The Year in FDA Approvals

The excitement over immunotherapy for cancer treatment shows no signs of waning, with several agents approved by the U.S. Food and Drug Administration (FDA) this year. Below is a list of immunotherapies that were recently approved by the FDA for the treatment of hematologic conditions or whose indications were expanded.


Leukemia

Tisagenlecleucel: On August 30, 2017, the chimeric antigen receptor (CAR) T-cell therapy tisagenlecleucel for the treatment of pediatric and young adult patients with B-cell precursor acute lymphocytic leukemia (ALL) that is refractory or in second or later relapse became the first FDA-approved gene therapy available in the United States. The drug carries a boxed warning for cytokine release syndrome (CRS) and neurologic events and, because of these risks, the drug was approved with a Risk Evaluation and Mitigation Strategy. On the same day as the approval, the FDA also expanded the indication for tocilizumab, a monoclonal antibody to treat CAR T-cell–induced, severe or life-threatening CRS in patients ≥2 years of age. (For more about CAR T-cell therapy for hematologic malignancies, see “Entering A New Era of Immunotherapy” on page 4.)

Gemtuzumab ozogamicin: On September 1, 2017, the FDA approved gemtuzumab ozogamicin (GO), a recombinant anti-CD33 drug conjugate, for the treatment of CD33-positive acute myeloid leukemia (AML). The agent was originally approved under the FDA’s accelerated approval program in 2000, but the manufacturer voluntarily withdrew the drug in 2010 following reports of adverse events and failure of the drug to show improvement in complete response (CR) rate, disease-free survival, or overall survival (OS) when combined with induction and consolidation chemotherapy for younger adults with AML in the Southwest Oncology Group S0106 phase III clinical trial. The present recommendation is based on results from the phase III ALFA-0701 trial, which evaluated GO in combination with daunorubicin for the treatment of de novo AML. At three-year follow-up, patients treated with GO had a longer median event-free survival (EFS) than patients who received chemotherapy alone (17.3 months vs. 9.5 months; p value not reported). The label contains a boxed warning for hepatotoxicity.

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 ALL. Previously, the FDA granted the drug priority review, as well as orphan-drug and breakthrough-therapy designations. Approval was based on data from the INO-VATE ALL trial, in which patients with Philadelphia chromosome (Ph)–positive or –negative relapsed or refractory B-cell precursor ALL were randomized to receive either inotuzumab ozogamicin (n=164) or investigator’s choice of chemotherapy (n=162). In the inotuzumab arm, 35.8 percent of patients achieved complete remission, lasting for a median of eight months (range not provided). Also, 89.7 percent of responders were negative for minimal residual disease (MRD). In the investigator-choice arm, only 17.4 percent of patients achieved complete remission, lasting a median of 4.9 months, and 31.6 percent were MRD negative. The drug carries a boxed warning for hepatotoxicity and an increased risk of death for use after a hematopoietic cell transplantation.

Blinatumomab: The bispecific T-cell engager blinatumomab received accelerated approval in December 2014 for the treatment of Ph-negative relapsed or refractory B-cell precursor ALL, and, on July 11, 2017, the FDA granted regular approval to blinatumomab for the treatment of relapsed or refractory B-cell precursor ALL in adults and children. The supplemental approval confirms clinical benefit required under accelerated approval and expands the indication to include Ph-positive relapsed or refractory B-cell precursor ALL. Clinical benefit was confirmed in the TOWER trial, in which blinatumomab lengthened OS, compared with standard-of-care chemotherapy (7.7 months vs. 4.0 months; p=0.012). The decision to expand the approval to patients with Ph-positive ALL was based on results from the ALCANTARA trial, in which 36 percent of patients with disease that was resistant or intolerant to treatment with second-generation tyrosine kinase inhibitors achieved a complete remission with complete or partial hematologic recovery.


Lymphoma

Rituximab and hyaluronidase combination: On June 22, 2017, the FDA approved the subcutaneous injection formula of rituximab and hyaluronidase for the treatment of adults with relapsed or refractory, previously untreated, or stable follicular lymphoma; previously untreated diffuse large B-cell lymphoma; or previously untreated or previously treated chronic lymphocytic leukemia. The approval offers patients a subcutaneous route of rituximab administration that shortens administration time from several hours to five to seven minutes. The approval was based on multiple randomized clinical trials in which rituximab and hyaluronidase demonstrated rituximab trough concentration levels that were non-inferior to intravenous (IV) rituximab 375 mg/m2 and IV rituximab 500 mg/m2. Efficacy and safety outcomes were also comparable between the two products.
Pembrolizumab: On March 15, 2017, the FDA granted accelerated approval to pembrolizumab, an anti-PD-1 monoclonal antibody, for adults and children with classic Hodgkin lymphoma that is refractory to treatment or has relapsed after three or more prior lines of therapy. This is the only anti-PD-1 therapy approved for this population. The approval was based on results from the KEYNOTE-087 trial, which included patients who received pembrolizumab 200 mg every three weeks. After a median follow-up of 9.4 months, the overall response rate was 69 percent (95% CI 62-75), which included a complete remission rate of 22 percent and a partial remission rate of 47 percent. The median duration of response was 11.1 months (range = 0-11.1 months)

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