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FDA Decision Alerts October 16, 2020

CDER-Approved NDA for KOSELUGO™ (selumetinib)

Christina Purpura and Elizabeth Dabrowski
Contributing writers, Aetion

On April 10, 2020, the FDA approved AstraZeneca’s KOSELUGO™ (selumetinib) “for the treatment of pediatric patients two years of age and older with neurofibromatosis type 1 (NF1) who have symptomatic, inoperable plexiform neurofibromas (PN).” Key findings from the FDA’s Multi-Discipline Review, Administrative and Correspondence Documents, and Package Insert:

The FDA approved KOSELUGO based on the results of the open-label, single-arm, multicenter National Cancer Institute (NCI) SPRINT trial (NCT01362803; n=99). (Note that 50 of the 99 patients were included in the efficacy population.) The applicant also submitted a natural history study of NF1, Study 01-C-0222 (NCT00021541; n=62). The FDA considered the results of the natural history study to be supportive because “the NCI natural history study provided sufficient evidence that spontaneous tumor regression or spontaneous reductions in PN-related morbidities do not occur as part of the natural history of disease, the observed effects (on NF1-related PN shrinkage) in the SPRINT trial could be reliably attributed to the selumetinib treatment effect.”

While the FDA considered the natural history study to be supportive, it found the study “inadequate for any comparative analyses.” In addition, the resultant package insert included a warning due to ocular serious adverse events among patients in the Expanded Access Program.

The natural history study and the Expanded Access Program are further described below.

Natural history study
Purpose: To demonstrate that the PN shrinkage observed in the SPRINT trial is attributed to the investigational drug, verus the natural history of the disease.

What was done: The NCI Pediatric Oncology Branch conducted a prospective study in patients 35 years old or younger with a confirmed NF1 mutation or a clinical diagnosis of NF1.

The demographics of the patients in the SPRINT trial and the natural history study were generally similar. The natural history study demonstrated the uncommon occurrence of spontaneous regression of NF1 PN.

Outcome: The FDA contrasted the results of the SPRINT trial with published data from the natural history study (Gross et al. 2018): the published data “showed that in the absence of surgical resection no symptomatic patients had improvement of their co-morbidities.” However, the FDA did not include the natural history study in its assessment of efficacy. The “FDA considered the comparisons of efficacy endpoints in SPRINT Phase II Stratum 1 to the placebo arm of Study 01-C-0222 or the Natural History study to be exploratory, due to potential between-study differences including patient eligibility criteria, assessment frequencies of endpoint, and endpoint definition. Furthermore, the lack of covariate information available for these external data limited the ability to compare data sources or to adjust for potential confounding or bias, and so the results of any comparisons are not interpretable.”

Expanded Access Program
Purpose: Given the limited treatment duration in the SPRINT trial, the FDA asked the applicant to submit additional safety analyses from the Expanded Access Program and the applicant’s global database for selumetinib.

What was done: The applicant followed the FDA’s request, submitting data from the Expanded Access Program (n=166 as of January 2019) and its global database for selumetinib (n=1860).

Outcome: “The FDA notes that determining true [adverse event (AE)] incidence rates from analysis of these datasets is not possible due to variable reporting requirements between countries (for the Expanded Access Program), data collection methods, and continued accrual in ongoing studies. Further, these datasets had missing elements for a substantial number of the events such as AE duration, toxicity grade, action taken in response to the event, and outcomes.”

The FDA’s review found that three pediatric patients had ocular serious adverse events (SAEs): “abnormal ocular finding, eye disorder, visual field defect.” The resultant package insert includes the following warning: “Left ventricular dysfunction or decreased [left ventricular ejection fraction (LVEF)] resulting in permanent discontinuation of KOSELUGO occurred in an unapproved population of adult patients with multiple tumor types who received KOSELUGO. Decreased LVEF resulting in permanent discontinuation of KOSELUGO occurred in a pediatric population with NF1 in an expanded access program.”

References:
Gross AM, Singh G, Akshintala S, Baldwin A, Dombi E, Ukwuani S, et al. Association of plexiform neurofibroma volume changes and development of clinical morbidities in neurofibromatosis 1. Neuro Oncol 2018;20(12): 1643-51.

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