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FDA Updates Highlighting the Latest Cancer Treatments FDA Updates Highlighting the Latest Cancer Treatments Pembrolizumab Plus Axitinib Approved for hepatic impairment with bilirubin >1.5 times the upper limit of nor- Advanced Renal Cell Carcinoma mal, or creatinine clearance <45 mL/min). The FDA approved pembrolizumab plus axitinib for the first-line Patients had a median age of 77 years (range, 64-87) and 68 percent treatment of patients with advanced renal cell carcinoma (RCC). This had AML with myelodysplasia-related changes. The primary endpoint decision was based on KEYNOTE-426, a randomized, multicenter, is the combined complete remission (CR) and complete remission open-label trial conducted in 861 patients who had not received sys- with partial hematologic improvement (CRh) rate. CRh is defined as temic therapy for advanced RCC. Patients were enrolled regardless of <5 percent of blasts in the bone marrow, no evidence of disease, and PD-L1 tumor expression status and were randomly allocated to receive partial recovery of peripheral blood counts (platelets >50,000/μl and either pembrolizumab 200 mg intravenously every 3 weeks in combi- ANC >500/μl). nation with axitinib 5 mg orally twice daily, or sunitinib 50 mg orally The safety profile of single-agent ivosidenib was evaluated in 28 once daily for 4 weeks and then off treatment for 2 weeks. Treatment patients with newly diagnosed AML with an IDH1 mutation treated continued until confirmed disease progression or unacceptable toxicity. with a dose of 500 mg daily. The median duration of exposure to Pembrolizumab was received for a maximum of 24 months. ivosidenib was 4.3 months (range, 0.3-40.9 months). In the clinical The main efficacy measures were overall survival (OS) and pro- trial, 25 percent of patients (7 of 28) treated with ivosidenib expe- gression-free survival (PFS), assessed by RECIST 1.1. The trial demon- rienced differentiation syndrome. strated a statistically significant improvement in OS in a pre-specified Of the seven patients with newly diagnosed AML who experienced interim analysis for patients on the pembrolizumab plus axitinib arm differentiation syndrome, six (86%) patients recovered. QTc interval (HR 0.53; 95% CI: 0.38, 0.74; p<0.0001). prolongation occurred in patients treated with ivosidenib. The most With deaths reported in 18 percent of patients, the median OS common adverse reactions (≥20%) of any grade in patients with newly was not reached in either arm. The 12-month OS rate was 90 per- diagnosed AML were diarrhea, fatigue, decreased appetite, edema, nau- cent in the pembrolizumab plus axitinib arm and 78 percent for sea, leukocytosis, arthralgia, abdominal pain, dyspnea, myalgia, con- those treated with sunitinib. The trial also demonstrated a PFS im- stipation, differentiation syndrome, dizziness, electrocardiogram QT provement for patients receiving pembrolizumab plus axitinib (HR prolonged, mucositis, and vomiting. 0.69; 95% CI: 0.57, 0.84; p=0.0001). Median PFS was 15.1 and 11.1 months for those receiving pembrolizumab plus axitinib versus suni- Ado-Trastuzumab Emtansine Approved for tinib, respectively. Early Breast Cancer Grade 3 or 4 hepatotoxicity occurred in 20 percent of patients and The FDA approved ado-trastuzumab emtansine for the adjuvant treatment resulted in permanent discontinuation of pembrolizumab or axitinib of patients with HER2-positive early breast cancer who have residual in- in 13 percent of patients. The most common adverse reactions in >20 vasive disease after neoadjuvant taxane and trastuzumab-based treatment. percent of patients who received pembrolizumab plus axitinib were Patients should be selected based on an FDA-approved compan- diarrhea, fatigue/asthenia, hypertension, hypothyroidism, decreased ion diagnostic for ado-trastuzumab emtansine. FDA also approved appetite, hepatotoxicity, palmar-plantar erythrodysesthesia, nausea, both the PATHWAY anti-HER-2/neu (4B5) Rabbit Monoclonal stomatitis/mucosal inflammation, dysphonia, rash, cough, and con- Primary Antibody assay and the INFORM HER2 Dual ISH DNA stipation. The recommended pembrolizumab dose for this indication Probe Cocktail assay as companion diagnostic devices. is 200 mg every 3 weeks with axitinib 5 mg orally twice daily. Approval was based on KATHERINE (NCT01772472), a random- ized, multicenter, open-label trial of 1,486 patients with HER2-positive Supplemental New Drug Application early breast cancer. Breast tumor samples were required to demonstrate Approved for Ivosidenib as AML Treatment HER2 overexpression defined as 3+ IHC or ISH amplification ratio≥ 2.0 The FDA has approved a supplemental New Drug Application (sNDA) determined at a central laboratory using the PATHWAY anti-HER2-/ to update the U.S. Prescribing Information for ivosidenib, an IDH1 neu (4B5) Rabbit Monoclonal Primary Antibody or INFORM HER2 inhibitor, to include adult patients with newly diagnosed acute myeloid Dual ISH DNA Probe Cocktail assays. leukemia (AML) with a susceptible IDH1 mutation as detected by an Patients were required to have had neoadjuvant taxane and trastu- FDA-approved test who are ≥75 years old or who have comorbidities zumab-based therapy with residual invasive tumor in the breast and/ that preclude use of intensive induction chemotherapy. or axillary lymph nodes. Patients received radiotherapy and/or hor- The sNDA was granted Priority Review and accepted under the monal therapy concurrent with study treatment per local guidelines. FDA’s Real-Time Oncology Review pilot program, which aims to make Patients were randomized (1:1) to receive ado-trastuzumab emtan- the review of oncology drugs more efficient by allowing the FDA access sine 3.6 mg/kg intravenously or trastuzumab 6 mg/kg intravenously to clinical trial data before it is formally submitted. Ivosidenib received on day 1 of a 21-day cycle for 14 cycles. initial FDA approval in July 2018 for adult patients with relapsed or The trial’s primary endpoint was invasive disease-free survival refractory (R/R) AML and an IDH1 mutation. (IDFS), defined as the time from the date of randomization to first “The phase I results for ivosidenib demonstrated that this oral, single- occurrence of ipsilateral invasive breast tumor recurrence, ipsilateral agent therapy can induce durable responses in newly diagnosed AML local or regional invasive breast cancer recurrence, distant recurrence, patients with an IDH1 mutation,” said Gail J. Roboz, MD, Professor contralateral invasive breast cancer, or death from any cause. of Medicine, Director of the Leukemia Program, and a member of the After a median follow-up of 40 months, the trial demonstrated Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine a statistically significant improvement in IDFS in patients who re- and NewYork-Presbyterian/Weill Cornell Medical Center. “Many pa- ceived ado-trastuzumab emtansine compared with those who re- tients included in the study had features associated with particularly ceived trastuzumab (HR 0.50; 95% CI: 0.39, 0.64; p<0.0001). Overall aggressive and challenging forms of AML, including secondary disease, survival data were not mature at the time of the IDFS analysis. adverse risk genetics, and prior treatment with hypomethylating agents.” The most common adverse reactions (≥25%) with ado-trastuzumab The efficacy of ivosidenib was evaluated in an open-label, single- emtansine were fatigue, nausea, increased transaminases, musculoskel- arm, multicenter clinical trial (Study AG120-C-001, NCT02074839) etal pain, hemorrhage, thrombocytopenia, headache, peripheral neu- that included 28 adult patients with newly diagnosed AML with an ropathy, and arthralgia. IDH1 mutation who were assigned to receive a 500 mg daily dose. The The recommended ado-trastuzumab emtansine dose is 3.6 mg/kg cohort included patients who were age 75 or older or had comorbidities given as an IV infusion every 3 weeks (21-day cycle) for a total of 14 that precluded the use of intensive induction chemotherapy (baseline cycles for patients with early breast cancer, unless there is disease recur- ECOG performance status of ≥2, severe cardiac or pulmonary disease, rence or unacceptable toxicity. OT 14 Oncology Times June 5, 2019.
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