Samotolisib

Pancreatic ductal adenocarcinomas (PDAC) are characterized by frequent cell cycle pathways aberrations. This study evaluated safety and efficacy of abemaciclib, a cyclin‐dependent kinase 4 and 6 inhibitor, as monotherapy or in combination with PI3K/mTOR dual inhibitor LY3023414 or TGFβ inhibitor galunisertib versus standard of care (SOC) chemotherapy in patients with pretreated metastatic PDAC.

This Phase 2 open‐label study enrolled patients with metastatic PDAC who progressed after 1–2 prior therapies. Patients were enrolled in a safety lead‐in (abemaciclib plus galunisertib) followed by a 2‐stage randomized design. Stage 1 randomization was planned 1:1:1:1 for abemaciclib, abemaciclib plus LY3023414, abemaciclib plus galunisertib, or SOC gemcitabine or capecitabine. Advancing to Stage 2 required a disease control rate (DCR) difference ≥0 in abemaciclib‐containing arms versus SOC. Primary objectives for Stages 1 and 2 were DCR and progression‐free survival (PFS), respectively. Secondary objectives included response rate, overall survival, safety, and pharmacokinetics.

One hundred and six patients were enrolled. Abemaciclib plus galunisertib did not advance to Stage 1 for reasons unrelated to safety or efficacy. Stage 1 DCR was 15.2% with abemaciclib monotherapy, 12.1% with abemaciclib plus LY3023414, and 36.4% with SOC. Median PFS was 1.7 months (95% CI: 1.4–1.8), 1.8 months (95% CI: 1.3–1.9), and 3.3 months (95% CI: 1.1–5.7), respectively. No arms advanced to Stage 2. No new safety signals were identified.

In patients with pretreated metastatic PDAC, abemaciclib‐based therapy did not improve DCRs or PFS compared with SOC chemotherapy. No treatment arms advanced to Stage 2. Abemaciclib remains investigational in patients with PDAC.

Pleural mesothelioma (PM) is an aggressive malignancy with limited treatment options. The first-line therapy has remained unchanged for two decades and consists of pemetrexed in combination with cisplatin. Immune-checkpoint inhibitors (nivolumab plus ipilimumab) have high response rates, resulting in recent updates in treatment recommendations by the U.S. Food and Drug Administration. However, the overall benefits of combination treatment are modest, suggesting that other targeted therapy options should be investigated.

We employed high-throughput drug sensitivity and resistance testing on five established PM cell lines using 527 cancer drugs in a 2D setting. Drugs of the greatest potential (n = 19) were selected for further testing in primary cell models derived from pleural effusions of seven PM patients.

All established and primary patient-derived PM cell models were sensitive to the mTOR inhibitor AZD8055. Furthermore, another mTOR inhibitor (temsirolimus) showed efficacy in most of the primary patient-derived cells, although a less robust effect was observed when compared with the established cell lines. Most of the established cell lines and all patient-derived primary cells exhibited sensitivity to the PI3K/mTOR/DNA-PK inhibitor LY3023414. The Chk1 inhibitor prexasertib showed activity in 4/5 (80%) of the established cell lines and in 2/7 (29%) of the patient-derived primary cell lines. The BET family inhibitor JQ1 showed activity in four patient-derived cell models and in one established cell line.

mTOR and Chk1 pathways had promising results with established mesothelioma cell lines in an ex vivo setting. In patient-derived primary cells, drugs targeting mTOR pathway in particular showed efficacy. These findings may inform novel treatment strategies for PM.