Abstract P4-01-16: High levels of RSK2 in breast cancer patients is associated with longer PFS in patients treated with PMD-026, a first in class RSK inhibitor
Authors: Wang Judy S. , Beeram Muralidhar , Chalasani Pavani , Mina Lida , Shatsky Rebecca A. , Hurvitz Sara , Trivedi Meghna S. , Wesolowski Robert , Han Hyo S. , Patnaik Amita , Bahadur Shakeela , Huynh My-my , Jayanthan Aarthi , Los Gerrit , Dunn Sandra E. , Dorr Andrew 
Published: March 2023

Background: Breast cancer (BC) is the most common malignancy in women and metastatic triple negative breast cancer (mTNBC) remains one of the most difficult to treat cancers with few targeted treatment options. RSK is recognized as a critical signaling component in the MAPK/PDK-1 pathways, is an important driver for BC and a signature of poor prognosis. PMD-026 is the first RSK inhibitor to enter clinical trials and is being developed alongside an immunohistochemistry (IHC) companion diagnostic to select patients with increased activated RSK2 in tumor tissue. A Phase 1/1b trial of PMD-026 in patients with metastatic breast cancer (mBC) or metastatic triple negative breast cancer (mTNBC) established safety at a dose of 200 mg Q12h. Efficacy signals in patients with heavily pretreated mBC/mTNBC are explored in this analysis along with evaluation of the effect of food (FE) on systemic exposure to treatment. Methods: PMD-026 was administered to 41 patients as a single agent in this phase 1/1b open-label study, with 30 patients evaluable for efficacy. Exploratory objectives were to identify subgroups of patients who may optimally benefit from PMD-026. Subgroup analysis of patients included 1) comparing BC patients who received ≤5 vs &gt;5 prior therapies; 2) comparing TNBC patients (de novo vs secondary subtypes)1, and 3) comparing patients with low RSK2 H-scores (&lt; 180) vs high (≥180). In addition, PMD 026 PK was evaluated at the 200 mg Q12h dose and a FE sub-study enrolled 12 patients administered a single 200 mg dose. Results: PMD-026 monotherapy was generally well-tolerated in the 41 mBC patients who were enrolled and treated. Kaplan-Meier PFS analysis of 30 evaluable BC patients who were dosed with PMD-026 showed that patients with less prior therapy (≤5) did significantly better (HR, 0.19; 95% CI [0.06–0.52], p=0.0014) than those with &gt; 5 prior therapies. Subgroup analysis of PFS in those with TNBC demonstrated that de novo TNBC (n=17) had longer time on treatment with PMD-026 compared with secondary TNBC (n=9) (HR, 0.31; 95% CI [0.10-0.99], p=0.0476). In those with de novo TNBC with ≤5 prior therapies, a high RSK2 H-score was associated with significantly longer PFS at the RP2D (4.2 vs 1.3 months, HR, 0.17; 95% CI [0.03-0.80], p=0.0254) than patients with a low RSK2 H-score. In patients with CDK4/6 resistant HR+ BC (n=3), PFS was 5.2 (RSK2 high) vs 1.3 months (RSK2 low). Stable disease was observed in 53% (9/17) of patients with de novo TNBC and in 67% (6/9) of de novo TNBC patients with high RSK2. Tumor necrosis or target lesion reduction (&lt; 30%) was observed in 17% of patients (5/30), all of whom had high RSK2 expression. In the FE sub-study, increased interpatient variability in PMD-026 Cmax and Tmax but not AUC, was observed when administered with food, favored dosing in a fasted state, which is consistent with the pH dependent solubility of PMD-026. Notably, all FE patients (12/12) achieved the target concentration of 1µM (IC90 in preclinical studies) within 4 hours when PMD-026 was taken without food. At the RP2D, PMD-026 taken without food showed relatively consistent exposure among patients over 24 hr timeframe. Conclusions: These findings demonstrate that in patients treated with PMD-026 who had received &lt; 5 prior treatment regimens, had de novo TNBC or CDK4/6 refractory HR+ disease and had high RSK2 scores had longer PFS. Overall, PMD-026 is a well-tolerated, orally available RSK2 inhibitor that will be evaluated further for efficacy in TNBC and CDK4/6i refractory HR+ mBC, in a trial that will prospectively enroll patients based on RSK2 activation as defined by the RSK2 IHC H-scores. Clinical trial information: NCT04115306. 1 Patients diagnosed and treated for TNBC from their initial diagnosis (de novo TNBC) vs patients previously treated for hormone receptor positive (HR+) or human epidermal growth factor 2 receptor positive (HER2+) BC, but became HR or HER2 negative (secondary TNBC)

Citation Format: Judy S. Wang, Muralidhar Beeram, Pavani Chalasani, Lida Mina, Rebecca A. Shatsky, Sara Hurvitz, Meghna S. Trivedi, Robert Wesolowski, Hyo S. Han, Amita Patnaik, Shakeela Bahadur, My-my Huynh, Aarthi Jayanthan, Gerrit Los, Sandra E. Dunn, Andrew Dorr. High levels of RSK2 in breast cancer patients is associated with longer PFS in patients treated with PMD-026, a first in class RSK inhibitor [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-01-16.