Abstract
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.
Highlights
Cancer of the pancreas is the third leading cause of cancer deaths in the United States, with an estimated 57,600 new diagnoses and 47,050 deaths attributable to the disease in 2020.1 Surgical resection offers the only chance of cure for pancreatic adenocarcinoma (PC)
Materials and Methods: The combination of ribociclib and everolimus was investigated in a phase I study in patients with Metastatic pancreatic adenocarcinoma (mPC) and progression on 5-fluorouracil- and gemcitabinebased chemotherapy
In patient-derived xenografts, we previously found that CDK4/6 inhibition was highly effective at limiting tumor growth, and had a profound impact on the proliferative index.[13]
Summary
Cancer of the pancreas is the third leading cause of cancer deaths in the United States, with an estimated 57,600 new diagnoses and 47,050 deaths attributable to the disease in 2020.1 Surgical resection offers the only chance of cure for pancreatic adenocarcinoma (PC). Only 15–20% of patients have resectable disease at initial diagnosis; the majority have either locally advanced or metastatic cancer (metastatic pancreatic adenocarcinoma [mPC]).
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