Table 1.

Activity of CDK4/6 inhibitors in clinical trials

IC50Target inhibition (p-RB)Clinical trial involving melanoma patients
CDK4/6 inhibitorCDK4/D1CDK6/D3CDK1/BCDK2/ACDK7CDK9/T1In vitroIn vivo (xenografts)PhenotypeTrialTumor typeReferences
PD0332991 (palbociclib)++++++++++++YesYesG1 arrest, senescence apoptosis- NCT01037790 Phase II (recruiting)Recurrent and stage IV melanoma(26, 84, 86)
LY2835219++++++++????YesYesG1 Arrest- NCT01394016 Phase I: MTD (recruiting)Advanced cancer (including melanoma)(80, 81)
LEE011++++++++++++YesYesG1 arrest, senescence apoptosis- NCT01237236 Phase I: LEE011 MTD (recruiting)Advanced solid tumors (including melanoma)(Sudha Parasuraman, Novartis; personal communication)
- NCT01781572NRAS mutant melanoma
Phase Ib & II: LEE011+ MEK162 MTD (recruiting)
- NCT01777776BRAF mutant melanoma
Phase I & II: LEE011 ± LGX818 MTD (recruiting)
P276-00++++++++++++++++++++YesYesG1–G2 arrest, apoptosis- NCT00835419 Phase II (complete)Melanoma positive for cyclin D1 expression(82, 83)
Flavopiridol++++++++++++++++++++YesNTG1–G2 arrest, apoptosis- NCT00005971 Phase II (completed; 44% SD, No OR)Metastatic melanoma(79, 101)
- NCT00003690 Phase I carboplatin/cisplatin/alvocidib + flavopiridol MTD (completed: 34%SD, no OR)Advanced solid tumors (including melanoma)

NOTE: IC50s should not be compared between compounds given different kinase assay conditions.

++++ IC50 < 100 nmol/L; +++ IC50 < 500 nmol/L; ++ IC50 < 5 μmol/L; + IC50 > 5 μmol/L.

Abbreviations: ?, Unknown; MTD, maximum tolerated dose; NT, not tested; OR, objective response; P-RB, phosphorylated retinoblastoma protein; SD, stable disease.