Besponsa (Inotuzumab Ozogamicin) Approved for Adults with Relapsed or Refractory B-Cell Precursor Acute Lymphoblastic Leukemia

March 2018, Vol 11, Ninth Annual Payers' Guide - FDA Approvals, News & Updates
Loretta Fala
Medical Writer

Acute lymphoblastic leukemia (ALL), also known as acute lymphocytic leukemia, is a cancer of the blood and bone marrow that affects the lymphocytes.1 In 2017, 6000 new cases of ALL were estimated to be diagnosed, and more than 1400 people to die from this disease in the United States.2 The ≥5-year survival rate of ALL is approximately 68%. Although the majority of new ALL cases occur in young people aged <20 years, approximately 44% of new patients are aged >20 years.2

B-cell precursor ALL, characterized by an excess of B-cell lymphocytes (immature white blood cells), is a particularly aggressive type of cancer, with poor prognosis.3

Besponsa a New Treatment Approved for ALL

On August 17, 2017, the US Food and Drug Administration (FDA) approved inotuzumab ozogamicin (Besponsa; Pfizer), a CD22-directed antibody drug conjugate, for the treatment of adults with relapsed or refractory B-cell precursor ALL.3,4

“For adult patients with B-cell ALL whose cancer has not responded to initial treatment or has returned after treatment, life expectancy is typically low,” said Richard Pazdur MD, Director, FDA’s Oncology Center of Excellence.3 “These patients have few treatments available, and today’s approval provides a new, targeted treatment option,” he added.3

The FDA granted inotuzumab ozogamicin a breakthrough therapy and an orphan drug designation for this indication.3

Mechanism of Action

Inotuzumab ozogamicin is a CD22-directed antibody drug conjugate that identifies and targets B-cell ALL cancer cells that express the CD22 antigen, thereby inhibiting the growth of cancer cells.3,4 The depletion of CD22-positive leukemic blasts typifies a response to treatment with inotuzumab ozogamicin.4

Dosing and Administration

Inotuzumab ozogamicin is available as a 0.9-mg lyophilized powder in a single-dose vial for reconstitution and further dilution for intravenous injection.4

Before all infusions with inotuzumab ozogamicin, patients should be premedicated with a corticosteroid, an antipyretic, and an antihistamine. Dosing regimens for cycle 1 and subsequent cycles are based on the treatment response, as outlined in the full prescribing information.4

The dosing regimen of inotuzumab ozogamicin for subsequent treatment cycles also depends on the patient’s treatment response, as outlined in the full prescribing information.4

Pivotal Clinical Trial: INO-VATE ALL

The FDA approval of inotuzumab ozogamicin was based on the safety and efficacy data from the randomized, open-label, phase 3, INO-VATE ALL clinical trial that included adults with relapsed or refractory B-cell precursor ALL. All evaluable patients had B-cell precursor ALL that expressed CD22 and were randomized to inotuzumab ozogamicin or to investigator’s choice of chemotherapy.4,5 Of the 326 patients (median age, 47 years), 218 were included in the primary analysis.4,5

The complete remission rate was significantly greater for patients who received inotuzumab ozogamicin compared with those who received standard chemotherapy (Table).4

Table

Overall, 80.7% in the inotuzumab ozogamicin arm achieved complete remission or complete remission with incomplete hematologic recovery versus 29.4% of patients in the chemotherapy arm. In addition, patients who received inotuzumab ozogamicin had a higher rate of minimal residual disease (MRD)-negative status than patients who received chemotherapy.4

Although overall survival (OS) was longer in the inotuzumab ozogamicin arm (median, 7.7 months; 95% confidence interval [CI], 6.0-9.2) than in the chemotherapy arm (median, 6.2 months; 95% CI, 4.7-8.3), the OS analysis did not meet the prespecified measure of significance (hazard ratio, 0.75; 97.5% CI, 0.57-0.99).4

Adverse Reactions

The most common (≥20%) adverse reactions associated with inotuzumab ozogamicin therapy were thrombocytopenia (51%), neutropenia (49%), infection (48%), anemia (36%), leukopenia (35%), fatigue (35%), hemorrhage (33%), pyrexia (32%), nausea (31%), headache (28%), febrile neutropenia (26%), increased transaminase levels (26%), abdominal pain (23%), increased gamma-glutamyltransferase levels (21%), and hyperbilirubinemia (21%).4

The most common (≥2%) serious adverse reactions were veno-occlusive disease (VOD), infection, febrile neutropenia, hemorrhage, abdominal pain, pyrexia, and fatigue. Permanent discontinuation of inotuzumab ozogamicin was most often because of infection, thrombocytopenia, hyperbilirubinemia, high transaminase levels, and hemorrhage.4

Inotuzumab ozogamicin has no contraindications.4

Drug Interactions

The concomitant use of inotuzumab ozogamicin with drugs known to prolong the QT interval should be avoided, or an alternative concomitant drug should be used.4

Use in Specific Populations

Women of reproductive potential should be cautioned about the potential risk to the fetus and should be advised to use effective contraception.4

Nursing women should not breastfeed during treatment with inotuzumab ozogamicin and for at least 2 months after the last dose.4

No differences were observed in patients aged ≥65 years and younger patients in the INO-VATE ALL study, in which 18% of patients who received inotuzu­mab ozogamicin were aged ≥65 years.4

No starting-dose adjustment of inotuzumab ozogamicin is required for patients with total bilirubin levels ≤1.5 × upper limit of normal (ULN) and aspartate aminotransferase/alanine aminotransferase (AST/ALT) levels ≤2.5 × ULN. Data are limited in patients with total bilirubin levels >1.5 × ULN and/or AST/ALT levels >2.5 × ULN before dosing. Dosing should be interrupted until total bilirubin levels recover to ≤1.5 × ULN and AST/ALT levels recover to ≤2.5 × ULN before each dose, unless caused by Gilbert’s syndrome or hemolysis. If total bilirubin levels do not recover to ≤1.5 × ULN or AST/ALT levels do not recover to ≤2.5 × ULN, treatment with inotuzumab ozogamicin should be permanently discontinued.4

Warnings and Precautions

Inotuzumab ozogamicin was approved with a boxed warning about the risk for hepatotoxicity, including fatal or life-threatening VOD that occurred in some patients who received inotuzumab ozogamicin. The boxed warning also cautions about the increased risk for post–hematopoietic stem-cell transplantation nonrelapse mortality in patients who receive inotuzumab ozogamicin.4

The patient’s complete blood count should be monitored before each dose of inotuzumab ozogamicin. Patients should also be monitored for infections, bleeding, or hemorrhage, or other effects of myelosuppression during treatment with inotuzumab ozogamicin. Signs and symptoms of myelosuppression should be managed appropriately.4

Patients should also be monitored for infusion-related reactions during infusion with inotuzumab ozogamicin and for at least 1 hour after the infusion ends.4

An electrocardiogram and electrolyte test should be conducted at baseline and monitored during treatment. Patients who receive concomitant medications that are known to prolong the QT interval should be monitored more frequently.4

Conclusion

The FDA approval of inotuzumab ozogamicin marks the availability of a new targeted therapy with a CD22-directed antibody drug conjugate that may improve outcomes for patients with relapsed or refractory B-cell precursor ALL, a rapidly progressing type of cancer. In the INO-VATE ALL clinical trial, a significantly greater percentage of patients who received inotuzumab ozogamicin achieved complete remission compared with patients who received chemotherapy. Furthermore, the median duration of remission and the rate of MRD-negative status were greater with inotuzumab ozogamicin versus with chemotherapy.

References
1. Mayo Clinic. Acute lymphocytic leukemia. www.mayoclinic.org/diseases-conditions/acute-lymphocytic-leukemia/basics/definition/con-20042915. Accessed November 28, 2017.
2. National Cancer Institute. SEER cancer stat facts: leukemia – acute lymphocytic leukemia (ALL). https://seer.cancer.gov/statfacts/html/alyl.html. Accessed November 28, 2017.
3. US Food and Drug Administration. FDA approves new treatment for adults with relapsed or refractory acute lymphoblastic leukemia. August 17, 2017. www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm572131.htm. Accessed November 22, 2017.
4. Besponsa (inotuzumab ozogamicin) for injection [prescribing information]. Philadelphia, PA: Pfizer; August 2017.
5. Kantarjian HM, DeAngelo DJ, Stelljes M, et al. Inotuzumab ozogamicin versus standard therapy for acute lymphoblastic leukemia. N Engl J Med. 2016;375:740-753.

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