Abstract CT116: A phase I study of ribociclib plus everolimus in patients with metastatic pancreatic adenocarcinoma refractory to chemotherapy
Authors: Weinberg Benjamin Adam , Wang Hongkun , Witkiewicz Agnieszka K. , Marshall John L. , He Aiwu R. , Knudsen Erik S. , Pishvaian Michael J. 
Published: September 2020

Abstract
Background: Metastatic pancreatic adenocarcinoma (mPC) has a poor prognosis, with a 5-year survival rate of 2.9%. CDK4/6 is often deregulated in mPC due to loss of CDKN2A via homozygous deletion or epigenetic silencing, resulting in the loss of the p16INK4a protein that naturally inhibits CDK4/6. CDK4/6 inactivates the retinoblastoma protein (RB), allowing E2F family transcription factors to promote cell cycle progression. Inhibitors of CDK4/6 have been ineffective as single agents in part due to Ras-mediated activation of alternate signaling pathways including the PI3K-mTOR pathway. We have shown that co-inhibition of the CDK4/6 and mTOR pathways suppresses growth in mPC patient-derived xenografts. Methods: The combination of ribociclib (RIBO; a CDK4/6 inhibitor) and everolimus (EVE; an mTOR inhibitor) was investigated in a phase I, third-line study in patients (pts) with mPC and disease progression on 5-fluorouracil- and gemcitabine-based chemotherapy regimens. A 3+3 design was used to test the safety of RIBO (250 or 300 mg daily on days 1-21) and fixed-dose EVE (2.5 mg daily on days 1-28) every 28 days. Secondary endpoints were median progression-free survival (mPFS), median overall survival (mOS), overall response rate by RECIST 1.1, and safety. Correlative studies included assessing the pharmacodynamic effects on the RB pathway using pre- and on-treatment tumor biopsies. Results: Twelve pts were enrolled between 2017 and 2019. One dose-limiting toxicity (DLT) of grade 3 rash was seen in a pt at the 250 mg dose level, so the 250 mg level was expanded. Six pts were treated at each dose level, and no other DLTs were seen. The recommended phase 2 dose was RIBO 300 mg. mPFS was 1.8 months (95% CI (0.6, 2.1)), and mOS was 3.7 months (95% CI (2.3, 5.6)). No clinical responses were seen. Three pts (25%) had stable disease at 8 weeks. There was a significant (&gt; 50% on average) decrease in expression of CDK4/6 regulated genes (e.g. BIRC5, CCNA2, STMN1, TOP2A) in pre- vs. post-treatment tumor samples (N = 6, p &lt; 0.001), indicating that there was on-target activity as observed in preclinical models. The baseline tumor sample from 1 patient with long term survival (17.1 months) had significantly less baseline expression of CDK4/6 regulated genes than other baseline patient samples (N = 5, p = 2.8 x 10^-18 using Student's paired t-test). Conclusions: The combination of RIBO 300 mg daily on days 1-21 and EVE 2.5 mg daily on days 1-28 every 28 days was safe and well tolerated in this heavily pre-treated patient population. Pharmacodynamic studies demonstrated a decrease in expression of CDK4/6 regulated genes. However, minimal efficacy was noted, and this combination should not be studied further in this treatment setting. NCT02985125.
Citation Format: Benjamin Adam Weinberg, Hongkun Wang, Agnieszka K. Witkiewicz, John L. Marshall, Aiwu R. He, Erik S. Knudsen, Michael J. Pishvaian. A phase I study of ribociclib plus everolimus in patients with metastatic pancreatic adenocarcinoma refractory to chemotherapy [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT116.