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

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-kinasemammalian 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 gemcitabinebased 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.

Prognostic Stratification Based on HIF-1 Signaling for Evaluating Hypoxic Status and Immune Infiltration in Pancreatic Ductal Adenocarcinomas

“…However, Wolpin et al demonstrated that daily everolimus administered as a single agent had little clinical efficacy in patients with gemcitabine-resistant PDAC (71). Similarly, the combination of everolimus with cytotoxic therapies (e.g., gemcitabine and cisplatin) also failed to achieve meaningful therapeutic responses in patients with PDAC (72)(73)(74). These results suggest that single-target therapy may not be sufficient for the eradication of pancreatic cancer cells, especially for refractory and chemoresistant cancer cells.…”

A randomized phase II study of SM‐88 plus methoxsalen, phenytoin, and sirolimus in patients with metastatic pancreatic cancer treated in the second line and beyond

“…In prospective trials of traditional chemotherapy, targeted therapy, and immunotherapy combinations, the mPFS in the second line ranged from 1.5 to 3.1 months. 9,[31][32][33][35][36][37]40,42,50 The mPFS achieved in the third line for SM-88 Regimen was 1.8 months versus an equivalent 1.8 months for ribociclib plus everolimus, 45 2.3 months for GVAX, and 2.1 months for chemotherapy. 43 We believe that our OS and PFS findings indicate a potential role for SM-88 Regimen in the second-line for patients with mPDAC, especially as the 920 mg dose appeared to be much more tolerable than traditional chemotherapy.…”

Anlotinib plus nab-paclitaxel/gemcitabine as first-line treatment prolongs survival in patients with unresectable or metastatic pancreatic adenocarcinoma: a retrospective cohort

“…The incidence of grade 3 or higher adverse events was 40% in the olaparib group and 23% in the placebo group. Two studies targeting CDK4/6 inhibitors in combination with mTOR inhibitors or paclitaxel are ongoing in PDAC (32,33). Other studies targeting low-incidence, operable mutations are ongoing, some with relatively significant results (34,35).…”