Osimertinib combined with dalpiciclib in EGFR-mutant, CDK4/6 pathway-altered, advanced NSCLC patients with acquired resistance to third-generation EGFR-TKIs: A phase II, prospective, multicenter, single-arm clinical trial

BackgroundAcquired resistance to third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), which is often mediated by alterations in the cyclin-dependent kinase 4/6 (CDK4/6) signaling pathway, poses a significant challenge in treating advanced EGFR-mutant non-small cell lung cancer (NSCLC). Preliminary evidence indicates that combining CDK4/6 inhibitors with third-generation EGFR-TKIs may overcome this resistance. However, there is limited clinical evidence for the safety and efficacy of this combination in advanced NSCLC patients who exhibit cell cycle gene dysregulation after progressing on earlier TKI therapies. Our trial assesses the efficacy of osimertinib and dalpiciclib co-administration for these patients, proposing a potentially more effective treatment strategy.Trial designIn this study subjects over 18 years old with EGFR-mutant advanced NSCLC were enrolled. Eligibility criteria included documented resistance to prior EGFR-TKIs, previous systemic chemotherapy, at least one measurable lesion as per RECIST 1.1, an Eastern Cooperative Oncology Group performance status between 0 to 2, and sufficient organ function. Specifically, patients that exhibited CDK4/6 pathway alternations, barring Rb mutations, received daily osimertinib (80mg) combined with dalpiciclib (125mg orally for 21 days followed by 7 days off) in each 28-day cycle. The study's primary endpoint is the objective response rate (ORR), while secondary endpoints involve progression-free survival (PFS), disease control rate (DCR), and safety outcomes. The study was based on Simon's two-stage design, with an alpha of 5% and a power of 80%, employing a null hypothesis ORR of 10% and an alternative ORR of 30%. In stage I,10 patients are accrued. If there are 1 or fewer responses, the study will be terminated early. Otherwise, an additional 19 patients will be accrued in stage II, resulting in a total sample size of 29. If there are 6 or more responses among these 29 patients, we claim the treatment is promising. The trial (NCT06363734) is actively recruiting.Legal entity responsible for the studyTianjin Medical University Cancer Hospital & Institute.FundingJiangsu Hengrui Pharmaceuticals Co.DisclosureAll authors have declared no conflicts of interest.