Epkinly Drug Information
Generic name: EPCORITAMAB-BYSP
Bispecific CD20-directed CD3 T Cell Engager [EPC]
Uses of Epkinly
DLBCL and High-grade B-cell Lymphoma EPKINLY is indicated for the treatment of adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL), not otherwise specified, including DLBCL arising from indolent lymphoma, and high-grade B-cell lymphoma 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 may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).
Follicular Lymphoma EPKINLY is indicated in combination with lenalidomide and rituximab for the treatment of adult patients with relapsed or refractory follicular lymphoma (FL). EPKINLY is indicated as monotherapy for the treatment of adult patients with relapsed or refractory FL after two or more lines of systemic therapy.
Dosage & Administration of Epkinly
Important Dosing Information
Certain doses of EPKINLY require dilution prior to administration. There are 2 available methods to prepare diluted EPKINLY: Empty sterile vial method as described in subsection 2.7, or Sterile syringe method as described in subsection 2.8. Preparation of 3 mg and 48 mg EPKINLY doses does not require dilution.
EPKINLY should only be administered by a qualified healthcare professional with appropriate medical support to manage severe reactions such as CRS and ICANS. Administer EPKINLY to well-hydrated patients. Premedicate before each dose in Cycle 1.
Administer EPKINLY subcutaneously according to the recommended step-up dosage schedule to reduce the incidence and severity of CRS. Due to the risk of CRS and ICANS, monitor all patients for signs and symptoms. Assess whether hospitalization or outpatient monitoring is appropriate based on comorbidities or other situational factors for the first 48 mg dosage of EPKINLY for patients with: DLBCL or high-grade B-cell lymphoma: on Cycle 1 Day 15.
FL: on Cycle 1 Day 22.
Recommended Dosage EPKINLY is for subcutaneous injection only. The recommended DLBCL dosage for Cycle 1 consists of 2 step-up doses, and the recommended FL dosage (monotherapy or in combination with lenalidomide and rituximab) consists of 3 step-up doses. EPKINLY as Monotherapy: Administer EPKINLY in 28-day cycles until disease progression or unacceptable toxicity.
Refer to the lenalidomide prescribing information and rituximab prescribing information for the respective dosage recommendations, including lenalidomide dosage recommendations for patients with renal insufficiency.
Restarting
EPKINLY after Dosage Delay If a dose of EPKINLY is delayed, restart therapy based on the recommendations made in Table 4 for patients with DLBCL or high-grade B-cell lymphoma, or Table 5 for patients with FL. Table 4: Recommendations for Restarting EPKINLY After Dosage Delay for Patients with DLBCL or High-grade B-cell Lymphoma Last Dose Administered Time Since the Last Dose Administered Action for Next Dose(s) Administer pretreatment medication prior to EPKINLY dose and monitor patients accordingly. Table 5: Recommendations for Restarting EPKINLY After Dosage Delay for Patients with FL Last Dose Administered Time Since the Last Dose Administered Action for Next Dose(s) Administer pretreatment medication prior to EPKINLY dose and monitor patients accordingly. s Administer pre- and post-administration medications as outlined in Table 6 to reduce the risk of CRS.
Table 6: EPKINLY Pre- and Post-
Recommended Prophylaxis
Pneumocystis jirovecii pneumonia (PJP) Provide PJP prophylaxis during treatment with EPKINLY. Herpesvirus Consider providing prophylaxis against herpesvirus during treatment with EPKINLY to prevent herpes simplex and herpes zoster. Thromboprophylaxis Refer to the lenalidomide prescribing information for recommendations on prophylaxis for venous and arterial thrombotic events.
Dosage Modifications and Management of Adverse Reactions See Tables 7 and 8 for recommended actions for adverse reactions of CRS and ICANS, respectively. See Tables 9 and 10 for recommended actions for other adverse reactions following administration of EPKINLY given as monotherapy and in combination with lenalidomide and rituximab, respectively. Cytokine Release Syndrome (CRS) Identify CRS based on clinical presentation.
Evaluate for and treat other causes of fever, hypotension, and hypoxia. If CRS is suspected, withhold EPKINLY until CRS resolves. Manage according to the recommendations in Table 7 and consider further management per current practice guidelines.
Administer supportive therapy for CRS, which may include intensive care for severe or life-threatening CRS. Table 7: Recommendations for Management of Cytokine Release Syndrome Withhold EPKINLY and manage per current practice guidelines. Refer to Table 4 or Table 5 for information on restarting EPKINLY after dosage delays.
Immune Effector Cell-Associated Neurological Toxicity Syndrome (ICANS) Monitor patients for signs and symptoms of ICANS. At the first sign of ICANS, withhold EPKINLY and consider neurology evaluation. Rule out other causes of neurologic symptoms.
Provide supportive therapy, which may include intensive care, for ICANS. Table 8: Recommendations for Management of Immune Effector Cell-Associated Neurotoxicity Syndrome Withhold EPKINLY until ICANS resolves. See Table 4 or Table 5 for recommendations on restarting EPKINLY after dosage delays.
Table 9: Recommended Dosage Modifications for Other Withhold EPKINLY in patients with active infection, until the infection resolves. Neutropenia Table 10: Recommended Dosage Modifications for Other Adverse Reactions when EPKINLY is Given in Combination with Lenalidomide and Rituximab Consider G-CSF. Febrile Neutropenia
Preparation of Diluted
EPKINLY using the Vial Method Read this entire section carefully before preparation of EPKINLY. Follow the preparation instructions provided below, as improper preparation may lead to improper dose. This section describes preparation of diluted EPKINLY using empty sterile vial method.
For preparation using sterile syringe method, see subsection 2.8. EPKINLY is prepared and administered by a healthcare provider as a subcutaneous injection. The administration of EPKINLY takes place over the course of 28-day cycles, following the step-up dosage schedule in Section 2.2.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Use aseptic technique to prepare EPKINLY. Filtration of the diluted solution is not required. 0.16 mg Dose Preparation Instructions ( 2 dilutions required ) – Empty Sterile Vial Method Use an appropriately sized syringe, vial, and needle for each transfer step.
Discard the vial containing unused EPKINLY. 0.8 mg Dose Preparation Instructions ( 1 dilution required ) – Empty Sterile Vial Method Use an appropriately sized syringe, vial, and needle for each transfer step. Discard the vial containing unused EPKINLY.
Preparation of 3 mg and 48 mg EPKINLY Doses
Use aseptic technique to prepare EPKINLY. 3 mg Dose Preparation Instructions (No dilution required) EPKINLY 3 mg dose is required for patients with FL only. Discard the vial containing unused EPKINLY. 48 mg Dose Preparation Instructions ( No dilution required ) EPKINLY 48 mg/0.8 mL vial is supplied as ready-to-use solution that does not need dilution prior to administration.
Storage and Administration Storage of EPKINLY Solution in the Syringe Use EPKINLY solution in the syringe immediately. If not used immediately, store the solution refrigerated at 2°C to 8°C (36°F to 46°F) for up to 24 hours or at room temperature at 20°C to 25°C (68°F to 77°F) for up to 12 hours. The total storage time from the start of dose preparation to administration should not exceed 24 hours.
Protect from direct sunlight. Discard unused EPKINLY solution beyond the allowable storage time. Administration of EPKINLY To minimize injection pain, allow EPKINLY solution to equilibrate to room temperature for no more than 1 hour before administration.
Inject the required volume of EPKINLY into the subcutaneous tissue of the lower part of the abdomen (preferred injection site) or the thigh. Change of injection site from the left or right side or vice versa is recommended, especially during the weekly administrations (Cycles 1 to 3). Do not inject into tattoos or scars or areas where the skin is red, bruised, tender, hard, or not intact.
| Cycle Cycle = 28 days | Day | Dose of EPKINLY | |
|---|---|---|---|
| Cycle 1 | 1 | Step-up dose 1 | 0.16 mg |
| 8 | Step-up dose 2 | 0.8 mg | |
| 15 | First full dose | 48 mg | |
| 22 | 48 mg | ||
| Cycles 2 and 3 | 1, 8, 15 and 22 | 48 mg | |
| Cycles 4 to 9 | 1 and 15 | 48 mg | |
| Cycle 10 and beyond | 1 | 48 mg | |
| Cycle Cycle = 28 days | Day | Dose of EPKINLY | |
|---|---|---|---|
| Cycle 1 | 1 | Step-up dose 1 | 0.16 mg |
| 8 | Step-up dose 2 | 0.8 mg | |
| 15 | Step-up dose 3 | 3 mg | |
| 22 | First full dose | 48 mg | |
| Cycles 2 and 3 | 1, 8, 15 and 22 | 48 mg | |
| Cycles 4 to 9 | 1 and 15 | 48 mg | |
| Cycle 10 and beyond | 1 | 48 mg | |
| Cycle Cycle = 28 days | Day | Dose of EPKINLY | |
|---|---|---|---|
| Cycle 1 | 1 | Step-up dose 1 | 0.16 mg |
| 8 | Step-up dose 2 | 0.8 mg | |
| 15 | Step-up dose 3 | 3 mg | |
| 22 | First full dose | 48 mg | |
| Cycles 2 and 3 | 1, 8, 15, and 22 | 48 mg | |
| Cycles 4 to 12 | 1 | 48 mg | |
| Indication | Cycle Cycle = 28 days. | Day | Dose of EPKINLY | |
|---|---|---|---|---|
| DLBCL or High-grade B-cell Lymphoma | Cycle 1 | 1 | Step-up dose 1 | 0.16 mg |
| 8 | Step-up dose 2 | 0.8 mg | ||
| 15 | First full dose | 48 mg | ||
| 22 | 48 mg | |||
| Cycles 2 and 3 | 1, 8, 15 and 22 | 48 mg | ||
| Cycles 4 to 9 | 1 and 15 | 48 mg | ||
| Cycle 10 and beyond | 1 | 48 mg | ||
| Indication | Cycle Cycle = 28 days. | Day | Dose of EPKINLY | |
|---|---|---|---|---|
| Follicular Lymphoma | Cycle 1 | 1 | Step-up dose 1 | 0.16 mg |
| 8 | Step-up dose 2 | 0.8 mg | ||
| 15 | Step-up dose 3 | 3 mg | ||
| 22 | First full dose | 48 mg | ||
| Cycles 2 and 3 | 1, 8, 15 and 22 | 48 mg | ||
| Cycles 4 to 9 | 1 and 15 | 48 mg | ||
| Cycle 10 and beyond | 1 | 48 mg | ||
| Indication | Cycle Cycle = 28 days. | Day | Dose of EPKINLY | |
|---|---|---|---|---|
| Follicular Lymphoma | Cycle 1 | 1 | Step-up dose 1 | 0.16 mg |
| 8 | Step-up dose 2 | 0.8 mg | ||
| 15 | Step-up dose 3 | 3 mg | ||
| 22 | First full dose | 48 mg | ||
| Cycles 2 and 3 | 1, 8, 15, and 22 | 48 mg | ||
| Cycles 4 to 12 | 1 | 48 mg | ||
| Last Dose Administered | Time Since the Last Dose Administered | Action for Next Dose(s) Administer pretreatment medication prior to EPKINLY dose and monitor patients accordingly [see Dosage and Administration (2.4, 2.6) ]. |
|---|---|---|
| 0.16 mg (e.g., on Cycle 1 Day 1) | More than 8 days | Repeat Cycle 1 schedule starting at step-up dose 1 (0.16 mg). Following the repeat of Cycle 1 schedule, resume the planned treatment schedule. |
| 0.8 mg (e.g., on Cycle 1 Day 8) | 14 days or less | Administer 48 mg, then resume the planned treatment schedule. |
| More than 14 days | Repeat Cycle 1 schedule starting at step-up dose 1 (0.16 mg). Following the repeat of Cycle 1 schedule, resume the planned treatment schedule. | |
| 48 mg (e.g., on Cycle 1 Day 15 onwards) | 6 weeks or less | Administer 48 mg, then resume the planned treatment schedule. |
| More than 6 weeks | Repeat Cycle 1 schedule starting at step-up dose 1 (0.16 mg). Following the repeat of Cycle 1 schedule, resume the planned treatment schedule. |
| Last Dose Administered | Time Since the Last Dose Administered | Action for Next Dose(s) Administer pretreatment medication prior to EPKINLY dose and monitor patients accordingly [see Dosage and Administration (2.4, 2.6) ]. |
|---|---|---|
| 0.16 mg (e.g., on Cycle 1 Day 1) | More than 8 days | Repeat Cycle 1 schedule starting at step-up dose 1 (0.16 mg). Following the repeat of Cycle 1 schedule, resume the planned treatment schedule. |
| 0.8 mg (e.g., on Cycle 1 Day 8) | More than 8 days | Repeat Cycle 1 schedule starting at step-up dose 1 (0.16 mg). Following the repeat of Cycle 1 schedule, resume the planned treatment schedule. |
| 3 mg (e.g., on Cycle 1 Day 15) | 14 days or less | Administer 48 mg, then resume the planned treatment schedule. |
| More than 14 days | Repeat Cycle 1 schedule starting at step-up dose 1 (0.16 mg). Following the repeat of Cycle 1 schedule, resume the planned treatment schedule. | |
| 48 mg (e.g., on Cycle 1 Day 22 onwards) | 6 weeks or less | Administer 48 mg, then resume the planned treatment schedule. |
| More than 6 weeks | Repeat Cycle 1 schedule starting at step-up dose 1 (0.16 mg). Following the repeat of Cycle 1 schedule, resume the planned treatment schedule. |
| Cycle | Patients requiring medication | Medication | Administration |
|---|---|---|---|
| Cycle 1 | All patients | Dexamethasone Dexamethasone is the preferred corticosteroid when available. (15 mg oral or intravenous) or Prednisolone (100 mg oral or intravenous) or equivalent | 30-120 minutes prior to each weekly administration of EPKINLY And for three consecutive days following each weekly administration of EPKINLY in Cycle 1 |
| Diphenhydramine (50 mg oral or intravenous) or equivalent Acetaminophen (650 mg to 1,000 mg oral) | 30-120 minutes prior to each weekly administration of EPKINLY | ||
| Cycle 2+ | Patients who experienced Grade 2 or 3 Patients will be permanently discontinued from EPKINLY after Grade 4 CRS. CRS with previous dose | Dexamethasone (15 mg oral or intravenous) or Prednisolone (100 mg oral or intravenous) or equivalent | 30-120 minutes prior to next administration of EPKINLY after a Grade 2 or 3 CRS event And for three consecutive days following the next administration of EPKINLY until EPKINLY is given without subsequent CRS of Grade 2 or higher |
| Grade Based on American Society for Transplantation and Cellular Therapy (ASTCT) 2019 grading for CRS. | Presenting Symptoms | Actions |
|---|---|---|
| Grade 1 | Temperature ≥ 100.4°F (38°C) Premedication may mask fever, therefore if clinical presentation is consistent with CRS, follow these management guidelines. | Withhold EPKINLY and manage per current practice guidelines. Ensure CRS symptoms are resolved prior to next dose of EPKINLY. Refer to Table 4 or Table 5 for information on restarting EPKINLY after dosage delays [see Dosage and Administration (2.3) ]. |
| Grade 2 | Temperature ≥ 100.4°F (38°C) with: Hypotension not requiring vasopressors and/or Hypoxia requiring low-flow oxygen Low-flow oxygen defined as oxygen delivered at < 6L/minute; high-flow oxygen defined as oxygen delivered at ≥ 6 L/minute. by nasal cannula or blow-by. | Withhold EPKINLY and manage per current practice guidelines. Ensure CRS symptoms are resolved prior to next dose of EPKINLY. Administer premedication If Grade 2 or 3 CRS occurs with the second full dose (48 mg) or beyond, administer CRS pre- and post-administration medications with each subsequent dose until a EPKINLY dose is given without subsequent CRS of Grade 2 or higher. Refer to Table 6 for additional information on pre- and post-administration medications. prior to next dose of EPKINLY. For the next dose of EPKINLY, monitor more frequently and consider hospitalization. |
| Grade 3 | Temperature ≥ 100.4°F (38°C) with: Hypotension requiring a vasopressor (with or without vasopressin) and/or Hypoxia requiring high-flow oxygen by nasal cannula, face mask, non-rebreather mask, or Venturi mask. | Withhold EPKINLY and manage per current practice guidelines, which may include intensive care. Ensure CRS symptoms are resolved prior to the next dose of EPKINLY. Administer premedication prior to next dose of EPKINLY. Hospitalize for the next dose of EPKINLY. |
| Recurrent Grade 3 CRS Permanently discontinue EPKINLY. Manage CRS per current practice guidelines and provide supportive therapy, which may include intensive care. | ||
| Grade 4 | Temperature ≥ 100.4°F (38°C) with: Hypotension requiring multiple vasopressors (excluding vasopressin) and/or Hypoxia requiring oxygen by positive pressure (e.g., CPAP, BiPAP, intubation and mechanical ventilation). | Permanently discontinue EPKINLY. Manage CRS per current practice guidelines and provide supportive therapy, which may include intensive care. |
| Grade Based on American Society for Transplantation and Cellular Therapy (ASTCT) 2019 grading for ICANS. | Presenting Symptoms Management is determined by the most severe event, not attributable to any other cause. | Actions |
|---|---|---|
| Grade 1 | ICE score 7-9 If patient is arousable and able to perform Immune Effector Cell-Associated Encephalopathy (ICE) Assessment, assess: Orientation (oriented to year, month, city, hospital = 4 points); Naming (names 3 objects, e.g., point to clock, pen, button = 3 points); Following Commands (e.g., "show me 2 fingers" or "close your eyes and stick out your tongue" = 1 point); Writing (ability to write a standard sentence = 1 point); and Attention (count backwards from 100 by ten = 1 point). If patient is unarousable and unable to perform ICE Assessment (Grade 4 ICANS) = 0 points., Or depressed level of consciousness Not attributable to any other cause.: awakens spontaneously. | Withhold EPKINLY until ICANS resolves. See Table 4 or Table 5 for recommendations on restarting EPKINLY after dosage delays [see Dosage and Administration (2.3) ]. Monitor neurologic symptoms and consider consultation with neurologist and other specialists for further evaluation and management, including consideration for starting non-sedating, anti-seizure medicines for seizure prophylaxis. |
| Grade 2 | ICE score 3-6, Or depressed level of consciousness: awakens to voice. | Withhold EPKINLY until ICANS resolves. Administer dexamethasone All references to dexamethasone administration are dexamethasone or equivalent. 10 mg intravenously every 6 hours. Continue dexamethasone use until resolution to Grade 1 or less, then taper. Monitor neurologic symptoms and consider consultation with neurologist and other specialists for further evaluation and management, including consideration for starting non-sedating, anti-seizure medicines for seizure prophylaxis. |
| Grade 3 | ICE score 0-2, Or depressed level of consciousness: awakens only to tactile stimulus, Or seizures, either: Any clinical seizure, focal or generalized, that resolves rapidly, or Non-convulsive seizures on electroencephalogram (EEG) that resolve with intervention, Or raised intracranial pressure: focal/local edema on neuroimaging. | First Occurrence of Grade 3 ICANS Withhold EPKINLY until ICANS resolves. Administer dexamethasone 10 mg intravenously every 6 hours. Continue dexamethasone use until resolution to Grade 1 or less, then taper. Monitor neurologic symptoms and consider consultation with neurologist and other specialists for further evaluation and management, including consideration for starting non-sedating, anti-seizure medicines for seizure prophylaxis. Provide supportive therapy, which may include intensive care. |
| Recurrent Grade 3 ICANS Permanently discontinue EPKINLY Administer dexamethasone 10 mg intravenously every 6 hours. Continue dexamethasone use until resolution to Grade 1 or less, then taper. Monitor neurologic symptoms and consider consultation with neurologist and other specialists for further evaluation and management, including consideration for starting non-sedating, anti-seizure medicines for seizure prophylaxis. Provide supportive therapy, which may include intensive care. | ||
| Grade 4 | ICE score 0, Or depressed level of consciousness: either: Patient is unarousable or requires vigorous or repetitive tactile stimuli to arouse, or Stupor or coma Or seizures, either: Life-threatening prolonged seizure (> 5 minutes), or Repetitive clinical or electrical seizures without return to baseline in between, Or motor findings: Deep focal motor weakness, such as hemiparesis or paraparesis, or raised intracranial pressure/cerebral edema, with signs/symptoms such as: Diffuse cerebral edema on neuroimaging, or Decerebrate or decorticate posturing, or Cranial nerve VI palsy, or Papilledema, or Cushing's triad. | Permanently discontinue EPKINLY. Administer dexamethasone 10 mg intravenously every 6 hours. Continue dexamethasone use until resolution to Grade 1 or less, then taper. Alternatively, consider administration of methylprednisolone 1,000 mg per day intravenously and continue methylprednisolone 1,000 mg per day intravenously for 2 or more days. Monitor neurologic symptoms and consider consultation with neurologist and other specialists for further evaluation and management, including consideration for starting non-sedating, anti-seizure medicines for seizure prophylaxis. Provide supportive therapy, which may include intensive care. |
| Adverse Reaction Based on National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), Version 5.0. | Severity | Action |
|---|---|---|
| Infections [see Warnings and Precautions (5.3) ] | Grades 1-4 | Withhold EPKINLY in patients with active infection, until the infection resolves. See Table 4 or Table 5 for recommendations on restarting EPKINLY after dosage delays [see Dosage and Administration (2.3) ]. For Grade 4, consider permanent discontinuation of EPKINLY. |
| Neutropenia [see Warnings and Precautions (5.4) ] | Absolute neutrophil count less than 0.5 × 10 9 /L | Withhold EPKINLY until absolute neutrophil count is 0.5 × 10 9 /L or higher. |
| Thrombocytopenia [see Warnings and Precautions (5.4) ] | Platelet count less than 50 × 10 9 /L | Withhold EPKINLY until platelet count is 50 × 10 9 /L or higher. |
| Other Adverse Reactions [see Adverse Reactions (6.1) ] | Grade 3 or higher | Withhold EPKINLY until the toxicity resolves to Grade 1 or baseline. |
| Adverse Reaction | Severity Based on National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), Version 5.0. | Action Refer to lenalidomide prescribing information for additional toxicity guidelines. |
|---|---|---|
| Neutropenia [see Warnings and Precautions (5.4) ] | Absolute neutrophil count less than 0.5 × 10 9 /L | Consider G-CSF. Withhold EPKINLY until absolute neutrophil count is 1 × 10 9 /L or higher. See Table 4 or 5 for recommendations on restarting EPKINLY after dosage delays [see Dosage and Administration (2.3) ]. Withhold lenalidomide for remainder of cycle. On Day 1 of next cycle, the dose of lenalidomide may be maintained if neutropenia was the only toxicity limiting lenalidomide dosing. |
| Febrile Neutropenia [see Warnings and Precautions (5.4) ] | Grade 3 or higher | Consider G-CSF. Withhold EPKINLY until fever resolves and absolute neutrophil count is 1 × 10 9 /L or higher. Withhold lenalidomide for remainder of cycle. On Day 1 of next cycle, dose of lenalidomide may be maintained if febrile neutropenia was the only toxicity limiting lenalidomide dosing. |
| Thrombocytopenia [see Warnings and Precautions (5.4) ] | Platelet count less than 50 × 10 9 /L | Withhold EPKINLY until platelet count is 50 × 10 9 /L or higher. Withhold lenalidomide for remainder of cycle. Decrease lenalidomide dose for next cycle. |
| Other Adverse Reactions [see Adverse Reactions (6.1) ] | Grade 3 | For first episode, withhold EPKINLY until improvement to Grade 2 or less or resolution to baseline. For second episode, permanently discontinue EPKINLY if clinically indicated. |
| Grade 4 | Permanently discontinue EPKINLY at discretion of healthcare provider. |
Side Effects of Epkinly
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Relapsed or Refractory Large B-cell Lymphoma (LBCL) EPCORE NHL-1 The safety of EPKINLY was evaluated in EPCORE NHL-1, a single-arm study of patients with relapsed or refractory LBCL after two or more lines of systemic therapy, including DLBCL not otherwise specified, DLBCL arising from indolent lymphoma, high grade B-cell lymphoma, and other B-cell lymphomas. There were no Black or African American or Hispanic or Latino patients treated in the clinical trial as reported.
The median number of prior therapies was 3 (range: 2 to 11). The study excluded patients with CNS involvement of lymphoma, allogeneic HSCT or solid organ transplant, an ongoing active infection, and any patients with known impaired T-cell immunity. The median duration of exposure for patients receiving EPKINLY was 5 cycles (range: 1 to 20 cycles).
Serious adverse reactions occurred in 54% of patients who received EPKINLY. Serious adverse reactions in ≥ 2% of patients included CRS, infections (including sepsis, COVID-19, pneumonia, and upper respiratory tract infections), pleural effusion, febrile neutropenia, fever, and ICANS. Fatal adverse reactions occurred in % of patients.
Adverse reactions which resulted in permanent discontinuation of EPKINLY included COVID-19, CRS, ICANS, pleural effusion, and fatigue. Dosage interruptions of EPKINLY due to an adverse reaction occurred in 34% of patients who received EPKINLY. Adverse reactions which required dosage interruption in ≥ 3% of patients included CRS, neutropenia, sepsis, and thrombocytopenia.
The most common (≥ 20%) adverse reactions were CRS, fatigue, musculoskeletal pain, injection site reactions, pyrexia, abdominal pain, nausea, and diarrhea. The most common Grade 3 to 4 laboratory abnormalities (≥ 10%) were decreased lymphocyte count, decreased neutrophil count, decreased white blood cell count, decreased hemoglobin, and decreased platelets. Table 11 summarizes the adverse reactions in EPCORE NHL-1.
Table 11: Adverse Reactions (≥ 10%) in Patients with Relapsed or Refractory LBCL Who Received Clinically relevant adverse reactions in < 10% of patients who received EPKINLY included ICANS, sepsis, pleural effusion, COVID-19, pneumonia (including pneumonia and COVID-19 pneumonia), tumor flare, febrile neutropenia, upper respiratory tract infections, and tumor lysis syndrome. Table 12 summarizes laboratory abnormalities in EPCORE NHL-1. Table 12: Select Laboratory Abnormalities (≥ 20%) That Worsened from Baseline in Patients with Relapsed or Refractory LBCL Who Received Relapsed or Refractory Follicular Lymphoma (FL) EPCORE FL-1 The safety of EPKINLY in combination with lenalidomide and rituximab was evaluated in EPCORE FL-1, an open-label, randomized, multicenter trial that included patients with relapsed or refractory FL after at least one line of systemic therapy.
Patients were randomized to receive EPKINLY in combination with lenalidomide and rituximab cycles or until disease progression or unacceptable toxicity, whichever occurred first. Of the 243 patients who received EPKINLY, 131 received the recommended 3 step-up dosage schedule. Safety results are based on all 243 patients who received EPKINLY, with the exception of data for CRS and ICANS which are based on patients who received EPKINLY at the recommended dosage schedule.
The median duration of exposure in this arm was 10 cycles for EPKINLY and 9 cycles for lenalidomide. Serious adverse reactions occurred in 51% of these patients, including serious infections in 28% of patients and serious CRS in 12% of patients. Fatal adverse reactions within 60 days of last treatment occurred in 0.8% of patients.
Adverse reactions led to permanent discontinuation of EPKINLY in 6% of patients and dose interruption in 75% of patients, with infection as a leading cause. Adverse reactions leading to interruption of EPKINLY in ≥ 5% of patients included respiratory tract infections, CRS, and rash. In the EPKINLY arm, adverse reactions led to lenalidomide dose interruption in 72%, dose reduction in 22%, and permanent discontinuation in 15%.
The most common (≥ 20%) adverse reactions in the EPKINLY arm were rash, upper respiratory tract infections, fatigue, injection site reactions, constipation, diarrhea, CRS, pneumonia, COVID-19, and fever. The most common Grade 3 to 4 laboratory abnormalities (≥ 10%) were decreases in neutrophil count, lymphocyte count, and platelets. Table 13 summarizes select adverse reactions in EPCORE FL-1.
Table 13: Adverse Reactions (≥ 10% All Grade and ≥ 5% Higher) in Patients with Relapsed or Refractory FL Who Received at the recommended dosage schedule. Grade 4 laboratory abnormalities in ≥ 2% of the % Higher That Worsened from Baseline in Patients with Relapsed or Refractory FL Who Received as monotherapy was evaluated in EPCORE NHL-1, a single-arm study of patients with relapsed or refractory FL after two or more lines of systemic therapy who received EPKINLY following a 2-step up dosage schedule (N=127). A separate dose optimization cohort evaluated the recommended 3-step up dosage schedule for CRS mitigation (N=86), where EPKINLY was administered via subcutaneous injection until disease progression or unacceptable toxicities according to the following mg on Day 1 With the exception of CRS, the safety results presented below and in Tables 15 and 16 represent data from patients who received the 2-step up dosage schedule.
The median duration of exposure for patients receiving EPKINLY was 8 cycles (range: 1 to 33 cycles). Serious adverse reactions in ≥ 5% of patients included CRS, COVID-19, pneumonia, and second primary malignancies. Fatal adverse reactions occurred in 9% of patients who received.
Adverse reactions which resulted in permanent discontinuation of EPKINLY in ≥ 2% of patients included COVID-19, Hepatitis E, pneumonitis, and second primary malignancy. Adverse reactions which required dosage interruption in ≥ 5% of patients included COVID-19, CRS, pneumonia, upper respiratory tract infection, and fatigue. The most common (≥ 20%) adverse reactions were injection site reactions, CRS, COVID-19, fatigue, upper respiratory tract infection, musculoskeletal pain, rash, diarrhea, pyrexia, cough, and headache.
Table 15: Adverse Reactions (≥ 10%) in Patients with Relapsed or Refractory FL Who Received patients with FL who received the recommended 3-step up dosage schedule in EPCORE NHL-1. Clinically relevant adverse reactions in < 10% of patients (N=127) who received EPKINLY included vomiting, pruritus, hepatotoxicity, ICANS, lower respiratory tract infections, cardiac arrhythmias, respiratory tract infections, pneumonitis, second primary malignancy, vision changes, cellulitis, febrile neutropenia, cardiac failure, cytomegalovirus infection and sepsis. Table 16 summarizes laboratory abnormalities in EPCORE NHL-1.
Table 16: Select Laboratory Abnormalities (≥ 20%) That Worsened from Baseline in Patients with Relapsed or Refractory FL Who Received Other Clinical Trials Experience The following adverse reactions have been reported following administration of epcoritamab-bysp: hypogammaglobulinemia.
Postmarketing Experience
The following adverse reaction has been identified during post-approval use of EPKINLY. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Immune system disorders: Hemophagocytic Lymphohistiocytosis (HLH)
| EPKINLY (N=157) | ||
|---|---|---|
| Adverse Reaction Adverse reactions were graded based on CTCAE Version 5.0 | All Grades (%) | Grade 3 or 4 (%) |
| Immune system disorders | ||
| Cytokine release syndrome CRS was graded using ASTCT consensus criteria (Lee et al., 2019). | 51 | 2.5 Only grade 3 adverse reactions occurred. |
| General disorders and administration site conditions | ||
| Fatigue Fatigue includes asthenia, fatigue, lethargy. | 29 | 2.5 |
| Injection site reactions Injection site reaction includes injection site erythema, injection site hypertrophy, injection site inflammation, injection site mass, injection site pain, injection site pruritus, injection site rash, injection site reaction, injection site swelling, injection site urticaria. | 27 | 0 |
| Pyrexia | 24 | 0 |
| Edema Edema includes edema, edema peripheral, face edema, generalized edema, peripheral swelling. | 14 | 1.9 |
| Musculoskeletal and connective tissue disorders | ||
| Musculoskeletal pain Musculoskeletal pain includes back pain, bone pain, flank pain, musculoskeletal chest pain, musculoskeletal pain, myalgia, neck pain, non-cardiac chest pain, pain, pain in extremity, spinal pain. | 28 | 1.3 |
| Gastrointestinal disorders | ||
| Abdominal pain Abdominal pain includes abdominal discomfort, abdominal pain, abdominal pain lower, abdominal pain upper, abdominal tenderness. | 23 | 1.9 |
| Diarrhea | 20 | 0 |
| Nausea | 20 | 1.3 |
| Vomiting | 12 | 0.6 |
| Skin and subcutaneous disorders | ||
| Rash Rash includes dermatitis bullous, erythema, palmar erythema, penile erythema, rash, rash erythematous, rash maculo-papular, rash pustular, recall phenomenon, seborrheic dermatitis, skin exfoliation. | 15 | 0.6 |
| Nervous system disorder | ||
| Headache | 13 | 0.6 |
| Metabolism and nutrition disorders | ||
| Decreased appetite | 12 | 0.6 |
| Cardiac disorders | ||
| Cardiac arrhythmias Cardiac arrhythmias includes bradycardia, sinus bradycardia, sinus tachycardia, supraventricular extrasystoles, supraventricular tachycardia, tachycardia. | 10 | 0.6 |
| Laboratory Abnormality Laboratory abnormalities were graded based on CTCAE Version 5.0 | EPKINLY The denominator used to calculate the rate varied from 146 to 153 based on the number of patients with a baseline value and at least one post-treatment value. | |
|---|---|---|
| All Grades (%) | Grade 3 or 4 (%) | |
| Hematology | ||
| Lymphocyte count decreased | 87 | 77 |
| Hemoglobin decreased | 62 | 12 |
| White blood cells decreased | 53 | 22 |
| Neutrophils decreased | 50 | 32 |
| Platelets decreased | 48 | 12 |
| Chemistry | ||
| Sodium decreased | 56 | 2.6 |
| Phosphate decreased CTCAE Version 5.0 does not include numeric thresholds for grading of hypophosphatemia; all grades represent patients with lab value < Lower Limit of Normal (LLN). | 56 | N/A |
| Aspartate aminotransferase increased | 48 | 4.6 |
| Alanine aminotransferase increased | 45 | 5.3 |
| Potassium decreased | 34 | 5.3 |
| Magnesium decreased | 31 | 0 |
| Creatinine increased | 24 | 3.3 |
| Potassium increased | 21 | 1.3 |
| Adverse Reaction Adverse reactions were graded using CTCAE Version 5.0. CRS was graded using ASTCT consensus criteria (Lee et al., 2019). | EPKINLY + Lenalidomide and Rituximab | Lenalidomide and Rituximab | ||
|---|---|---|---|---|
| All Grades (%) | Grade 3 or 4 (%) | All Grades (%) | Grade 3 or 4 (%) | |
| This table includes a combination of grouped and ungrouped terms. | ||||
| (N=131) | (N=238) | |||
| Immune system disorders | ||||
| Cytokine release syndrome | 24 The frequency of CRS is based on 131 patients who received EPKINLY at the recommended dosage schedule [see Dosage and Administration (2.2) ]. Grade 1 CRS: 19%; Grade 2 CRS: 5%. The frequency of CRS among the 243 patients who received either the 2-step up or 3-step up dosage schedule was the following: Any grade CRS 35%; Grade 1 CRS: 28%; Grade 2 CRS: 7%. | 0 | 0.8 | 0 |
| (N=243) | (N=238) | |||
| Skin and subcutaneous tissue disorders | ||||
| Rash Rash includes blister, dermatitis, erythema, rash, skin exfoliation, skin reaction, toxic skin eruption, urticaria and related terms. | 46 | 11 Only Grade 3 adverse reactions occurred. | 34 | 6 |
| Infections and infestations | ||||
| Upper respiratory tract infections Upper respiratory tract infections include sinusitis, laryngitis, nasopharyngitis, pharyngitis, rhinitis, rhinovirus infection, upper respiratory tract infection, and related terms. | 33 | 3.3 | 18 | 0.4 |
| Pneumonia Pneumonia includes pneumonia, COVID-19 pneumonia, pneumonia fungal, Pneumocystis jirovecii pneumonia, pneumonia cytomegaloviral, and related terms. | 24 | 16 | 8 Includes one case with a fatal outcome. | 4.6 |
| COVID-19 COVID-19 includes COVID-19, COVID-19 pneumonia, coronavirus infection, coronavirus pneumonia. | 23 | 5 | 13 | 1.3 |
| General disorders and administration site conditions | ||||
| Fatigue Fatigue includes asthenia, fatigue, lethargy, malaise. | 31 | 4.9 | 24 | 2.1 |
| Injection site reactions | 27 | 0 | 0.4 | 0 |
| Fever | 23 | 0.4 | 11 | 1.3 |
| Gastrointestinal disorders | ||||
| Constipation | 26 | 0.8 | 21 | 0 |
| Mucositis Mucositis includes gingival pain, glossitis, mouth ulceration, mucosal infection, mucosal inflammation, oral discomfort, oral mucosal exfoliation, oropharyngeal pain, stomatitis. | 12 | 0 | 3.4 | 0 |
| Nervous system disorders | ||||
| Neurological changes Neurological changes include brain fog, cognitive disorder, confusional state, disturbance in attention, dysphonia, epilepsy, essential tremor, gait disturbance, hypoacusis, lethargy, loss of consciousness, memory impairment, somnolence, syncope, tremor, vertigo, and ICANS. | 15 | 1.2 | 8 | 1.3 |
| Headache | 11 | 0 | 3.8 | 0 |
| Psychiatric disorders | ||||
| Insomnia | 14 | 0 | 2.9 | 0 |
| Laboratory Abnormality | EPKINLY + Lenalidomide and Rituximab The denominator used to calculate the rate varied from 240 to 242 in the EPKINLY arm, and 225 to 236 in the comparator arm, based on the number of patients with a baseline value and at least one post-treatment value. | Lenalidomide and Rituximab | ||
|---|---|---|---|---|
| All Grades (%) | Grade 3 or 4 (%) | All Grades (%) | Grade 3 or 4 (%) | |
| Laboratory abnormalities were graded based on CTCAE Version 5.0 | ||||
| Hematology | ||||
| Neutrophils decreased | 86 | 67 | 75 | 41 |
| Lymphocytes decreased | 86 | 62 | 56 | 15 |
| Hemoglobin decreased | 66 | 7 | 52 | 4.7 |
| Platelets decreased | 50 | 10 | 37 | 7 |
| Chemistry | ||||
| Alanine aminotransferase increased | 58 | 7 | 36 | 0.9 |
| Phosphate decreased CTCAE Version 5.0 does not include numeric thresholds for grading of hypophosphatemia; all grades represent patients with lab value < Lower Limit of Normal (LLN). | 49 | N/A | 28 | N/A |
| Sodium decreased | 43 | 4.1 | 23 | 2.6 |
| Potassium decreased | 41 | 9 | 20 | 4.7 |
| Aspartate aminotransferase increased | 40 | 2.9 | 29 | 0.9 |
| Adverse Reaction Adverse reactions were graded based on CTCAE Version 5.0. | EPKINLY | |
|---|---|---|
| All Grades (%) | Grade 3 or 4 (%) | |
| (N=86) The frequency of CRS is based on 86 patients with FL who received the recommended 3-step up dosage schedule in EPCORE NHL-1 [see Dosage and Administration (2.2) ]. | ||
| Immune system disorders | ||
| Cytokine release syndrome CRS was graded using ASTCT consensus criteria (Lee et al., 2019). The frequency of CRS based on the 127 patients with FL who received the 2-step up dosage schedule in EPCORE NHL-1 was the following: Any grade CRS 66%; Grade 1 CRS: 50%; Grade 2 CRS: 26%; Grade 3 CRS: 1.6%. | 49 | 0 |
| (N=127) | ||
| General disorders and administration site conditions | ||
| Injection site reactions Includes related grouped terms. | 58 | 0 |
| Fatigue | 37 | 5 Only Grade 3 adverse reactions occurred. |
| Pyrexia | 26 | 2 |
| Edema | 17 | 0 |
| Infections and Infestations | ||
| COVID-19 COVID-19 includes COVID-19, COVID-19 pneumonia, SARS-CoV-2 test positive. | 40 | 19 |
| Upper respiratory tract infection Upper respiratory tract infection includes preferred terms with upper respiratory infection and sinusitis, laryngitis viral, nasopharyngitis, oropharyngitis fungal, pharyngitis, rhinitis, rhinovirus infection, tonsillitis. | 29 | 2 |
| Pneumonia Pneumonia includes preferred terms with pneumonia, bronchopulmonary aspergillosis, infectious pleural effusion, infective exacerbation of bronchiectasis, Pneumocystis jirovecii pneumonia, pneumonia respiratory syncytial viral. | 17 | 13 |
| Urinary tract infection | 13 | 5 |
| Herpesvirus infection Herpesvirus infection includes herpes simplex, herpes simplex reactivation, herpes virus infection, herpes zoster, oral herpes, varicella zoster virus infection. | 12 | 1.6 |
| Musculoskeletal and connective tissue disorders | ||
| Musculoskeletal pain | 28 | 0.8 |
| Arthralgia | 14 | 0.8 |
| Skin and subcutaneous disorders | ||
| Rash | 28 | 0 |
| Gastrointestinal disorders | ||
| Diarrhea | 26 | 1.6 |
| Nausea | 17 | 0 |
| Abdominal pain | 17 | 0.8 |
| Constipation | 16 | 0 |
| Mucositis Mucositis includes aphthous ulcer, mouth ulceration, mucosal inflammation, oral pain, oropharyngeal pain, stomatitis, tongue ulceration. | 12 | 0 |
| Respiratory disorders | ||
| Cough | 20 | 0 |
| Dyspnea | 17 | 0 |
| Nervous system disorders | ||
| Headache | 20 | 0 |
| Neurological changes Neurological changes includes amnesia, aphasia, balance disorder, brain fog, confusional state, dysphonia, encephalopathy, extrapyramidal disorder, hallucination, hypoacusis, memory impairment, mental status changes, tremor, vertigo. | 13 | 0 |
| Peripheral neuropathy and paresthesia Peripheral neuropathy and paresthesia includes bell's palsy, hypoesthesia, neuralgia, neuropathy peripheral, paresthesia, peripheral sensory neuropathy, polyneuropathy. | 13 | 1.6 |
| Dizziness | 11 | 0 |
| Psychiatric disorders | ||
| Insomnia | 13 | 0 |
| Renal and urinary disorders | ||
| Renal insufficiency Renal insufficiency includes acute kidney injury, blood creatinine increased, renal impairment. | 10 | 1.6 |
| Laboratory Abnormality Laboratory abnormalities were graded based on CTCAE Version 5.0 | EPKINLY The denominator used to calculate the rate varied from 123 to 127 based on the number of patients with a baseline value and at least one post-treatment value. (N=127) | |
|---|---|---|
| All Grades | Grade 3 or 4 (%) | |
| Hematology | ||
| Lymphocytes decreased | 94 | 82 |
| Hemoglobin decreased | 59 | 10 |
| White blood cells decreased | 58 | 19 |
| Neutrophils decreased | 55 | 30 |
| Platelets decreased | 49 | 8 |
| Chemistry | ||
| Sodium decreased | 51 | 1.6 |
| ALT increased | 47 | 8 |
| AST increased | 44 | 6 |
| Creatinine increased | 36 | 0.8 |
| Alkaline phosphatase increased | 29 | 0 |
| Bilirubin increased | 28 | 1.6 |
| Potassium decreased | 20 | 3.1 |
| Magnesium decreased | 20 | 0.8 |
Warnings & Cautions for Epkinly
Cytokine Release Syndrome EPKINLY can cause
CRS, including serious or fatal reactions. Recurrent CRS occurred in 31% of these patients. Most CRS events (92%) occurred during Cycle 1.
The median time to onset of CRS from the most recent EPKINLY dose was 24 hours (range: 0 to 10 days). For patients with LBCL, assess whether hospitalization or outpatient monitoring for the first 48 mg dose (Cycle 1 Day 15) is appropriate based on comorbidities or other situational factors. During outpatient monitoring after the first 48 mg dose, patients should remain in proximity to a healthcare facility that can assess and manage CRS.
Recurrent CRS occurred in 48% of patients. Most CRS events (88%) occurred during Cycle 1. The median time to onset of CRS from the most recent EPKINLY dose was 59 hours (range: 0.1 to 7 days).
Recurrent CRS occurred in 41% of patients. The median time to onset of CRS from the most recent EPKINLY dose was 78 hours (range: 0.2 to 12 days). Among patients with LBCL or FL who experienced CRS, signs and symptoms included pyrexia, hypotension, hypoxia, dyspnea, chills, and tachycardia.
Concurrent neurological adverse reactions associated with CRS occurred in 2.5% of patients with LBCL, 4.7% of patients with FL receiving EPKINLY monotherapy, and 1.5% of patients receiving EPKINLY in combination with lenalidomide and rituximab. Concurrent neurological adverse reactions included headache, confusional state, tremors, dizziness, and ataxia. Initiate EPKINLY according to the recommended step-up dosage schedule.
Administer pretreatment medications to reduce the risk of CRS and monitor patients for potential CRS accordingly. At the first signs or symptoms of CRS, immediately evaluate patients for hospitalization, manage per current practice guidelines, and administer supportive care as appropriate. Withhold or discontinue EPKINLY based on the severity of CRS.
Patients who experience CRS (or other adverse reactions that impair consciousness) should be evaluated and advised not to drive and to refrain from operating heavy or potentially dangerous machinery until resolution.
Immune Effector Cell-Associated Neurotoxicity Syndrome EPKINLY can cause life-threatening and fatal immune effector cell-associated neurotoxicity syndrome (ICANS). There was one (0.6%) fatal ICANS occurrence. Relative to the most recent administration of EPKINLY, the median time to onset of ICANS was 3 days (range: 1 to 13 days).
The median time to onset of ICANS was 22 days (range: 14 to 66 days) from the start of treatment. Relative to the most recent administration of EPKINLY, the median time to onset of ICANS was 3 days (range: 0.4 to 7 days). Among patients with FL who received EPKINLY at the recommended dosage schedule in combination with lenalidomide and rituximab in EPCORE FL-1, ICANS occurred in 0.8% (1/131, Grade 1).
For patients with LBCL or FL, clinical manifestations of ICANS included, but were not limited to confusional state, lethargy, tremor, dysgraphia, aphasia, and non-convulsive status epilepticus. The onset of ICANS can be concurrent with CRS, following resolution of CRS, or in the absence of CRS. Monitor patients for potential ICANS following EPKINLY.
At the first signs or symptoms of ICANS, immediately evaluate patient and provide supportive therapy based on severity. Withhold or discontinue EPKINLY per recommendations and consider further management per current practice guidelines.
Infections EPKINLY can cause fatal and serious infections
Serious infections, including opportunistic infections, were reported in 15% of patients with LBCL receiving EPKINLY at the recommended dosage schedule in EPCORE NHL-1 and were most commonly due to sepsis (4.5%) and pneumonia (3.2%). Fatal infections occurred in 1.3% of patients and were due to COVID-19. Serious infections, including opportunistic infections, were reported in 40% of patients with FL receiving EPKINLY monotherapy following the 2-step up dosage schedule in EPCORE NHL-1 and were most commonly due to COVID-19 (20%), pneumonia (13%), and urinary tract infections (3%).
Among 243 patients with FL who received EPKINLY in combination with lenalidomide and rituximab in EPCORE FL-1, serious infections occurred in 28% of patients. The most common opportunistic infections of any grade were CMV infection (7%) and herpesvirus infection (7%). Progressive multifocal leukoencephalopathy (PML), including fatal cases, has occurred in patients treated with EPKINLY.
Across a broader clinical trial population, PML was reported in 0.4% (11/3072) of patients, including in the first-line treatment setting. Of the 11 cases of PML, six resulted in fatal outcomes and one was unresolved at the time of death. Monitor patients for signs and symptoms of infection and treat appropriately.
Avoid administration of EPKINLY in patients with active infections. Provide PJP prophylaxis during treatment with EPKINLY, and consider initiating prophylaxis against herpesvirus. Consider monitoring immunoglobulin levels during treatment and administration of immunoglobulin treatment as appropriate.
Withhold or consider permanent discontinuation of EPKINLY based on severity.
Cytopenias EPKINLY can cause serious or severe cytopenias, including neutropenia, lymphopenia, anemia, and thrombocytopenia. Febrile neutropenia occurred in 2.5% (Grade 4, 0.6%). Febrile neutropenia occurred in 3.1% (Grade 4, 0%).
Febrile neutropenia occurred in 6% (Grade 4, 2.1%). Monitor complete blood counts throughout treatment. Consider prophylactic granulocyte colony-stimulating factor administration as applicable.
Embryo-Fetal Toxicity Based on its mechanism of action, EPKINLY may cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to the fetus. Advise females of reproductive potential to use effective contraception during treatment with EPKINLY and for 4 months after the last dose.
Drug Interactions with Epkinly
For certain CYP substrates, minimal changes in the concentration may lead to serious adverse reactions. Monitor for toxicity or drug concentrations of such CYP substrates when co-administered with EPKINLY. Epcoritamab-bysp causes release of cytokines that may suppress activity of CYP enzymes, resulting in increased exposure of CYP substrates.
Increased exposure of CYP substrates is more likely to occur after the first dose of EPKINLY and up to 14 days after the first 48 mg dose, and during and after CRS.
Pregnancy Safety for Epkinly
Pregnancy Risk Summary Based on the mechanism of action, EPKINLY may cause fetal harm when administered to a pregnant woman. There are no available data on the use of EPKINLY in pregnant women to evaluate for a drug-associated risk. No animal reproductive or developmental toxicity studies have been conducted with epcoritamab-bysp.
Epcoritamab-bysp causes T-cell activation and cytokine release; immune activation may compromise pregnancy maintenance. In addition, based on expression of CD20 on B-cells and the finding of B-cell depletion in non-pregnant animals, epcoritamab-bysp can cause B-cell lymphocytopenia in infants exposed to epcoritamab-bysp in-utero. Human immunoglobulin G (IgG) is known to cross the placenta; therefore, EPKINLY has the potential to be transmitted from the mother to the developing fetus.
Advise women of the potential risk to the fetus. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is respectively.
Pediatric Use of Epkinly
Pediatric Use The safety and efficacy of EPKINLY in pediatric patients have not been established.
Clinical Studies of Epkinly
DLBCL and High-grade B-cell Lymphoma
The efficacy of EPKINLY was evaluated in EPCORE NHL-1 (Study GCT3013-01; NCT03625037), an open-label, multi-cohort, multicenter, single-arm trial in 157 patients with relapsed or refractory large B-cell lymphoma (LBCL) after two or more lines of systemic therapy. The study excluded patients with CNS involvement of lymphoma, allogeneic HSCT or solid organ transplant, ongoing active infection, and any patients with known impaired T-cell immunity. In the setting of a suspected tumor flare reaction, continued treatment was permitted.
The efficacy population includes 148 patients with DLBCL, not otherwise specified (NOS), including DLBCL arising from indolent lymphoma, and high-grade B-cell lymphoma. There were no Black or African American or Hispanic or Latino patients treated in the clinical trial as reported. The diagnosis was DLBCL NOS in 86%, including 27% with DLBCL transformed from indolent lymphoma, and high-grade B-cell lymphoma in 14%.
Eighteen percent had prior autologous HSCT, and 39% had prior chimeric antigen receptor (CAR) T-cell therapy. Eighty-two percent of patients had disease refractory to last therapy and 29% of patients were refractory to CAR T-cell therapy. Efficacy was established based on overall response rate (ORR) and duration of response as assessed by an Independent Review Committee (IRC) using Lugano 2014 criteria.
The efficacy results are summarized in Table 18. Among responders, the median follow-up for DOR was 9.8 months (range: 0.0 to 17.3 months).
Follicular Lymphoma EPKINLY in Combination with Lenalidomide and Rituximab for FL The efficacy of EPKINLY in combination with lenalidomide and rituximab was evaluated in EPCORE FL-1 (Study M20-638; NCT05409066), an open-label, randomized, multicenter, global trial in patients with relapsed or refractory FL after at least one line of systemic therapy. Patients were randomized to receive EPKINLY in combination with lenalidomide and rituximab, or lenalidomide and rituximab alone. The study excluded patients with known CNS involvement by lymphoma, prior allograft, and known active infection.
Patients received EPKINLY via subcutaneous injection in 28-day cycles for a total of 12 cycles or until disease progression or unacceptable toxicity, whichever occurred first. Forty-one percent had progressive disease within 24 months of first systemic therapy. Efficacy was established based on progression free survival (PFS) and overall response rate (ORR) as assessed by Independent Review Committee (IRC) using Lugano 2014 criteria.
The efficacy results, based on a prespecified interim analysis, are summarized in Table 19 and the Kaplan-Meier plot of PFS presented in Figure 1. The results are based on a median duration of follow-up of 10.4 months in the intention-to-treat population. EPKINLY as Monotherapy for FL The efficacy of EPKINLY as monotherapy was evaluated in EPCORE NHL-1 (Study GCT3013-01; NCT03625037), an open-label, multi-cohort, multicenter, single-arm trial that included patients with relapsed or refractory follicular lymphoma (FL) after at least 2 lines of systemic therapy.
Among the 127 patients with FL, the median age was 65 years range: years of age or older, and 62% were male. Seventy-nine percent of patients were refractory to prior anti-CD20 monoclonal antibody therapy, 70% were refractory to both anti-CD20 monoclonal antibody and alkylator therapy, 21% had prior rituximab plus lenalidomide therapy, 19% received prior autologous HSCT, and 5% received prior chimeric antigen receptor (CAR) T-cell therapy. Fifty-two percent of patients had progression of disease within 24 months of first systemic therapy.
The efficacy results are summarized in Table 20. In a separate dose optimization cohort in EPCORE NHL-1, 86 patients received the recommended 3-step up dosage schedule in Cycle 1. The efficacy results in this cohort were comparable to the primary efficacy population.
Figure 1
| Endpoint Determined by Lugano criteria (2014) as assessed by independent review committee (IRC). | EPKINLY (N=148) |
|---|---|
| ORR = overall response rate; CI = confidence interval; CR = complete response; PR = partial response; DOR = duration of response; NR = not reached. | |
| ORR Early response assessments were evaluated in the context of potential flare reactions. Of 90 patients who achieved an objective response, 9 patients had early flare reactions identified with objective response demonstrated on subsequent imaging per Lugano criteria., n (%) | 90 (61) |
| (95% CI) | (52.5, 68.7) |
| CR, n (%) | 56 (38) |
| (95% CI) | (30.0, 46.2) |
| PR, n (%) | 34 (23) |
| (95% CI) | (16.5, 30.6) |
| DOR | |
| Median (95% CI), months | 15.6 (9.7, NR) |
| 9-month estimate Kaplan-Meier estimate. (95% CI), % | 63 (51.5, 72.4) |
| Outcome per IRC | EPKINLY + Lenalidomide and Rituximab (N=243) | Lenalidomide and Rituximab (N=245) |
|---|---|---|
| PFS = progression free survival; CI = confidence interval; NR = not reached; ORR = overall response rate; CR = complete response. | ||
| PFS | ||
| Number of events, n (%) | 23 (9) | 75 (31) |
| Progressive disease | 19 (83) | 63 (84) |
| Death | 4 (17) | 12 (16) |
| Median (95% CI), months | NR (21.9, NR) | 11.2 (10.5, NR) |
| Hazard ratio Cox proportional hazards hazard ratio stratified by disease history and region. (95% CI) | 0.21 (0.13, 0.33) | |
| P-value Log-rank p-value (one sided) stratified by disease history and region. | < 0.0001 | |
| ORR, n (%) | 216 (89) | 181 (74) |
| (95% CI) | (84, 93) | (68, 79) |
| P-value P-value is based on a prespecified analysis of the first 232 patients randomized., P-value (one sided) is from a Cochran-Mantel-Haenszel test stratified by disease history and region. | < 0.0001 | |
| CR, n (%) | 181 (74) | 106 (43) |
| (95% CI) | (69, 80) | (37, 50) |
| P-value | < 0.0001 | |
| Endpoint Determined by Lugano criteria (2014) as assessed by independent review committee (IRC). | EPKINLY (N=127) |
|---|---|
| ORR = overall response rate; CI = confidence interval; CR = complete response; PR = partial response; DOR = duration of response; NR = not reached. | |
| ORR, n (%) | 104 (82) |
| (95% CI) | (74.1, 88.2) |
| CR, n (%) | 76 (60) |
| (95% CI) | (50.8, 68.4) |
| PR, n (%) | 28 (22) |
| (95% CI) | (15.2, 30.3) |
| DOR | |
| Median (95% CI), months | NR (13.7, NR) |
| 12-month estimate Kaplan-Meier estimate. % (95% CI) | 68.4 (57.6, 77.0) |
Drug information sourced from the FDA. This content is for informational purposes only and does not constitute medical advice. Consult a healthcare professional before making any medication decisions.
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