Table 3.

HR+ breast cancer clinical trials of CDK 4/6 inhibitors in combination with other agents

Combination therapy/setting	Study drug	Trial reference/ NCT number	Phase	Patient population	Combination agent(s)	Primary endpoint	Results (primary endpoint)
Combination with endocrine therapy
Metastatic BC setting
Letrozole	Palbociclib	PALOMA-1/TRIO-18; NCT00721409	II	ER+, HER2− advanced BC	Letrozole	PFS	Median PFS was 20.2 mos with palbociclib + letrozole vs 10.2 mos with letrozole (p = 0.0004)
		PALOMA-2; NCT01740427	III	Postmenopausal women with ER+, HER2− advanced BC	Letrozole	PFS	N/A
		PALOMA-4; NCT02297438	III	Postmenopausal women with ER+/HER2− advanced BC who have not received prior systemic anticancer therapies for advanced/metastatic disease	Letrozole	PFS	N/A
	Ribociclib	MONALEESA-2; NCT01958021	III	Postmenopausal women with HR+, HER2− advanced BC	Letrozole	PFS	N/A
	Abemaciclib	MONARCH-3; NCT02246621	III	Postmenopausal women with BC	Anastrozole or letrozole	PFS	N/A
Fulvestrant	Palbociclib	PALOMA-3; NCT01942135	III	HR+, HER2− metastatic BC whose disease has progressed after prior endocrine therapy	Fulvestrant	PFS	Median PFS was 9.2 mos with palbociclib + fulvestrant vs 3.8 mos with fulvestrant (p < 0.001)
	Ribociclib	MONALEESA-3; NCT02422615	III	Postmenopausal women with HR+, HER2− advanced BC, who have had no or only one line of prior endocrine treatment	Fulvestrant	PFS	N/A
	Abemaciclib	MONARCH-2; NCT02107703	III	HR+, HER2− locally advanced or metastatic breast cancer, who have had no or only one line of prior endocrine treatment	Fulvestrant	PFS	N/A
		NCT01394016	I	HR+ metastatic BC (among 5 different tumor types)	Fulvestrant	Safety	Grade 3 AEs (no Grade 4 AE) Diarrhea: 8% Fatigue: 8% Neutropenia: 31% Leukopenia: 23%
Tamoxifen	Ribociclib	MONALEESA-7; NCT02278120	III	Pre- or peri-menopausal women with HR+, HER2− advanced BC	Tamoxifen or letrozole or anastrozole Goserelin	PFS	N/A
Other/various therapies	Palbociclib	PEARL; NCT02028507	III	HR+, HER2− metastatic BC with resistance to NSAIs	Capecitabine Exemestane	PFS	N/A
	Abemaciclib	NCT02057133	Ib	HR+, HER2−/HER2+ metastatic BC	Letrozole Anastrozole Tamoxifen Everolimus + exemestane Trastuzumab	Safety	N/A
Early BC setting
Neoadjuvant	Palbociclib	NCT01723774	II	Women with Stage II/III ER+, HER2− BC	Anastrozole Goserelin	pCR Ki67 levels	N/A
	Palbociclib	PALLET; NCT02296801	II	Postmenopausal women with ER+, primary BC	Letrozole	Change in Ki67 from baseline to 14 weeks Clinical complete response	N/A
	Abemaciclib	neoMONARCH; NCT02441946	II	Postmenopausal women with HR+, HER2−, early-stage BC	Anastrozole	Ki67 levels	N/A
Adjuvant	Palbociclib	PENELOPE-B; NCT01864746	III	HR+, HER2− negative BC with residual disease after neoadjuvant chemotherapy	Standard anti-hormonal therapy	iDFS	N/A
	Palbociclib	NCT02040857	II	HR+/HER2− invasive BC	Letrozole, anastrozole, or exemestane	Treatment discontinuation rate	N/A
	Palbociclib	ABCSG-42; BIG 03/14	III	HR+/HER2− Stage II/III BC	Endocrine therapy	N/A	N/A
Combination with targeted signaling pathway inhibitors
mTOR inhibitors	Ribociclib	NCT01857193	Ib	Advanced/metastatic ER+ BC	Exemestane Everolimus	Incidence of DLTs	DLTs with triplet therapy: Grade 3 febrile neutropenia (n = 1) Grade 3 ALT elevation (n = 2)
			II	Advanced/metastatic ER+ BC	Exemestane Everolimus	PFS	N/A
PI3K inhibitors	Ribociclib	NCT01872260	Ib (dose escalation/expansion)	Advanced ER+ BC (dose expansion phase only includes patients in the first-line setting)	Letrozole Alpelisib	Incidence of DLTs	1 DLT with ribociclib + letrozole (Grade 4 neutropenia)
			II	Advanced ER+ BC (first-line only)	Letrozole Alpelisib	PFS	N/A
	Palbociclib	NCT02389842	Ib	PIK3CA-mutant BC	Taselisib (GDC-0032) or Pictilisib (GDC-0941) Fulvestrant	RP2D Safety Preliminary antitumor assessments	N/A
Combination with chemotherapy
	Palbociclib	NCT01320592	I	Rb-positive metastatic BC	Paclitaxel	Safety	DLT was Grade 3 AST and ALT elevations Grade 3/4 neutropenia: 10/15 patients

ALT alanine transaminase, AST aspartate transaminase, BC breast cancer, DLT dose-limiting toxicity, ER+ estrogen receptor-positive, HER2− human epidermal growth factor receptor 2-negative, HR+ hormone receptor-positive, iDFS invasive disease-free survival, PFS progression-free survival, NSAI non-steroidal aromatase inhibitors, Rb retinoblastoma, RP2D recommended Phase II dose