FDA Pipeline: Priority Reviews in Solid Tumors and Lymphoma; Plus an sNDA in Acute Myeloid Leukemia
Over the past week, the U.S. Food and Drug Administration (FDA) granted multiple Priority Reviews and accepted a supplemental new drug application:
Priority Review for Entrectinib in NTRK Fusion–Positive Solid Tumors and Metastatic, ROS1-Positive NSCLC
This week, the FDA accepted new drug applications (NDAs) and granted Priority Review for entrectinib in the treatment of adult and pediatric patients with neurotrophic tropomyosin receptor kinase (NTRK) fusion–positive, locally advanced or metastatic solid tumors whose disease has either progressed following prior therapies or as initial therapy when there are no acceptable standard therapies. Another NDA, also granted Priority Review, was accepted for entrectinib in the treatment of patients with metastatic, ROS1-positive non–small cell lung cancer (NSCLC).
Entrectinib is a selective tyrosine kinase inhibitor designed to inhibit the kinase activity of the TRK A/B/C and ROS1 proteins, whose activating fusions drive proliferation in certain types of cancer. The drug was granted Breakthrough Therapy designation by the FDA in May 2017 for the treatment of NTRK fusion–positive, locally advanced or metastatic solid tumors in adult and pediatric patients who have either had disease progression following prior therapies or have no acceptable standard therapies.
These NDAs are based on results from the integrated analysis of the phase II STARTRK-2, phase I STARTRK-1 and phase I ALKA-372-001 trials, and data from the phase I/Ib STARTRK-NG study. The FDA is expected to make a decision on approval by August 18, 2019.
The integrated analysis included data from 53 people with ROS1-activating gene fusions and 54 people with locally advanced or metastatic NTRK fusion–positive solid tumors (10 tumor types, > 19 histopathologies) from the STARTRK-2, STARTRK-1, and ALKA-372-001 trials. In addition, data from the STARTRK-NG study in pediatric patients were also included in the NDAs. The studies enrolled people across 15 countries and more than 150 clinical trial sites. Cancers evaluated in the studies to date included breast, colorectal, gynecologic, neuroendocrine, non–small cell lung, salivary gland, pancreatic, and thyroid cancers, as well as cholangiocarcinoma and sarcoma.
- STARTRK-2 is a phase II, global, multicenter, open-label basket study in people with solid tumors that harbor an NTRK1/2/3, ROS1, or ALK-positive gene fusion.
- STARTRK-1 is a phase I, multicenter, open-label dose-escalation study of a daily continuous dosing schedule in people with solid tumors with NTRK1/2/3, ROS1, or ALK gene fusions in the United States and South Korea.
- ALKA-372-001 is a phase I, multicenter, open-label dose escalation study of an intermittent and continuous entrectinib dosing schedule in people with advanced or metastatic solid tumors with TRKA/B/C, ROS1, or ALK gene fusions in Italy.
- STARTRK-NG is a phase I/Ib dose escalation and expansion study evaluating the safety and efficacy of entrectinib in children and adolescent patients with no curative first-line treatment option, recurrent or refractory extracranial solid tumors or primary central nervous system (CNS) tumors, with or without TRK, ROS1, or ALK fusions.
Results from the integrated analysis showed an objective response rate of 57.4% in patients treated with entrectinib with NTRK fusion–positive solid tumors. Objective responses to entrectinib were seen across 10 different solid tumor types (median duration of response = 10.4 months), including in people with and without CNS metastases at baseline. In these studies, entrectinib showed an intracranial response rate of 54.5%, with more than a quarter of these people having a complete response.
Entrectinib shrank tumors in 77.4% of people with locally advanced or metastatic ROS1-positive NSCLC. In addition, entrectinib demonstrated a durable response of more than 2 years (median duration of response = 24.6 months). The drug was shown to shrink intracranial tumors in more than half of people with CNS metastases at baseline.
The safety profile of entrectinib was consistent with that seen in previous analyses. The most commonly reported adverse reactions included fatigue, constipation, dysgeusia, edema, dizziness, diarrhea, nausea, dysesthesia, dyspnea, pain, anemia, cognitive disorders, weight increased, vomiting, cough, blood creatinine increase, arthralgia, pyrexia, and myalgia.
Priority Review for Polatuzumab Vedotin in Previously Treated DLBCL
The FDA also accepted a biologics license application (BLA) and granted Priority Review for polatuzumab vedotin in combination with bendamustine plus rituximab for the treatment of people with relapsed or refractory diffuse large B-cell lymphoma (DLBCL). Polatuzumab vedotin is a first-in-class anti-CD79b antibody-drug conjugate. The FDA is expected to make a decision on approval by August 19, 2019.
The BLA is based on results of the GO29365 study, which showed that polatuzumab vedotin plus bendamustine and rituximab improved median overall survival compared to bendamustine and rituximab alone (12.4 vs. 4.7 months) in patients with R/R DLBCL not eligible for a hematopoietic stem cell transplant. The study also showed that 40% of people treated with polatuzumab vedotin plus bendamustine and rituximab achieved a complete response, compared to only 18% of people treated with bendamustine and rituximab alone.
Polatuzumab vedotin plus bendamustine and rituximab increased median progression-free survival and led to a 66% reduction in risk of disease worsening or death compared to bendamustine and rituximab alone. Patients treated with polatuzumab vedotin plus bendamustine and rituximab showed a longer time between first response to treatment and disease worsening than those receiving bendamustine and rituximab alone. Moreover, the 3-drug combination produced a median overall survival of over 1 year compared to the bendamustine-and-rituximab arm (12.4 vs. 4.7 months) in patients with relapsed or refractory DLBCL not eligible for a hematopoietic stem cell transplant.
Polatuzumab vedotin was also granted Breakthrough Therapy designation by the FDA in 2017.
Priority Review for Pembrolizumab Monotherapy for Third-Line Treatment of Patients With Advanced Small Cell Lung Cancer
The FDA accepted and granted Priority Review to a new supplemental Biologics License Application (sBLA) for pembrolizumab monotherapy for the treatment of patients with advanced small cell lung cancer (SCLC) whose disease has progressed after two or more lines of prior therapy. This sBLA, which is seeking accelerated approval for this new indication, is based on data from the SCLC cohorts of the phase II KEYNOTE-158 and phase Ib KEYNOTE-028 trials. The FDA has set a target action date of June 17, 2019.
sNDA for Ivosidenib in Newly Diagnosed IDH1-Mutated AML Not Eligible for Standard Therapy
Lastly, the FDA accepted a supplemental new drug application (sNDA) for ivosidenib for the treatment of patients with newly diagnosed acute myeloid leukemia (AML) with an isocitrate dehydrogenase 1 (IDH1) mutation who are not eligible for standard therapy.
The sNDA was granted Priority Review and has been given a target action date of June 21, 2019. In addition, the FDA accepted the ivosidenib sNDA under its 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 the information is formally submitted to the agency.
Ivosidenib is a first-in-class, oral, targeted inhibitor of mutant IDH1. The sNDA submission is based on results from the untreated patients with AML from the phase I dose-escalation and expansion study of ivosidenib in patients with newly diagnosed AML ineligible for standard treatment.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
