Recent FDA Actions Include New Formulation, Expanded Indications for Oncology-Hematology Drug Products


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The U.S. Food and Drug Administration (FDA) recently granted approval to olaparib tablets (Lynparza) as a maintenance therapy for ovarian cancer and to inotuzumab ozogamicin (Besponsa), for the treatment of adults with relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL). 

Olaparib Tablets

On August 17, 2017, the FDA granted regular approval to olaparib tablets for the maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a complete or partial response to platinum-based chemotherapy.

With the addition of the new indication, a tablet formulation of olaparib was introduced. 

The FDA approved olaparib capsules in 2014 for the treatment of patients with deleterious or suspected deleterious germline BRCA-mutated advanced ovarian cancer who have been treated with three or more prior lines of chemotherapy. On August 17, 2017, the FDA also approved olaparib tablets for this indication. Olaparib tablets and capsules are not interchangeable, the FDA noted, adding that olaparib capsules are being phased out of the U.S. market.

Maintenance Therapy: Approval in the maintenance setting was based on two randomized, placebo-controlled, double-blind, multicenter trials in patients with recurrent ovarian cancer who were in response to platinum-based therapy.

SOLO-2 (ClinicalTrials.gov identifier NCT01874353) randomized 295 patients with recurrent germline BRCA-mutated ovarian, fallopian tube, or primary peritoneal cancer (2:1) to receive olaparib tablets at 300 mg orally twice daily or placebo.1,2 SOLO-2 demonstrated a statistically significant improvement in investigator-assessed progression-free survival in patients randomized to receive olaparib compared with those who received placebo, with a hazard ratio of 0.30 (95% confidence interval [CI] = 0.22–0.41; P < .0001). The estimated median progression-free survival was 19.1 and 5.5 months in the olaparib and placebo arms, respectively. The data were presented at the 2017 Society of Gynecologic Oncology Annual Meeting. 

Study 19 (ClinicalTrials.gov identifier NCT00753545) randomized 265 patients regardless of BRCA status (1:1) to receive olaparib capsules at 400 mg orally twice daily or placebo.2 Study 19 demonstrated a statistically significant improvement in investigator-assessed progression-free survival in patients treated with olaparib vs placebo with a hazard ratio of 0.35 (95% CI = 0.25–0.49; P < .0001). The estimated median progression-free survival was 8.4 months and 4.8 months in the olaparib and placebo arms, respectively. 

Safety and Toxicity: The most common adverse reactions (≥ 20%) in clinical trials were anemia, nausea, fatigue (including asthenia), vomiting, nasopharyngitis, diarrhea, arthralgia/myalgia, dysgeusia, headache, dyspepsia, decreased appetite, constipation, and stomatitis. The most common laboratory abnormalities (≥ 25%) were a decrease in hemoglobin, increase in mean corpuscular volume, decrease in lymphocytes, decrease in leukocytes, decrease in absolute neutrophil count, increase in serum creatinine, and decrease in platelets.

The recommended olaparib tablet dose for both the maintenance therapy and later-line treatment setting is 300 mg (two 150 mg tablets) taken orally twice daily with or without food.

Inotuzumab Ozogamicin

On August 17, 2017, the FDA approved inotuzu-mab ozogamicin for the -treatment of adults with relapsed or refractory B-cell -precursor ALL.

The approval was based on data from INO-VATE ALL (NCT01564784), a randomized (1:1), open label, international, multicenter study in 326 patients with Philadelphia chromosome–negative or Philadelphia chromosome–positive relapsed or refractory B-cell precursor ALL. 3 Patients were required to have ≥ 5% bone marrow blasts and to have received one or two previous induction chemotherapy regimens for ALL. Patients with Philadelphia chromosome–positive B-cell precursor ALL were required to have disease that failed to respond to treatment with at least one tyrosine kinase inhibitor and standard chemotherapy. 

Patients were randomized to receive inotuzumab ozogamicin (n = 164) or investigator’s choice of chemotherapy (n = 162). Of the initial 218 randomized patients, 35.8% of those who received inotuzumab ozogamicin experienced complete remission for a median 8.0 months, and 89.7% of those patients achieved minimal residual disease negativity. Of the patients who received chemotherapy, 17.4% experienced complete remission for a median 4.9 months, and 31.6% of those patients achieved minimal residual disease negativity. 

Safety and Administration: The most common adverse reactions occurring in greater than 20% of patients were thrombocytopenia, neutropenia, infection, anemia, leukopenia, fatigue, hemorrhage, pyrexia, nausea, headache, febrile neutropenia, increased transaminases, abdominal pain, increased gamma-glutamyltransferase, and hyperbilirubinemia. The most common (≥ 2%) adverse reactions reported as the reason for permanent discontinuation of inotuzumab ozogamicin treatment were infection, thrombocytopenia, hyperbilirubinemia, increased transaminases, and hemorrhage.

For the first cycle, the recommended dose of inotuzumab ozogamicin for all patients is 1.8 mg/m2 per cycle, administered as three divided doses on day 1 (0.8 mg/m2), day 8 (0.5 mg/m2), and day 15 (0.5 mg/m2). The recommended dosing for subsequent cycles depends on response to treatment. 

The FDA had previously granted Orphan Drug and Breakthrough Therapy designations to inotuzu-mab ozogamicin for the treatment of ALL, as well as priority review. 

For full prescribing information and additional information, visit www.FDA.gov.

For these and other recent approvals from the FDA’s Oncology Centers of Excellence, listen to the new podcast, Drug Information Soundcast in Clinical Oncology (DISCO), available at www.fda.gov/-DISCO. ■

References

1. Pujade-Lauraine E, Ledermann J, Penson R, et al: Treatment with olaparib monotherapy in the maintenance setting significantly improves progression-free survival in patients with platinum-sensitive relapsed ovarian cancer: Results from the phase III SOLO2 study. 2017 SGO Annual Meeting. Abstract 2. Presented March 14, 2017.

2. Ledermann J, Harter P, Gourley M, et al: Olaparib maintenance therapy in platinum-sensitive relapsed ovarian cancer. N Engl J Med 366:1382–1392, 2012.

3. Kantarjian HM, DeAngela DJ, Stelljes M, et al: Inotuzumab ozogamicin versus standard therapy for acute lymphoblastic leukemia. N Engl J Med 375:740–753, 2016.



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