Recently, the U.S. Food and Drug Administration (FDA) granted Priority Review to agents for several kinds of lymphoma, as well as nasopharyngeal cancer; a Breakthrough Therapy designation for a treatment for patients with NTRK-positive advanced solid tumors; and Fast Track designation for combination therapies in platinum-resistant ovarian cancer and advanced melanoma.
Priority Review for Tisagenlecleucel in Relapsed or Refractory Follicular Lymphoma
The FDA and the European Medicines Agency (EMA) have accepted a supplemental biologics license application and type II variation, respectively, for tisagenlecleucel—a CD19-directed genetically modified autologous T-cell immunotherapy—as a treatment for adult patients with relapsed or refractory follicular lymphoma after two prior lines of treatment. The FDA has also granted Priority Review to the supplemental biologics license application for tisagenlecleucel in adult patients with relapsed or refractory follicular lymphoma.
The regulatory submissions are based on positive data from the pivotal phase II ELARA trial, which investigated the efficacy and safety of tisagenlecleucel in adult patients with relapsed or refractory follicular lymphoma. The trial met the primary endpoint, with responses observed in heavily pretreated patients. No patients enrolled in the trial experienced grade 3 or higher cytokine-release syndrome—the most common side effect associated with chimeric antigen receptor T-cell therapy therapy—related to tisagenlecleucel within the first 8 weeks following infusion. Data from the trial were presented earlier this year as an oral presentation during the 2021 ASCO Annual Meeting (Abstract 7508).
ELARA is a phase II, single-arm, multicenter, open-label trial investigating the efficacy and safety of tisagenlecleucel in adult patients with relapsed or refractory follicular lymphoma after at least two prior therapies. This international trial has enrolled patients from over 30 sites in 12 countries worldwide. The primary endpoint is complete response rate based on best response by central review (Lugano 2014 criteria). Patients evaluable for efficacy had measurable disease at infusion and more than 6 months of follow-up from infusion or discontinued early. After infusion, disease assessments were performed every 3 months. Secondary endpoints include overall response rate, duration of response, progression-free survival, overall survival, and safety. Primary analysis data announced at the 2021 ASCO Annual Meeting showed tisagenlecleucel led to responses for the majority of patients treated, with 66% achieving a complete response (95% confidence interval [CI] = 56%–75%). The overall response rate was 86% (95% CI = 78%–92%).
Priority Review for Toripalimab in Nasopharyngeal Carcinoma
The FDA accepted for review the biologics license application for toripalimab in combination with gemcitabine and cisplatin for the first-line treatment for patients with advanced recurrent or metastatic nasopharyngeal carcinoma, and toripalimab monotherapy for the second-line or above treatment of recurrent or metastatic nasopharyngeal carcinoma after platinum-containing chemotherapy. The FDA has granted Priority Review to the toripalimab application and has set a PDUFA action date for April 2022.
Toripalimab is an anti–PD-1 monoclonal antibody developed for its ability to block PD-1 interactions with its ligands, PD-L1 and PD-L2, and for enhanced receptor internalization (endocytosis function). Blocking PD-1 interactions with PD-L1 and PD-L2 is thought to recharge the immune system’s ability to attack and kill tumor cells.
The application was supported by the results from the clinical studies POLARIS-02 and JUPITER-02. The POLARIS-02 study is a multicenter, open-label, pivotal phase II trial, the results of which were published by Wang et al in the Journal of Clinical Oncology. The JUPITER-02 study is a randomized, double blind, placebo-controlled, international multi-center phase III clinical trial, the results of which were recently presented at the 2021 ASCO Annual Meeting (Abstract LBA2) and were published by Mai et al in Nature Medicine.
New Drug Application Accepted for Parsaclisib for Three Types of Relapsed or Refractory Non-Hodgkin Lymphoma
The FDA accepted a new drug application for parsaclisib—an investigational, novel, potent, highly selective, next-generation oral inhibitor of phosphatidylinositol 3-kinase delta (PI3Kδ)—for the treatment of patients with relapsed or refractory follicular lymphoma, marginal zone lymphoma, and mantle cell lymphoma.
Parsaclisib has been granted Priority Review by the FDA for the treatment of adult patients with relapsed or refractory marginal zone lymphoma who have received at least one prior anti–CD20-based regimen and for the treatment of adult patients with mantle cell lymphoma who have received at least one prior therapy. The Prescription Drug User Fee Act (PDUFA) target action date for these indications is April 30, 2022. The new drug application for the use of parsaclisib in adult patients with relapsed or refractory follicular lymphoma who have received at least two prior systemic therapies will have a standard review and a PDUFA target action date of August 30, 2022.
The submission is based on data from several phase II studies (CITADEL-203, -204, and -205) evaluating parsaclisib as a treatment for relapsed or refractory non-Hodgkin lymphomas. Parsaclisib was generally well tolerated in all studies, with a manageable safety profile.
Confirmatory phase III studies are in preparation for parsaclisib in patients with mantle cell lymphoma (CITADEL-310) and relapsed or refractory follicular lymphoma and marginal zone lymphoma (CITADEL-302).
Breakthrough Therapy Designation for Repotrectinib in Pretreated Patients with NTRK-Positive Advanced Solid Tumors
The FDA granted Breakthrough Therapy designation to repotrectinib—a small (low molecular–weight), macrocyclic tyrosine kinase inhibitor of ROS1, TRK, and ALK—for the treatment of patients with advanced solid tumors that have an NTRK gene fusion whose disease has progressed following treatment with one or two prior TRK tyrosine kinase inhibitors, with or without prior chemotherapy, and have no satisfactory alternative treatments.
Additional clinical data from the TRIDENT-1 study of repotrectinib were presented during the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics (Abstract P224).
Fast Track Designation for Nemvaleukin Alfa in Combination With Pembrolizumab for Platinum-Resistant Ovarian Cancer
The FDA granted Fast Track designation to nemvaleukin alfa (nemvaleukin), a novel, investigational, engineered interleukin-2 (IL-2) variant immunotherapy, in combination with pembrolizumab, an anti–PD-1 antibody, for the treatment of platinum-resistant ovarian cancer.
Nemvaleukin is an investigational, novel, engineered fusion protein comprised of modified IL-2 and the high affinity IL-2 alpha receptor chain, designed to preferentially expand tumor-killing immune cells while avoiding the activation of immunosuppressive cells by selectively binding to the intermediate-affinity IL-2 receptor complex. The selectivity of nemvaleukin is designed to leverage the proven antitumor effects of existing IL-2 therapy while mitigating certain limitations.
A phase III trial, ARTISTRY-7 (ClinicalTrials.gov identifier: NCT05092360) was recently initiated to further study the combination.
Dual Fast Track Designation for UV1 in Advanced Malignant Melanoma
The universal cancer vaccine, UV1, has received Fast Track designation from the FDA for the treatment of unresectable or metastatic melanoma—either in combination with pembrolizumab or ipilimumab. UV1 is currently being evaluated in combination with these checkpoint inhibitors as a first-line treatment for unresectable or metastatic melanoma in a phase II study named INITIUM (ClinicalTrials.gov identifier: NCT04382664).
The Fast Track designation is based on data from two separate phase I trials of UV1 in combination with checkpoint inhibitors, either with pembrolizumab (anti-PD-1) or with ipilimumab (anti–CTLA-4). According to their findings, UV1 in combination with pembrolizumab as first-line treatment in advanced melanoma was shown to be safe, with promising early efficacy data; an objective response rate of 57% was reached, with 30% of patients achieving a complete response. At 24-month follow-up, 80% of patients were alive. In addition, data published by Brunsvig et al in Frontiers in Immunology demonstrated that UV1 in combination with ipilimumab was safe and showed signals of prolonged efficacy in advanced melanoma, with patients treated with the combination achieving an overall response rate of 33% and a 5-year overall survival rate of 50%.
