Table 2. Reported clinical trials with targeted CDK4 and CDK6 inhibitors.

Tumour type	Phase	Dosage	Response rate	Refs
Palbociclib (PD-0332991)
Advanced melanoma, breast cancer, renal cancer, ovarian cancer, liposarcoma and colon cancer, among others	Phase Ia (dose escalation) N = 41	Administered over 6 cohorts (standard 3 + 3) 3 weeks on, 1 week off RP2D: 125 mg PO OD	SD: 27% (10/37)	178
Liposarcoma, colon cancer and melanoma, among others	Phase Ia N = 33 (RB positive)	Administered over 4 cohorts 2 weeks on; 1 week off RP2D: 200 mg PO OD	PR: 3% (1/31; testicular cancer) SD: 29% (9/31)	163
Relapsed mantle cell lymphoma with ≥1 of: CCND1 positivity by immunostaining, t(11;14) translocation on cytogenetic analysis and molecular evidence of CCND1–IGH rearrangement	Phase I N = 17	100–125 mg PO OD	CR: 6% (1/16) PR: 12% (2/16) SD: 43% (7/16)	165
ER-positive and HER2-negative metastatic breast cancer	Phase Ib N = 12	Palbociclib (125mg PO OD; 2 weeks on; 1 week off) + letrozole (2.5mg PO OD; continuous)	PR: 25% (3/12) SD: 75% (9/12)	198
ER-positive and HER2-negative metastatic breast cancer	Phase II (PALOMA-1; TRIO-18) Palbociclib + letrozole versus letrozole alone in 1:1 randomization N = 165	Palbociclib (125 mg; 3 weeks on; 1 week off) + letrozole (2.5 mg; continuous)	PFS: 20.2 months for palbociclib + letrozole versus 10.2 months for letrozole alone (HR = 0.488 (95% CI: 0.319–0.748) and 1-sided p = 0.0004) OS: 37.5 months for palbociclib + letrozole versus 33.3 months for letrozole alone (HR = 0.813; p = 0.2105)	173
Metastatic breast cancer (64% ER-positive; 7% ER-positive and HER2-positive; 29% TNBC)	Phase II N = 37 (RB positive)	125 mg PO 3 weeks on; 1 week off	PR: 7% (2/28) SD: 50% (14/28) PFS: 4.1 months for ER-positive (95% CI: 2.3–7.7) PFS: 18.8 months for ER-positive and HER2-positive (95% CI: 5.1-∞) PFS: 1.8 months (95% CI 0.9-∞) for TNBC	199
Well-differentiated (17%) and dedifferentiated (83%) liposarcoma with CDK4 amplification detected by FISH and RB expression detected by IHC	Phase II N = 30	200 mg PO OD 2 weeks on; 1 week off	PR: 3% (1/30) at 74 weeks; 19/30 were progression-free at 12 weeks PFS: median 18 weeks PFS: 66% (90% CI: 51–100%) at 12 weeks Met primary end point of exceeding PFS rate of 40% at 12 weeks for active second-line agent	166
LEE011
RB-positive advanced solid tumours and lymphomas	Phase I N = 132	Stage 1 (N = 85): Treatment arm 1: escalating LEE011 doses (3 weeks on; 1 week off) Treatment arm 2: escalating LEE011 doses (continuous) Stage 2 (N = 47): RP2D expansion MTD: 900mg; RP2D: 600 mg using 3 weeks on; 1 week off schedule	PR: 2.9% (2/70) at 600 mg per day SD: 26% with >4 cycles and 14% with >6 cycles	167
Post-menopausal ER-positive, HER2-negative metastatic breast cancer	Phase Ib LEE011 + everolimus (mTOR inhibitor) + exemestane (aromatase inhibitor) N = 6	Treatment arm 1: escalating LEE011 doses (starting 200 mg per day; 3 weeks on; 1 week off) + everolimus (2.5 mg per day, fixed continuous) + exemestane (25 mg per day; continuous) Treatment arm 2: safety run-in with LEE011 (600 mg per day; 3 weeks on; 1 week off) + exemestane (25 mg per day; continuous)	Preliminary results indicate that triple combination is tolerable Efficacy data not yet available	200
Post-menopausal ER-positive, HER2-negative locally advanced or metastatic breast cancer	Phase Ib LEE011 + BYL719 (PI3Kα inhibitor) + letrozole N = 11	Treatment arm 1: LEE011 (3 weeks on; 1 week off) + letrozole (2.5 mg; continuous); 4 week cycle Treatment arm 2: BYL719 (continuous) + letrozole (2.5 mg; continuous); 4 week cycle Treatment arm 3: LEE011 + BYL719 (continuous) + letrozole (2.5 mg; continuous); 4 week cycle	Efficacy data not yet available	201
NRAS-mutant metastatic melanoma	Phase Ib (single arm) LEE011 + binimetinib (MEK inhibitor) N = 14	LEE011 (starting 200 mg per day OD; 3 weeks on; 1 week off) + binimetinib (45 mg PO BD)	PR: 43% (6/14) SD: 43% (6/14) Promising preliminary antitumour activity	202
Abemaciclib (LY2835219)
Non-small cell lung cancer (KRAS wild type and KRAS mutant)	Phase I N = 49	MTD already established at 200 mg in earlier stage of study Treatment arm 1 (N = 25): 200 mg PO BD continuous (28-day cycle) Treatment arm 2 (N = 24): 150 mg PO BD continuous (28-day cycle)	RR: 2% PR (1/49) Overall DCR: 51% DCR 37% (19/49) for KRAS wild type and 54% (26/49) for KRAS mutant PFS: 2.1 months	203
Hormone receptor-positive metastatic breast cancer	Phase I Abemaciclib + fulvestrant N = 60	Treatment arm 1 (N = 47): abemaciclib (200 mg BD PO; continuous; 28-day cycle) Treatment arm 2 (N = 13): abemaciclib + fulvestrant (500 mg IM every 4 weeks)	PR: 17% (8/47) with 6% (3/47) unconfirmed Single-agent activity demonstrated; acceptable safety profile in combination with fulvestrant Further evaluation required	204

BD, twice daily; CCND1, cyclin D1; CDK, cyclin-dependent kinase; CR, complete response; DCR, disease control rate (CR+PR+SD); ER, oestrogen receptor; FISH, fluorescence in situ hybridization; HR, hazard ratio; IHC, immunohistochemistry; IGH, immunoglobulin heavy locus; IM, intramuscularly; MTD, maximum tolerated dose; mTOR, mammalian target of rapamycin; N, number of patients; OD, once daily; OS, overall survival; PFS, progression-free survival; PI3Kα, phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K), catalytic subunit-α; PO, oral route; PR, partial response; RB, retinoblastoma protein; RP2D, recommended Phase II dose; RR, response rate; SD, stable disease; TNBC, triple-negative breast cancer.