FDA Grants Fast Track Designation to Gedatolisib for Metastatic Breast Cancer

January 19, 2022

The FDA has granted a fast track designation to gedatolisib for use as a potential therapeutic option in patients with hormone receptor–positive, HER2-negative metastatic breast cancer who experienced disease progression on CDK4/6 therapy.

The potent, reversible dual inhibitor selectively targets all class I isoforms of PI3K and mTOR. Notably, the agent was designed to have a mechanism of action and pharmacokinetic properties that are highly differentiated from other available and investigational agents that target PI3K, mTOR, or both.

Because gedatolisib can inhibit all class I PI3K isoforms, it can limit the potential development of drug resistance better than other isoform-specific PI3K inhibitors. Moreover, the drug can address possible resistance mechanisms that can result when PI3K isoforms are targeted without mTOR inhibition.

“There is an urgent need for better treatment options for hormone receptor–positive, HER2-negative metastatic breast cancer patients whose disease progressed after treatment with a CDK4/6 inhibitor and endocrine therapy,” Brian Sullivan, chief executive officer and co-founder of Celcuity, stated in a press release. “We are very encouraged by the clinical data for gedatolisib and believe that fast track designation will facilitate our efforts to advance its development for patients as quickly as possible.”

Preclinical data have indicated that gedatolisib, when combined with palbociclib (Ibrance) and fulvestrant (Faslodex), had superior activity to any single agent or dual combination in an estrogen receptor–positive, HER2-negative, PIK3CA-mutated breast cancer mouse xenograft model.² As such, investigators hypothesized that simultaneous inhibition of these pathways would improve efficacy.

In a multicenter, open-label, phase 1b trial (NCT02684032), investigators set out to explore this further.³ In the dose-escalation portion of the research, they sought to identify the maximum-tolerated dose for the combinations of gedatolisib plus palbociclib and letrozole (L cohort) and gedatolisib plus palbociclib and fulvestrant (F cohort). In the expansion portion, they wanted to learn more about clinical activity in the form of objective response rate (ORR) for the different combination regimens.

The trial enrolled women with a histologically or cytologically proven diagnosis of breast cancer and evidence of metastasis, estrogen receptor positivity, and HER2 negativity, who were at least 18 years of age. To be included in the dose-escalation portion of the trial, patients needed to have metastatic disease with progression.

For the dose-expansion portion of the research, patients must have not received prior endocrine-based systemic treatment in the metastatic setting, had metastatic disease during or after 1 previous endocrine-based therapy in the metastatic setting without prior CDK inhibition, or they needed to have metastatic disease during or following 1 or 2 previous endocrine-based treatments in the metastatic setting after previous CDK inhibition.

Patients also needed to have measurable disease per RECIST v1.1 criteria, an ECOG performance status of 0 or 1, and acceptable bone marrow, kidney, liver, and cardiac functions.

If patients previously received an mTOR inhibitor or a PI3K inhibitor, received more than 1 prior line of chemotherapy for metastatic disease, had bone-only disease during the expansion portion of the research, symptomatic visceral spread or complications requiring immediate treatment, a history of interstitial pneumonitis, impairment of gastrointestinal function, or known active, uncontrolled, or symptomatic central nervous system metastases, they were excluded.

Intravenous gedatolisib was given at a weekly dose on days 1, 8, 15, and 22 of each cycle, as part of 28-day cycles, in combination with palbociclib at a daily dose of 125 mg and either oral letrozole at a daily dose of 2.5 mg, 3-weeks-on and 1-week-off for 28-day cycles or fulvestrant via intramuscular injection at a dose of 500 mg on days 1 and 15 in cycle 1 followed by day 1 of subsequent 28-day cycles.

In the L cohort, patients who received gedatolisib at dose level -1 received 150 mg weekly, those in dose level 1 had a starting dose of 180 mg weekly, and those who received dose level 2 received 215 mg weekly. The dose escalation of gedatolisib was the same for the F cohort.

The primary end point of the dose-escalation portion of the research was first-cycle dose-limiting toxicities (DLTs), and the primary end point for the expansion portion of the research was investigator-assessed 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 QTc interval, and pharmacokinetics. Investigators also assessed biomarkers in the tumor tissue in blood as an exploratory end point of the research.

Earlier data presented during the 2018 ASCO Annual Meeting found that all gedatolisib combinations had manageable toxicity and encouraging preliminary antitumor activity, even in patients who were pretreated.

At the 2021 San Antonio Breast Cancer Symposium, investigators reported data from the dose-expansion portion of the study, where patients had received gedatolisib the recommended phase 2 dose of 180 mg.

A total of 103 patients were included in the expansion portion of the trial, which was comprised of 4 treatment arms. Those enrolled to arm A received gedatolisib plus palbociclib and letrozole as first-line treatment (n = 31), those enrolled to arm B were CDK inhibitor naïve and received gedatolisib plus palbociclib/fulvestrant as second-line treatment (n = 13), those in arm C previously received CDK inhibitors and received gedatolisib plus palbociclib/fulvestrant in the second- or third-line setting on a weekly basis (n = 32), and those in arm D had previously received CDK inhibitors and received gedatolisib plus palbociclib/fulvestrant as second- or third-line treatment on a 3-weeks-on and 1-week-off basis (n = 27).

Results showed that the ORRs in arms A, B, C, and D were 85% (95% CI, 66%-96%), 77% (95% CI, 46%-95%), 32% (95% CI, 16%-52%), and 63% (95% CI, 42%-81%), respectively. The clinical benefit rates in these arms were 96% (95% CI, 81%-100%), 100% (95% CI, 75%-100%), 79% (95% CI, 59%-92%), and 96% (95% CI, 81%–approximately 100%), respectively.

Additionally, the median PFS was longest in arm A, at 31.1 months (95% CI, 16.9–not reached [NR]), followed by 12.9 months (95% CI, 7.4-16.7) in arm D, 11.9 months (95% CI, 3.7–NR) in arm B, and 5.1 months (95% CI, 3.4-7.5) in arm C.

An exploratory analysis of ORR and duration of treatment showed a significantly higher ORR and longer duration of treatment in arm D vs arm C in those who had progressed within 6 months and 12 months. Moreover, the ORR was found to be superior in arm D relative to arm C, irrespective of prior therapies received.

The most common grade 3 and 4 adverse effects reported across the expansion arms included stomatitis (grade 3, 27%), decreased neutrophil count (grade 3, 53%; grade 4, 14%), fatigue (grade 3, 11%), vomiting (grade 3, 1%), anemia (grade 3, 12%), diarrhea (grade 3, 4%), leukopenia (grade 3, 13%; grade 4, 3%), constipation (grade 3, 1%), pruritus (grade 3, 5%), rash (grade 3, 7%), maculopapular rash (grade 3, 14%), hyperglycemia (grade 3, 5%; grade 4, 2%), and decreased lymphocyte count (grade 3, 12%; grade 4, 1%).

Moreover, in arms A, B, C, and D, 64.5%, 76.9%, 100.0%, and 88.9% of patients, respectively, discontinued treatment; conversely, 32.3%, 23.1%, 0%, and 11.1%, of patients, respectively, were still on treatment at the time of data cutoff, which was May 10, 2021.

Based on these data, a phase 3 clinical trial is planned, according to Celcuity, Inc.

The company also shared plans to initiate two phase 2 clinical trials that will examine gedatolisib in patients with hormone receptor–positive, HER2-negative breast cancer. One of these trials will examine the agent plus fulvestrant in up to 25 patients with metastatic breast cancer; the other trial will look at gedatolisib in combination with palbociclib/letrozole in up to 15 patients with early-stage breast cancer.

References

Celcuity receives FDA fast track designation for gedatolisib in HR+/HER2- metastatic breast cancer and provides corporate update. News release. Celcuity, Inc.; January 18, 2022. Accessed January 19, 2022. https://yhoo.it/3KqNHIw
Layman RM, Wesolowski R, Han H, et al. Phase 1b expansion study of gedatolisib in combination with palbociclib and endocrine therapy in women with ER+ advanced breast cancer. Presented at: 2021 San Antonio Breast Cancer Symposium; December 7-10, 2021; San Antonio, TX. Abstract 1017. https://bit.ly/3ry0qjZ
Forero-Torres A, Han H, Dees EC, et al. Phase 1b study of gedatolisib in combination with palbociclib and endocrine therapy (ET) in women with estrogen receptor (ER) positive (+) metastatic breast cancer (MBC) (B2151009). J Clin Oncol. 2018;36(suppl 15):1040. doi:10.1200/JCO.2018.36.15_suppl.1040