The Year in FDA Approvals

In 2017, the U.S. Food and Drug Administration (FDA) approved several therapies for the treatment of lymphoid malignancies, including the first two chimeric antigen receptor (CAR) T-cell therapies approved for any indication. Below, we review the therapies that became available in the last year.


Inotuzumab Ozogamicin

On August 17, 2017, the FDA approved inotuzumab ozogamicin, an anti-CD22 monoclonal antibody, for the treatment of adults with relapsed or refractory B-cell precursor acute lymphocytic leukemia (ALL). The agency previously granted inotuzumab ozogamicin priority review and breakthrough-therapy designation.

The safety and efficacy of inotuzumab ozogamicin were evaluated in the randomized, phase III INO-VATE 1022 trial, which enrolled 326 patients who had previously received one or two ALL treatments. Of the 218 evaluated patients, 35.8 percent in the inotuzumab ozogamicin cohort achieved a complete remission (CR) for a median of 8.0 months (range not provided), compared with 17.4 percent who experienced CR for a median of 4.9 months (range not provided) in the alternative chemotherapy cohort.

The most common adverse events (AEs) related to inotuzumab ozogamicin include thrombocytopenia, neutropenia, leukopenia, infection, anemia, fatigue, hemorrhage, pyrexia, nausea, headache, and febrile neutropenia. Serious AEs include myelosuppression, infusion-related reactions, and prolonged QT interval.

The drug carries a boxed warning for the risk of severe hepatotoxicity, including veno-occlusive disease and sinusoidal obstruction syndrome. The warning also includes an increased risk of death for patients who take inotuzumab ozogamicin after receiving a hematopoietic cell transplantation.

Tisagenlecleucel

Tisagenlecleucel was approved on August 30, 2017, for the treatment of pediatric and young adult patients with B-cell precursor ALL that is refractory or in second or later relapse. This is the first gene therapy available in the U.S. and the first CAR T-cell therapy to receive approval.

The safety and efficacy of tisagenlecleucel (a CD19-directed CAR T-cell therapy) were demonstrated in the open-label, phase II ELIANA trial, which included 63 pediatric and young adult patients with relapsed or refractory B-cell precursor ALL. At three months after infusion, 52 patients (83%) achieved CR or CR with incomplete blood count recovery.

The most common AEs (occurring in >20% of patients) were cytokine release syndrome (CRS), hypogammaglobulinemia, infections (pathogens unspecified), pyrexia, decreased appetite, headache, encephalopathy, hypotension, bleeding episodes, tachycardia, nausea, diarrhea, vomiting, viral infectious disorders, hypoxia, fatigue, acute kidney injury, and delirium.

The drug carries a boxed warning for CRS and neurologic events. Because of the increased risks for these events, tisagenlecleucel was approved with a Risk Evaluation and Mitigation Strategy.

Copanlisib

On September 14, 2017, the FDA granted accelerated approval for copanlisib for adults with relapsed follicular lymphoma (FL) who have received at least two prior systemic therapies. This is the first approval of an intravenous phosphatidylinositol 3-kinase inhibitor. Copanlisib previously received priority-review and orphan-drug designations.

The approval was based on results from the single-arm, phase II CHRONOS-1 study, which included people with follicular B-cell non-Hodgkin lymphoma that had relapsed after at least two prior treatments. The overall response rate (ORR) among copanlisib-treated patients was 59 percent, with 14 percent achieving a complete response for a median duration of 12.2 months (range not provided).

The most common AEs included hyperglycemia, leukopenia, diarrhea, decreased general strength and energy, hypertension, neutropenia, nausea, thrombocytopenia, and lower respiratory tract infections.

Axicabtagene Ciloleucel

On October 18, 2017, the FDA approved the CD19-directed CAR T-cell therapy axicabtagene ciloleucel for the treatment of adults with relapsed or refractory large B-cell lymphoma following two or more lines of therapy. The indications include diffuse large B-cell lymphoma (DLBCL) not otherwise specified, primary mediastinal large B-cell lymphoma, high-grade B-cell lymphoma, and DLBCL arising from FL.

The safety and efficacy of axicabtagene ciloleucel were demonstrated in the ZUMA-1 trial, in which 101 patients received axicabtagene ciloleucel 2×106 cells/kg, following conditioning with low-dose cytarabine and fludarabine. The ORR (assessed by independent central review) was 72 percent, with a complete response rate of 51 percent. The median duration of response was 8.1 months (range not provided) and was not reached for patients who achieved complete response. The median overall survival (OS) was also not reached during study follow-up, and the six-month OS rate was 80 percent.

The most common grade ≥3 treatment-related AEs included neutropenia, leukopenia, anemia, febrile neutropenia, thrombocytopenia, and encephalopathy.

The drug carries a boxed warning for CRS and neurologic events and was approved with a Risk Evaluation and Mitigation Strategy.

Acalabrutinib

The FDA approved the kinase inhibitor acalabrutinib on October 31, 2017, for the treatment of patients with previously treated relapsed or refractory mantle cell lymphoma (MCL). The agent previously received priority review, as well as breakthrough-therapy and orphan-drug designations for this indication.

The approval was based on findings from the single-arm, phase II ACE-LY-004 study, which included patients with MCL who had received at least one prior treatment. Patients received acalabrutinib 100 mg orally twice-daily. After a median follow-up of 15.2 months (range not provided), the objective response rate was 81 percent, including 40 percent who achieved a complete response and 41 percent who achieved a partial response. The median time to best response was 1.9 months (range not provided), and the median duration of response had not been reached.

The most common AEs associated with acalabrutinib included headache, diarrhea, bruising, fatigue, myalgia, anemia, thrombocytopenia, and neutropenia. Second primary malignancies were also reported.

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