Semimechanistic Physiologically-Based Pharmacokinetic/Pharmacodynamic Model Informing Epcoritamab Dose Selection for Patients With B-Cell Lymphomas.

Epcoritamab is a CD3xCD20 bispecific antibody (bsAb) that induces T-cell-mediated cytotoxicity against CD20-positive B cells. Target engagement and crosslinking of CD3 and CD20 (trimer formation) leads to activation and expansion of T cells and killing of malignant B cells. The primary objective of the dose-escalation part of the phase I/II trial of epcoritamab was to determine the maximum tolerated dose, recommended phase II dose (RP2D), or both. For bsAbs, high target saturation can negatively affect trimer formation. The unique properties and mechanisms of action of bsAbs require novel pharmacokinetic (PK) modeling methods to predict clinical activity and inform RP2D selection. Traditional PK/pharmacodynamic (PD) modeling approaches are inappropriate because they may not adequately predict exposure-response relationships. We developed a semimechanistic, physiologically-based PK/PD model to quantitatively describe biodistribution, trimer formation, and tumor response using preclinical, clinical PK, biomarker, tumor, and response data from the dose-escalation part of the phase I/II trial. Clinical trial simulations were performed to predict trimer formation and tumor response in patients with diffuse large B-cell lymphoma (DLBCL) or follicular lymphoma (FL). Model-predicted trimer formation plateaued at doses of 48 to 96 mg. Simulation results suggest that the 48-mg dose may achieve optimal response rates in DLBCL and FL. Exposure-safety analyses showed a flat relationship between epcoritamab exposure and risk of cytokine release syndrome in the dose range evaluated. This novel PK/PD modeling approach guided selection of 48 mg as the RP2D and provides a framework that may be applied to other CD3 bsAbs.

Dose escalation of subcutaneous epcoritamab in patients with relapsed or refractory B-cell non-Hodgkin lymphoma: an open-label, phase 1/2 study.

BACKGROUND: Patients with relapsed or refractory B-cell non-Hodgkin lymphoma have few treatment options. We aimed to establish the safety and recommended phase 2 dose of epcoritamab, a novel bispecific antibody that targets CD3 and CD20 and induces T-cell-mediated cytotoxic activity against CD20+ malignant B cells. METHODS: For the dose-escalation part of this phase 1/2 study, we enrolled adults (aged ≥18 years) with relapsed or refractory CD20+ B-cell non-Hodgkin lymphoma at ten sites across four countries (Denmark, the Netherlands, the UK, and Spain). Eligible patients received priming and intermediate doses followed by full doses of subcutaneous epcoritamab administered in 28-day cycles; each subsequent cohort involved escalation of the priming, intermediate, or full dose (0·0128-60 mg). The primary objectives were to determine the maximum tolerated dose and the recommended phase 2 dose. Safety, antitumour activity, pharmacokinetics, and immune biomarkers were also assessed. This study is registered with ClinicalTrials.gov, NCT03625037, with the dose-expansion part ongoing. FINDINGS: Between June 26, 2018, and July 14, 2020, we enrolled 73 patients with relapsed, progressive, or refractory CD20+ mature B-cell non-Hodgkin lymphoma. 68 patients received escalating full doses (0·0128-60 mg) of subcutaneous epcoritamab. No dose-limiting toxic effects were observed, and the maximum tolerated dose was not reached; the full dose of 48 mg was identified as the recommended phase 2 dose. All 68 patients received at least one dose of epcoritamab and were included in safety analyses: common adverse events were pyrexia (47 patients [69%]), primarily associated with cytokine release syndrome (CRS; 40 [59%], all grade 1-2), and injection site reactions (32 [47%]; 31 grade 1). There were no grade 3 or higher CRS events. No discontinuations occurred due to treatment-related adverse events or treatment-related deaths. Overall response rate in patients with relapsed or refractory diffuse large B-cell lymphoma was 68% (95% CI 45-86), with 45% achieving a complete response at full doses of 12-60 mg. At 48 mg, the overall response rate was 88% (47-100), with 38% achieving a complete response. Patients with relapsed or refractory follicular lymphoma had an overall response rate of 90% (55-100), with 50% achieving a complete response at full doses of 0·76-48 mg. Epcoritamab induced robust and sustained B-cell depletion, and CD4+ and CD8+ T-cell activation and expansion, with modest increases in cytokine levels. INTERPRETATION: Single-agent subcutaneous epcoritamab for treatment of patients with relapsed or refractory B-cell non-Hodgkin lymphoma merits investigation in ongoing phase 2 and phase 3 studies. FUNDING: Genmab and AbbVie.

A noninterventional observational registry of patients with multiple myeloma treated with lenalidomide in Taiwan.

BACKGROUND/PURPOSE: The incidence of multiple myeloma in Asia has risen in the past 30 years. Lenalidomide, an IMiD immunomodulatory agent, has improved the overall survival in patients with relapsed/refractory multiple myeloma (RRMM) when used with dexamethasone versus dexamethasone alone. This observational registry (T-CC-MM-009; NCT01752075) assessed the safety and efficacy of lenalidomide plus dexamethasone in a large Chinese population of patients with RRMM. METHODS: This registry followed the first 100 patients treated with lenalidomide plus dexamethasone in Taiwan. Patients were ≥18 years old and had ≥1 prior treatment. The recommended starting dose for the first four 28-day cycles was 25 mg lenalidomide on days 1-21 and 40 mg dexamethasone on days 1-4, 9-12, and 17-20. Thereafter, dexamethasone was given on days 1-4 only. The primary objective was safety; secondary objectives were efficacy, lenalidomide dosage, and reasons for discontinuation. RESULTS: The median duration of treatment was 34.6 weeks, and 75.5% completed ≥3 cycles. Most patients (82.7%) experienced ≥1 treatment-related adverse event; the most commonly reported were neutropenia (23.5%), thrombocytopenia (19.4%), anemia (16.3%), fatigue (16.3%), and hypoesthesia (15.3%). Bleeding events (25.5% of patients) were mostly grade 1/2 (80%). Three patients (3%) had venous thromboembolic events. Two invasive second primary malignancies were reported; however, time to onset was <1 year, suggesting they may not be related to lenalidomide. The overall response rate was 34.7%; median time to disease progression was 20.5 months. CONCLUSION: These data confirm the safety and efficacy of lenalidomide plus dexamethasone for patients with RRMM in Taiwan.

Long-term use of lenalidomide and low-dose dexamethasone in Chinese patients with relapsed/refractory multiple myeloma: MM-024 Extended Access Program.

BACKGROUND: The efficacy and safety of lenalidomide plus low-dose dexamethasone (Rd) in Chinese patients with relapsed/refractory multiple myeloma (RRMM) was demonstrated in a phase 2, multicenter trial (MM-021). MM-024 was an Extended Access Program (EAP) that allowed responding patients in the MM-021 trial to continue to receive Rd, and to provide additional safety and efficacy data with longer follow-up. METHODS: Chinese patients with RRMM who completed ≥ 1 year of Rd therapy in MM-021 and who remained progression-free under Rd entered the Treatment Phase of the MM-024 EAP, continuing Rd at the same dose and schedule. Patients in MM-021 who discontinued Rd treatment or progressed were allowed to enroll in the Safety Follow-Up Phase of the MM-024 EAP. Safety data, including the incidence of second primary malignancies (SPMs), were collected for ≥ 5 years from the time the last on-study patient enrolled in the MM-021 trial (primary end point). Efficacy outcomes (time to progression [TTP], progression-free survival [PFS], and overall survival [OS]) were secondary end points. RESULTS: Median follow-up was 38.4 months for the safety population (n = 80) and 43.3 months for the treatment cohort (n = 41). In the safety population, Grade 3-4 adverse events (AEs) occurred in 60.0 % of patients; the most common grade 3-4 AEs were neutropenia (20.0%), decreased neutrophil count (13.8%), and anemia (11.3%). There was no evidence of cumulative toxicity, and no patients discontinued Rd due to AEs; 2 patients had SPMs. In the treatment cohort, median duration of response was 35.1 months, median TTP was 36.9 months, and median PFS was 36.0 months; median OS was not reached due to the low number of deaths (n = 5). CONCLUSION: Long-term treatment with Rd has a predictable and manageable safety profile and provides sustained efficacy in Chinese patients with RRMM. TRIAL REGISTRATION: China State Food and Drug Administration (SFDA) registration (CTA reference numbers: 209L10808; 209L10809; 209L10810; and 209L10811) and ClinicalTrials.gov Identifier: NCT02348528. First received January 23, 2015; last updated November 12, 2015; last verified November 2015; study start date September 2012.

Lenalidomide plus low-dose dexamethasone in Chinese patients with relapsed or refractory multiple myeloma and renal impairment.

Lower starting doses of lenalidomide (LEN) are recommended for patients with renal impairment (RI). In the present study, we conducted a subgroup analysis of the MM-021 registration trial to investigate the efficacy and safety of LEN plus low-dose dexamethasone (LoDEX) in Chinese patients with advanced relapsed or refractory multiple myeloma (RRMM) based on levels of RI. Patients received LEN+LoDEX until disease progression or discontinuation. Patients were divided according to RI: no/mild [creatinine clearance (CrCl) ≥60 mL/min, n = 131], moderate (CrCl ≥30 to <60 mL/min, n = 54), and severe (CrCl <30 mL/min, n = 14). LEN starting dose was 25 mg/day on days 1-21, adjusted for baseline renal function. Best overall response rate was 48 %; in patients with no/mild, moderate, or severe RI, response rates were 50, 42, and 42 %, respectively. Median progression-free survival and overall survival were longer in patients with no/mild RI (9.3 and 22.4 months, respectively) versus those with moderate (6.9 and 16.0 months) or severe RI (4.8 and 11.1 months). LEN+LoDEX was well tolerated, although incidences of grade 3-4 neutropenia, anemia, and thrombocytopenia were higher in patients with severe RI. In Chinese patients with advanced RRMM and RI, adjusting the starting dose of LEN according to renal function did not compromise the efficacy or safety of LEN+LoDEX.