Recent advances of cyclin-dependent kinases as potential therapeutic targets in HR+/HER2− metastatic breast cancer: a focus on ribociclib

Figures & data

Figure 1 Illustrated description of cell cycle progression and potential pathways for cancer therapy.

Notes: += stimulates; − = inhibits.

Table 1 Overview of common FDA-approved/investigational CDK4/6 inhibitors and their potential treatment profile

Drug name	First year of FDA approval	Clinical condition for which the drug is approved or under clinical trial	Route (dosage form)	Dose (mg/day)	Targeted regulator	References
Palbociclib (PD0332991; IBRANCE^®)	2015	HR+/HER2− advanced or metastatic breast cancer in combination with:  ○ an aromatase inhibitor as initial endocrine-based therapy in postmenopausal women OR  ○ fulvestrant in women who have received prior endocrine therapy	Oral (capsule)	• 125 mg PO once daily on 3-weeks-on/1-week-off schedule	CDK4/6	IBRANCE^®,^Citation49,Citation50 EMA,^Citation51 Beaver et al^Citation52
Abemaciclib (LY2835219)	2016	As single agent in women with refractory HR+/HER2− metastatic breast cancer who had progressed on or after prior endocrine therapy and had 1 or 2 chemotherapy regimens in the metastatic setting	Oral (tablet)	• 200 mg PO on a continuous schedule every 12 hour until disease progression or unacceptable toxicity	CDK4/6	Dickler et al,^Citation53 Kondo et al^Citation54
	2017	HR+/HER2− advanced breast cancer in combination with:  ○ an aromatase inhibitor as initial endocrine-based therapy in postmenopausal women OR  ○ fulvestrant in patients who progressed on endocrine-based therapy		• 150 mg twice daily on 3-weeks-on/1-week-\off schedule		Eli Lilly and Company,^Citation55,Citation56 Sledge et al^Citation57
Ribociclib (KISQALI^®; LEE011; Novartis)	2017	Postmenopausal women with HR+/HER2− advanced or metastatic breast cancer in combination with:  ○ an aromatase inhibitor (e.g., letrozole) as initial endocrine-based therapy	Oral (tablet)	• 600 mg daily on 3-weeks-on/1-week- off schedule	CDK4/6	KISQALI^®,^Citation58 Choy^Citation59
		Postmenopausal women with HR+/HER2− resectable (early) breast cancer in combination with letrozole		• 400 or 600 mg daily on 3-weeks-on/1-week-off schedule		Curigliano et al^Citation60

Abbreviations: CDK4/6, cyclin-dependent kinases 4 and 6; FDA, US Food and Drug Administration; HR+/HER2−, hormone receptor positive/human epidermal growth factor receptor 2 negative.

Table 2 Selected completed clinical trials of CDK4/6 inhibitors in HR+/HER2− metastatic breast cancer

Study/arms	N	n	ORR (%)	CBR (%)	Median TTP or PFS (months)	Median OS (months)
Ribociclib-letrozole versus placebo-letrozole (MONALEESA-2 trial number, NCT01958021)^Citation15	668
Ribociclib and letrozole		334	52.7	80.1	Not reached*	–
Placebo and letrozole		334	37.1	71.8	14.7	–
Palbociclib-letrozole versus placebo-letrozole (PALOMA-2 trial number, NCT01740427)^Citation14	666
Palbociclib and letrozole		444	55.3	84.3	24.8*	–
Placebo and letrozole		222	44.4	70.8	14.5	–
Palbociclib versus placebo (PALOMA-3 trial number, NCT01942135)^Citation62	521
Palbociclib and fulvestrant		347	10.4	34.0	9.2*	–
Placebo and fulvestrant		174	6.3	19.0	3.8	–
Abemaciclib-fulvestrant versus placebo-fulvestrant (MONARCH-2)^Citation57	669
Abemaciclib and fulvestrant		446	48.1	73.3	16.4*	–
Placebo and fulvestrant		223	21.3	51.8	9.3	–
Phase II study of Abemaciclib (MONARCH-1)^Citation53	132		19.7	42.4	6.0*	17.9

Notes: Asterisk (*) shows a statistical significant difference; N, sample size of total study participants; n, sample size in each study arm. The dashes indicate that there are no value (finding) for median OS.

Abbreviations: CDK4/6, cyclin-dependent kinases 4 and 6; CBR, clinical benefit rate; HR+/HER2−, hormone receptor positive/human epidermal growth factor receptor 2 negative; ORR, objective response rate; OS, overall survival; PFS, progression-free survival; TTP, time to progression.

Figure 2 Chemical structure of ribociclib.

Table 3 Pivotal undergoing clinical trials of ribociclib or LEE011 for the treatment of various cancers (www.clinicaltrials.gov)

Trial identifier (number)	Phase	Trial design	Intervention	Primary endpoint	Status
NCT03096847	III	Study for women and men with hormone receptor-positive locally advanced or metastatic breast cancer	Ribociclib +letrozole	CBR	Recruiting
NCT02278120	III	Study of efficacy and safety in premenopausal women with hormone receptor-positive, HER2− advanced breast cancer	LEE011 + letrozole	PFS	Active, not recruiting
NCT02941926	III	Study to assess the safety and efficacy of ribociclib (LEE011) in combination with letrozole for the treatment of men and pre/postmenopausal women with HR+/HER2− aBC	Ribociclib + Letrozole	Number of adverse events	Recruiting
NCT02422615	III	Postmenopausal women with ER+/HER2 who did not have prior treatment or only one line of treatment for locally advanced/metastatic disease	Fulvestrant ± ribociclib	PFS	Active, not recruiting
NCT02278120	III	Premenopausal women with ER+/HER2 who did not have prior treatment for locally advanced/metastatic disease	Tamoxifen or NSAI plus goserelin ± ribociclib	PFS	Active, not recruiting
NCT02632045	II	Study of efficacy of ribociclib after progression on CDK4/6 inhibition in patients with HR+ H2N− advanced breast cancer	LEE011/Fulvestrant	Percent PFS at 24 weeks	Recruiting
NCT02420691	II	LEE011 in neuroendocrine tumors of foregut origin	LEE011	Overall response	Active, not recruiting
NCT03070301	II	A study of LEE011 with everolimus in patients with advanced neuroendocrine tumors	LEE011 + everolimus	PFS	Recruiting
NCT03008408	II	Study of ribociclib (LEE011), everolimus, and letrozole in patients with advanced or recurrent endometrial carcinoma	Everolimus + letrozole + ribociclib	DLT and CBR	Recruiting
NCT03114527	II	Phase II trial of ribociclib and everolimus in advanced dedifferentiated liposarcoma and leiomyosarcoma	Ribociclib + everolimus	Progression free rate	Recruiting
NCT02300987	II	A randomized, blinded, placebo-controlled, Phase II trial of LEE011 in patients with relapsed, refractory, incurable teratoma with recent progression	LEE011	PFS	Active, not recruiting
NCT02732119	I /II	Study of ribociclib with everolimus + exemestane in HR+/HER2− locally advanced/metastatic breast cancer post-progression on CDK4/6 inhibitor	Ribociclib + everolimus + exemestane	Phase I: MTD and RP2D Phase II: CBR	Recruiting
NCT02088684	I / II	Study of LEE011 with fulvestrant and BYL719 or BKM120 in advanced breast cancer	LEE011 + fulvestrant + BYL71 or BKM120 LEE011 + fulvestrant	Phase I: incidence of DLTs Phase II: PFS	Active, not recruiting
NCT02657343	I / II	An open-label, Phase Ib/II clinical trial of CDK4/6 inhibitor, ribociclib (Lee011), in combination with trastuzumab or T-Dm1 for advanced/metastatic HER2-positive breast cancer	Cohort A: ribociclib + T-DM1 Cohort B: ribociclib + trastuzumab	MTD and RP2D	Recruiting
NCT02703571	I/II	Study of safety and efficacy of ribociclib and trametinib in patients with metastatic or advanced solid tumors	Ribociclib + trametinib	Phase I: DLTs Phase II: ORR	Recruiting
NCT02555189	I/II	Enzalutamide with and without ribociclib for metastatic, castrate-resistant, chemotherapy-naive prostate cancer that retains Rb expression	Enzalutamide + ribociclib	Phase I: DLT Phase II: 50% reduction in PSA	Recruiting
NCT02985125	I/II	LEE011 plus everolimus in patients with metastatic pancreatic adenocarcinoma refractory to chemotherapy	LEE011 + everolimus	PFS	Recruiting
NCT01857193	Ib	Phase Ib trial of LEE011 with everolimus (RAD001) and exemestane in the treatment of HR+/HER2− advanced breast cancer	Arm 1: LEE011 + everolimus + exemestane Arm 2: LEE011 + exemestane	Incidence of DLT	Recruiting
NCT02754011	I	Phase I evaluating the combination of ribociclib + capecitabine in locally advanced/metastatic breast cancer HER2−	Ribociclib + capecitabine	MTD and RP2D	Recruiting
NCT02154776	I	Dose escalation study of LEE011 in combination with buparlisib and letrozole in HR+, HER2− postmenopausal women with advanced breast cancer	LEE011 + letrozole + buparlisib	Incidence of DLTs	Completed but result not reported
NCT01734615	I	Phase I/Ib trial of LSZ102 single agent or LSZ102 + LEE011 or LSZ102 + BYL719 in ER+ breast cancers	Arm A: LSZ102 single agent Arm B: LEE011 + LSZ102 Arm C: LSZ102 + BYL719	Incidence of DLTs	Recruiting
NCT03056833	I	Ribociclib (ribociclib [LEE-011]) with platinum- based chemotherapy in recurrent platinum sensitive ovarian cancer	Ribociclib + paclitaxel + carboplatin	MTD for ribociclib	Recruiting
NCT03009201	I	Ribociclib and doxorubicin in treating patients with metastatic or advanced soft tissue sarcomas that cannot be removed by surgery	Ribociclib + doxorubicin	Incidence of DLTs	Recruiting
NCT03237390	I	Ribociclib and gemcitabine hydrochloride in treating patients with advanced or metastatic solid tumors	Ribociclib + gemcitabine hydrochloride	MTD	Recruiting
NCT01237236	I	A trial of LEE011 in patients with advanced solid tumors or lymphoma	LEE011	MTD	Recruiting
NCT01747876	I	Study of safety and efficacy in patients with MRT and neuroblastoma	LEE011	DLTs, MTD, and/or RDE	Completed but result not reported
NCT02345824	I	Early phase study to assess inhibitor ribociclib in patients with recurrent glioblastoma or anaplastic glioma	Ribociclib	Inhibition of CDK4/6 signaling pathway	Recruiting

Abbreviations: CBR, clinical benefit rate; CDK4/6, cyclin-dependent kinases 4 and 6; DLTs, dose-limiting toxicities; ER+, estrogen receptor positive; H2N⁻, dihyrdidonitrogen negative; MRT, malignant rhabdoid tumors; PFS, progression-free survival; LEE011, ribociclib; MTD, maximum tolerated dose; NSAI, non-steroidal aromatase inhibitor; ORR, objective response rate; PSA, prostate-specific antigen; Rb, retinoblastoma; RDE, recommended dose for expansion; RP2D, recommended dose for Phase II; T-DM1, trastuzumab emtansine; HR+, hormone receptor positive; HER2−, human epidermal growth factor receptor 2 negative; aBC, advanced breast cancer.

Table 4 Most common adverse event profiles of ribociclib in adult and pediatric patients

Adverse events	Treatment^Citation15,Citation74,Citation78
	Ribociclib and letrozole (N=334)	Placebo and letrozole (N=330)	Ribociclib alone (dose escalation) (N=132)	Ribociclib in pediatric (280, 350, or 470 mg/m^2) (N=32)
Neutropenia
All grades (%)	248 (74.3)	17 (5.2)	60 (46)	23 (72)
Grade 3/4 (%)	198 (59.3)	3 (0.9)	36 (27)	20 (63)
Leukopenia
All grades (%)	110 (32.9)	13 (3.9)	57 (43)	20 (63)
Grade 3/4 (%)	70 (21)	2 (0.6)	22 (17)	12 (38)
Thrombocytopenia
All grades (%)	NA	NA	40 (30)	14 (44)
Grade 3/4 (%)	NA	NA	10 (8)	9 (28)
Lymphopenia
All grades (%)	NA	NA	32 (24)	12 (38)
Grade 3/4 (%)	NA	NA	21 (16)	6 (19)
Increased ALT
All grades (%)	52 (15.6)	13 (3.9)	NA	NA
Grade 3/4 (%)	31 (9.3)	4 (1.2)	NA	NA
Increased AST
All grades (%)	50 (15.0)	12 (3.6)	NA	5 (16)
Grade 3/4 (%)	19 (5.7)	4 (1.2)	NA	1 (3)
Infections
All grades (%)	168 (50.3)	140 (42.4)	NA	NA
Grade 3/4 (%)	14 (4.2)	8 (2.4)	NA	NA
Nausea
All grades (%)	172 (51.5)	94 (28.5)	56 (42)	8 (25)
Grade 3/4 (%)	8 (2.4)	2 (0.6)	2 (2.0)	0
Fatigue
All grades (%)	122 (36.5)	99 (30.0)	59 (45)	8 (25)
Grade 3/4 (%)	8 (2.4)	3 (0.9)	3 (2)	0
Diarrhea
All grades (%)	117 (35.0)	73 (22.1)	31 (23)	NA
Grade 3/4 (%)	4 (1.2)	3 (0.9)	2 (2)	NA
Alopecia
All grades (%)	111 (33.2)	51 (15.5)	NA	NA
Grade 3/4 (%)	NA	NA	NA	NA
Vomiting
All grades (%)	98 (29.3)	51 (15.5)	34 (26)	12 (38)
Grade 3/4 (%)	12 (3.6)	3 (0.9)	0	0
Electrocardiogram QTc prolonged
All grades (%)	NA	NA	14 (11)	7 (22)
Grade 3/4 (%)	NA	NA	2 (2)	0
Anemia
All grades (%)	62 (18.6)	15 (4.5)	34 (26)	14 (44)
Grade 3/4 (%)	4 (1.2)	4 (1.2)	4 (3)	1 (3)
Decreased appetite
All grades (%)	62 (18.6)	50 (15.2)	13 (10)	6 (19)
Grade 3/4 (%)	5 (1.5)	1 (0.3)	0	1 (3)

Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; NA, not applicable.

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