FDA D.I.S.C.O. Burst Edition: FDA approvals of Rituxan (rituximab) plus chemotherapy for pediatric cancer indications, and Keytruda (pembrolizumab) for adjuvant treatment of Stage IIB or IIC melanoma
Welcome back to the D.I.S.C.O., FDA’s Drug Information Soundcast in Clinical Oncology, Burst Edition, brought to you by FDA’s Division of Drug Information in partnership with FDA’s Oncology Center of Excellence. Today we’ll provide a quick update on two recent FDA cancer drug approvals.
On December 2, 2021, the FDA approved rituximab (brand name Rituxan) in combination with chemotherapy for pediatric patients 6 months to 18 years with previously untreated, advanced stage, CD20-positive diffuse large B-cell lymphoma, Burkitt lymphoma, Burkitt-like lymphoma, or mature B-cell acute leukemia.
Efficacy was evaluated in Inter-B-NHL Ritux 2010, a global multicenter, open-label, randomized 1:1 trial of patients 6 months in age or older with previously untreated, advanced stage, CD20-positive diffuse large B-cell lymphoma, Burkitt lymphoma, Burkitt-like lymphoma, or B-cell acute leukemia. Advanced stage was defined as Stage III with elevated lactose dehydrogenase level (lactose dehydrogenase greater than twice the institutional upper limit of normal values) or stage IV B-cell non-Hodgkin’s lymphoma or B-cell acute leukemia. Patients were randomized to Lymphome Malin B chemotherapy that consisted of corticosteroids, vincristine, cyclophosphamide, high-dose methotrexate, cytarabine, doxorubicin, etoposide, and triple drug (methotrexate/cytarabine/corticosteroid) intrathecal therapy alone or in combination with rituximab or non-U.S. licensed rituximab, administered as 6 infusions of rituximab IV at a dose of 375 mg/m2 as per the Lymphome Malin B scheme.
The main efficacy outcome measure was event-free survival, defined as progressive disease, relapse, second malignancy, death from any cause, or non-response as evidenced by detection of viable cells in residue after the second Cytarabine plus Veposide course, whichever occurs first. A prespecified interim efficacy analysis at 53% information fraction was performed in 328 randomized patients with a median follow-up of 3.1 years. There were 28 event-free survival events in the Lymphome Malin B group and 10 in the rituximab-Lymphome Malin B group. At the time of the interim analysis, there were 20 deaths in the Lymphome Malin B chemotherapy arm compared to 8 deaths in the rituximab plus Lymphome Malin B chemotherapy arm, with an estimated overall survival hazard ratio of 0.36. No formal statistical test was conducted for overall survival and the overall survival result is considered descriptive. Randomization was discontinued after the interim analysis and an additional 122 patients received rituximab plus Lymphome Malin B chemotherapy and contributed to the safety analysis.
Adverse reactions of grade 3 or higher occurred in more than 15% of pediatric patients treated with rituximab and chemotherapy were febrile neutropenia, stomatitis, enteritis, sepsis, increased alanine aminotransferase, and hypokalemia. Grade 3 or higher adverse reactions that occurred more often in the rituximab plus Lymphome Malin B chemotherapy arm compared to Lymphome Malin B chemotherapy included sepsis, stomatitis, and enteritis. Fatal adverse reactions occurred in less than 2% of patients in both the rituximab plus Lymphome Malin B chemotherapy and Lymphome Malin B chemotherapy arms.
This review used the Assessment Aid, a voluntary submission from the applicant to facilitate the FDA’s assessment, and Streamlined Review.
On December 3, 2021, the FDA approved pembrolizumab (brand name Keytruda) for the adjuvant treatment of adult and pediatric patients 12 years or older with stage IIB or IIC melanoma following complete resection.
Efficacy was evaluated in KEYNOTE-716, a multicenter, randomized 1:1, double-blind, placebo-controlled trial in patients with completely resected stage IIB or IIC melanoma. Patients were randomized to pembrolizumab 200 mg or the pediatric dose of 2 mg/kg intravenously, up to a maximum of 200 mg, every three weeks or placebo for up to one year until disease recurrence or unacceptable toxicity. The major efficacy outcome measure was investigator-assessed recurrence-free survival. The trial demonstrated a statistically significant improvement in recurrence-free survival at the time of the first interim analysis for patients randomized to the pembrolizumab arm compared with placebo, with a hazard ratio of 0.65. The median recurrence-free survival was not reached in either arm.
The most common adverse reactions reported in more than 20% of patients in KEYNOTE-716 were fatigue, diarrhea, pruritus, and arthralgia.
This review used the Real-Time Oncology Review pilot program, which streamlined data submission prior to the filing of the entire clinical application, and the Assessment Aid, a voluntary submission from the applicant to facilitate the FDA’s assessment.
Full prescribing information for these approvals can be found on the web at www.fda.gov/drugsatFDA.
Health care professionals should report serious adverse events to FDA’s MedWatch Reporting Program at www.fda.gov/medwatch.
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