding, or milk production.⁷ However, because of the severity of adverse events in a breastfed child, patients are advised not to breastfeed during treatment with epcoritamab-bysp and for 4 months after the last dose.⁷

There are no current data that demonstrate the efficacy and safety of epcoritamab-bysp use in pediatric patients.⁷ In patients aged younger than 65 years, there was no difference observed in terms of efficacy.⁷ However, patients aged >65 years were observed to have a higher rate of fatal adverse events, which were comprised primarily of infections.⁷

Warnings, Precautions

As with most bispecific agents, CRS is a serious and life-threatening reaction that can occur and is characterized by pyrexia, hypotension, hypoxia, and other nonspecific symptoms.⁷ Optimal patient outcomes rely on recognizing and quickly resolving the symptoms of CRS. Treatment will vary based on the severity, but will generally involve withholding treatment, the provision of pre-medications on the next cycle, and discontinuation in some scenarios.⁷ Risk of CRS can be mitigated by utilizing the recommended step-up dosing and pre-medication protocols described earlier.⁷

Similarly, ICANS is another serious adverse event that is associated with epcoritamab-bysp, and can be characterized by altered mental state, lethargy, tremor, dysgraphia, and aphasia.⁷ ICANS can appear concurrently or separately before or after CRS.⁷ When ICANS is recognized, supportive care will be necessary.⁷ Often, treatment may need to be withheld or perhaps even discontinued.⁷ Based on severity and Immune Effector-Cell Associated Encephalopathy assessment, steroid and seizure prophylaxis may be warranted.⁷

Other warnings for epcoritamab-bysp use include infections, cytopenia, and embryo-fetal toxicity.⁷

Conclusion

Although patients diagnosed with FL often have a good prognosis, they face a large burden of treatment. Most systemic therapies are combination infusions that require the patient to make a significant time investment to receive all their agents. Particularly for these combination treatments, the adverse event profile must be weighed with potential benefit in making treatment decisions. Epcoritamab-bysp represents a novel and efficacious way for patients to receive their therapy in a more convenient manner. Furthermore, the novel mechanism of action is ideal for further research into more difficult tumor types.

References

1. Kaseb H, Ali MA, Gasalberti DP, et al. Follicular Lymphoma. StatPearls Publishing; 2024. Accessed November 6, 2024. https://www.ncbi.nlm.nih.gov/books/NBK538206/
2. National Cancer Institute. SEER. Cancer Stat Facts: NHL - Follicular Lymphoma. Accessed July 20, 2024. https://seer.cancer.gov/statfacts/html/follicular.html
3. FDA. FDA grants accelerated approval to epcoritamab-bysp for relapsed or refractory follicular lymphoma. Accessed July 20, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-epcoritamab-bysp-relapsed-or-refractory-follicular-lymphoma
4. Casulo C, Nastoupil L, Fowler NH, et al. Unmet needs in the first-line treatment of follicular lymphoma. Ann Oncol. 2017;28:2094-2106.
5. Ghione P, Palomba ML, Ghesquieres H, et al. Treatment patterns and outcomes in relapsed/refractory follicular lymphoma: results from the international SCHOLAR-5 study. Haematologica. 2023;108:822-832.
6. Genmab. EPKINLY (epcoritamab-bysp) Approved by U.S. FDA for patients with relapsed or refractory (R/R) follicular lymphoma (FL). June 27, 2024. Accessed October 11, 2024. https://ir.genmab.com/news-releases/news-release-details/epkinlyr-epcoritamab-bysp-approved-us-fda-patients-relapsed-or
7. FDA. EPKINLY™ (epcoritamab-bysp) injection [prescribing information]. Accessed November 6, 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/761324s003lbl.pdf
8. Linton KM, Vitolo U, Jurczak W, et al. Epcoritamab monotherapy in patients with relapsed or refractory follicular lymphoma (EPCORE NHL-1): a phase 2 cohort of a single-arm, multicentre study. Lancet Haematol. 2024;11(8).