Efficacy and safety of tenalisib, a PI3K δ/γ and SIK3 inhibitor in patients with locally advanced or metastatic breast cancer: Initial results from a 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 2022

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Background: Hyperactivation of the PI3K pathway in breast cancer is implicated in malignant transformation, cancer progression, and resistance to endocrine therapy. Salt Inducible Kinase- 3 (SIK3) is highly expressed in breast cancer and elevated SIK3 expressions are shown to contribute to tumorigenesis. Tenalisib (RP6530), a highly selective PI3K δ/γ and SIK3 inhibitor has been evaluated in > 150 patients with haematological malignancies and demonstrated encouraging activity in T-cell lymphoma with a differentiated safety profile. Tenalisib has a major metabolite (IN0385) which shows potent SIK3 inhibition. Preclinical studies in breast cancer cell lines have demonstrated that Tenalisib potentiated the activity of taxol 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 (MBC). Methods: This randomized, open-label study was designed to evaluate two doses (800 mg BID and 1200 mg BID) of Tenalisib in HR+/HER2- locally advanced or MBC patients including TNBC patients whose disease had progressed following at least one line of therapy. Tenalisib was given orally in a 28-days cycle until disease progression. Forty pts (20 pts at each dose level) were planned to be enrolled with the primary outcome being the percentage of pts without disease progression at the end of 6 months. The investigator-assessed ORR, PFS, and Clinical Benefit Rate (CBR = CR+PR+SD), using RECIST v1.1 were secondary outcomes. Results: All forty pts have been enrolled in the study. Pts had a median of 3 (range 1-7) lines of prior therapy; of these, 87% pts had prior endocrine therapy, and 40% and 30% pts had aromatase inhibitor or fulvestrant as their last prior therapy respectively. The median age was 63.8 (31-71) years, 52.5% of pts had PS 1, 77.5% had visceral disease, and 95.0% had ≥ 2 metastatic lesions at the time of enrollment. As of 07-Feb 2022, twenty-eight pts were efficacy evaluable. Of the 28, 2 pts had a PR (7%), 17 pts had SD (61%) and 6 pts had PD (21%) at the first efficacy assessment after completion of 2 cycles. Three pts discontinued from the study due to adverse events (11%) before the first efficacy assessment. The CBR was 68%. On safety, the most common TEAEs (≥5%) of any grade were transaminitis (All: 22%, ≥G3: 10%), GGT elevation (All: 7%, ≥G3: 5%), fatigue (All: 7%, ≥G3: 0%), rash (All: 7%, ≥G3: 2.5%). Discontinuations due to related TEAEs were infrequent (7%). There were no unexpected TEAEs. Two pts were discontinued due to related TEAEs (rash and GGT elevation). Conclusions: Based on the data from the ongoing study, Tenalisib showed encouraging preliminary efficacy as a single agent in patients with advanced MBC. Updated efficacy and tolerability data will be provided at the time of presentation. Clinical trial information: NCT05021900.