FDA Approves Obinutuzumab for Select Patients With Previously Treated Follicular Lymphoma.

February 26, 2016.

FDA  approved obinutuzumab (Gazyva Injection, Genentech, Inc.) for use in combination with bendamustine followed by obinutuzumab monotherapy for the treatment of patients with follicular lymphoma (FL) who relapsed after, or are refractory to, a rituximab-containing regimen.(1)

Obinutuzumab was previously approved in 2013 for use in combination with chlorambucil for the treatment of patients with previously untreated chronic lymphocytic leukemia.(2)

This new approval was based on demonstration of an improvement in progression-free survival (PFS) in a randomized, open-label, multicenter trial in patients with FL who had no response to or have progressed during or within 6 months of a rituximab-containing regimen. This trial compared 6 cycles of obinutuzumab plus bendamustine combination therapy followed by continued obinutuzumab monotherapy for up to 2 years with 6 cycles of bendamustine therapy.

DESCRIPTION

  • Obinutuzumab is a humanized anti-CD20 monoclonal antibody of the IgG1 subclass.
  • It recognizes a specific epitope of the CD20 molecule found on B cells.
  • The molecular mass of the antibody is approximately 150 kDa.
  • It is produced by mammalian cell (CHO) suspension culture.
  • Obinutuzumab was engineered for reduced fucose content as compared to a typical IgG1 produced in CHO cells.

CLINICAL PHARMACOLOGY

Mechanism of Action

Obinutuzumab is a monoclonal antibody that targets the CD20 antigen expressed on the surface of pre B- and mature B-lymphocytes.

While the variable region binds the same epitope of the CD20 antigen as rituximab, it binds to CD20 in a different orientation, leading to a different rearrangement of CD20 within the cell membrane and higher programmed cell death (apoptosis) than rituximab (type 2 vs type 1).

 Upon binding to CD20, obinutuzumab mediates B-cell lysis through

  • A. engagement of immune effector cells,
  • B. by directly activating intracellular death signaling pathways (direct cell death), and/or
  • C. activation of the complement cascade.
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MECHANISM OF ACTION OF OBINUTUZUMAB (3)

 

The immune effector cell mechanisms include antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis.

As an antibody with reduced fucose content, obinutuzumab induces greater ADCC activity than rituximab in vitro using human cancer cell lines.

Obinutuzumab also demonstrated an increased ability to induce direct cell death when compared to rituximab.

As a result, obinutuzumab’s mechanisms of action are primarily ADCC and apoptosis, while rituximab is capable of inducing both ADCC and complement-mediated cytotoxicity with minimal apoptosis

Obinutuzumab binds to FcγRIII  using purified proteins with a higher affinity than rituximab.

Obinutuzumab and rituximab bind with similar affinity to overlapping epitopes on CD20.

INDICATIONS AND USAGE

  • Chronic Lymphocytic Leukemia GAZYVA, in combination with chlorambucil, is indicated for the treatment of patients with previously untreated chronic lymphocytic leukemia (CLL).
  • Follicular Lymphoma GAZYVA, in combination with bendamustine followed by GAZYVA monotherapy, is indicated for the treatment of patients with follicular lymphoma (FL) who relapsed after, or are refractory to, a rituximab-containing regimen.

DOSAGE AND ADMINISTRATION

Recommended Dosage Regimen

  • Premedicate before each infusion
  • Provide prophylactic hydration and anti-hyperuricemics to patients at high risk of tumor lysis syndrome
  • Administer only as an intravenous infusion through a dedicated line
  • Do not administer as an intravenous push or bolus.
  • Monitor blood counts at regular intervals.
  • GAZYVA should only be administered by a healthcare professional with appropriate medical support to manage severe infusion reactions that can be fatal if they occur.

Recommended Premedication Infusion Reactions

  • Hypotension may occur during GAZYVA intravenous infusions.Consider withholding antihypertensive treatments for 12 hours prior to and throughout each GAZYVA infusion and for the first hour after administration.
  •  Tumor Lysis Syndrome Patients with high tumor burden, high circulating absolute lymphocyte counts (greater than 25 x 109 /L) or renal impairment are considered at risk of tumor lysis syndrome and should receive prophylaxis.
  • Premedicate with anti-hyperuricemics (e.g., allopurinol or rasburicase) and ensure adequate hydration prior to start of GAZYVA therapy. Continue prophylaxis prior to each subsequent GAZYVA infusion, as needed

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Efficacy & Safety

Efficacy was assessed in 321 patients with follicular lymphoma randomized to either obinutuzumab plus bendamustine (n=155) or bendamustine (n=166). The median age was 63 years (range 34-87). Patients had received a median of 2 prior therapies (range 1-10). The independent review assessed median PFS was 13.8 months in the bendamustine arm while the median PFS was not reached in the obinutuzumab plus bendamustine arm [HR 0.48 (95% CI: 0.34-0.68), log-rank test p-value < 0.0001).

This trial also enrolled 46 patients with marginal zone lymphoma and 28 with small lymphocytic lymphoma who were also included in the safety analysis.

WARNINGS AND PRECAUTIONS

  • Infusion reactions: Premedicate patients with glucocorticoid, acetaminophen, and anti-histamine. Monitor patients closely during infusions. Interrupt or discontinue infusion for reactions.
  • Tumor Lysis Syndrome: Anticipate tumor lysis syndrome; premedicate with anti-hyperuricemics and adequate hydration especially for patients with high tumor burden, high circulating lymphocyte count or renal impairment. Correct electrolyte abnormalities, provide supportive care, and monitor renal function and fluid balance.
  • Neutropenia: Monitor for infection.
  • Thrombocytopenia: Monitor platelet counts and for bleeding. Management of hemorrhage may require blood product support.
  • Immunization: Do not administer live virus vaccines prior to or during GAZYVA treatment.

 ADVERSE REACTIONS

  • The most common adverse reactions (incidence ≥ 10%) were: • CLL: infusion reactions, neutropenia, thrombocytopenia, anemia, pyrexia, cough, nausea, and diarrhea.
  • Indolent NHL: infusion reactions, neutropenia, nausea, fatigue, cough, diarrhea, constipation, pyrexia, thrombocytopenia, vomiting, upper respiratory tract infection, decreased appetite, arthralgia, sinusitis, anemia, asthenia and urinary tract infection

References:

1.Research C for DE and. Approved Drugs – Obinutuzumab [Internet]. [cited 2016 Feb 27].

Available from: http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm488013.htm

2.Press Announcements – FDA approves Gazyva for chronic lymphocytic leukemia [Internet]. [cited 2016 Feb 27].

Available from: http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm373209.htm

3.The Emerging Role of Obinutuzumab in the Treatment of B-Cell Lymphoid Malignancies [Internet]. Targeted Oncology. [cited 2016 Feb 27].

Available from: http://www.targetedonc.com/publications/targeted-therapies-cancer/2014/feb-2014/the-emerging-role-of-obinutuzumab-in-the-treatment-of-b-cell-lymphoid-malignancies.

4. Prescribing Information