Gedatolisib Plus Palbociclib Shows Promise in Treating ER+/HER2- Advanced Breast Cancer

Gedatolisib, a first-in-class PI3K/mTOR inhibitor, plus palbociclib (Ibrance) and endocrine therapy demonstrated tolerability and preliminary efficacy in patients with ER+/HER2- advanced or metastatic breast cancer, according to early results on a phase 1b study announced in a press release by Celucity, Inc.

The data were considered to be encouraging and the company plans to initiate a phase 2/3 pending feedback from the FDA to further explore the novel combination.

Gedatolisib is a potent, reversible dual inhibitor that targets PI3K and mTOR. It is currently being studied in multiple trials pertaining to its effectiveness as a breast cancer treatment.

At the preliminary phase 1b data cutoff on January 11, 2021, 103 patients were enrolled in 1 of 6 dose-expansion arms. Of those 103 patients, 88 were evaluable for response and the objective response rate (ORR) was 60%. The clinical benefit rate (CBR) observed was 75%, which was defined as objective response or stable disease for at least 24 weeks.

Additionally, 22 patients continued to receive gedatolisib in combination with the other study drugs after the data cutoff date. Of those 22 patients, 17 had been on the study treatment for more than 2 years.

Overall, gedatolisib was well tolerated, with the majority of treatment related adverse events (TRAE) being grade 1 or 2. Stomatitis and rash were the most common TRAE’s associated with the agent. Gedatolisib was discontinued in 10% of patients.

The multicenter, non-randomized, open-label phase 1b B2151009 trial (NCT02684032) aim to enroll 141 patients and has an estimated completion date of June 2022. The coprimary end points of the study number of participants with dose-limiting toxicities and ORR in patients in the dose expansion portion. Secondary outcomes include tumor response, duration of response (DoR), QTc interval, maximum observed plasma concentration, and progression-free survival (PFS).

In order to participate patients must be female and 18 years old or older. They must have an ER-positive and HER2-negative tumor. Patients previously treated with a mechanistic target rapamycin inhibitor or PI3K inhibitor or who have more than 1 prior line of chemotherapy for the treatment of metastatic or locally advanced/recurrent disease are not eligible to participate.

The study was made up of 6 arms. In the experimental letrozole (Femara) cohort, patients received gedatolisib weekly at 180mg per week in a 4-week cycle. Palbociclib (Ibrance) initiated at 125 mg daily, 3 out of 4 weeks in a 4-week cycle. Patients also received letrozole daily at 2.5mg. In the experimental fulvestrant (Faslodex) cohort, patients received the same combination of gedatolisib and palbociclib, but also received 500 mg of fulvestrant on day 1, 15, and 28, and then every 28 days. The remaining 4 arms were the same combinations in the dose-expansion phases.

"We are very encouraged by this preliminary data for gedatolisib from our ongoing Phase 1b trial in patients with breast cancer," said Brian Sullivan, chief executive officer and co-founder of Celcuity, in a press release. "The robust response rate and the observed tolerability profile are particularly compelling given the need for a therapeutic regimen that can address endocrine therapy resistance. We look forward to sharing additional data from the study at a future medical conference in 2021."

_REFERENCE:

_{Celcuity reports preliminary data from phase 1b trial of gedatolisib plus Ibrance® and endocrine therapy for patients with ER+/HER2- metastatic breast cancer and provides corporate update. News release. Celcuity, Inc. April 8, 2021. Accessed April 12, 2021. https://bit.ly/3sbCIs0.}