The expression of CDK4/6 in tumors
CDK4/6-related signaling pathways
The expression of CDK4/6 in different tumors
Role of the CDK4/6 gene in tumor progression and prognosis
Clinical application of CDK 4/6 inhibitors in breast cancer and other tumors
Application of CDK 4/6 inhibitors in breast cancer
CDK inhibitors | Study ID | Phase | Lines | Patients | Regimens | Efficacy |
---|---|---|---|---|---|---|
Palbociclib | PALOMA-1 [25] | II | First-line | HR+/HER2− ABC | Palbociclib + letrozole (n = 84)/letrozole (n = 81) | mPFS 20.2 m vs 10.2 m, HR 0.488, 95% CI 0.319–0.748, p = 0.0004 |
PALOMA-2 [36] | III | First-line | HR+/HER2− ABC | Palbociclib + letrozole (n = 444)/letrozole (n = 222) | mPFS 24.8 m vs 14.5 m, HR 0.58, 95% CI 0.46–0.72, p < 0.001 | |
PALOMA-3 [30] | III | First/second-line | HR+/HER2− ABC with previous ET | Palbociclib + fluvastatin (n = 347)/fluvastatin (n = 174) | mOS 34.9 m vs 28.0 m, HR 0.81, 95% CI 0.64–1.03, p = 0.09 | |
NCT01684215 [37] | II | First-line | Postmenopausal Japanese patients with HR+/HER2− ABC | Palbociclib + letrozole (n = 42) | PFS at 1 year 75.0%, mPFS NR, ORR 40.5%, DCR 85.75% | |
NCT02592746 (active, not recruiting) | II | First/second/third-line | Premenopausal Women With HR+ MBC | Palbociclib + exemestane + leuprolide acetate/capecitabine (N = 182) | mPFS 9.2 m vs 3.8 m, p < 0.001 | |
Ribociclib | MONALEESA-2 [38] | III | First-line | Postmenopausal women with HR+/HER2− ABC | Ribociclib + letrozole (n = 334)/letrozole (n = 334) | mPFS NR vs 14.7 m, HR 0.56, 95% CI 0.43–0.72, p < 0.001 |
MONALEESA-3 [39] | III | First/second-line | HR+/HER2− ABC | Ribociclib + fulvestrant (n = 484)/fulvestrant (n = 242) | mPFS 20.5 m vs 12.8 m, HR 0.59, 95% CI 0.48–0.73, p < 0.001 | |
MONALEESA-7 [40] | III | First/second-line | Premenopausal women with HR+/HER2− ABC | Ribociclib + ET (n = 335)/ET (n = 337) | mPFS 23.8 m vs 13.0 m, HR 0.55, 95% CI 0.44–0.69, p < 0.001 | |
TRINITI-1 NCT02732119 (active, not recruiting) | I/II | Non-first line | Patients with HR+/HER2− ABC | Ribociclib + everolimus + exemestane (n = 107) | mPFS 5.7 m, ORR 8.4% | |
Abemaciclib | MONARCH-1 [35] | II | Non-first line | Refractory HR+/HER2− ABC | Abemaciclib (n = 132) | ORR 19.7%, clinical benefit rate (CR + PR + SD ≥ 6.0 m) 42.4%, mPFS 6.0 m, mOS 17.7 m |
MONARCH-2 [31] | III | Non-first line | HR+/HER2− ABC | Abemaciclib + fulvestrant (n = 446)/fulvestrant (n = 223) | mPFS 16.4 m vs 9.3 m, HR 0.55, 95% CI 0.45–0.68, p < 0.001 | |
MONARCH 3 [33] | III | First-line | Postmenopausal women with HR+/HER2− ABC | Abemaciclib + nonsteroidal AI (n = 223)/nonsteroidal AI (n = 223) | mPFS NR vs 14.7 m, HR 0.54, 95% CI 0.41–0.72, p < 0.001, ORR 59% vs 44%, p = 0.004 |
Application and expansion of CDK4/6 inhibitors in other solid tumors
CDK inhibitors | Study ID | Phase | Lines | Patients | Regimens | Efficacy |
---|---|---|---|---|---|---|
Palbociclib | NCT01209598 [47] | II | Non-first line | Advanced WD/DDLS | Palbociclib (n = 60) | PFS at 12 weeks 57.2%; mPFS 17.9 weeks |
NCT02101034 [46] | II | Non-first line | HNSCCs | Palbociclib + cetuximab (n = 62) | ORR 39% (in platinum-resistant patients), ORR 19% (in cetuximab-resistant patients) | |
NCT01037790 (recruiting) | II | UK | RB/germ cell tumors | Palbociclib (n = 205) | PFS at 6 months 28%; mPFS 11 weeks | |
NCT01536743 (active, not recruiting) | II | Non-first line | Ovarian epithelial carcinoma | Palbociclib (n = 26) | PFS at 6 months 15% | |
NCT00420056 [48] | Ib | UK | MCL | Palbociclib (n = 17) | 6% CR, 12% PR, 41% SD, mPFS 4.0 m | |
Ribociclib | CLEE011X2105 [45] | Ib/II | Non-first line | BRAF V600-mutant melanoma | Ribociclib (n = 18) | 2 PR, 6 SD |
CMEK162X2114 [49] | Ib/II | UK | NRAS-mutant melanoma | Ribociclib + binimetinib (n = 22) | 7 PR, 11 SD, 33% had 20–30% tumor shrinkage | |
Abemaciclib | NCT01394016 [44] | I | UK | Breast cancer; NSCLC; Melanoma; Glioblastoma; CRC | Abemaciclib (n = 225) | Breast cancer (n = 47) 23% PR, 47% SD, 23% ORR, 49% CBR, 70%DCR, mPFS 5.8 m; NSCLC (n = 68), 3% PR, 46% SD, 3% ORR, 49% DCR, mPFS 2.0 m; melanoma (n = 26) 4% PR, 23% SD, 4% ORR, 27% DCR; glioblastoma (n = 17) 18% SD, 18% DCR; CRC (n = 15) 13% SD, 13% DCR |
NCT02014129 [50] | I | Non-first line | Various advanced cancer | Abemaciclib (n = 12) | tumor size changed from 35% decrease to 25% increase, > 30% tumor shrinkage in 2 patients |
Correlations between CDK4/6-related proteins and classical tumor signaling pathway molecules
CDK4/6 inhibitors combined with endocrine therapy
CDK4/6 inhibitors combined with immunotherapy
CDK4/6 inhibitors combined with targeted therapy
CDK4/6 inhibitor combined with other treatments
The resistance and efficacy prediction of CDK4/6 inhibitors
Resistance type | Resistance mechanism |
---|---|
Cyclin-CDK complex increase | CDK6 amplification |
CCNE1 amplification | |
Cyclin D-CDK4/6-Rb pathway regulation | Cyclin D deficiency Rb inactivation or deletion |
FAT1 loss | |
Others | FGFR1 amplification |