Pembrolizumab Plus Axitinib Approved for Advanced Renal Cell Carcinoma
The FDA approved pembrolizumab plus axitinib for the first-line treatment of patients with advanced renal cell carcinoma (RCC). This decision was based on KEYNOTE-426, a randomized, multicenter, open-label trial conducted in 861 patients who had not received systemic therapy for advanced RCC. Patients were enrolled regardless of PD-L1 tumor expression status and were randomly allocated to receive either pembrolizumab 200 mg intravenously every 3 weeks in combination with axitinib 5 mg orally twice daily, or sunitinib 50 mg orally once daily for 4 weeks and then off treatment for 2 weeks. Treatment continued until confirmed disease progression or unacceptable toxicity. Pembrolizumab was received for a maximum of 24 months.
The main efficacy measures were overall survival (OS) and progression-free survival (PFS), assessed by RECIST 1.1. The trial demonstrated a statistically significant improvement in OS in a pre-specified interim analysis for patients on the pembrolizumab plus axitinib arm (HR 0.53; 95% CI: 0.38, 0.74; p<0.0001).
With deaths reported in 18 percent of patients, the median OS was not reached in either arm. The 12-month OS rate was 90 percent in the pembrolizumab plus axitinib arm and 78 percent for those treated with sunitinib. The trial also demonstrated a PFS improvement for patients receiving pembrolizumab plus axitinib (HR 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 sunitinib, respectively.
Grade 3 or 4 hepatotoxicity occurred in 20 percent of patients and resulted in permanent discontinuation of pembrolizumab or axitinib in 13 percent of patients. The most common adverse reactions in >20 percent of patients who received pembrolizumab plus axitinib were diarrhea, fatigue/asthenia, hypertension, hypothyroidism, decreased appetite, hepatotoxicity, palmar-plantar erythrodysesthesia, nausea, stomatitis/mucosal inflammation, dysphonia, rash, cough, and constipation. The recommended pembrolizumab dose for this indication is 200 mg every 3 weeks with axitinib 5 mg orally twice daily.
Supplemental New Drug Application Approved for Ivosidenib as AML Treatment
The FDA has approved a supplemental New Drug Application (sNDA) to update the U.S. Prescribing Information for ivosidenib, an IDH1 inhibitor, to include adult patients with newly diagnosed acute myeloid leukemia (AML) with a susceptible IDH1 mutation as detected by an FDA-approved test who are >=75 years old or who have comorbidities that preclude use of intensive induction chemotherapy.
The sNDA was granted Priority Review and accepted under the FDA's Real-Time Oncology Review pilot program, which aims to make the review of oncology drugs more efficient by allowing the FDA access to clinical trial data before it is formally submitted. Ivosidenib received initial FDA approval in July 2018 for adult patients with relapsed or refractory (R/R) AML and an IDH1 mutation.
"The phase I results for ivosidenib demonstrated that this oral, single-agent therapy can induce durable responses in newly diagnosed AML patients with an IDH1 mutation," said Gail J. Roboz, MD, Professor of Medicine, Director of the Leukemia Program, and a member of the Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine and NewYork-Presbyterian/Weill Cornell Medical Center. "Many patients included in the study had features associated with particularly aggressive and challenging forms of AML, including secondary disease, adverse risk genetics, and prior treatment with hypomethylating agents."
The efficacy of ivosidenib was evaluated in an open-label, single-arm, multicenter clinical trial (Study AG120-C-001, NCT02074839) that included 28 adult patients with newly diagnosed AML with an IDH1 mutation who were assigned to receive a 500 mg daily dose. The cohort included patients who were age 75 or older or had comorbidities that precluded the use of intensive induction chemotherapy (baseline ECOG performance status of >=2, severe cardiac or pulmonary disease, hepatic impairment with bilirubin >1.5 times the upper limit of normal, or creatinine clearance <45 mL/min).
Patients had a median age of 77 years (range, 64-87) and 68 percent had AML with myelodysplasia-related changes. The primary endpoint is the combined complete remission (CR) and complete remission with partial hematologic improvement (CRh) rate. CRh is defined as <5 percent of blasts in the bone marrow, no evidence of disease, and partial recovery of peripheral blood counts (platelets >50,000/[mu]l and ANC >500/[mu]l).
The safety profile of single-agent ivosidenib was evaluated in 28 patients with newly diagnosed AML with an IDH1 mutation treated with a dose of 500 mg daily. The median duration of exposure to ivosidenib was 4.3 months (range, 0.3-40.9 months). In the clinical trial, 25 percent of patients (7 of 28) treated with ivosidenib experienced differentiation syndrome.
Of the seven patients with newly diagnosed AML who experienced differentiation syndrome, six (86%) patients recovered. QTc interval prolongation occurred in patients treated with ivosidenib. The most common adverse reactions (>=20%) of any grade in patients with newly diagnosed AML were diarrhea, fatigue, decreased appetite, edema, nausea, leukocytosis, arthralgia, abdominal pain, dyspnea, myalgia, constipation, differentiation syndrome, dizziness, electrocardiogram QT prolonged, mucositis, and vomiting.
Ado-Trastuzumab Emtansine Approved for Early Breast Cancer
The FDA approved ado-trastuzumab emtansine for the adjuvant treatment of patients with HER2-positive early breast cancer who have residual invasive disease after neoadjuvant taxane and trastuzumab-based treatment.
Patients should be selected based on an FDA-approved companion diagnostic for ado-trastuzumab emtansine. FDA also approved both the PATHWAY anti-HER-2/neu (4B5) Rabbit Monoclonal Primary Antibody assay and the INFORM HER2 Dual ISH DNA Probe Cocktail assay as companion diagnostic devices.
Approval was based on KATHERINE (NCT01772472), a randomized, multicenter, open-label trial of 1,486 patients with HER2-positive early breast cancer. Breast tumor samples were required to demonstrate HER2 overexpression defined as 3+ IHC or ISH amplification ratio >=2.0 determined at a central laboratory using the PATHWAY anti-HER2-/neu (4B5) Rabbit Monoclonal Primary Antibody or INFORM HER2 Dual ISH DNA Probe Cocktail assays.
Patients were required to have had neoadjuvant taxane and trastuzumab-based therapy with residual invasive tumor in the breast and/or axillary lymph nodes. Patients received radiotherapy and/or hormonal therapy concurrent with study treatment per local guidelines. Patients were randomized (1:1) to receive ado-trastuzumab emtansine 3.6 mg/kg intravenously or trastuzumab 6 mg/kg intravenously on day 1 of a 21-day cycle for 14 cycles.
The trial's primary endpoint was invasive disease-free survival (IDFS), defined as the time from the date of randomization to first occurrence of ipsilateral invasive breast tumor recurrence, ipsilateral local or regional invasive breast cancer recurrence, distant recurrence, contralateral invasive breast cancer, or death from any cause.
After a median follow-up of 40 months, the trial demonstrated a statistically significant improvement in IDFS in patients who received ado-trastuzumab emtansine compared with those who received trastuzumab (HR 0.50; 95% CI: 0.39, 0.64; p<0.0001). Overall survival data were not mature at the time of the IDFS analysis.
The most common adverse reactions (>=25%) with ado-trastuzumab emtansine were fatigue, nausea, increased transaminases, musculoskeletal pain, hemorrhage, thrombocytopenia, headache, peripheral neuropathy, and arthralgia.
The recommended ado-trastuzumab emtansine dose is 3.6 mg/kg given as an IV infusion every 3 weeks (21-day cycle) for a total of 14 cycles for patients with early breast cancer, unless there is disease recurrence or unacceptable toxicity.