Table 3. Major past clinical trials with CDK4/6-inhibitors.

ER+, estrogen receptor-positive; HER2−, human epidermal growth factor receptor 2-negative; HR+, hormone receptor-positive. PFS, progression-free survival.

Inhibitor	Trial name	Trial details	T reatment	Patients	Outcome	Reference	Other outcomes
Palbociclib	PALOMA-1	randomized phase 2	aromatase inhibitor letrozole alone (standard of care) versus letrozole plus palbociclib	postmenopausal women with advanced ER+/HER2-breast cancer who had not received any systemic treatment for their advanced disease.	Addition of palbociclib dramatically increased median progression free survival (PFS) from 10.2 months in the letrozole group to 20.2 months in the palbociclib plus letrozole group.	ref. 78	Based on this result, palbociclib received a ‘Breakthrough Therapy’ designation status from the FDA and was granted accelerated approval, in combination with letrozole, for the treatment of ER+/HER2-metastatic breast cancer.
Palbociclib	PALOMA-2	double-blind phase 3	palbociclib plus letrozole as first-line therapy	postmenopausal women with ER+/HER2-breast cancer	Addition of palbociclib strongly increased the median PFS: 14.5 months in the placebo-letrozole group versus 24.8 month for the palbociclib-letrozole group.	ref. 123	Palbociclib was equally efficacious in patients with luminal A and B breast cancers, and there was no single biomarker associated with the lack of clinical benefit, except for RB1 loss. CDK4 amplification was associated with endocrine resistance, but this was mitigated by addition of palbociclib. Tumors with high levels of FGFR2 and ERBB3 mRNA displayed greater PFS gain after addition of palbociclib (79).
Palbociclib	PALOMA-3	randomized phase 3	estrogen receptor antagonist fulvestrant plus placebo versus fulvestrant plus palbociclib	women with HR+/HER2-metastatic breast cancer that had progressed on previous endocrine therapy	The study demonstrated a substantial prolongation of median PFS in the palbociclib-treated group: 4.6 months in the placebo plus fulvestrant group versus 9.5 months in the palbociclib plus fulvestrant group. Addition of palbociclib also extended median overall survival from 28.0 months (placebo-fulvestrant) to 34.9 months (palbociclib-fulvestrant). The estimated rate of survival at 3 years was 41% vs. 50%, respectively.	ref. 124, 125, 135
Palbociclib	NeoPalAna	palbociclib in an neoadjuvant setting (i.e., prior to surgery)	compared the effects of an aromatase inhibitor anastrozole versus palbociclib plus anastrozole on tumor cell proliferation	women with newly diagnosed clinical stage II/III ER+/HER2-breast cancer	Addition of palbociclib enhanced the anti-proliferative effect of anastrozole.	ref. 161
Palbociclib	PALLAS	randomized phase 3	palbociclib plus standard endocrine therapy versus endocrine therapy alone	patients with early (stage 2 or 3), HR+/HER2-breast cancer	Preliminary results indicate that the trial is unlikely to show a statistically significant improvement of invasive disease-free survival.	ref. 138
Palbociclib	PENELOPE-B		palbociclib in patients with early breast cancer at high risk of recurrence		ongoing
Ribociclib	MONALEESA-2	randomized phase 3	ribociclib plus letrozole versus placebo plus letrozole	fist-line treatment for postmenopausal women with HR+/HER2-recurrent or metastatic breast cancer who had not received previous systemic therapy for advanced disease	At 18 months, the progression free-survival rate was 42.2% in the placebo-letrozole group and 63.0% in the ribociclib-letrozole group.	ref. 126
Ribociclib	MONALEESA-3	phase 3	ribociclib plus fulvestrant	patients with advanced (metastatic or recurrent) HR+, HER2-breast cancer who have either received no treatment for the advanced disease, or previously received a single line of endocrine therapy for the advanced disease	Addition of ribociclib significantly extended the median PFS, from 12.8 months (placebo-fulvestrant) to 20.5 months (ribociclib-fulvestrant). The overall survival at 42 months was also extended from 45.9% (placebo-fulvestrant) to 57.8% (ribociclib-fulvestrant).	ref. 127, 133
Ribociclib	MONALEESA-7	phase 3 randomized, double-blind	ribociclib versus placebo together with an antiestrogen tamoxifen or an aromatase inhibitor (letrozole or anastrozole)	premenopausal and perimenopausal women with HR+/HER2-advanced breast cancer who had not received previous treatment with CDK4/6 inhibitors	Ribociclib significantly increased median PFS from 13.0 months in the placebo-endocrine therapy group to 23.8 months in the ribociclib-endocrine therapy group. The overall survival was also strongly prolonged in the ribociclib group (the estimated overall survival at 42 months was 46.0% for the placebo group and 70.2% in the ribociclib group).	ref. 128, 132
Ribociclib	EarLEE-1	phase 3 trial	ribociclib in the treatment of early-stage, high risk HR+/HER2-breast cancers		ongoing
Abemaciclib	MONARCH 1	phase 2 trial	abemaciclib as a single agent	women with 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	Abemaciclib exhibited promising activity in these heavily pretreated patients with poor prognosis; median PFS was 6.0 months and overall survival 17.7 months.	ref. 136	The most common adverse events were diarrhea, fatigue and nausea (136).
Abemaciclib	MONARCH 2	double-blind phase 3	abemaciclib in combination with fulvestrant	women with HR+/HER2-breast cancer who had progressed while receiving endocrine therapy, or while receiving first line endocrine therapy for metastatic disease	Addition of abemaciclib significantly increased PFS from 9.3 months in the placebo-fulvestrant to 16.4 in the abemaciclib-fulvestrant group. The median overall survival was also extended from 37.3 months to 46.7 months.	ref. 129, 134
Abemaciclib	MONARCH 3	randomized, phase 3 double-blind	abemaciclib plus an aromatase inhibitor (anastrozole or letrozole)	postmenopausal women with advanced HR+/HER2-breast cancer who had no prior systemic therapy in the advanced setting	Addition of abemaciclib prolonged the PFS from 14.8 months (in the placeboaromatase inhibitor group) to 28.2 months (abemaciclib-aromatase inhibitor group).	ref. 130, 131
Abemaciclib	MonrarchE	phase 3 study	endocrine with or without abemaciclib	patients with HR+/HER2-lymph node-positive, high-risk early breast cancer	Preliminary analysis indicates that addition of abemaciclib resulted in a significant improvement of invasive disease-free survival and of distant relapse-free survival.	ref. 137
Trilaciclib		randomized phase 2 study	chemotherapy alone (gemcitabine and carboplatin), versus concurrent administration of trilaciclib plus chemotherapy, versus administration of trilaciclib prior to chemotherapy (to mitigate the cytotoxic effect of chemotherapy on bone marrow)	patients with recurrent or metastatic triple-negative breast cancer who had no more than two previous lines of chemotherapy	Addition of trilaciclib did not offer detectable myeloprotection, however it resulted in increased overall survival from 12.8 months in the chemotherapy only group to 20.1 months in concurrent trilaciclib and chemotherapy group and 17.8 month in trilaciclib before chemotherapy group.	ref. 162	The most common adverse events were neutropenia, thrombocytopenia and anemia (162).