Over the past month, the U.S. Food and Drug Administration (FDA) has granted Priority Review to therapies for multiple myeloma, cervical cancer, chemotherapy-induced neutropenia, and myelofibrosis. The FDA also granted a number of Breakthrough Therapy designations, including those for treatments in patients with prostate cancer, polycythemia vera, and multiple myeloma.
Priority Review for Ciltacabtagene Autoleucel in Relapsed/Refractory Multiple Myeloma
The FDA accepted for Priority Review a biologics license application for ciltacabtagene autoleucel, an investigational B-cell maturation antigen (BCMA)-directed chimeric antigen receptor (CAR) T-cell therapy, in the treatment of patients with relapsed or refractory multiple myeloma. The Prescription Drug User Fee Act (PDUFA) target action date has been set for November 29, 2021.
The regulatory submission for ciltacabtagene autoleucel is based on results from the pivotal phase Ib/II CARTITUDE-1 study, which evaluated the efficacy and safety of ciltacabtagene autoleucel in the treatment of patients with relapsed and/or refractory multiple myeloma. Updated longer-term follow-up data were featured during the 2021 ASCO Annual Meeting (Abstract 8005) and the European Hematology Association 2021 Virtual Congress (Abstract EP964).
CARTITUDE-1 (ClinicalTrials.gov identifier: NCT03548207) is a phase Ib/II, open-label, multicenter study evaluating the safety and efficacy of ciltacabtagene autoleucel in adults with relapsed and/or refractory with multiple myeloma who have received at least three prior lines of therapy or are double-refractory to a proteasome inhibitor and immunomodulatory drug. Patients also had to have received as part of previous therapy a proteasome inhibitor, an immunomodulatory drug, and an anti-CD38 antibody; and have documented evidence of progressive disease based on investigator's determination of response by the IMWG criteria on or within 12 months of their last line of therapy. The primary objective of the phase Ib portion of the study was to characterize the safety and confirm the recommended phase II dose of ciltacabtagene autoleucel, informed by the first-in-human study with LCAR-B38M CAR-T cells (LEGEND-2). The phase II portion further evaluated the efficacy of ciltacabtagene autoleucel with overall response rate as the primary endpoint.
Priority Review for Balstilimab in Recurrent or Metastatic Cervical Cancer
The FDA accepted a biologics license application for balstilimab, an anti–PD-1 antibody, for the treatment of patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy. The FDA has granted Priority Review to this submission; under the PDUFA, the FDA has set a target action date of December 16, 2021.
Balstilimab is a novel, fully human monoclonal immunoglobulin G4 (IgG4) designed to block PD-1 from interacting with its ligands, PD-L1 and PD-L2. Balstilimab is currently being investigated in clinical trials as monotherapy and in with the anti–CTLA-4 agent zalifrelimab in an ongoing phase II study for recurrent/metastatic cervical cancer.
Priority Review for Plinabulin and G-CSF Combination for the Prevention of Chemotherapy-Induced Neutropenia
The FDA accepted a new drug application seeking approval for the use of plinabulin in combination with granulocyte colony-stimulating factor (G-CSF) for the prevention of chemotherapy-induced neutropenia. The FDA granted this application Priority Review and set a PDUFA target action date set for November 30, 2021.
Plinabulin, a novel, intravenous infused small molecule, acts as a selective immunomodulating microtubule-binding agent, with immune anticancer activities and broad activities in prevention of chemotherapy-induced neutropenia across chemotherapy and cancer types.
The FDA and China’s National Medical Products Administration previously granted Breakthrough Therapy designation in September 2020 for plinabulin and G-CSF combination for “concurrent administration with myelosuppressive chemotherapeutic regimens in patients with nonmyeloid malignancies for the prevention of chemotherapy-induced neutropenia.”
The new drug application submission included phase III data from the pivotal study PROTECTIVE-2, in addition to five supportive trials of over 1,200 patients. PROTECTIVE-2 is a randomized, double-blind, controlled global trial, which showed that plinabulin in combination with pegfilgrastim demonstrated superior chemotherapy-induced neutropenia prevention benefit compared to pegfilgrastim alone. The study met the primary endpoint, in the rate of prevention of grade 4 neutropenia in cycle 1 (improved from 13.6% to 31.5%, P = .0015) and met all key secondary endpoints, including duration of severe neutropenia and absolute neutrophil count nadir. In addition, the combination reduced clinical complications such as incidence and severity of febrile neutropenia and incidence and duration of hospitalization for patients who did develop febrile neutropenia. The combination is well tolerated, with an over 20% reduction of grade 4 treatment-emergent adverse events, including bone pain reduction a quality-of-life benefit compared to pegfilgrastim alone.
Priority Review for Pacritinib in the Treatment of Myelofibrosis
The FDA accepted a new drug application for pacritinib as a treatment for patients with myelofibrosis patients and severe thrombocytopenia (platelet counts < 50 × 109/L), and granted the application Priority Review. The PDUFA target action date for the application has been set for November 30, 2021.
Pacritinib is an investigational oral kinase inhibitor with specificity for JAK2, IRAK1, and CSF1R, but not JAK1.
The new drug application was accepted based on the data from the phase III PERSIST-2 and PERSIST-1 and the phase II PAC203 clinical trials, with a focus on the severely thrombocytopenic (platelet counts < 50 × 109/L) patients enrolled in these studies who received pacritinib at 200 mg twice a day, including both front-line treatment–naive patients and patients with prior exposure to JAK2 inhibitors. In the PERSIST-2 study, in patients with severe thrombocytopenia who were treated with pacritinib at 200 mg twice a day, 29% of patients had a reduction in spleen volume of at least 35%, compared to 3% of patients receiving the best available therapy, which included ruxolitinib. Twenty-three percent of patients had a reduction in total symptom scores of at least 50%, compared to 13% of patients receiving the best available therapy. In the same population of patients treated with pacritinib, adverse events were generally low-grade, manageable with supportive care, and rarely led to discontinuation. Platelet counts and hemoglobin levels were also stabilized.
Breakthrough Therapy Designation for Lu-177–PSMA-617 in Metastatic Castration-Resistant Prostate Cancer
The FDA has granted Breakthrough Therapy designation to Lutetium-177–PSMA-617 (Lu-177–PSMA-617), an investigational radioligand therapy for the treatment of metastatic castration-resistant prostate cancer.
Breakthrough therapy designation was granted based on positive data from the pivotal, phase III VISION study (recently presented at the 2021 ASCO Annual Meeting) evaluating Lu-177–PSMA-617 plus standard of care compared to standard of care alone, in patients with progressive prostate-specific membrane antigen (PSMA)-positive metastatic castration-resistant prostate cancer. The trial demonstrated that Lu-177–PSMA-617 significantly improved overall survival and radiographic progression-free survival for men with progressive PSMA-positive metastatic castration-resistant prostate cancer.
Two additional studies with Lu-177–PSMA-617 radioligand therapy in earlier lines of treatment for metastatic prostate cancer are ongoing, investigating potential clinical utility in the metastatic castration-resistant prostate cancer pre-taxane setting (PSMAfore) and in the metastatic hormone-sensitive setting (PSMAddition).
Breakthrough Therapy Designation for Rusfertide in Polycythemia Vera
The FDA has granted Breakthrough Therapy designation to rusfertide for the treatment of patients with polycythemia vera for the reduction of erythrocytosis in those patients who do not require further treatment for thrombocytosis and/or leukocytosis.
The designation for rusfertide was supported in part by data from an ongoing phase II clinical trial in patients with polycythemia vera, presented at the 2020 American Society of Hematology Annual Meeting & Exposition (Abstract 482). The data showed that when treated with rusfertide, a majority of patients were able to eliminate therapeutic phlebotomies, maintain a target hematocrit level of less than 45%, reverse iron deficiency, and experienced symptom improvements.
Updated data from the ongoing phase II study was also presented at the European Hematology Association 2021 Virtual Congress (Abstract S200).
Breakthrough Therapy Designation for Teclistamab in Relapsed or Refractory Multiple Myeloma
The FDA granted Breakthrough Therapy designation to teclistamab for the treatment of relapsed or refractory multiple myeloma. This distinction for teclistamab, an off-the-shelf, T-cell–redirecting, bispecific antibody targeting both B-cell maturation antigen (BCMA) and CD3 receptors, follows a PRIME (Priority Medicines) designation from the European Medicines Agency (EMA) received earlier this year.
The Breakthrough Therapy and PRIME designations are supported by data from the phase I MajesTEC-1 study (ClinicalTrials.gov identifier: NCT03145181), an open-label, multicenter clinical trial evaluating the safety and efficacy of teclistamab in adults with measurable multiple myeloma that is relapsed or refractory to established therapies or intolerant of those established multiple myeloma therapies.
Updated results from the MajesTEC-1 study were presented at the 2021 ASCO Annual Meeting (Abstract 8007).
