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FDA Pipeline: Label Update for Durvalumab in NSCLC; Applications Accepted in Epithelioid Sarcoma, AML

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Recently, the U.S. Food and Drug Administration (FDA) approved the inclusion of overall survival from the PACIFIC trial in the U.S. prescribing information for durvalumab and accepted applications for a new drug in the treatment of epithelioid sarcoma and two orphan drugs in the treatment of acute myeloid leukemia (AML).

Durvalumab U.S. Label Updated With Overall Survival Data in Unresectable Stage III NSCLC

The FDA approved the inclusion of overall survival (OS) data from the phase III PACIFIC trial in an update to the durvalumab U.S. prescribing information for patients with unresectable stage III non–small cell lung cancer (NSCLC) whose disease has not progressed following concurrent platinum-based chemotherapy and radiation therapy.

The label update was based on results from the primary OS analysis published by Antonia et al in The New England Journal of Medicine, which demonstrated an OS benefit for treatment with durvalumab vs placebo in this setting, reducing the risk of death by 32% (hazard ratio [HR] = 0.68; 95% confidence interval [CI] = 0.53–0.87, P = .0025).

In a follow-up 3-year post-hoc OS analysis presented by Gray et al at the 2019 ASCO Annual Meeting (Abstract 8526), results for durvalumab remained consistent with the 2-year data =, showing a 31% reduction in the risk of death vs placebo (HR = 0.69; 95% CI = 0.55–0.86) and showing that 57% (95% CI = 52.3–61.4) of patients on durvalumab were still alive vs 44% (95% CI = 37.0–49.9) of patients on placebo.

Durvalumab is approved for the treatment of unresectable stage III NSCLC in more than 45 countries, including the U.S., European Union, and Japan, based on data from the PACIFIC trial. The National Comprehensive Cancer Network® (NCCN®) Clinical Practice Guidelines in Oncology (NCCN Guidelines®) recommend durvalumab as the only category 1 post–chemotherapy and radiation therapy consolidation immunotherapy for patients with unresectable stage III NSCLC.

New Drug Application Acceptance and Priority Review for Tazemetostat in Epithelioid Sarcoma

The FDA accepted the filing of a new drug application for accelerated approval of tazemetostat in metastatic or locally advanced epithelioid sarcoma not eligible for curative surgery. The FDA granted Priority Review for the new drug application and has set a target action date of January 23, 2020.

Tazemetostat is an oral, potent, first-in-class EZH2 inhibitor.

The submission is based primarily on data from the 62-patient epithelioid sarcoma cohort from an ongoing phase II study of tazemetostat. Findings from the trial reported by Stacchiotti et al at the 2019 ASCO Annual Meeting (Abstract 11003), showed that treatment with tazemetostat resulted in clinically meaningful and durable responses and was generally well-tolerated.

A 1:1 randomized, controlled clinical trial in the front-line treatment setting comparing tazemetostat in combination with doxorubicin vs placebo plus doxorubicin in approximately 150 patients is planned. The primary efficacy endpoint will be progression-free survival, and secondary efficacy endpoints will include overall survival, disease control rate, overall response rate, and duration of response. The confirmatory study will include a safety run-in that is expected to begin in the second half of 2019.

Orphan Drug Designation for KO-539 in AML

The FDA has granted Orphan Drug designation to the menin-mixed lineage leukemia (menin-MLL) inhibitor KO-539 for the treatment of AML.

KO-539 is a potent and selective small molecule inhibitor of the menin-MLL protein-protein interaction. MLL-rearranged leukemias are characterized by chromosomal translocations of the MLL gene that are primarily found in patients with AML and acute lymphoblastic leukemia (ALL). These translocations form oncogenes encoding MLL fusion proteins, which play a causative role in the onset, development, and progression of MLL-rearranged leukemias. The target genes of the MLL fusion proteins are also found to be overexpressed in a broader subset of AMLs characterized by oncogenic driver mutations in genes such as NPM1. These mutations also appear to be dependent on the interaction between menin and MLL, suggesting that the menin-MLL complex is a central node in epigenetic dysregulation driven by distinct oncogenic driver mutations known to be important in AML and other hematologic malignancies. In preclinical studies, KO-539 has demonstrated potent and selective inhibition of the proliferation of MLL-rearranged leukemia cell lines. There is also preclinical data showing robust and durable efficacy in multiple in vivo models of AML characterized by MLL rearrangements or oncogenic driver mutations in genes such as NPM1.

Orphan Drug Designation for MB-102 in AML

The FDA granted Orphan Drug designation to MB-102 (CD123 CAR T) for the treatment of acute myeloid leukemia (AML). The FDA also previously granted Orphan Drug designation to MB-102 (CD123 CAR T) for the treatment of blastic plasmacytoid dendritic cell neoplasm (BPDCN).

MB-102 is a chimeric antigen receptor (CAR) T-cell therapy that is produced by engineering patient T cells to recognize and eliminate CD123-expressing tumors. CD123 is widely expressed on bone marrow cells of patients with myelodysplastic syndromes, as well as in hematologic malignancies including AML, B-cell acute lymphoblastic leukemia, hairy cell leukemia, BPDCN, chronic myeloid leukemia, and Hodgkin lymphoma.

In a first-in-human clinical trial at City of Hope, MB-102 has demonstrated complete responses at low doses in AML and BPDCN without dose-limiting toxicities. Dose escalation continues at City of Hope in both indications.

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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