Place in Therapy of Cyclin-Dependent Kinase 4/6 Inhibitors in Breast Cancer: A Targeted Literature Review

Abstract

Cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6i) are the preferred regimen for patients with hormone receptor-positive and human epidermal growth factor receptor 2-negative (HR+/HER2-) advanced or metastatic breast cancer. However, the optimal treatment sequencing for CDK4/6i with other available therapeutic options is unclear. We conducted a targeted literature review to identify the current evidence on CDK4/6i treatment patterns in patients with breast cancer. The search was initially conducted in October 2021 and subsequently updated in October 2022. Biomedical databases and gray literature were searched, and bibliographies of included reviews were screened for relevant studies. The search identified ten reviews published since 2021 and 87 clinical trials or observational studies published since 2015. The included reviews discussed CDK4/6i usage with or without endocrine therapy (ET) in first-line and second-line treatment for patients with HR+/HER2- advanced or metastatic breast cancer, followed by ET, chemotherapy, or targeted therapy with ET. Clinical studies reported similar treatment sequences consisting of ET, chemotherapy, or targeted therapy with ET prior to CDK4/6i with ET, followed by ET monotherapy, chemotherapy, targeted therapy with ET, or continued CDK4/6i with ET. Current evidence suggests CDK4/6i are effective for HR+/HER2- advanced or metastatic breast cancer in earlier lines of therapy. Efficacy of CDK4/6i as measured by progression-free survival and overall survival was similar within a line of therapy regardless of the type of prior therapy. Survival on different post-CDK4/6i treatments was also similar within the same line of therapy. Additional research is needed to investigate the optimal place in therapy of CDK4/6i and the sequencing of treatments following progression on CDK4/6i.

Fig. 1

Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) study selection flow diagram. EudraCT European Union Drug Regulating Authorities Clinical Trials Database, WHO World Health Organization. MA meta-analysis, NMA network meta-analysis, SLR systematic literature review. Source: adapted from The PRISMA 2020 statement [101]

Fig. 2

Median progression-free survival (PFS, months) for cyclin-dependent kinase 4/6 inhibitor treatment are presented in the first-line setting. Each included patient population is presented along the X-axis with a unique reference number. The size of each bubble represents the sample size. A complete list of included studies and reported PFS is presented in Table 3. Ref # reference number

Fig. 3

Median progression-free survival (PFS, months) for cyclin-dependent kinase 4/6 inhibitor treatments are presented in the first-line (1L) to second-line (2L) setting. Each included patient population is presented along the X-axis with a unique reference number. The size of each bubble represents the sample size. Data were further grouped and color coded by the treatment received prior to cyclin-dependent kinase 4/6 inhibitor treatment. A complete list of included studies and reported PFS is presented in Table 3. #L number of lines of therapy, CT chemotherapy, ET endocrine therapy, NR not reported, Ref # reference number

Fig. 4

Median progression-free survival (PFS, months) for cyclin-dependent kinase 4/6 inhibitor treatment are presented in the second-line plus (2L+) to third-line (3L) setting. Each included patient population is presented along the X-axis with a unique reference number. The size of each bubble represents the sample size. Data were further grouped and color coded by the treatment received prior to cyclin-dependent kinase 4/6 inhibitor treatment. A complete list of included studies and reported PFS is presented in Table 3. #L number of lines of therapy, CT chemotherapy, NR not reported, Ref # reference number

Fig. 5

Median progression-free survival (PFS) for cyclin-dependent kinase 4/6 inhibitor treatment are presented in the third-line plus (3L+) setting. Each included patient population is presented along the X-axis with a unique reference number. The size of each bubble represents the sample size. Data were further grouped and color coded by the treatment received prior to cyclin-dependent kinase 4/6 inhibitor treatment. A complete list of included studies and reported PFS are presented in Table 3. #L number of lines of therapy, 4L fourth line, 6L sixth line, CT chemotherapy, ET endocrine therapy, NR not reported, Ref # reference number

Fig. 6

Median overall survival (OS, months) for cyclin-dependent kinase 4/6 inhibitor treatment is presented in the first-line setting. Each included patient population is presented along the X-axis with a unique reference number. The size of each bubble represents the sample size. A complete list of included studies and reported OS is presented in Table 4. #L number of lines of therapy, Ref # reference number

Fig. 7

Median overall survival (OS, months) for cyclin-dependent kinase 4/6 inhibitor treatment is presented in the first-line plus (1L+) to second-line (2L) setting. Each included patient population is presented along the X-axis with a unique reference number. The size of each bubble represents the sample size. Data were further grouped and color coded by the treatment received prior to cyclin-dependent kinase 4/6 inhibitor treatment. A complete list of included studies and reported OS is presented in Table 4. #L number of lines of therapy, 3L third line, ET endocrine therapy, Ref # reference number

Fig. 8

Median overall survival (OS, months) for cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) treatment is presented in the second line plus (2L+) setting. Each included patient population is presented along the X-axis with a unique reference number. The size of each bubble represents the sample size. Data were further grouped and color coded by the treatment received prior to CDK4/6i treatment. A complete list of included studies and reported OS is presented in Table 4. #L number of lines of therapy, 1L first line, 3L third line, 4L fourth line, CT chemotherapy, ET endocrine therapy, Ref # reference number

Fig. 9

Median progression-free survival [PFS, months] (A) and median overall survival [OS, months] (B) of post-cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) treatments grouped by the therapy line in which subsequent therapy was received. Each subsequent treatment is presented along the X-axis with a unique reference number. The size of each bubble represents the sample size. Data were further grouped and color coded by the subsequent treatment received. Complete lists of included studies and reported PFS and OS are presented in Tables 5 and 6, respectively. #L number of lines of therapy, 2L second line, 3L third line, 4L fourth line, CT chemotherapy, ET endocrine therapy, NR not reported, Ref # reference number