Advances in cyclin-dependent kinase inhibitors for the treatment of melanoma

Figures & data

Figure 1. Image illustrating the phosphorylation of Rb by the CyclinD/CDK4/6 complex, releasing E2F transcription factors to dissociate, subsequently driving G1/S transition through the cell cycle. This also permits further phosphorylation of Rb by the Cyclin E/CDK2 complex. The image also demonstrates the integration of other oncogenic pathways (e.g. JAK/STAT and PI3K/AKT/mTOR) within the Cyclin D/CDK4/6/Rb/p16INK4A axis. CDK 4/6 inhibitors disrupt this oncogenic pathway. Other sites of action of alternative CDK/cyclin complexes are also demonstrated and have been investigated as potential targets for therapy

Table 1. Summary of CDK inhibitor trials in melanoma

Compound (company)	Target	Phase and status	Trial details	NCT Identifier
Pan-CDKi’s (1^st and 2^nd generation)
Flavopiridol Alvocidib (Sanofi-Aventis)	CDK 1,2,4,7,9	Phase II Completed Phase I Completed	Advanced melanoma Flavopiridol+ cisplatin/carboplatin. Solid tumors including melanoma	NCT00005971 [76] NCT00003690 [77]
Roniciclib BAY-10,094 (Bayer)	CDK 1,2,3,4,7,9	Phase I Completed	Solid tumors including melanoma	NCT02047890 [78]
P1446A (Piramal)	CDK 1,4,9	Phase I Completed Phase I/II Suspended	Solid tumors including melanoma P1446A+vemurafenib in BRAF mutant advanced melanoma	NCT00840190 [82] NCT01841463 [83]
Dinaciclib SCH727695 (Sanofi-Aventis)	CDK 1,2,5,9	Phase I Completed Phase I/II Terminated Phase II Active, not recruiting	Solid tumors including melanoma Advanced melanoma Advanced melanoma	NCT00871663 [79] NCT01026324 [80] NCT00937937 [81]
Riviciclib P276-00 (Piramal)	CDK 1,4,9	Phase II Completed	Advanced melanoma with Cyclin D1 expression	NCT00835419 [58]
AT7519 (Astex)	CDK 1,2,4,5,9	Phase I Completed	Solid tumors including melanoma	NCT00390117 [59]
Specific CDKi’s
Single agent
Palbociclib PD033991 (Pfizer)	CDK 4,6	Phase I Completed Phase II Completed	Solid tumors including melanoma Solid tumors including melanoma	NCT00141297 [84] NCT01037790 [60]
Ribociclib LEE0011 (Novartis, Astex)	CDK 4,6	Phase I Completed	Solid tumors including melanoma	NCT01237236 [85]
Abemaciclib LY283519 (Eli Lily)	CDK 4,6	Phase I Active, not recruiting Phase I Completed Phase II Completed	Solid tumors including melanoma Solid tumors including melanoma Solid tumors including melanoma, with brain metastases	NCT01394016 [87] NCT02014129 [61] NCT02308020 [88]
Combination
Palbociclib+ Trametinib	CDK 4,6 MEK 1,2	Phase I/II Completed	Solid tumors including melanoma	NCT02065063 [90]
Ribociclib+ Encorafenib	CDK 4,6 BRAF^V600	Phase I/II Terminated Phase II Terminated	BRAF mutant melanoma BRAF mutant melanoma	NCT01777776 [89] NCT01820364 (LOGIC)
Ribociclib+ Binimetinib	CDK 4,6 MEK 1,2	Phase I/II Completed	NRAS mutant melanoma	NCT01781572 [91]
Ribociclib+ Encorafenib+ Binimetinib	CDK 4,6 BRAF ^V600 MEK 1,2	Phase I/II Active not recruiting Phase II Active, not recruiting	BRAF mutant melanoma BRAF mutant melanoma	NCT01543698 [92] NCT02159066 (LOGIC-2)
Abemaciclib+ LY3300054	CDK 4,6 Anti-PD-L1	Phase I Recruiting	Solid tumors including melanoma	NCT02791334 [95]

Table 2. Comparative pharmacokinetics of palbociclib, ribociclib and abemaciclib

	Palbociclib [48]	Ribociclib [70]	Abemaciclib [71]
Peak Drug Concentration (Cmax)	6–12 hours	1–5 hours	8 hours
Oral Bioavailability	46%	Unknown	45%
Elimination Half-life (hours)	28.8 hours	32 hours	24.8 hours
Volume of Distribution (Liters)	2583	1090	750
Metabolism	CYP3A4^a SULT2A1^b	CYP3A4^a	CYP3A4^a
Clearance (Liters/Hour)	63	25.5	21.8
Protein Binding	85%	93–98%	70%
Steady State (days)	8 days	8 days	5 daysggg

^aCytochrome P450 3A4

^bSulfotransferases 2A1

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