FDA approved stamp

Nine Agents Gain FDA Approvals for Use in Hematology and Oncology in August

In August, the United States Food and Drug Administration (FDA) approved nine new indications in hematology and oncology, including the first chimeric antigen receptor (CAR) T-cell immunotherapy.

  • First CAR T-Cell Immunotherapy Approved for B-Cell Precursor ALL. On 30 August, the FDA issued historic approval of the first gene therapy in the United States. Tisagenlecleucel (Kymriah™, Novartis) is a genetically modified autologous T-cell immunotherapy and is approved for use in children and young adults with B-cell acute lymphoblastic leukemia (ALL) that is refractory or in second or later relapse. Approval is based on efficacy and safety data from multicenter single arm phase II ELIANA trial involving 63 pediatric or young adult patients with this disease. Patients received a single dose of tisagenlecleucel intravenously within 2 to 14 days after the completion of lymphodepleting chemotherapy. Confirmed overall remission rate by independent review was an impressive 82.5% (63% complete remission [CR] and 19% with CR with incomplete hematological recovery). Median remission duration was not reached. However, this treatment was associated with grade 3/4 adverse events (AEs) in 84% of patients, including life-threatening cytokine release syndrome (CRS) and neurologic adverse events. Because of these AEs, the FDA approved tisagenlecleucel with a Risk Evaluation and Mitigation Strategy, which provides requirements to ensure safe use.
    • For managing severe or life threatening CRS induced by CAR T-cells in patients two years of age or older, the FDA expanded the approval of the IL-6receptor antagonist tocilizumab (ACTEMRA®, Genentech, Inc.), an immunosuppressive agent that is commonly used for treatment of rheumatoid arthritis. In clinical trials of patients with CRS after CAR T-cells, 69% had complete resolution of CRS within two weeks after one or two doses of tocilizumab.
  • Another agent also approved for treatment of relapsed or refractory B-cell precursor ALL, reported in the 17 August prIME LINES edition, is inotuzumab ozogamicin (Besponsa®, Pfizer Inc.), an antibody-drug conjugate targeting CD22. However, this agent has an indication for adult patients only.
  • Enasidenib: New Option for Relapsed, IDH2-Mutated AML. The FDA approved enasidenib (Idhifa®, Celgene), an isocitrate dehydrogenase 2 gene (IDH2) inhibitor, for the treatment of adults with relapsed or refractory acute myeloid leukemia (AML) with an IDH2 Approval was based on findings in a phase I/II study in 199 patients with relapsed/refractory IDH2-mutated AML, where enasidenib 100 mg daily resulted in a CR rate of 19.3% with a median duration of 8.2 months. Median overall survival (OS) was 9.3 months in all patients treated and 19.7 months in patients achieving a CR. The most common adverse reactions associated with enasidenib were nausea, vomiting, diarrhea, elevated bilirubin, and decreased appetite. Enasidenib will contain a box warning about the risk of differentiation syndrome. A companion diagnostic, the RealTime IDH2 Assay, was approved for use alongside enasidenib.
  • Liposomal Chemotherapy Combination Approved for two Forms of High Risk AML. A liposome-encapsulated combination of daunorubicin and cytarabine (Vyxeos™, Jazz Pharmaceuticals) was approved for use in adults with newly diagnosed therapy-related AML (t-AML) or AML with myelodysplasia-related changes (AML-MRC). Both forms of AML are associated with poor prognosis and few effective treatment options. The approval was based on results from a phase III trial in which the liposomal formulation significantly improved OS compared to the standard 7+3 regimen of cytarabine and daunorubicin (9.6 months vs 5.9 months; HR 0.69, P = .005) in patients with newly diagnosed t-AML or AML-MRC.
  • Ibrutinib: First FDA-Approved Treatment for Chronic Graft Versus Host Disease. The indication of ibrutinib (Imbruvica®, Pharmacyclics), a Bruton’s tyrosine kinase (BTK) inhibitor currently approved for the treatment of several hematologic malignancies, was extended to include patients with chronic graft versus host disease (cGVHD), a condition that develops in nearly half of patients after allogenic hematopoietic stem cell transplantation. Approval was based on data from the single arm phase Ib/II PCYC-1129 trial that included 42 patients after failure of corticosteroid therapy. Treatment with ibrutinib was associated with a 67% overall response rate (ORR), including CR in 21% of responders. Responses were seen in all organs involved with cGVHD (skin, mouth, gastrointestinal tract, and liver) and lasted five months or longer in 48% of patients.
  • Olaparib Tablets Now Available in the United States for Maintenance Therapy in Recurrent Ovarian Cancer Regardless of BRCA Mutation Status. The tablet form of the PARP inhibitor olaparib (Lynparza®, AstraZeneca) received approval as maintenance therapy (300 mg twice daily) following complete or partial response to platinum-based chemotherapy for patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer. Importantly, olaparib has been approved for patients regardless of BRCA mutation status. The approval is based on results from two randomized, placebo-controlled clinical trials that demonstrated the safety and efficacy of olaparib maintenance in patients with ovarian cancer. In the phase III SOLO2 trial, olaparib maintenance resulted in a 13.6-month improvement in progression-free survival (PFS) compared to placebo (HR 0.3, P<.0001) in patients with platinum-sensitive, relapsed, BRCA-mutated ovarian cancer. The recent update of the phase II Study 19 expanded these findings to patients without BRCA mutation, demonstrating a 65% reduction in the risk of progression or death regardless of BRCA mutation status.
  • Nivolumab: New Option for Mismatch Repair Deficient Metastatic CRC. The programmed death receptor 1 (PD-1) inhibitor nivolumab (Opdivo®, Bristol-Meyers Squibb) received accelerated approval for treatment of patients with mismatch repair deficient (dMMR) or microsatellite instability high (MSI-H) metastatic colorectal cancer (mCRC) that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan. This is the second PD-1 inhibitor approved for this indication, following the approval of pembrolizumab for all MSI-H tumors earlier this year. Approval of nivolumab was based on the phase II CheckMate-142 trial, in which nivolumab was associated with an ORR of 28%, including one CR. No new safety signals were observed with nivolumab in this new indication.
  • Fulvestrant Approved as First-Line Endocrine Therapy for HR-Positive Advanced Breast Cancer. The FDA expanded indication for fulvestrant (Faslodex®, AstraZeneca) as monotherapy for use in postmenopausal women with HR-positive, HER2-negative advanced breast cancer that has not previously been treated with an endocrine therapy. This approval was based on results from the phase III FALCON trial, where fulvestrant improved PFS by 2.8 months compared to anastrozole (16.6 months vs 13.8 months; HR 0.797, P = .049).

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