FDA Approves Ivosidenib for Relapsed/Refractory Myelodysplastic Syndromes
The Food and Drug Administration (FDA) approved ivosidenib for adult patients with relapsed or refractory myelodysplastic syndromes (MDS) with a susceptible isocitrate dehydrogenase-1 (IDH1) mutation, as detected by an FDA-approved test. The FDA also approved the Abbott RealTime IDH1 Assay as a companion diagnostic device to select patients for ivosidenib.
Approval was based on trial AG120-C-001 (NCT02074839), an open-label, single-arm, multicenter trial of 18 adult patients with relapsed or refractory MDS with an IDH1 mutation. These mutations were detected in peripheral blood or bone marrow by a local or central diagnostic test and confirmed retrospectively by an IDH1 assay.
Ivosidenib was administered orally at a starting dose of 500 mg daily continuously for 28-day cycles until disease progression, unacceptable toxicity, or hematopoietic stem cell transplantation. The median treatment duration was 9.3 months. One patient underwent a stem cell transplantation following ivosidenib.
Efficacy was established by the rate of complete remission (CR) or partial remission (PR) (2006 International Working Group response for MDS), CR+PR durations, and conversion rate from transfusion dependence to independence. All observed responses were CRs. The CR rate was 38.9 percent (95% CI: 17.3, 64.3). The median time-to-CR was 1.9 months (range: 1.0-5.6 months), and the median CR duration was not estimable (range: 1.9, 80.8+ months). Among nine patients dependent on red blood cell (RBC) and/or platelet transfusions at baseline, six (67%) became RBC and platelet transfusion independent during any 56-day post-baseline period. Of the nine patients independent of both RBC and platelet transfusions at baseline, seven (78%) remained transfusion independent during any 56-day post-baseline period.
The most common adverse reactions were similar to common ones observed with ivosidenib monotherapy for AML. These include GI toxicities (diarrhea, constipation, mucositis, and nausea), arthralgia, fatigue, cough, myalgia, and rash. Ivosidenib may also cause QTc prolongation. The prescribing information contains a Boxed Warning alerting health care professionals and patients about the risk of differentiation syndrome, which may be life-threatening or fatal.
FDA Expands Pediatric Indication for Entrectinib & New Pellet Formulation
Entrectinib was granted accelerated approval for pediatric patients older than 1 month with solid tumors that have a neurotrophic tyrosine receptor kinase (NTRK) gene fusion without a known acquired resistance mutation, are metastatic or where surgical resection is likely to result in severe morbidity, and have progressed following treatment or have no satisfactory standard therapy. In August 2019, the FDA granted accelerated approval to entrectinib for pediatric patients 12 years of age and older for this indication. The FDA also approved a new oral pellet formulation for entrectinib, and the prescribing information now includes instructions for making an oral suspension from the capsules.
Efficacy in NTRK-positive tumors was investigated in 33 pediatric patients who received entrectinib based on body surface area (20 mg to 600 mg orally or via enteral feeding tube once daily) in one of two multicenter, single-arm clinical trials: STARTRK-NG (NCT02650401) or TAPISTRY (NCT04589845). Identification of positive NTRK gene fusion status was determined in local laboratories or a central laboratory using nucleic acid-based tests prior to enrollment.
The major efficacy outcome measure was overall response rate (ORR), as assessed by Blinded Independent Central Review according to RECIST v1.1 for extracranial tumors and Response Assessment in Neuro-Oncology for primary central nervous system tumors.
An additional efficacy outcome measure was duration of response (DOR). Among the 33 pediatric patients, the ORR was 70 percent (95% CI: 51, 84) and median DOR was 25.4 months (95% CI: 14.3, not evaluable). The most common cancers were primary central nervous system tumors and infantile fibrosarcoma.
In the pooled safety population of pediatric patients receiving entrectinib (n=76), the most common (>= 20%) adverse reactions were pyrexia, constipation, increased weight, vomiting, diarrhea, nausea, cough, fatigue, pain in extremity, skeletal fracture, decreased appetite, headache, abdominal pain, urinary tract infection, upper respiratory tract infection, and nasal congestion.
The recommended dose for pediatric patients >1 month to <=6 months of age is 250 mg/m2 orally once daily. The recommended dose for pediatric patients >6 months is based on body surface area (up to a maximum of 600 mg once daily). See the prescribing information for specific dosing information.
Neoadjuvant/Adjuvant Pembrolizumab Approved for Resectable Non-Small Cell Lung Cancer
The FDA approved pembrolizumab with platinum-containing chemotherapy as neoadjuvant treatment and with continuation of single-agent pembrolizumab as post-surgical adjuvant treatment for resectable (tumors >=4 cm or node-positive) non-small cell lung cancer (NSCLC).
Efficacy was evaluated in KEYNOTE-671 (NCT03425643), a multicenter, randomized, double-blind, placebo-controlled trial in 797 patients with previously untreated and resectable Stage II, IIIA, or IIIB (N2) NSCLC by AJCC 8th edition. Patients were randomized (1:1) to either pembrolizumab or placebo with platinum-based chemotherapy every 3 weeks for 4 cycles (neoadjuvant treatment) followed by either continued single-agent pembrolizumab or placebo every 3 weeks for up to 13 cycles (adjuvant treatment).
The major efficacy outcome measures were overall survival (OS) and investigator-assessed event-free survival (EFS). Median OS was not reached in the pembrolizumab arm (95% CI: not estimable [NE], NE) and 52.4 months for those receiving placebo (95% CI: 45.7, NE) (HR: 0.72; [95% CI: 0.56, 0.93]; p=0.0103). Median EFS was not reached in the pembrolizumab arm (95% CI: 34.1 months, NE) and 17 months in the placebo arm (95% CI: 14.3, 22.0) (HR: 0.58; [95% CI: 0.46, 0.72]; p=<0.0001).
In KEYNOTE-671, the most common adverse reactions reported in >=20 percent of patients were nausea, fatigue, neutropenia, anemia, constipation, decreased appetite, decreased white blood cell count, musculoskeletal pain, rash, cough, vomiting, diarrhea, and dyspnea. Of the patients who received neoadjuvant treatment in the pembrolizumab arm, 6 percent were unable to receive surgery due to adverse reactions compared with 4.3 percent in the placebo arm. In addition, 3.1 percent of patients who received neoadjuvant treatment and surgery in the pembrolizumab arm had delays in surgery due to adverse reactions compared with 2.5 percent in the placebo arm.
The recommended pembrolizumab dose is 200 mg every 3 weeks or 400 mg every 6 weeks. Administer pembrolizumab prior to chemotherapy when given on the same day.