FAST-TRACK FDA REVIEW

FDA Grants Gedatolisib, a Dual PI3K and mTOR Inhibitor, Fast-Track Review for ER-Positive, HER2-Negative Breast Cancer

JHOP - February 2022 Vol 12, No 1 - FDA Oncology Update
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On January 18, 2022, the FDA granted a fast-track designation to the investigational drug gedatolisib (from Celcuity Inc), a PI3K and mTOR inhibitor, as a potential therapeutic option in patients with hormone receptor–positive, HER2-negative metastatic breast cancer whose disease progressed during CDK4/6 therapy, based on data from the phase 2 dose-escalation portion of a dose-expansion clinical trial. Gedatolisib is a potent, reversible, dual inhibitor that selectively targets all class I isoforms of PI3K and mTOR.

Preclinical data have indicated that the combination of gedatolisib, palbociclib, and fulvestrant had superior activity to any single agent or to dual combinations in a mouse xenograft model of an estrogen receptor (ER)-positive, HER2-negative breast cancer and PIK3CA mutation.

In a phase 1b multicenter, open-label clinical trial, investigators sought to identify the maximum-tolerated dose of the triplet of gedatolisib, palbociclib, and letrozole (L cohort) or of gedatolisib, palbociclib, and fulvestrant (F cohort).

The phase 2 dose-escalation portion of the dose-expansion study enrolled women with a diagnosis of ER-positive, HER2-negative metastatic breast cancer aged ≥18 years. For the dose-escalation portion, patients had to have progressing metastatic disease. For the dose-expansion portion of the study, patients must have not received previous endocrine-based systemic treatment in the metastatic setting, had metastatic disease during or after 1 endocrine-based therapy in the metastatic setting and no CDK4/6 inhibitor, or they had to have metastatic disease during or after 1 or 2 endocrine-based treatments in the metastatic setting after previous CDK inhibition.

The primary end point of the dose-escalation portion was first-cycle dose-limiting toxicities, and the primary end point for the expansion portion of the study was investigator-assessed objective response rate (ORR). Key secondary end points included safety, tumor response in the dose-escalation portion, duration of response and progression-free survival (PFS) in the expansion portion only, corrected QT interval, and pharmacokinetics. Investigators also assessed potential biomarkers as an exploratory end point of the research.

Data from the dose-expansion portion of the study, in which patients had received gedatolisib 180 mg, were presented at the 2021 San Antonio Breast Cancer Symposium. That study portion included 103 patients, who were divided into 4 treatment arms. The patients in arm A received gedatolisib, palbociclib, and letrozole as first-line treatment (N = 31); patients in arm B were CDK inhibitor–naïve and received gedatolisib plus palbociclib or fulvestrant as second-line treatment (N = 13); those in arm C had previously received a CDK inhibitor and now received gedatolisib plus palbociclib or fulvestrant in the second- or third-line setting on a weekly basis (N = 32); finally, patients in arm D had previously received CDK inhibitors and now received gedatolisib plus palbociclib or fulvestrant as second- or third-line treatment on a 3-weeks-on, 1-week-off basis (N = 27).

The ORRs in arms A, B, C, and D were 85%, 77%, 32%, and 63%, respectively, and the clinical benefit rates were 96%, 100%, 79%, and 96%, respectively. In addition, the median PFS was 31.1 months in arm A, 12.9 months in arm D, 11.9 months in arm B, and 5.1 months in arm C.

An exploratory analysis of ORR and the duration of therapy (DOT) showed a significantly higher ORR and longer DOT in arm D versus arm C in those whose disease progressed within 6 months and 12 months. Moreover, the ORR was superior in arm D relative to arm C, regardless of previous therapies received.

The most common (>1%) grade 3 or 4 adverse effects reported across the 4 arms included stomatitis, decreased neutrophils, fatigue, vomiting, anemia, diarrhea, leukopenia, constipation, pruritus, rash, maculopapular rash, hyperglycemia, and decreased lymphocyte count. The treatment discontinuing rates were 64.5% in arm A, 76.9% in arm B, 100% in arm C, and 88.9% in arm D. Conversely, 32.3%, 23.1%, 0%, and 11.1% of patients, respectively, were still using the treatment at the time of the data cutoff, on May 10, 2021.

A phase 3 clinical trial is planned based on these data.

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