Polo-like kinase 1 inhibition in NSCLC: mechanism of action and emerging predictive biomarkers

Figures & data

Figure 1 Structure and function of the human Polo-like kinases: (A) Polo-like kinases in human cells. Schematic representation of the five identified PLKs in human cells. The open reading frame amino-acid lengths are shown on the right, the kinase domain is shown in red color with the corresponding amino-acid position. Polo-box domains are shown in blue color. (B) Schematic diagram of the cell cycle functions of PLK1.

Abbreviations: PLK, Polo-like kinases; KD, kinase domain; PB, Polo-box domain; aa, amino acids.

Table 1 PLK1 inhibitors invovled in clinical trials with lung cancer

Compound	Company	Mode of action	Target structure	PLK1 IC50	Clinical trial DLT	Status
BI 2536	Boehringer Ingelheim	ATP-competitive	PLK1, PLK2, PLK3	0.8 nM	Neutropenia, neutropenic infection, GIT	On hold
BI 6727 (Volasertib)	Boehringer Ingelheim	ATP-competitive	PLK1	0.87 nM	Neutropenia, thrombocytopenia	Ongoing in solid and hemat. malignancies
GSK461364A	Glaxo-Smith-Kline	ATP-competitive	PLK1, PLK2, PLK3	2.2 nM	Neutropenia, thrombocytopenia	On hold
ON01910.Na (Rigosertib)	Onconova Therapeutics	non ATP-competitive	PLK1, PLK2, PI3K, Abl, Flt-1, PDGFR	9 nM	Neutropenia, hyponatriemia, delirium, urinary symptoms, pelvic pain	Ongoing in hemat. malignancies
MK-1496	Merck	ATP-competitive	PLK1	n/a	Neutropenia, thrombocytopenia, anemia
NMS-1,286,937	Nerviano Medical Sciences	ATP-competitive	PLK1	2 nM	Neutropenia, thrombocytopenia, hypokaliemia	On hold
TAK-960	Takeda	ATP-competitive	PLK1, PLK2	0.8 nM	Not reported	Clinical trial was terminated, on hold
HMN-214	Nippon Shinyaku Co. Ltd.	Not reported	PLK1	0.12 µM	GIT, arthralgia, myalgia	On hold

Abbreviations: PLK, Polo-like kinases; GIT, gastrointestinal toxicity; ATP, adenosine triphosphate.

Table 2 Clinical trials involving PLK1 inhibitors and patients with lung cancer

Compound	Author	Year	Phase	Lung cancer patients enrolled	Primary and secondary study aims	Efficacy	Intervention/treatment	Safety issues/DLT
BI 2536	Sebastian et al^Citation44	2010	II	R/R NSCLC, n=59	ORR, PFS, OS	ORR, 2%; PFS, 49 days; OS, 201 days;	150–200 mg total dose/cycle	Neutropenia, fatigue, GIT
BI 2536	Hofheinz et al^Citation43	2010	I	R/R solid tumors, n=1 NSCLC, n=1 SCLC	MTD, safety, ORR, PK	No response in SCLC	50–200 mg total dose/cycle	Neutropenie, thrombopenia, exanthema
BI 2536	Ellis et al^Citation45	2013	I	R/R NSCLC, n=41	MTD, safety, ORR, PK	ORR (5%)	100–325 mg total dose/cycle + Pemetrexed	Neutropenia, fatigue, exanthema, GIT
BI 6727	Gil et al^Citation51	2010	I	R/R solid tumors, n=10 NSCLC	MTD, safety, ORR, PK	No response in NSCLC	12–450 mg total dose/cycle	Neutropenia, thrombocytopenia, fatigue
BI 6727	Lin et al^Citation53	2014	I	R/R solid tumors, n=4, NSCLC	MTD, safety, ORR, PK	No response in NSCLC	100–400 mg total dose/cycle	Neutropenia, Thrombopenia, anemia
BI 6727	Machiels et al^Citation54	2015	I	R/R solid tumors, n=1 NSCLC	MTD, safety, PFS, PK	PR in NSCLC	150–300 mg total dose/cycle + Afatinib	Neutropenia, thrombocytopenia, GIT
BI 6727	Ellis et al^Citation45	2015	II	R/R NSCLC, n=131	PFS, ORR, safety, PK	PFS, ORR 3.3 m, 21% (Volasertib + Pemetexed) vs 5.3 m, 10.6% (Pemetrexed) vs 1.4 m, 8.1% (Volasertib)	300 mg total dose/cycle + Pemetrexet vs Volasertib mono vs Pemetrexet mono	Fatuige, neutropenia
BI 6727	Braud et al^Citation56	2015	I	R/R solid tumors, n=5, NSCLC	MTD, safety, PFS, PK	1 PR in NSCLC	100–400 mg total dose/cycle + Nintedanib	Neutropenia, thrombopenia
BI 6727	Nokihara et al^Citation55	2015	I	R/R solid tumors, n=5, NSCLC	MTD, safety, ORR, PK	No response in NSCLC	200–350 mg total dose/cycle	Neutropenia, thrombopenia
HMN-214	Garland et al^Citation62	2006	I	R/R solid tumors, n=7, NSCLC	MTD, safety, ORR, PK	No response in NSCLC	3–9.9 mg/m^2 total dose/cycle	Fatigue, arthralgia, GIT
NMS-1286937	Weiss et al^Citation63	2018	I	R/R solid tumors, n=2, NSCLC	MTD, safety, ORR, PK, biomarker	No response in NSCLC	6–48 mg/m^2 total dose/cycle	Neutropenia, thrombocytopenia
ON01910.Na	Ohnuma et al^Citation60	2013	I	R/R solid tumors, n=2, NSCLC	MTD, safety, ORR, PK	No response in NSCLC	50–1,700 mg total dose/cycle	Neutropenia, delirium, confusion, GIT
ON01910.Na	Bowles et al^Citation61	2014	I	R/R solid tumors, n=1, NSCLC	MTD, safety, ORR, PK, biomarker	No response in NSCLC	70–700 mg total dose/cycle	Urinary symptoms, pelvic pain, fatigue

Abbreviations: R/R, relapsed or refractory; ORR, overall response rate; PFS, progression-free survival; OS, overall survival; PK, pharmacokinetics; MTD, maximum tolerated dose; SCLC, small cell lung cancer; NSCLC, non-small cell lung cancer.

Table 3 Active clinical trials with PLK1 inhibitors in solid malignancies/NSCLC

Compound	Study start date	Estimated study completion date	Phase	Intervention/treatment	Key eligibility criteria (planned enrollment)	Primary and secondary study aims	NCT number
BI 6727 (Volasertib)	04-11-2005	26-08-2022	I	BI6727 dose escalation	R/R solid tumors (n=65)	MTD, ORR, PFS, PK	NCT02273388
BI 6727 (Volasertib)	13-05-2014	15-04-2019	I	BI6727+ Itraconazol	R/R solid tumors (n=28)	PK	NCT01772563

Abbreviations: R/R, relapsed or refractory; ORR, overall response rate; PFS, progression-free survival; OS, overall survival; PK, pharmacokinetics; MTD, maximum tolerated dose; NSCLC, non-small cell lung cancer.

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