A Phase I Study of Ribociclib Plus Everolimus in Patients with Metastatic Pancreatic Adenocarcinoma Refractory to Chemotherapy.

Purpose: Metastatic pancreatic adenocarcinoma (mPC) has a poor prognosis. CDK4/6 is often deregulated in mPC due to CDKN2A loss, resulting in the loss of p16INK4a that inhibits CDK4/6. CDK4/6 inhibitor monotherapy is ineffective due to RAS-mediated activation of alternative pathways, including phosphatidylinositol 3-kinase-mammalian target of rapamycin (PI3K-mTOR). We conducted a phase I study combining CDK4/6 and mTOR inhibition in patients with mPC refractory to standard chemotherapy. Materials and Methods: The combination of ribociclib (a CDK4/6 inhibitor) and everolimus (an mTOR inhibitor) was investigated in a phase I study in patients with mPC and progression on 5-fluorouracil- and gemcitabine-based chemotherapy. A 3 + 3 design was used to find the recommended phase II dose (RP2D) of ribociclib (250 or 300 mg daily for days 1-21) in combination with everolimus (2.5 mg daily for days 1-28) every 28 days. Secondary endpoints were median progression-free survival (mPFS), median overall survival (mOS), response rate, safety, and effect on the retinoblastoma pathway. Results: Twelve patients were enrolled, six at each dose level. Only one patient had a dose-limiting toxicity of a grade 3 rash at the 250 mg dose. The RP2D of ribociclib was 300 mg. mPFS was 1.8 months (95% confidence interval [CI] [0.6-2.1]), and mOS was 3.7 months (95% CI [2.3-5.6]). Two patients (17%) had stable disease at 8 weeks. Pharmacodynamic evaluation demonstrated that CDK4/6-regulated gene expression was significantly decreased on treatment (n = 6, p < 0.001). Conclusion: Ribociclib 300 mg daily for days 1-21 plus everolimus 2.5 mg daily was well tolerated and associated with decreased CDK4/6-regulated gene expression. This combination was not effective as a third-line therapy but does pharmacologically target CDK4/6 in mPC, revealing the potential for benefit in other settings.