The U.S. Food and Drug Administration (FDA) has approved brentuximab vedotin (Adcetris) in combination with lenalidomide and a rituximab product for adults with relapsed or refractory large B-cell lymphoma (LBCL)—including diffuse large B-cell lymphoma (DLBCL) not otherwise specified, DLBCL arising from indolent lymphoma, or high-grade B-cell lymphoma. This approval was with these tumors regardless of CD30 expression after two or more lines of systemic therapy in patients who are ineligible for autologous hematopoietic stem cell transplantation (auto-HSCT) or chimeric antigen receptor (CAR) T-cell therapy.
Approval was based on ECHELON-3 (ClinicalTrials.gov identifier NCT04404283), a randomized, double-blind, placebo-controlled trial which enrolled 230 adults with relapsed or refractory LBCL who were ineligible to receive auto-HSCT or CAR T-cell therapy. Patients were randomly assigned 1:1 to receive brentuximab vedotin plus lenalidomide and rituximab (BV+R2) or placebo plus lenalidomide and rituximab (Pbo+R2) until disease progression or unacceptable toxicity.
The major efficacy outcome measure was overall survival; additional efficacy outcome measures included progression-free survival and objective response rate per 2014 Lugano Criteria. The trial demonstrated a statistically significant overall survival improvement, with a median overall survival of 13.8 months (95% confidence interval [CI] = 10.3–18.8 months) in the BV+R2 arm and 8.5 months (95% CI = 5.4–11.7 months) in the Pbo+R2 arm (hazard ratio [HR] = 0.63, 95% CI = 0.45–0.89; P = .0085). The trial also demonstrated a statistically significant improvement in progression-free survival and objective response rate. Median progression-free survival was 4.2 months (95% CI = 2.9–7.1 months) with BV+R2 and 2.6 months (95% CI = 1.4–3.1 months) with Pbo+R2 (HR = 0.53, 95% CI = 0.38–0.73; P < .0001). The objective response rates were 64.3% (95% CI = 54.7%–73.1%) and 41.5% (95% CI = 32.5%–51.0%), respectively.
The most common adverse reactions (occurring in ≥ 20% of patients)—excluding laboratory abnormalities in the BV+R2 arm—were fatigue, diarrhea, peripheral neuropathy, rash, pneumonia, and COVID-19 infection. Grade 3 to 4 laboratory abnormalities occurring in more than 10% of patients were decreased neutrophils, decreased lymphocytes, decreased platelets, and decreased hemoglobin. Peripheral neuropathy developed or worsened in 27% of patients, was predominantly sensory, and led to brentuximab vedotin dose reduction in 6% and discontinuation in 4.5%.
The recommended brentuximab vedotin dose is 1.2 mg/kg up to a maximum of 120 mg in combination with lenalidomide and rituximab administered every 3 weeks until disease progression or unacceptable toxicity.
Vimseltinib for Symptomatic TGCT
The FDA has approved vimseltinib (Romvimza), a colony-stimulating 1 kinase inhibitor, for adults with symptomatic tenosynovial giant cell tumor (TGCT) for which surgical resection may cause worsening functional limitation or severe morbidity.
Efficacy was evaluated in MOTION (NCT05059262), a double-blind, multicenter, randomized, placebo-controlled trial. Eligible patients had a confirmed diagnosis of TGCT with measurable disease (per Response Evaluation Criteria in Solid Tumors version 1.1) with at least one lesion being at least 2 cm.
Patients were randomly assigned 2:1 to receive placebo or vimseltinib at 30 mg twice weekly administered for 24 weeks during the double-blind period (Part 1). During the open-label period (Part 2), patients could continue vimseltinib and those receiving placebos could cross over to vimseltinib. Random assignment was stratified by tumor location (lower limb vs all other sites) and region (United States vs non–United States). A total of 123 patients were randomly assigned (83 to the vimseltinib arm and 40 to placebo) during Part 1.
The major efficacy outcome measure was overall response rate assessed by blinded independent radiological review at week 25. Overall response rate was 40% (95% CI = 29%–51%) in the vimseltinib arm and 0% (95% CI = 0%–9%) in the placebo arm (P < .0001). Median duration of response was not reached in the vimseltinib arm, and based on an additional 6 months of follow-up, 28 responders (85%) had a duration of response lasting at least 6 months, and 19 (58%) had a duration of response lasting at least 9 months. The primary endpoint was supported by statistically significant improvements in active range of motion, patient-reported physical functioning, and patient-reported pain observed in the vimseltinib arm compared with the placebo arm at week 25.
The most common adverse reactions (occurring in ≥ 20% of patients), including laboratory abnormalities, were increased aspartate aminotransferase, periorbital edema, fatigue, rash, increased cholesterol, peripheral edema, face edema, decreased neutrophils, decreased leukocytes, pruritus, and increased alanine aminotransferase.
The recommended vimseltinib dose is 30 mg orally twice weekly, with a minimum of 72 hours between doses.
Mirdametinib Approved for Neurofibromatosis Type 1
On February 11, the FDA approved mirdametinib (Gomekli), a kinase inhibitor, for adult and pediatric patients aged 2 years and older with neurofibromatosis type 1 (NF1) who have symptomatic plexiform neurofibromas not amenable to complete resection.
Efficacy was evaluated in ReNeu (NCT03962543), a multicenter, single-arm trial in 114 patients ≥ 2 years of age (58 adults, 56 pediatric patients) with symptomatic, inoperable NF1-associated plexiform neurofibromas causing significant morbidity. An inoperable plexiform neurofibroma was defined as a plexiform neurofibroma that could not be completely surgically removed without risk for substantial morbidity due to encasement or close proximity to vital structures, invasiveness, or high vascularity.
The major efficacy outcome measure was confirmed overall response rate, defined as the percentage of patients with complete response (disappearance of the target plexiform neurofibroma) or partial response (≥ 20% reduction in the volume of plexiform neurofibroma). Responses were assessed by blinded independent central review using volumetric magnetic resonance imaging analysis per Response Evaluation in Neurofibromatosis and Schwannomatosis criteria, modified to require confirmation of responses within 2 to 6 months during the 24-cycle treatment phase.
Confirmed overall response rate was 41% for adults (95% CI = 29%–55%) and 52% in the pediatric cohort (95% CI = 38%–65%).
The most common adverse reactions (occurring in at least 25% of participants) in adults were rash, diarrhea, nausea, musculoskeletal pain, vomiting, and fatigue. The most common Grade 3 or 4 laboratory abnormality (occurring in more than 2%) was increased creatine phosphokinase.
The most common adverse reactions (occurring in more than 25%) in pediatric patients were rash, diarrhea, musculoskeletal pain, abdominal pain, vomiting, headache, paronychia, left ventricular dysfunction, and nausea. The most common Grade 3 or 4 laboratory abnormalities (occurring in more than 2%) were decreased neutrophil count and increased creatine phosphokinase.
Mirdametinib can also cause left ventricular dysfunction and ocular toxicity including retinal vein occlusion, retinal pigment epithelial detachment, and blurred vision. Mirdametinib should be withheld, dosage reduced, or permanently discontinued based on the severity of adverse reactions.
Recommended dose is based on body surface area.
This review used the Assessment Aid, a voluntary submission from the applicant to facilitate the FDA’s assessment. This application was granted Priority Review, Fast Track designation, and Orphan Drug designation. A Priority Review voucher was issued for this rare pediatric disease product application.
