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Brexucabtagene Autoleucel for R/R B-Cell Precursor Acute Lymphoblastic Leukemia

The FDA approved brexucabtagene autoleucel for adult patients with relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL). Efficacy was evaluated in ZUMA-3 (NCT02614066), a single-arm multicenter trial that evaluated brexucabtagene autoleucel, a CD19-directed chimeric antigen receptor (CAR) T-cell therapy, in adults with relapsed or refractory B-cell precursor ALL. Patients received a single infusion of brexucabtagene autoleucel following completion of lymphodepleting chemotherapy.

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The efficacy outcome measures used to support approval were complete response (CR) achieved within 3 months from infusion and duration of CR. Of the 54 patients evaluable for efficacy, 28 (52%; 95% CI: 38, 66) achieved CR within 3 months. With a median follow-up for responders of 7.1 months, the median duration of CR was not reached; the duration of CR was estimated to exceed 12 months for more than half the patients.


The prescribing information for brexucabtagene autoleucel has a boxed warning for cytokine release syndrome (CRS) and neurologic toxicities. CRS occurred in 92 percent (Grade >=3, 26%) and neurologic toxicities occurred in 87 percent (Grade >=3, 35%). The most common non-laboratory adverse reactions (incidence >= 20%) included fever, CRS, hypotension, encephalopathy, tachycardia, nausea, chills, headache, fatigue, febrile neutropenia, diarrhea, musculoskeletal pain, hypoxia, rash, edema, tremor, infection with pathogen unspecified, constipation, decreased appetite, and vomiting.


The recommended brexucabtagene autoleucel dose is a single intravenous infusion of 1 x 106 CAR-positive viable T cells per kg body weight (maximum 1 x 108 CAR-positive viable T cells), preceded by fludarabine and cyclophosphamide for lymphodepleting chemotherapy.


FDA Recognizes Database of Molecular Tumor Marker Information

The FDA granted recognition to a partial listing of the Memorial Sloan Kettering Cancer Center's Oncology Knowledge Base (OncoKB) as the first tumor mutation database to be included in the Public Human Genetic Variant Databases.


Also recognized was a portion of the OncoKB as a source of valid scientific evidence for Level 2 (clinical significance) and Level 3 (potential clinical significance) biomarkers. Under the FDA's database recognition program, test developers can use these data to support the clinical validity of tumor profiling tests in premarket submissions. Determining the mutation profile of a tumor using DNA sequencing enables the use of targeted therapies and investigational treatment options.


The OncoKB database contains detailed information regarding specific alterations in 682 cancer genes. The information is curated from various worldwide sources, including government agencies, medical professional groups, medical and scientific literature, and clinical trials.


FDA reviewed the operating and governance procedures and policies, processes for the database and for variant evaluation and curation, and method of assignment of clinical significance. The data are sorted into one of two levels of clinical significance consistent with FDA-authorized tumor profiling tests and displayed on a tab referred to as "FDA recognized alterations."


CT Imaging Technology Approved By FDA

"Computed tomography is an important medical imaging tool that can aid in diagnosing disease, trauma, or abnormality; planning and guiding interventional or therapeutic procedures; and monitoring the effectiveness of certain therapies," said Laurel Burk, PhD, Assistant Director of the Diagnostic X-ray Systems Team in the FDA's Center for Devices and Radiological Health. "Today's action represents the first major new technology for computed tomography imaging in nearly a decade and underscores the FDA's efforts to encourage innovation in areas of scientific and diagnostic progress."


The device uses the emerging CT technology of photon-counting detectors that can measure each individual X-ray that passes through a patient's body, as opposed to current systems which use detectors that measure the total energy contained in many X-rays at once. By counting each individual X-ray photon, more detailed information about the patient can be obtained and used to create images with less information that is not useful in the review and analysis.


The new diagnostic imaging device, called Siemens Naeotom Alpha, is designed to transform the information from X-ray photons that pass through a patient's body, and are received by a detector, into a detailed 3-dimensional image. The images delivered by the system can be used by a trained physician as an aid in diagnosis or can be used by trained staff as an aid in diagnosis, treatment preparation, and radiation therapy planning.


The FDA reviewed the imaging device through the 510(k) premarket clearance pathway, which is a premarket submission to the FDA demonstrating that a new device is substantially equivalent to a legally marketed predicate device.


Pediatric Disease Designation of 177Lu-omburtamab-DTPA for Medulloblastoma

The FDA granted Rare Pediatric Disease Designation for a lutetium labelled omburtamab antibody program for the treatment of medulloblastoma. 177Lu-omburtamab-DTPA, a monoclonal B7-H3 antibody that has been radiolabeled with lutetium-177, is currently in a multicenter Phase I clinical trial in pediatric patients with refractory medulloblastoma. The treatment is also in a multicenter Phase I clinical trial targeting B7-H3 positive CNS/LM tumors in adults.


Cemiplimab-Rwlc for Priority Review for Advanced Cervical Cancer

The FDA accepted for priority review the supplemental Biologics License Application (sBLA) for PD-1 inhibitor cemiplimab-rwlc to treat patients with recurrent or metastatic cervical cancer whose disease progressed on or after chemotherapy. The target action date for the FDA decision is January 30, 2022. The sBLA is also being reviewed under the FDA's Project Orbis initiative, which will allow for concurrent review by participating health authorities in Australia, Brazil, Canada, and Switzerland. Additional global regulatory submissions are planned, including in the European Union (EU) by the end of 2021.


The sBLA is supported by results from a Phase III trial that enrolled patients irrespective of PD-L1 expression status and is being conducted with The GOG Foundation (GOG), the European Network for Gynaecological Oncological Trial groups (ENGOT), and NRG Oncology-Japan. Detailed results were first presented as part of a European Society for Medical Oncology (ESMO) Virtual Plenary in May 2021.


The Phase III, open-label, multi-center trial, known as EMPOWER-Cervical 1, is the largest randomized clinical trial in advanced cervical cancer. The trial investigated cemiplimab-rwlc monotherapy versus an investigator's choice of chemotherapy in patients with recurrent or metastatic cervical cancer who had progressed on platinum-based chemotherapy. Patients were enrolled regardless of tumor PD-L1 expression status or histology in 14 countries, including the U.S., Japan, Taiwan, South Korea, Canada, Russia, Poland, Spain, Brazil, Australia, the U.K., Italy, Greece, and Belgium.


Patients (median age: 51 years) were randomized to receive cemiplimab-rwlc monotherapy (350 mg every 3 weeks) or commonly used chemotherapy regimens (e.g., pemetrexed, vinorelbine, topotecan, irinotecan, or gemcitabine). The primary endpoint for the trial was overall survival, analyzed first among patients with SCC histology, then in the total population.