This week, the U.S. Food and Drug Administration (FDA) granted Priority Review to agents in lymphoma, lung cancer, gastrointestinal stromal tumors, and breast cancer, and granted Fast Track designation to a first-in-class radioenhancer hafnium oxide nanoparticle in head and neck cancer.
Priority Review for Lisocabtagene Maraleucel in Adult Patients With Relapsed or Refractory Large B-Cell Lymphoma
The FDA accepted for Priority Review a biologics license application for lisocabtagene maraleucel, an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell immunotherapy with a defined composition of purified CD8-positive and CD4-positive CAR T cells, for the treatment of adult patients with relapsed or refractory large B-cell lymphoma after at least two prior therapies. The FDA has set a Prescription Drug User Fee Act (PDUFA) goal date of August 17, 2020.
The biologics license application is based on the safety and efficacy results from the TRANSCEND-NHL-001 trial, which is evaluating lisocabtagene maraleucel in 268 patients with relapsed or refractory large B-cell lymphoma, including diffuse large B-cell lymphoma (DLBCL), high-grade lymphoma, primary mediastinal B-cell lymphoma, and grade 3B follicular lymphoma. TRANSCEND-NHL-001 is the largest study of CD19-directed CAR T cells to support a biologics license application to date.
Lisocabtagene maraleucel was previously granted Breakthrough Therapy designation and regenerative medicine advanced therapy designation by the FDA for relapsed or refractory aggressive large B-cell non-Hodgkin lymphoma, including DLBCL, not otherwise specified (de novo or transformed from indolent lymphoma), primary mediastinal B-cell lymphoma, or grade 3B follicular lymphoma. It was also granted Priority Medicines scheme by the European Medicines Agency (EMA) for relapsed or refractory diffuse large B-cell lymphoma.
Priority Review for KTE-X19 in Relapsed or Refractory Mantle Cell Lymphoma
The FDA accepted a biologics license application and granted Priority Review designation to KTE-X19, an investigational anti-CD19 CAR T-cell therapy, for the treatment of adult patients with relapsed or refractory mantle cell lymphoma. The PDUFA target action date is August 10, 2020.
The biologics license application is supported by data from the single-arm, open-label, phase II ZUMA-2 trial, which is still ongoing. The trial showed that 93% of patients responded to a single infusion of KTE-X19, including 67% of patients who achieved a complete response. In the safety analysis, grade 3 or higher cytokine release syndrome and neurologic events were seen in 15% and 31% of patients, respectively. No grade 5 cytokine release syndrome or neurologic events occurred.
The EMA recently validated the marketing authorization application for KTE-X19 in the European Union. KTE-X19 has been granted Breakthrough Therapy designation by the FDA and priority medicines designation by the EMA for relapsed or refractory mantle cell lymphoma.
Priority Review for Tazemetostat in Follicular Lymphoma
The FDA accepted a new drug application for the accelerated approval of tazemetostat for patients with relapsed or refractory follicular lymphoma who have received at least two prior lines of systemic therapy. The FDA granted the application Priority Review and has designated the application as a supplemental new drug application with a PDUFA target action date of June 18, 2020.
Tazemetostat is a methyltransferase inhibitor. The submission is based primarily on updated phase II efficacy and safety data for tazemetostat in this patient population, which were presented by Morschhauser et al at the 2019 American Society of Hematology (ASH) Annual Meeting & Exposition. The data demonstrated that treatment with tazemetostat resulted in clinical benefit and was shown to be generally well tolerated in patients with follicular lymphoma and EZH2 activating mutations (n = 45) and patients with follicular lymphoma and wild-type EZH2 (n = 54).
To support a full approval of tazemetostat for follicular lymphoma, a single, global, randomized, adaptive trial is being conducted to evaluate the combination of tazemetostat with lenalidomide/rituximab in the second-line or later treatment setting. The trial is expected to enroll approximately 500 patients with follicular lymphoma, who will be stratified based on their EZH2 mutation status.
Priority Review for Capmatinib in METex14-Mutated NSCLC
The FDA accepted and granted Priority Review to a new drug application for capmatinib. Capmatinib is a MET inhibitor being evaluated as a treatment for first-line and previously treated patients with locally advanced or metastatic MET exon 14 skipping (METex14)-mutated non–small cell lung cancer (NSCLC). There are currently no approved therapies that specifically target METex14-mutated advanced NSCLC. METex14 mutations occur in 3%–4% of newly diagnosed advanced NSCLC.
Capmatinib was previously granted Breakthrough Therapy designation. Capmatinib is an investigational, oral, potent, and selective MET inhibitor. The NDA submission for capmatinib is supported by results from the GEOMETRY mono-1 phase II study, which demonstrated an overall response rate of 67.9% (95% confidence interval [CI] = 47.6–84.1) and 40.6% (95% CI = 28.9%–53.1%) among treatment-naive and previously treated patients. The study also demonstrated that capmatinib provided durable responses among all patients: median duration of response was 11.14 months in treatment-naive patients and 9.72 months in previously treated patients.
The most common treatment-related adverse events (≥ 10% all grades) across all cohorts (n = 334), were peripheral edema (42%), nausea (33%), creatinine increase (20%), vomiting (19%), fatigue (14%), decreased appetite (13%), and diarrhea (11%). The majority of adverse events were grade 1 and 2.
Companion diagnostics for capmatinib are in development for both tumor tissue and liquid biopsies to be included on FoundationOne CDx and the forthcoming version of Foundation Medicine’s liquid biopsy platform, which is currently under review with the FDA.
Priority Review for Ripretinib in Advanced Gastrointestinal Stromal Tumors
The FDA accepted for Priority Review a new drug application for ripretinib, an investigational broad-spectrum KIT and PDGFRα inhibitor, for the treatment of patients with advanced gastrointestinal stromal tumors (GIST). The FDA assigned a PDUFA target action date of August 13, 2020.
The FDA previously granted Breakthrough Therapy designation for ripretinib for the treatment of patients with advanced GIST who have received prior treatment with imatinib, sunitinib, and regorafenib.
The submission is supported by positive results from the phase III INVICTUS study of ripretinib in advanced GIST. INVICTUS is a randomized, double-blind, placebo-controlled, international, multicenter study designed to evaluate the efficacy and safety of ripretinib compared to placebo in 129 patients with advanced GIST whose previous therapies have included at least imatinib, sunitinib, and regorafenib. The study achieved its primary endpoint of improved progression-free survival compared to placebo in patients with fourth-line and fourth-line plus GIST, as determined by blinded independent central radiologic review using modified Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1.
Priority Review for in Locally Advanced or Metastatic HER2-Positive Breast Cancer
The FDA accepted for Priority Review a new drug application for the investigational drug tucatinib. The new drug application requests FDA approval of tucatinib in combination with trastuzumab and capecitabine for treatment of patients with locally advanced unresectable or metastatic HER2-positive breast cancer, including patients with brain metastases, who have received at least three prior HER2-directed agents separately or in combination, in the neoadjuvant, adjuvant, or metastatic setting. The FDA set a PDUFA target action date of August 20, 2020.
Tucatinib is an oral, small molecule tyrosine kinase inhibitor that is highly selective for HER2.
The filing is based on the results of HER2CLIMB, a randomized pivotal trial comparing tucatinib added to trastuzumab and capecitabine vs trastuzumab and capecitabine alone. HER2CLIMB trial results were recently presented at the 2019 San Antonio Breast Cancer Symposium and published in The New England Journal of Medicine.
Tucatinib was recently granted Breakthrough Therapy designation by the FDA in combination with trastuzumab and capecitabine for the treatment of patients with locally advanced unresectable or metastatic HER2-positive breast cancer, including patients with brain metastases, who have been treated with trastuzumab, pertuzumab, and ado-trastuzumab emtansine (T-DM1). This designation was based on data from the pivotal HER2CLIMB trial.
Fast Track Designation for NBTXR3 in Head and Neck Cancer
The FDA granted Fast Track designation for the investigation of NBTXR3 activated by radiation therapy with or without cetuximab for the treatment of patients with locally advanced head and neck squamous cell cancer who are not eligible for platinum-based chemotherapy.
NBTXR3 is a first-in-class radioenhancer hafnium oxide nanoparticle that is designed to destroy tumors through physical cell death when activated by radiotherapy. NBTXR3 has a high degree of biocompatibility, requires one single administration before the first radiotherapy treatment session, and has the ability to fit into current worldwide radiotherapy radiation therapy standards of care.
