The Year in FDA Approvals

In the past year, the FDA approved a record-breaking number of drugs, several of which were indicated for the treatment of lymphoid and plasma cell malignancies. Here, we review the regulatory approvals since our last “Focus on Lymphoid Malignancies” special edition published in March 2019. The list includes two new biosimilar versions of commonly used drugs and a treatment approved as part of the FDA’s Project Orbis, a new framework that allows for concurrent review of cancer therapies with the agency’s international partners.


Polatuzumab vedotin-piiq

On June 10, 2019, the FDA approved the CD79b-directed antibody drug conjugate polatuzumab vedotin-piiq, in combination with bendamustine and rituximab (BR), to treat adults with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) who have received at least two prior therapies.

The approval was based on results from an open-label, multicenter clinical trial that enrolled 80 adult patients and randomized patients 1:1 to receive either BR alone or BR with polatuzumab vedotin-piiq for six 21-day cycles. All participants received rituximab 375 mg/m2 on day 1 of each cycle, plus bendamustine 90 mg/m2 on days 2-3 of cycle 1 and on days 1-2 of subsequent cycles; in the polatuzumab + BR group, participants also received polatuzumab vedotin-piiq, 1.8 mg/kg by intravenous infusion on day 2 of cycle 1 and on day 1 of subsequent cycles.

The complete response (CR) rate, the study’s primary endpoint, was 40% in the polatuzumab + BR group, compared with 18% in the BR-alone group. The overall response rate (ORR; including CRs and partial responses) was also higher with polatuzumab: 63% versus 25%. Among the 25 patients who responded to treatment with polatuzumab + BR, 16 (64%) had response durations ≥6 months and 12 (48%) had response durations ≥12 months.

The most common adverse events (AEs; occurring in ≥20% of patients) in the polatuzumab group included neutropenia, thrombocytopenia, anemia, peripheral neuropathy, fatigue, diarrhea, pyrexia, decreased appetite, and pneumonia. Serious AEs occurred in 64% of patients, most often from infection. Cytopenias (seen in 18% of patients) were the most common reason for treatment discontinuation.

Polatuzumab vedotin-piiq was approved with priority review, breakthrough therapy, and orphan drug designations.

Selinexor

On July 3, 2019, selinexor, an oral selective inhibitor of nuclear export (SINE), received accelerated approval for patients with relapsed/refractory multiple myeloma (MM) who have received four or more prior therapies and whose disease has not responded to treatment with two or more proteasome inhibitors or immunomodulatory agents.

The FDA’s approval decision was based on its review of safety and efficacy data from a prespecified subgroup analysis of the single-arm, open-label, phase II STORM trial, which included 83 patients with heavily pretreated MM. The ORR was 25.3%, including one stringent CR, four very good partial responses, and 16 partial responses. The median time to first response was 4 weeks (range = 1-10 weeks) and the median response duration was 3.8 months (range = 2.3 to not estimable).

In February 2019, the FDA’s Oncologic Drugs Advisory Committee (ODAC) expressed concerns about these trial data, and recommended delaying approval until the results of the phase III BOSTON trial, which evaluated the safety and efficacy of bortezomib plus low-dose dexamethasone with or without selinexor, became available. While the ODAC panel noted that selinexor did not demonstrate strong single-agent activity in the STORM trial, the reviewers expressed concerns about trial safety data.

In STORM, the most common AEs (occurring in ≥20% of patients) included thrombocytopenia, fatigue, nausea, anemia, decreased appetite, decreased weight, diarrhea, vomiting, hyponatremia, neutropenia, leukopenia, constipation, dyspnea, and upper respiratory tract infection.

Selinexor was approved with the FDA’s fast track and orphan drug designation.

Biosimilar: Rituximab-pvvr

On July 24, 2019, the FDA approved rituximab-pvvr, a biosimilar of rituximab (Rituxan), for the treatment of adults with chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphoma. The agent also was approved for other indications of its reference product, including granulomatosis with polyangiitis and microscopic polyangiitis.

Rituximab-pvvr is a cytolytic antibody biosimilar to rituximab that targets the protein CD20 present on the surface of B cells.

The FDA’s approval was based on a review of a clinical comparative study that found no clinically meaningful differences in the efficacy, safety, immunogenicity, pharmacokinetics, and pharmacodynamics between rituximab-pvvr and its reference product.

Like its reference product, rituximab-pvvr carries a boxed warning for increased risks of the following: fatal infusion-related reactions, severe skin and mouth reactions, hepatitis B virus reactivation, and progressive multifocal leukoencephalopathy.

Daratumumab

On September 26, 2019, the FDA approved the combination of daratumumab, bortezomib, thalidomide, and dexamethasone (DVTd) to treat adults with newly diagnosed MM who are eligible for autologous hematopoietic cell transplantation.

Approval of this frontline, quadruplet regimen was based on data from the open-label, randomized phase III CASSIOPEIA trial, which compared induction and consolidation treatment with either daratumumab 16 mg/kg plus bortezomib, thalidomide, and dexamethasone (VTd) or VTd alone. After a median follow-up of 18.8 months (range = 0-32.2), DVTd was associated with a 53% reduction in the risk of progression or death compared with VTd alone. DVTd also appeared to be associated with higher rates of stringent CR at 100 days post-transplant (28.9% vs. 20.3%).

There were no significant differences in the number or type of serious AEs between the two arms, but AEs that occurred ≥5% more frequently in the DVTd arm than the VTd arm included infusion reactions, nausea, neutropenia, thrombocytopenia, lymphopenia, and cough.

The application for this combination was granted priority review. Daratumumab also is approved, in combination or as monotherapy, for the treatment of patients with newly diagnosed, transplant-ineligible MM and those with previously treated MM.

Biosimilar: Pegfilgrastim-bmez

On November 5, 2019, the FDA approved pegfilgrastim-bmez, a leukocyte growth factor biosimilar to pegfilgrastim (Neulasta), to decrease the incidence of febrile neutropenia in patients with non-myeloid malignancies who are receiving myelosuppressive chemotherapy.

The biosimilar’s approval was based on data demonstrating that no clinically meaningful differences between pegfilgrastim-bmez and its reference product, including findings from a pharmacokinetics and pharmacodynamics study comparing U.S.-sourced and E.U.-sourced reference pegfilgrastim.

The FDA noted that pegfilgrastim-bmez is not indicated for the mobilization of peripheral blood progenitor cells for hematopoietic cell transplantation.

Zanubrutinib

On November 14, 2019, the FDA granted accelerated approval to zanubrutinib, an inhibitor of Bruton tyrosine kinase (BTK), to treat adults with mantle cell lymphoma (MCL) who have received ≥1 prior therapy. Zanubrutinib is the third BTK inhibitor to be approved by the FDA for treatment of MCL, after ibrutinib in 2013 and acalabrutinib in 2017.

The zanubrutinib approval was based on results from a single-arm clinical trial with a primary endpoint of ORR (defined as complete or partial shrinkage of tumors after treatment) in 86 patients. Eighty-four percent of patients had a response, and the median duration of response was 19.5 months (range not provided). An additional single-arm trial, in which 84% of 32 patients had a response with a median duration of response of 18.5 months (range not provided), supported these findings.

Notably, these trials were conducted outside the U.S., and this approval is the first based on efficacy data predominantly collected from Chinese research, according to zanubrutinib’s manufacturer, BeiGene.

AEs associated with zanubrutinib include neutropenia, thrombocytopenia, leukopenia, anemia, upper respiratory tract infection, bruising, rash, diarrhea, and cough. The FDA’s approval notes that patients should be monitored for bleeding, infection, cardiac arrhythmias, and cytopenias.

In addition to accelerated approval, zanubrutinib was granted priority review and orphan product and breakthrough therapy designations.

Acalabrutinib

On November 21, 2019, the FDA granted a supplemental approval to acalabrutinib for the treatment of adults with CLL or small lymphocytic lymphoma (SLL). Acalabrutinib was previously approved by the FDA for the treatment of MCL.

This new indication for CLL/SLL was based on results from two randomized clinical trials that compared acalabrutinib with other standard treatments: ELEVATE-TN, which enrolled 535 patients with treatment-naïve CLL, and ASCEND, which enrolled 310 patients with previously treated CLL. In both trials, participants who received acalabrutinib had longer progression-free survival, compared with the standard treatment arms.

The most common AEs related to acalabrutinib were anemia, neutropenia, upper respiratory tract infection, thrombocytopenia, headache, diarrhea, and musculoskeletal pain. The approval letter also noted that patients should be monitored for symptoms of arrhythmia, based on the risk of atrial fibrillation and atrial flutter observed in clinical trials.

This approval decision was made as part of Project Orbis, a collaboration with the Australian Therapeutic Goods Administration and Health Canada that provides a framework for concurrent submission and review of oncology drug applications among the FDA’s international partners. Both partner countries approved acalabrutinib for the CLL/SLL indication.

This review also used the FDA’s Real-Time Oncology Review program, through which the agency can access clinical trial data before the information is formally submitted.