Efficacy and safety of tenalisib, a PI3K δ/γ and SIK3 inhibitor, in patients with locally advanced or metastatic breast cancer: Updated results from an on-going phase II study.
Authors: Makharadze Tamta , Kiladze Ivane , Dzagnidze Giorgi , Semionova Nino , Katselashvili Lika , Vekua Natia , Routhu Kasi V. , Barde Prajak J. , Nair Ajit 
Published: June 2023

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Background: Several studies have shown that the upregulation of the PI3K–AKT–mTOR pathway interacts with the Estrogen Receptor pathway and confers endocrine resistance. Elevated Salt Inducible Kinase-3 (SIK3) expression, which often is overexpressed breast cancer, is shown to contribute to tumorigenesis. Tenalisib (RP6530), a highly selective, PI3Kδ/γ and SIK3 inhibitor, has shown promising efficacy in T-cell lymphoma with a distinct safety profile. Tenalisib’s major metabolite, IN0385 is a SIK3 inhibitor. Breast cancer cell line studies have demonstrated that tenalisib potentiated the activity of paclitaxel and doxorubicin. The aim of this phase II study was to investigate the efficacy and safety of single-agent tenalisib in patients (pts) with HR+ HER2- locally advanced or metastatic Breast cancer. Methods: This randomized, open-label study was designed to evaluate two doses (800 mg BID and 1200 mg BID) of Tenalisib in MBC pts (including TNBC) whose disease had progressed following at least one line of therapy. Tenalisib was administered orally daily for every 28 days cycles until the disease progression. The study would enroll forty pts (20 at each dosage level), with the primary outcome being the proportion of patients who did not have disease progression at the end of six months. Other outcomes were investigator-assessed ORR, PFS, DCR (DCR=CR+PR+SD) and Clinical Benefit Rate (CBR= CR+PR+SD≥24 weeks) as per RECIST v1.1 criteria. Results: The trial enrolled 40 pts. Pts had a median of 3 (range 1-7) prior therapies of which, 87% pts had prior endocrine therapy, which included 40% pts treated with an aromatase inhibitor and 30% of pts treated with fulvestrant as their last therapy respectively. Prior chemotherapy in any setting included taxane (60%), and anthracycline (47.5%). The median age was 63.8(31-71) years, 77.5% pts had visceral disease, and 95.0% had 2 or more metastatic lesions. As of 06-Feb-2023, of the 40 pts, 5 pts (12.5%) showed PR and 22 (55%) had SD. The CBR was 57.5% while the DCR was 67.5%. The median duration of response in PR pts and median duration of clinical benefit were 9.36 and 7.46 months respectively. The progression free survival (PFS) was 5.6 months (range: 0.93 to 15.26+ months). Drug related AEs were manageable. The most common AEs (≥10%) of any grade were transaminitis, GGT elevation, and rash. Grade 3/ 4 events were limited to GGT elevation (12.5%), and transaminitis (12.5%). Discontinuations due to related AEs were infrequent (<5%) and limited to two events (one event each of rash and GGT elevation). Conclusions: Based on the data from the ongoing study, tenalisib shows encouraging efficacy as a single agent in pts with relapsed/refractory HR+ HER2- difficult to treat MBC patients. Updated efficacy and tolerability data will be provided at the time of presentation. Clinical trial information: NCT05021900 .