Gazyva (Obinutuzumab) Approved for Patients with Rituximab-Refractory Follicular Lymphoma

March 2017, Vol 10, Eighth Annual Payers' Guide - FDA News & Updates, Payers' Guide
Loretta Fala
Medical Writer
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Non-Hodgkin lymphomas (NHL), a heterogeneous group of malignancies that originate in lymphoid tissues, have varying patterns of progression and responses to treatment.1 In 2013, it was estimated that 569,536 patients were living with NHL in the United States, with 72,580 new cases diagnosed annually.2 In 2016, NHL was the 7th most often diagnosed cancer, claiming the lives of 20,150 individuals.2 NHL is less predictable than Hodgkin lymphoma and more likely to metastasize to extranodal sites.1

Follicular lymphoma, a type of indolent NHL that involves B-cells, occurs most frequently in people aged ≥50 years.1,3 Follicular lymphoma accounts for 20% of all cases of NHL and nearly 70% of all indolent lymphomas.1 At diagnosis, many patients with follicular lymphoma already have widespread disease, often with nodal involvement accompanied by disease of the bone marrow and spleen.1

Treatment for the various types of lymphoma include chemotherapy, radiation therapy, radioimmunotherapy, and immunotherapy (monoclonal antibodies).3 The use of rituximab (Rituxan), an anti-CD20 monoclonal antibody, in combination with chemotherapy, has improved clinical outcomes for patients with follicular lymphoma.4-6 However, disease relapse is common, even in patients who achieve complete response.1,7 Indeed, the disease may relapse in some patients, or become refractory to rituximab-containing regimens.4,6 Thus, there is a need for additional therapeutic options to address an unmet need for patients with follicular lymphoma.

Obinutuzumab Approved for Follicular Lymphoma

On February 26, 2016, obinutuzumab (Gazyva; Genentech) was approved by the US Food and Drug Administration (FDA), in combination with bendamustine, for the treatment of patients with follicular lymphoma whose disease relapsed after, or is refractory to, a rituximab-containing regimen.8 Obinutuzumab, a CD20-directed cytolytic antibody, was initially approved by the FDA in 2013 for use, in combination with chlor­ambucil, in patients with treatment-naïve chronic lymphocytic leukemia.8,9

Mechanism of Action

Obinutuzumab is a CD20-directed cytolytic monoclonal antibody that targets the CD20 antigen expressed on the surface of pre–B-lymphocytes and mature B-lymphocytes. Obinutuzumab binds to CD20 and mediates B-cell lysis by activating the immune effector cells, intracellular death-signaling pathways, and the complement cascade.9

Obinutuzumab induces greater antibody-dependent cellular cytotoxicity activity than rituximab and greater ability to induce direct cell death than rituximab.9

Dosing and Administration

Patients who receive obinutuzumab should be premedicated for infusion reactions and tumor lysis syndrome.9

Obinutuzumab is diluted and administered as an intravenous (IV) infusion and should not be administered as an IV push or bolus. For follicular lymphoma, the recommended dose is 1000 mg on day 1, 8, and 15 of cycle 1, 1000 mg on day 1 of cycles 2 to 6, and then every 2 months for 2 years.9 Obinutuzumab is available in a 1000-mg/40-mL (25-mg/mL) single-dose vial.9

Obinutuzumab Distribution

Obinutuzumab is ordered through authorized specialty pharmacies and wholesalers, including AmerisourceBergen Drug Corporation, ASD Healthcare, BioSolutions Direct, Cardinal Health Specialty Distribution, CuraScript SD, Dakota Drug, DMS Pharmaceutical, McKesson Plasma Biologics, McKesson Specialty Health, McKesson US Pharmaceutical, Morris and Dickson Specialty Distribution, Oncology Supply, and Smith Medical Partners.10

Pivotal Clinical Trial: GADOLIN

The FDA approval of obinutuzumab for follicular lymphoma was based on results from the open-label, randomized, phase 3 GADOLIN study, which included 321 patients (median age, 63 years) with follicular lymphoma whose disease did not respond to, or had progressed during or within 6 months of treatment with rituximab or a rituximab-containing regimen.6,9

Patients had received a median of 2 previous therapies (range, 1-10)8; they were randomized to receive obinutuzumab in combination with bendamustine for 6 cycles of 28 days each or bendamustine alone. At the end of 6 cycles, patients in the obinutuzumab plus bendamustine treatment group whose disease had not progressed continued to receive obinutuzumab monotherapy for 2 years.9

The primary end point was progression-free survival (PFS), defined as time from randomization to first disease progression, relapse, or death.6,9 The median observation period was 21.1 months.9

The efficacy results are shown in the Table. The median PFS with bendamustine monotherapy was 13.8 months and was not reached with obinutuzumab plus bendamustine.9 Patients who received obinutuzumab plus bendamustine, followed by obinutuzumab alone, showed a significant reduction in disease worsening and improvement in PFS compared with bendamustine alone.6,9 Based on a 24.1-month median observation analysis, the median overall survival was not yet reached in either group.9

Adverse Reactions

In clinical studies, the most common (≥10%) adverse reactions in patients with indolent NHL were 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. The incidence of thrombocytopenia was lower in the combination group (15%) than in the bendamustine monotherapy group (24%).9

The most common (≥10%) grade 3 or 4 adverse reactions reported in patients with indolent NHL who received obinutuzumab-containing treatment were neutropenia, thrombocytopenia, and infusion reactions.9

Obinutuzumab has no contraindications.9

Warnings and Precautions

Patients should be premedicated with glucocorticoid, acetaminophen, and antihistamine, and monitored closely during infusions with obinutuzumab. If reactions occur, obinutuzumab treatment should be interrupted or discontinued.9

Tumor lysis syndrome (TLS), including fatal cases, has been reported with obinutuzumab. Patients with high tumor burden, high circulating lymphocyte count, or renal impairment are at risk for TLS and should receive premedication with antihyperuricemics and adequate hydration, and be monitored closely. If TLS occurs, correct the electrolyte abnormalities, monitor renal function and fluid balance, and use supportive care, including dialysis as indicated.9

Infections, some severe and life-threatening, have been reported with obinutuzumab. Monitor patients for infection; avoid obinutuzumab use in patients with active infections.9

Severe, life-threatening neutropenia has been reported with obinutuzumab. Monitor patients with grade 3 or 4 neutropenia and consider dose delays.9

Severe and life-threatening thrombocytopenia has been reported during treatment with obinutuzumab. Patients should be monitored frequently for thrombocytopenia and hemorrhagic events, especially in the first cycle.9

Live virus vaccines should not be administered before or during obinutuzumab treatment.9

Use in Specific Populations

The safety and efficacy of obinutuzumab in pediatric patients have not been established.9

In clinical studies involving patients with chronic lymphocytic leukemia and NHL who received obinutuzumab, no significant differences in efficacy were observed between patients aged ≥65 years and younger patients.9

Conclusion

Obinutuzumab, a CD20-directed monoclonal antibody, is a new treatment option for patients with follicular lymphoma whose disease relapsed after, or is refractory to, a rituximab-containing regimen. In the phase 3 GADOLIN study, treatment with obinutuzumab plus bendamustine, resulted in a significant improvement in PFS and reduction of disease worsening versus bendamustine alone. The median PFS had not yet been reached with the combination.

References

1. National Cancer Institute. Adult non-Hodgkin lymphoma treatment (PDQ)—health professional version. www.cancer.gov/types/lymphoma/hp/adult-nhl-treatment-pdq. Accessed January 23, 2017.
2. National Cancer Institute. SEER cancer stat facts: non-Hodgkin lymphoma. https://seer.cancer.gov/statfacts/html/nhl.html. Accessed January 23, 2017.
3. Mayo Clinic staff. Diseases and conditions: non-Hodgkin’s lymphoma: definition. January 28, 2016. www.mayoclinic.org/diseases-conditions/non-hodgkins-lymphoma/basics/definition/con-20027792. Accessed January 23, 2017.
4. Gabellier L, Cartron G. Obinutuzumab for relapsed or refractory indolent non-Hodgkin’s lymphomas. Ther Adv Hematol. 2016;7:85-93.
5. Hiddemann W, Kneba M, Dreyling M, et al. Frontline therapy with rituximab added to the combination of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) significantly improves the outcome for patients with advanced-stage follicular lymphoma compared with therapy with CHOP alone: results of a prospective randomized study of the German Low-Grade Lymphoma Study Group. Blood. 2005;106:3725-3732.
6. Sehn LH, Chua N, Mayer J, et al. Obinutuzumab plus bendamustine versus bendamustine monotherapy in patients with rituximab-refractory indolent non-Hodgkin lymphoma (GADOLIN): a randomised, controlled, open-label, multicentre, phase 3 trial. Lancet Oncol. 2016;17:1081-1093.
7. Kahl BS, Yang DT. Follicular lymphoma: evolving therapeutic strategies. Blood. 2016;127:2055-2063. Erratum in: Blood. 2016;128:463.
8. US Food and Drug Administration. Obinutuzumab. www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm488013.htm. Accessed January 23, 2016.
9. Gazyva (obinutuzumab) injection [prescribing information]. South San Francisco, CA: Genentech; February 2016.
10. Genentech. Gazyva distribution. www.genentech-access.com/hcp/brands/gazyva/learn-about-our-services/product-distribution.html. Accessed January 23, 2017.

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