Efficacy of subsequent treatments after disease progression on CDK4/6 inhibitors therapy in patients with hormone receptor-positive metastatic breast cancer: A Kaplan-Meier derived individual-patient data meta-analysis.

person Lis Victoria Ravani Faculdade de Medicina da Universidade de São Paulo, Sao Paulo, Brazil info_outline Lis Victoria Ravani, Pedro Calomeni, Maysa Vilbert, Thiago Madeira, Ming Wang, Daxuan Deng, Laura Testa, Katherine Clifton, Seth Andrew Wander, Maryam B. Lustberg

Authors person Lis Victoria Ravani Faculdade de Medicina da Universidade de São Paulo, Sao Paulo, Brazil info_outline Lis Victoria Ravani, Pedro Calomeni, Maysa Vilbert, Thiago Madeira, Ming Wang, Daxuan Deng, Laura Testa, Katherine Clifton, Seth Andrew Wander, Maryam B. Lustberg Organizations Faculdade de Medicina da Universidade de São Paulo, Sao Paulo, Brazil, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil, Massachusetts General Hospital Cancer Center, Boston, MA, Federal University of Minas Gerais (UFMG), Belo Horizonte, Minas Gerais, Brazil, Case Western Reserve University, Cleveland, OH, Penn State University College of Medicine, Hershey, PA, Instituto do Câncer do Estado de São Paulo (ICESP), São Paulo, Brazil, Washington University School of Medicine, St. Louis, MO, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, Yale School of Medicine, New Haven, CT Abstract Disclosures Research Funding No funding sources reported Background: Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) combined with endocrine therapy (ET) are standard-of-care for patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/ HER2-) metastatic breast cancer (mBC). Yet, disease progression is common in these patients. In the absence of established guidelines for optimal sequencing post-progression, we conducted a pooled analysis of patient data to assess the efficacy of subsequent treatment options following disease progression on CDK4/6i therapy. Methods: We conducted a systematic review and meta-analysis, searching PubMed, Embase, Cochrane, and conference proceedings for randomized controlled trials (RCTs) and observational cohort studies reporting subsequent treatment post-CDK4/6i progression in patients with HR+HER2-mBC from 2016 to December 2023. We performed a pooled analysis of Kaplan-Meier-derived individual patient data for progression-free survival (PFS) and overall survival (OS). Subgroups analysis according to drug type, and a sensitivity analysis including only RCTs were also conducted. Statistical analysis was performed with R Statistical Software. Results: Of 12,895 identified records, 18 studies (7 RCTs and 11 cohort studies) comprising 4,868 patients with HR+HER2-mBC were included. Maintaining treatment with a CDK4/6i post-CDK4/6i progression was associated with longer PFS (HR: 0.64; 95% CI: 0.54-0.76; p<0.01; n=1,397) and prolonged OS (HR: 0.70; 95% CI: 0.61-0.79; p<0.01; n=2,369) compared with ET monotherapy. The PFS benefit was seen in both continuing the prior CDK4/6i (HR 0.62; 95%CI: 0.54-0.72; p<0.01; n=1,178) or switching to a different CDK4/6i (HR 0.49; 95%CI: 0.30-0.82; p<0.01; n=638). Subsequent therapy with PI3K/AKT/mTOR inhibitors plus ET also achieved longer PFS (HR: 0.74; 95% CI: 0.61-0.90; p<0.01; n=744), but significantly shorter OS (HR 1.36; 95%CI: 1.09-1.71; p<0.01; n=1,564) compared with ET monotherapy. PFS with chemotherapy was not different from ET monotherapy (HR 0.93; 95%CI: 0.76-1.13; p=0.45; n=879) but exhibited shorter OS (HR 1.55; 95%CI: 1.38-1.72; p < 0.01; n=2,476). Sensitivity analyses including only RCTs, confirmed the greater PFS of maintaining CDK4/6i plus ET compared with ET monotherapy (HR: 0.69 95% CI: 0.57-0.83; p<0.01; n=751). Conclusions: This extensive data pool of RCTs and cohort studies suggests the potential clinical benefit of continued CDK4/6i after disease progression compared to ET monotherapy. Data from phase III trials will further aid in understanding this question. Our data also supports current guideline recommendations of ET-based therapies over chemotherapy as the preferred treatment sequencing in HR+ HER2- mBC.