Accelerated Approval of Sacituzumab Govitecan-Hziy for Metastatic Triple-Negative Breast Cancer
The FDA granted accelerated approval to sacituzumab govitecan-hziy for adult patients with metastatic triple-negative breast cancer (mTNBC) who received at least two prior therapies for metastatic disease.
Efficacy was demonstrated in IMMU-132-01 (NCT01631552), a multicenter, single-arm trial enrolling 108 patients with mTNBC who received at least two prior treatments for metastatic disease. Patients received sacituzumab govitecan-hziy 10 mg/kg intravenously on days 1 and 8 every 21 days. Tumor imaging was obtained every 8 weeks, and patients were treated until disease progression or intolerance to therapy.
The primary efficacy outcome measures were investigator-assessed overall response rate (ORR) using RECIST 1.1 and response duration. The ORR was 33.3 percent (95% CI: 24.6, 43.1). The median response duration was 7.7 months (95% CI: 4.9, 10.8).
The most common adverse reactions (>=25% of patients) were nausea, neutropenia, diarrhea, fatigue, anemia, vomiting, alopecia, constipation, rash, decreased appetite, and abdominal pain. Sacituzumab govitecan-hziy can also cause severe neutropenia and diarrhea.
The recommended dose is 10 mg/kg administered by intravenous infusion administered on days 1 and 8 every 21 days until disease progression or unacceptable toxicity.
Niraparib for First-Line Maintenance of Advanced Ovarian Cancer
The FDA approved niraparib for the maintenance treatment of adult patients with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a complete or partial response to first-line platinum-based chemotherapy.
Efficacy was investigated in PRIMA (NCT02655016), a double-blind, placebo-controlled trial that randomized 733 patients to niraparib or matched placebo. Patients were in a complete or partial response to first-line platinum-based chemotherapy.
The main efficacy outcome measure, progression-free survival (PFS), was first tested in the homologous recombination deficient population, then in the overall population, and was determined by blinded independent central review per RECIST 1.1. Tumor samples were tested for homologous recombination deficiency status; homologous recombination deficient was defined by either presence of tumor breast cancer susceptibility gene (tBRCA) mutation or genomic instability score >=42. An FDA-approved companion diagnostic is not required to initiate treatment with niraparib for this indication.
The trial demonstrated a statistically significant improvement in PFS for patients randomized to niraparib compared with placebo in the homologous recombination deficient and overall population. Median PFS in the homologous recombination deficient population was 21.9 months (19.3, NE) for patients receiving niraparib compared with 10.4 months (8.1, 12.1) for those receiving placebo (HR 0.43; 95% CI: 0.31, 0.59; p<0.0001). Median PFS in the overall population was 13.8 months (11.5, 14.9) for patients receiving niraparib compared with 8.2 months (7.3, 8.5) for those receiving placebo (HR 0.62; 95% CI: 0.50, 0.76; p<0.0001).
The most common adverse reactions in >=10 percent of all patients receiving niraparib in the PRIMA trial were thrombocytopenia, anemia, nausea, fatigue, neutropenia, constipation, musculoskeletal pain, leukopenia, headache, insomnia, vomiting, dyspnea, decreased appetite, dizziness, cough, hypertension, AST/ALT elevation, and acute kidney injury.
The recommended niraparib dose for first-line maintenance treatment of advanced ovarian cancer is based on body weight or platelet count. For patients weighing less than 77 kg (170 lbs) or with a platelet count of less than 150,000/[mu]L, the recommended dose is 200 mg taken orally once daily. For patients weighing greater than or equal to 77 kg (170 lbs) and who have a platelet count greater than or equal to 150,000/[mu]L, the recommended dose is 300 mg taken orally once daily.
Daratumumab & Hyaluronidase-Fihj for Multiple Myeloma
The FDA approved daratumumab and hyaluronidase-fihj for adult patients with newly diagnosed or relapsed/refractory multiple myeloma. This new product allows for subcutaneous dosing of daratumumab.
The combination of daratumumab and hyaluronidase-fihj is approved for the following indications that intravenous daratumumab had previously received:
* in combination with bortezomib, melphalan, and prednisone in newly diagnosed patients who are ineligible for autologous stem cell transplant;
* in combination with lenalidomide and dexamethasone in newly diagnosed patients who are ineligible for autologous stem cell transplant and in patients with relapsed or refractory multiple myeloma who have received at least one prior therapy;
* in combination with bortezomib and dexamethasone in patients who have received at least one prior therapy;
* as monotherapy, in patients who have received at least three prior lines of therapy including a proteasome inhibitor and an immunomodulatory agent or who are double-refractory to a PI and an immunomodulatory agent.
Efficacy of daratumumab and hyaluronidase-fihji (monotherapy) was evaluated in COLUMBA (NCT03277105), an open-label non-inferiority trial randomizing 263 patients to daratumumab and hyaluronidase-fihj and 259 to intravenous daratumumab (daratumumab IV). The trial's co-primary endpoints were overall response rate (ORR) and pharmacokinetic endpoint of the maximum Ctrough on cycle 3, day 1 pre-dose. The combination of daratumumab and hyaluronidase-fihj was non-inferior to daratumumab IV in evaluating these two endpoints.
The ORR was 41.1 percent for daratumumab and hyaluronidase-fihj and 37.1 percent for daratumumab IV with a risk ratio of 1.11 (95% CI: 0.89, 1.37). The geometric mean ratio comparing daratumumab and hyaluronidase-fihj to daratumumab IV for maximum Ctrough was 108 percent (90% CI: 96,122).
Efficacy of daratumumab and hyaluronidase-fihj in combination with VMP (D-VMP) was evaluated in a single-arm cohort of PLEIADES (NCT03412565), a multi-cohort, open-label trial. Eligible patients were required to have newly diagnosed multiple myeloma and were ineligible for transplant. The major efficacy outcome measure, ORR, was 88.1 percent (95% CI: 77.8, 94.7).
Efficacy of daratumumab and hyaluronidase-fihj in combination with Rd (D-Rd) was evaluated in a single-arm cohort of this trial. Eligible patients had received at least one prior line of therapy. ORR was 90.8 percent (95% CI: 81.0, 96.5).
The most common adverse reaction (>=20%) with daratumumab and hyaluronidase-fihj monotherapy is upper respiratory tract infection. The most common adverse reactions (>=20%) with D-VMP are upper respiratory tract infection, constipation, nausea, fatigue, pyrexia, peripheral sensory neuropathy, diarrhea, cough, insomnia, vomiting, and back pain. The most common adverse reactions (>=20%) with D-Rd are fatigue, diarrhea, upper respiratory tract infection, muscle spasms, constipation, pyrexia, pneumonia and dyspnea.
The most common hematology laboratory abnormalities (>=40%) with daratumumab and hyaluronidase-fihj are decreased leukocytes, decreased lymphocytes, decreased neutrophils, decreased platelets, and decreased hemoglobin.
The recommended dose of daratumumab and hyaluronidase-fihj is 1,800 mg daratumumab and 30,000 units hyaluronidase administered subcutaneously into the abdomen over approximately 3-5 minutes according to recommended schedule.