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FDA Pipeline: Reviews for Agents in Acute Graft-vs-Host Disease, Nasopharyngeal and Ovarian Cancers


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Recently, the U.S. Food and Drug Administration (FDA) granted Priority Review to an agent for the prevention of acute graft-vs-host disease; Breakthrough Therapy designation to an anti–PD-1 monoclonal antibody for the treatment of metastatic nasopharyngeal carcinoma; and Fast Track designation to a folate receptor alpha–targeting antibody-drug conjugate in advanced ovarian cancer.

Priority Review for Abatacept in the Prevention of Acute Graft-vs-Host Disease

The FDA has accepted a supplemental biologics license application for abatacept for the prevention of moderate to severe acute graft-vs-host disease in patients aged 6 years and older receiving unrelated donor hematopoietic stem cell transplantation (HSCT). The FDA granted the application Priority Review and assigned a Prescription Drug User Fee Act goal date of December 23, 2021.

Graft-vs-host disease occurs when the donor T cells infused during stem cell transplant recognize the patient’s healthy cells as foreign and start attacking healthy tissues and organs. To initiate this attack, T cells require activation through a signaling process called costimulation. Between 30% and 70% of transplant recipients develop acute graft-vs-host disease, depending on donor type, transplant technique, and other features. Abatacept, a therapy currently approved to treat various arthritic conditions, binds to and inhibits protein targets involved in costimulation, thus inhibiting T-cell activation.

The application submitted to the FDA is based on results from the phase II ABA2 trial and a registry trial based on real-world evidence. The ABA2 trial assessed the impact of abatacept on the prevention of severe acute graft-vs-host disease when added to a standard graft-vs-host disease prophylactic regimen administered to patients with hematologic malignancies receiving a stem cell transplant from an unrelated HLA-matched or mismatched donor. A mismatch in HLA increases the risk of acute graft-vs-host disease. Results from ABA2 showed that treatment with abatacept resulted in a significant reduction in severe acute graft-vs-host disease and associated morbidity without an increase in disease relapse. The findings of the real-world analysis were consistent with those of ABA2.

“While stem cell transplants are an effective treatment for aggressive leukemias and other hematologic malignancies, patients who receive stem cell transplants from unrelated and human leukocyte antigens (HLA)-mismatched donors are at high risk for developing graft-vs-host disease,” said study lead investigator Leslie Kean, MD, PhD, Director of the Pediatric Stem Cell Transplantation Program at Boston Children's Hospital/Dana-Farber Cancer Institute. “There is a tremendous need to expand the stem cell donor pool by lowering the risk of acute graft-vs-host disease in both adults and children receiving unrelated donor stem cell transplants.”

More About ABA2

The ABA2 study was a multicenter, phase II, investigator-sponsored trial conducted by Dr. Kean. ABA2 had two cohorts: a single arm cohort for patients receiving transplants from mismatched unrelated donors (MMUD; “7/8” cohort), and a randomized, double-blind, placebo-controlled cohort for patients receiving transplants from 8/8 matched unrelated donors (MUD; “8/8” cohort). All subjects received a calcineurin inhibitor, with dosing starting on day 2 and continuing through at least day 100 as tolerated, and methotrexate on days 1, 3, 6, and 11 (transplant day is day 0). Abatacept-treated particpants received 10 mg/kg of the agent on days -1, 5, 14, and 28.

In the ABA2 clinical trial, addition of abatacept to standard-of-care acute graft-vs-host disease prophylaxis of methotrexate and a calcineurin inhbitor resulted in a significantly higher acute graft-vs-host disease–free survival rate compared to registry controls in the single-arm 7/8 HLA-matched cohort, and numerically higher severe acute graft-vs-host disease–free survival rate rate in the double-blind, placebo-controlled 8/8 HLA-matched cohort at 180 days post-transplant.

Breakthrough Therapy Designation for Toripalimab for First-Line Treatment of Nasopharyngeal Carcinoma

The FDA granted Breakthrough Therapy designation to toripalimab in combination with chemotherapy (gemcitabine and cisplatin) for the first-line treatment of recurrent or metastatic nasopharyngeal carcinoma. The FDA had earlier granted Breakthrough Therapy designation for toripalimab monotherapy for patients with recurrent or metastatic nasopharyngeal carcinoma with disease progression on or after platinum-containing chemotherapy.

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).

The Breakthrough Therapy designation is supported by data from the phase III JUPITER-02 clinical trial evaluating toripalimab in combination with chemotherapy for the first-line treatment of nasopharyngeal carcinoma. In this study, toripalimab in combination with chemotherapy demonstrated a statistically significant and clinically meaningful improvement in progression free survival compared to chemotherapy alone (assessed by a blinded independent review committee per Response Evaluation Criteria in Solid Tumors version 1.1). JUPITER-02 also met secondary endpoints of progression-free survival. There was also a longer duration of response, a higher disease control rate, and higher 1- and 2-year survival rates for the toripalimab arm. The safety profile of toripalimab is consistent with that observed in previously reported toripalimab clinical trials and the safety profile of this class of drugs.

The results of JUPITER-02 were recently presented at the 2021 ASCO Annual Meeting (Abstract LBA2) and published by Mai et al in Nature Medicine.

Fast Track Designation for STRO-002 in Advanced Ovarian Cancer

The FDA granted Fast Track designation for STRO-002, a folate receptor alpha (FolRα)-targeting antibody-drug conjugate for the treatment of patients with platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer who have received one to three prior lines of systemic therapy.

STRO-001-GM1 is a phase I trial of STRO-002 for patients with advanced ovarian cancer that have progressed or relapsed after standard-of-care treatments to assess efficacy, safety, and tolerability. The dose-escalation cohort has been completed and the dose-expansion cohort has enrolled patients from sites in the United States and in Spain, with enrollment ongoing. Patients are not preselected for FolRα expression but are required to provide a tissue sample for FolRα analysis prior to study treatment. Patients are randomly assigned 1:1 and treated with STRO-002 at either 4.3 or 5.2 mg/kg every 3 weeks.

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®.
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