Quizartinib Approved for Newly Diagnosed Acute Myeloid Leukemia
The FDA approved quizartinib with standard cytarabine and anthracycline induction and cytarabine consolidation, and as maintenance monotherapy following consolidation chemotherapy, for the treatment of adult patients with newly diagnosed acute myeloid leukemia (AML) that is FLT3 internal tandem duplication (ITD)-positive as detected by an FDA-approved test. The FDA also approved LeukoStrat CDx FLT3 Mutation Assay as a companion diagnostic for quizartinib.
Efficacy of quizartinib with chemotherapy was evaluated in QuANTUM-First (NCT02668653), a randomized, double-blind, placebo-controlled trial of 539 patients with newly diagnosed FLT3-ITD positive AML. FLT3-ITD status was determined prospectively with a clinical trial assay and verified retrospectively with the companion diagnostic LeukoStrat CDx FLT3 Mutation Assay.
Patients were randomized (1:1) to receive quizartinib (n=268) or placebo (n=271) with induction and consolidation therapy and as maintenance monotherapy according to the initial assignment. There was no re-randomization at the initiation of post-consolidation therapy. Patients who proceeded to hematopoietic stem cell transplantation (HSCT) initiated maintenance therapy after HSCT recovery.
The main efficacy outcome measure was overall survival (OS), measured from randomization date until death by any cause. The primary analysis was conducted after a minimum follow-up of 24 months after the last patient was randomized. The trial demonstrated a statistically significant improvement in OS for the quizartinib arm (HR: 0.78; 95% CI: 0.62, 0.98; 2-sided p=0.0324). The CR rate in the quizartinib arm was 55 percent (95% CI: 48.7, 60.9) with a median duration of 38.6 months (95% CI: 21.9, NE), and the CR rate in those receiving placebo was 55 percent (95% CI: 49.2, 61.4) with a median duration of 12.4 months (95% CI: 8.8, 22.7).
Quizartinib is not indicated as maintenance monotherapy following allogeneic HSCT. Improvement in OS with quizartinib has not been demonstrated in this setting. A boxed warning for quizartinib notes QT prolongation, torsades de pointes, and cardiac arrest. Quizartinib is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS), called the Vanflyta REMS. See the prescribing information for the full list of adverse reactions. The recommended quizartinib dose is as follows:
* Induction: 35.4 mg orally once daily on Days 8-21 of "7 + 3" (cytarabine [100 or 200 mg/m2/day] on Days 1-7 plus daunorubicin [60 mg/m2/day] or idarubicin [12 mg/m2/day] on Days 1-3) and on Days 8-21 or 6-19 of an optional second induction ("7 + 3" or "5 + 2" [5 days cytarabine plus 2 days daunorubicin or idarubicin], respectively);
* Consolidation: 35.4 mg orally once daily on Days 6-19 of high-dose cytarabine (1.5-3 g/m2 every 12 hours on Days 1, 3, and 5) for up to 4 cycles;
* Maintenance: 26.5 mg orally once daily on Days 1-14 and 53 mg once daily, thereafter, for up to 36 28-day cycles.
IND Application for First-In-Class TCR NK Cell Therapy for Multiple Myeloma
The FDA has issued a "safe to proceed" for the Investigational New Drug (IND) application for NY-ESO-1 TCR/IL-15 NK, a first-in-class engineered T-cell receptor natural killer (TCR NK) cell therapy for relapsed or refractory multiple myeloma. The University of Texas MD Anderson Cancer Center is the IND sponsor.
NY-ESO-1 TCR/IL-15 NK is based upon the scientific discoveries of Katy Rezvani, MD, PhD, Professor of Stem Cell Transplantation & Cellular Therapy at MD Anderson. A study in patients with synovial sarcoma and myxoid/round cell liposarcoma received IND clearance from the FDA in June 2023.
"NY-ESO-1 is highly expressed in certain patients with multiple myeloma and associated with a poor prognosis, so this clinical study will be key to further understanding the potential of our TCR NK platform in hematological malignancies," Rezvani said. "I look forward to the study beginning later this year."
Fast-Track Designation for the Antibody-Drug Conjugate ARX517
The anti-PSMA antibody-drug conjugate (ADC) investigational therapy, ARX517, has been granted fast-track designation for the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC) upon progression on an androgen receptor pathway inhibitor. Fast-track designation is a process designed to facilitate the development and expedite the review of drugs that may demonstrate substantial improvement over available therapy for serious conditions with unmet medical need.
ARX517 is currently being studied in APEX-01, a Phase I/II, first-in-human, open-label, dose-escalation and dose-expansion trial enrolling patients with mCRPC whose tumors have progressed on at least two prior FDA-approved treatments for prostate cancer. Patients must have one of the following three criteria met: 1) PSA progression defined by a minimum of two rising PSA values; 2) radiographic progression by RECIST v 1.1; or 3) disease progression by the presence of new bone lesions. APEX-01 is the only ongoing clinical trial in the U.S. targeting PSMA with an ADC.
ARX517 is an antibody-drug conjugate composed of a fully humanized anti-PSMA mAb linked to AS269, a proprietary and potent microtubule inhibitor. PSMA is highly expressed (>89%) in mCRPC and has been shown to be a validated therapeutic target. Upon binding to PSMA on the surface of cancer cells, ARX517 is internalized and pAF-AS269, its cancer cell-killing payload, is released following lysosomal metabolism.
ARX517's site-specific linkage, non-cleavable linker, and stable conjugation chemistry are enabled by a proprietary expanded genetic code technology. ARX517's linker has exceptional stability, and the resulting ADC exhibits a homogenous drug-to-antibody ratio and mAb-like biophysical properties. Researchers believe ARX517 can promote highly specific tumor cell killing with minimal off-target toxicity. ARX517 has the potential to be a first- and best-in-class anti-PSMA ADC addressing the high unmet medical need in mCRPC.