Poster #3 – DIACCURATE : DIACC3010, optimized inhibitor of S6 kinase, combined with endocrine therapy, has potent antitumor activity in treatment-resistant ER+ HER2 – metastatic breast cancer

Authors

Christel NAVARRO, Apostolia M. TSIMBERIDOU, Cécile BOUGERET, Dominique BRIDON, Elsa BORGHI, Hélène SICARD

Abstract

Background: Ribosomal protein S6 kinase (S6K) is a key regulator of estrogen receptor (ER) function, and  its high expression is associated with poor clinical
outcomes in breast cancer (BC). Recent data have demonstrated that S6K is involved in resistance to CDK4/6 inhibitors in metastatic BC (MBC). DIACC3010 (formerly M2698) is an oral brain-penetrant potent inhibitor of S6K. By design, DIACC3010 also selectively inhibits AKT1 and AKT3, while sparing AKT2. DIACC3010 was previously evaluated in a phase 1 trial (NCT01971515). We performed exploratory correlative analyses of the phase 1 trial in ER+ HER2-negative MBC patients in addition to nonclinical  experiments to evaluate its role in the CDK4/6 and endocrine therapy (ET) resistant setting.

Methods:

DIACC3010 was evaluated as monotherapy, or combined with either trastuzumab or tamoxifen, in a multicenter phase 1 trial that accrued 101 patients with advanced/refractory solid tumors (1). The current analysis focused on patients with ER+ HER2-negative MBC and aimed to explore the efficacy of DIACC3010 according to ESR1 mutational status. DIACC3010 was also evaluated patient-derived xenograft (PDX) mouse models, in monotherapy and combined with tamoxifen or palbociclib, and in xenograft models alone and in combination with elacestrant or abemaciclib. Results: Twenty patients were evaluable at baseline for their tumor mutational status and included in the analysis. Median age was 60 years and median number of prior lines of therapy was 5.5. Twelve of 20 (60%) patients had received prior treatment with CDK4/6 inhibitors. Nine of 20 patients (45%) had ESR1 mutations, of whom 4 had received CDK4/6 inhibitor. Median progression free survival was 5.6 months in patients with ESR1 mutations, and 2.6 months in patients with ESR1 wild-type tumors. Among the 13 ER+ BC PDX models evaluated, 12 provided interpretable results. The combination of DIACC3010 with tamoxifen or palbociclib induced respectively 10/12 (83%) and 11/12 (92%) significant tumor growth control in PDX models, of which 42% were resistant to tamoxifen and 50% were resistant to palbociclib. The combination of DIACC3010 with elacestrant or abemaciclib induced respectively 77% and 75% significant tumor growth control in MCF7 xenograft model. Furthermore, DIACC3010 monotherapy resulted in significant tumor growth control in 3/5 (60%) of the tamoxifen-resistant PDX models and 5/6 (83%) of the Palbociclib-resistant PDX models.

Download the poster here: posterAACR 2023 - DIACC3010_final