Table 2.

Highlights of representative completed and ongoing clinical trials with CDK4/6 inhibitors

Cancer typeDrug(s) (trial phase)Description and outcomeReferences
Monotherapy trials
Advanced solid tumors (various)PalbociclibDrug dosage, PK/PD, and dose-limiting toxicities were established. Stable disease realized in 19 of 74 patients.(69, 70)
NCT00141297(phase I, completed)
Advanced solid tumors (various)RibociclibDrug dosage, PK/PD, and dose-limiting toxicities established in 85 patients. Reductions in Ki67 and phosphorylated RB documented in paired pre- and posttreatment tumor biopsies. Stable disease for >6 treatment cycles in 14% of patients.(90, 91)
NCT01237236(phase I)
Advanced solid tumors (various)AbemaciclibDrug dosage, PK/PD, and dose-limiting toxicities determined. Drug efficiently crosses the blood:brain barrier to equal plasma concentrations.(92)
NCT01394016(phase I)
Advanced solid tumors or hematologic malignancies (various)RibociclibSIGNATURE: to determine efficacy of treatment in previously treated patients preidentified as having CDK4/6 pathway–activated tumors (including p16 loss or CDK4/6 or cyclin D1/D3 amplification).(133)
NCT02187783(phase II)Outcome not reported
MCLPalbociclibOf 17 patients receiving drug on the 3/1 schedule, reductions in RB phosphorylation and tumor proliferation (Ki67 and fluorothymidine PET) occurred during the first cycle in most patients. Five heavily pretreated patients achieved PFS of >1 year.(75)
NCT00420056(PD study, completed)
MCLAbemaciclibOf 22 patients with relapsed or refractory disease who received >6 treatment cycles, there were five partial responses, and 9 patients with stable disease.(105)
NCT01739309(phase II)
LiposarcomaPalbociclibOf 30 patients who had progressed on prior therapy, 66% were progression-free after 12 weeks on a 2/1 schedule. Eight patients remained on study for >40 weeks with tumor regressions in 4 patients and one complete response.(69, 77, 80)
NCT01209598(phase II)
Breast cancerPalbociclib37 patients enrolled with 2 partial responses and 5 with stable disease for a clinical benefit rate of 19% overall and 29% in HR+/HER2 negative disease.(82)
NCT01037790(phase II)
Breast cancerAbemaciclibExpansion cohort of phase I trial. Evaluation in 25 heavily pretreated patients with ER+/HER2 disease in which 72% exhibited overall clinical benefit. Drug was also evaluated in 11 patients with HR+/HER2+ disease (with 100% control rate); 5 patients with HR/HER2+ disease exhibited stable disease of only brief duration. Median duration of response for all treated HR+ patients was 13.4 months with 8.8-month PFS.(92, 95, 96)
NCT01394016(phase I)
Breast cancerAbemaciclibMONARCH-1. Based on monotherapy responses seen in expansion cohort of the phase I trial. Evaluating monotherapy for patients whose disease has progressed despite prior chemotherapy.Not reported
NCT02102490(phase II)
Breast cancerAbemaciclibDesigned to exploit traversal of the blood–brain barrier by abemaciclib. Assessment in breast cancer patients with brain metastases in 3 cohorts: (1) HR+/HER2+; (2) HR+/HER2; (3) patients eligible for resection, 5–14 days prior to surgery.Not reported
NCT02308020(phase I)
NSCLCPalbociclib16 patients enrolled with advanced disease and evidence of CDKN2A loss on the 3/1 schedule. 8 patients were progression-free >4 months.(101)
NCT01291017(phase II)
NSCLCAbemaciclibExpansion cohort in phase I trial. In 15 of 31 patients who remained on trial for >6 months, overall disease control rate was 49% with 6-month PFS in 26%. Patients with tumors harboring KRAS mutation showed greater disease control.(92, 102)
NCT01394016(phase I)
GBMAbemaciclibExpansion cohort in phase I trial. Two of 17 patients showed decreases in tumor size and prolonged time to progression.(92)
NCT01394016(phase I)
MelanomaAbemaciclibExpansion cohort in phase I trial. 26 patients enrolled. Partial response observed in a patient with tumor harboring NRAS mutation and CDKN2A loss.(92)
NCT01394016(phase I)
Germ cell tumorPalbociclib30 patients enrolled to 3/1 schedule, based on preliminary efficacy seen in patients with growing teratoma syndrome in phase I trial. 24-week PFS rate 28%, with efficacy predominantly in patients with teratoma or teratoma with malignant transformation.(73, 74)
NCT01037790(phase II)
Hormonal combinations in ER+ breast cancer
Breast cancerPalbociclibPALOMA-1: 165 postmenopausal women with advanced ER+/HER2 disease who had not received systemic treatment for advanced disease were randomized to receive letrozole vs. letrozole/palbociclib. Mean PFS was 10.2 months with letrozole alone and 20.2 months for the combination. CCND1 amplification and CDKN2A loss did not predict benefit. Provisional FDA approval for this indication was obtained in early 2015, and data are awaited from phase III evaluation (PALOMA-2).(83)
NCT00721409Letrozole
NCT01740427(phase II/III)
Breast cancerPalbociclibPALOMA-3: Interim analysis of ongoing phase III study of pre- and postmenopausal women with advanced ER+/HER2 disease reported PFS of 9.2 months with combination vs. 3.8 months with fulvestrant alone.(84)
NCT01942135Fulvestrant
(phase III)
Breast cancerAbemaciclibMONARCH-2: Fulvestrant with or without abemaciclib.Not reported
NCT02107703Fulvestrant
(phase III)
Breast cancerAbemaciclibMONARCH-3: Anastrozole or letrozole with placebo or abemaciclib.Not reported
NCT02246621Aromatase inhibitors
(phase III)
Breast cancerRibociclibMONALEESA 1: Presurgical study of letrozole vs. letrozole/ribociclib in early breast cancer patients.Results pending
NCT01919229Letrozole
(phase II, completed)
Breast cancerRibociclibMONALEESA 2: First-line metastatic trial in postmenopausal patients randomizing letrozole to letrozole/ribociclib.Not reported
NCT01958021Letrozole
(phase III)
Breast cancerRibociclibMONALEESA 3: Randomized double-blind, placebo-controlled study in postmenopausal women with HR+/HER2 advanced disease who have received no or 1 line of endocrine treatment.Not reported
NCT02422615Fulvestrant
(phase III)(phase III)
Breast cancerRibociclibMONALEESA 7: Randomized double-blind, placebo-controlled study of tamoxifen or an aromatase inhibitor with goserelin along with ribociclib or placebo in pre- or perimenopausal women with HR+/HER2 breast cancer.Not reported
NCT02278120Aromatase inhibitors
Tamoxifen
Goserelin
(phase III)
Breast cancerRibociclibExample of triplet therapy combining CDK4/6 inhibition, hormonal therapy, and an α isoform-selective PI3K inhibitor.(116)
NCT01872260Letrozole
BYL719
(phase I/II)
MAP kinase pathway combinations
BRAF-mutant melanomaRibociclibPhase I study followed by the randomized phase II of LGX818 vs. LGX818/ribociclib in BRAF inhibitor–naïve population and assessment of LGX818/ribociclib in BRAF inhibitor–resistant population.Not reported
LGX818
NCT01777776(phase I/II)
NRAS-mutant melanomaRibociclibPreliminary phase I results among 14 patients demonstrated 6 with partial response and 6 with stable disease (4 of whom had >20% regression).(114)
Binimetinib
NCT01781572(phase Ib/II)
RAS-mutant cancersPalbociclibPhase I trial with expansion in KRAS-mutant NSCLC.Not reported
PD0325901
NCT02022982(phase I/II)
RAS-mutant cancersPalbociclibPhase I trial with expansion in NRAS-mutant melanoma.(137)
Trametinib
NCT02065063(phase I)
Other combinations
MCLPalbociclibTrial of palbociclib and ibrutinib in previously treated MCL.Not reported
NCT02159755Ibrutinib
(phase I)
Small cell lung cancerG1T28Phase I followed by randomization of etoposide/carboplatin ± G1T28; first trial utilizing CDK4/6 inhibitor to protect bone marrow function from effects of chemotherapy in an RB-negative tumor type.Not reported
(ref. 130)
NCT02499770Etoposide
Carboplatin
(phase I)

Abbreviation: GBM, glioblastoma multiforme.