Gedatolisib, a new therapy for CDK4/6 resistance in breast cancer, receives FDA Fast Track designation.
For those patients with hormone receptor-positive and HER2-negative metastatic breast cancer who have progressed after using CDK4/6 inhibitors and endocrine therapy, they urgently need better treatment options. Recently, the FDA has granted Gedatolisib the fast-track designation as a potential treatment option for hormone receptor-positive and HER2-negative patients with metastatic breast cancer who have developed disease progression after receiving CDK4/6 treatment.
Introduction to Gedatolisib new drug
Gedatolisib is a powerful, reversible dual inhibitor that selectively targets all Class I isomers of PI3K and mTOR. It is worth noting that the design of this drug has a highly different mechanism of action and pharmacokinetic properties from other existing and under-development drugs for PI3K, mTOR, or both. Since Gedatolisib can inhibit all Class I PI3K isomers, it can better limit the development of potential drug resistance than other isomer-specific PI3K inhibitors. In addition, the drug can solve the drug resistance mechanism that may arise when the PI3K isomer is targeted without mTOR inhibition.
Preclinical data show that when Gedatolisib is used in combination with palbociclib (Ibrance) and Fluvestrant (Faslodex), its activity is better than that of any single drug or dual combination in a xenograft model of breast cancer with estrogen receptor positive, HER2 negative, and PIK3CA mutations.
Drug name: Gedatolisib
Other drug names: PKI-587
Manufacturer: Celcuity
Latest treatment data of Gedatolisib
In a multicenter, open-label phase 1b trial (NCT02684032), researchers began to explore this issue further. 3 In the dose increment part of the study, they tried to determine the maximum tolerated dose of Gedatolisib plus palbociclib and letrozole (group L) and the combination of Gedatolisib plus palbociclib and fluvestrel (group F). In the expansion part, they hope to further understand the clinical activity of different combinations in the form of objective response rate (ORR).
The trial recruited women with a histological or cytological diagnosis of breast cancer and evidence of metastasis, estrogen receptor positive and HER2 negative, who were at least 18 years old. To join the dose increment part of the trial, the patient needs to have metastatic disease and progress. Patients also need to have measurable diseases according to the RECIST v1.1 standard, with an ECOG status of 0 or 1, and acceptable bone MARROW, kidney, liver, and heart functions.
For the dose expansion part of the study, patients must have not received endocrine-based metastatic systemic treatment in advance, have metastatic disease during or after the previous endocrine-based metastatic treatment, and have not undergone CDK inhibition beforehand, or they need to have one or two previous endocrine-based metastatic treatments.There are metastatic diseases during or after metastatic treatment, and CDK inhibition is performed in advance.
If the patient has previously received mTOR inhibitors or PI3K inhibitors, and has previously received chemotherapy for more than one metastatic disease, in the extended part of the study there are only bone diseases, symptomatic visceral spread or complications that require immediate treatment, a history of interstitial pneumonia, impaired gastrointestinal function, or known activitiesUncontrolled or symptomatic central nervous system metastasis, they will be ruled out.
Intravenous injection of Gedatolisib, on the 1st, 8th, 15th and 22nd days of each cycle, as part of the 28-day cycle, in combination with palbociclib, with a daily dose of 125 mg, oral letrozole, with a daily dose of 2.5mg, once in 3 weeks, 28-day cycle, or by intramuscular injection of fluvivirGroup, the dose is 500 mg, on the first and 15th days of cycle 1, and the first day of the subsequent 28-day cycle. In group L, patients receiving dose-1 of Gedatolisib received 150 mg per week, patients at dose 1 received an initial dose of 180 mg per week, and patients at dose 2 received 215 mg per week. The dose escalation of Gedatolisib was the same for group F.
The main endpoint of the dose escalation part of the study is dose-restricted toxicity (DLTs) in the first cycle, and the main endpoint of the extension part of the study is the ORR evaluated by the researcher. The main and secondary endpoints include safety, tumor response in the dose-increasing part, response duration and progression-free survival (PFS) in the extended part, corrected QTc interval, and pharmacokinetics. The investigators also evaluated biomarkers of tumor tissue in the blood as the exploratory end point of the study.
At the 2021 San Antonio Breast Cancer Symposium, researchers reported data from the dose extension portion of the study in which patients received the phase 2 recommended dose of 180 mg of Gedatolisib. A total of 103 patients were enrolled in the extension portion of the trial, which consisted of four treatment groups. Patients in group A received Gedatolisib plus palbociclib and letrozole as first-line therapy (n = 31), and patients in group B were CDK inhibitor beginners and received Gedatolisib plus palbociclib/fulvestrant as second-line therapy (n = 13). Patients in group C were prior CDK inhibitor recipients and received Gedatolisib/fulvestrant weekly as second- or third-line therapy (n = 32), and patients in group D were prior CDK inhibitor recipients and received Gedatolisib/fulvestrant as second- or third-line therapy, on a 3-week and 1-week basis (n = 27).
The results showed that the objective responses (ORRs) for groups 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 for these drugs were 96% (95% CI, 81%-100%), 100% (95% CI, 75%-100%), 79% (95% CI, 59%-92%), and 96% (95% CI, 81%-approximately 100%), respectively.
Furthermore, group A had the longest median progression-free survival (PFS) at 31.1 months (95% CI, 16.9–not reached [NR]), followed by group D at 12.9 months (95% CI, 7.4–16.7), group B at 11.9 months (95% CI, 3.7–NR), and group C at 5.1 months (95% CI, 3.4–7.5). Exploratory analyses of objective response rate (ORR) and treatment duration showed that among patients who progressed within 6 and 12 months, group D had a significantly higher ORR and longer treatment duration than group C. Moreover, regardless of prior treatment, group D consistently showed a better ORR than group C.
The most common grade 3 and 4 adverse reactions in the amplification group included stomatitis (grade 3, 27%), neutropenia (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 leukopenia (grade 3, 12%; grade 4, 1%). Furthermore, in groups 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 data cutoff date (i.e., May 10, 2021).
Reminder: The latest trial data show that for patients with hormone receptor-positive and HER2-negative metastatic breast cancer who have progressed after using CDK4/6 inhibitors and endocrine therapy, the new drug Gedatolisib has controllable toxicity and encouraging antitumor activity. Activity. It is hoped that this therapy will obtain better trial results, be approved as soon as possible and be used clinically for the benefit of more patients.
