FDA Approval Summary: Accelerated Approval of Sacituzumab Govitecan-hziy for Third-line Treatment of Metastatic Triple-negative Breast Cancer.

On April 22, 2020, the FDA granted accelerated approval to sacituzumab govitecan-hziy (TRODELVY; Immunomedics, Inc.) for the treatment of patients with metastatic triple-negative breast cancer (mTNBC) who have received at least two prior therapies for metastatic disease. Approval was based on data from the IMMU-132-01 trial, a single-arm, multicohort, multicenter, phase I/II trial of sacituzumab govitecan. The assessment of efficacy was based on 108 patients with mTNBC who had previously received at least two prior lines of therapy in the metastatic setting and who received sacituzumab govitecan 10 mg/kg i.v. The assessment of safety was based on 408 patients with advanced solid tumors who had received sacituzumab govitecan at doses up to 10 mg/kg i.v. The primary efficacy endpoint was investigator-assessed objective response rate (ORR) and duration of response (DoR) was a key secondary endpoint. The ORR was 33.3% [36/108; 95% confidence interval (CI), 24.6-43.1], and median DoR among responders was 7.7 months (95% CI, 4.9-10.8). The most common adverse reactions occurring in ≥25% of patients were nausea, neutropenia, diarrhea, fatigue, anemia, vomiting, alopecia, constipation, rash, decreased appetite, and abdominal pain. This article summarizes the FDA review process and data supporting the approval of sacituzumab govitecan.

U.S. Food and Drug Administration Approval: Neratinib for the Extended Adjuvant Treatment of Early-Stage HER2-Positive Breast Cancer.

On July 17, 2017, the FDA approved neratinib (NERLYNX; Puma Biotechnology, Inc.) for the extended adjuvant treatment of adult patients with early-stage HER2-overexpressed/amplified breast cancer, to follow adjuvant trastuzumab-based therapy. Approval was based on data from ExteNET, a randomized, double-blind, placebo-controlled multicenter trial. Women with early-stage HER2-positive breast cancer and within 2 years of completing adjuvant trastuzumab were randomized to neratinib (n = 1,420) or placebo (n = 1,420) for 1 year. The primary endpoint was invasive disease-free survival (iDFS), defined as the time between randomization date to first occurrence of invasive recurrence (local/regional, ipsilateral, or contralateral breast cancer), distant recurrence, or death from any cause, with 2 years and 28 days of follow-up. The trial showed a statistically significant treatment effect favoring neratinib with a stratified HR of 0.66 [95% confidence interval (CI), 0.49-0.90, P = 0.008]. The estimated iDFS rate at 2 years was 94.2% (95% CI, 92.6%-95.4%) in patients treated with neratinib versus 91.9% (95% CI, 90.2%-93.2%) in those receiving placebo. Diarrhea was the most common adverse event (AE), with a 40% incidence of grade 3 or 4 diarrhea, and represents the most common AE leading to treatment discontinuation. Other frequent AEs (>10% incidence) were nausea, abdominal pain, fatigue, vomiting, rash, stomatitis, decreased appetite, and muscle spasms. Other than diarrhea, neratinib is associated with a low incidence of severe AEs; toxicities are generally reversible and manageable with dose interruptions, dose reductions, and/or standard medical care. This article summarizes FDA decision-making and data supporting the neratinib approval. Clin Cancer Res; 24(15); 3486-91. ©2018 AACRSee related commentary by Unni et al., p. 3483.

The ability of the aryl hydrocarbon receptor to regulate ovarian follicle growth and estradiol biosynthesis in mice depends on stage of sexual maturity.

The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that mediates the toxicity of environmental chemicals and regulates many physiological functions, including processes in female reproduction. Previous studies demonstrated that Ahr deletion leads to slow ovarian follicle growth because of impaired estradiol production and reduced gonadotropin responsiveness in prepubertal mice. These studies, however, did not determine how Ahr deletion impairs estradiol production or whether the effects of Ahr deletion on follicle growth and estradiol production persist in adulthood. Thus, the present study evaluated the effect of Ahr deletion on steroid precursors in the estradiol biosynthesis pathway. Furthermore, this study evaluated follicle growth and estradiol biosynthesis in wild-type (WT) and Ahr knockout (AhrKO) antral follicles at different stages of sexual maturity. AhrKO antral follicles from prepubertal mice had slower growth, produced lower estradiol levels, and had reduced cyclin D2 (Ccnd2) expression compared to WT follicles. AhrKO follicles from adult mice, however, produced higher androgen levels and expressed higher levels of Ccnd2 compared to WT follicles. Furthermore, AhrKO follicles from adult mice had growth to that of WT follicles. These findings suggest that the AHR regulates follicle growth by altering factors involved in the estradiol biosynthesis pathway as well as key regulators of follicle growth and that this role of AHR depends on stage of sexual maturity.