Exploration of Targeted Anti-tumor Therapy

Table 2

Summary of clinical trials leading to the approval of new drugs to overcome endocrine resistance in HR⁺/HER2^– BC

Drug	Target	Study	Phase	Population	Therapy line	Treatment arms	Outcome	Reference(s)
CDK4/6i
Palbociclib	CDK4/6	PALOMA-3 NCT01942135	III	HR⁺/HER2^– postmenopausal advanced BC	Second or later lines	Palbociclib + FULV vs. placebo + FULV	mPFS: 11.2 mo vs. 4.6 mo; hazard ratio: 0.46; P < 0.0001 mOS: 34.9 mo vs. 28 mo; hazard ratio: 0.81; P = 0.09	[72, 74]
Ribociclib	CDK4/6	MONALEESA-3 NCT02422615	III	HR⁺/HER2^– postmenopausal advanced BC	First or second line	Ribociclib + FULV vs. placebo + FULV	mPFS: 21.0 mo vs. 13 mo; hazard ratio: 0.59; P < 0.001 mOS: 54 mo vs. 42 mo; hazard ratio: 0.73; P < 0.01	[75, 76]
Abemaciclib	CDK4/6	MONARCH 2 NCT02107703	III	HR⁺/HER2^– postmenopausal advanced BC	Second or later lines	Abemaciclib + FULV vs. placebo + FULV	mPFS: 16.4 mo vs. 9.3 mo; hazard ratio: 0.55; P < 0.001 mOS: 46.7 mo vs. 37.3 mo; hazard ratio: 0.75; P = 0.01	[73, 77]
Palbociclib	CDK4/6	PALOMA-2 NCT01740427	III	HR⁺/HER2^– postmenopausal advanced BC	First line	Palbociclib + letrozole vs. placebo + letrozole	mPFS: 27.6 mo vs. 14.5 mo; hazard ratio 0.56, P < 0.001 ORR: 42% vs. 35%	[69, 78]
Ribociclib	CDK4/6	MONALEESA-2 NCT01958021	III	HR⁺/HER2^– postmenopausal advanced BC	First line	Ribociclib + letrozole vs. placebo + letrozole	mPFS: 25.3 mo vs. 16 mo; hazard ratio: 0.57; P < 0.001 ORR: 43% vs. 29%	[79]
Ribociclib	CDK4/6	MONALEESA-7 NCT02278120	III	HR⁺/HER2^– premenopausal advanced BC	First line	Ribociclib + letrozole/anastrozole/TAM + goserelin vs. placebo + letrozole/anastrozole/TAM + goserelin	mPFS: 24 mo vs. 13 mo; hazard ratio: 0.55, P < 0.0001 mOS: n.r. vs. 40.7 mo; hazard ratio: 0.71; P = 0.00973	[70, 80]
Abemaciclib	CDK4/6	MONARCH 3 NCT02246621	III	HR⁺/HER2^– postmenopausal advanced BC	First line	Abemaciclib + letrozole vs. placebo + letrozole	mPFS: 28.2 mo vs. 14.2 mo; hazard ratio: 0.54; P < 0.001 ORR: 59% vs. 44%	[81]
PI3K/AKT/mTOR inhibitors
Everolimus	mTOR1	BOLERO-2 NCT00863655	III	HR⁺/HER2^– postmenopausal advanced BC	Second or later lines	Everolimus + exemestane vs. placebo + exemestane	mPFS: 10.6 mo vs. 4.1 mo; hazard ratio: 0.36, P < 0.001 ORR: 7% vs. 0.4%	[82]
		MANTA NCT02216786	II	HR⁺/HER2^– postmenopausal advanced BC	Second or later lines	Everolimus + FULV vs. placebo + FULV	mPFS: 12.3 mo vs. 5.4 mo; hazard ratio: 0.63, P = 0.01	[83]
		PrE0102 NCT01797120	II	HR⁺/HER2^– postmenopausal advanced BC	Second or later lines	Everolimus + FULV vs. placebo + FULV	mPFS: 10.3 mo vs. 5.1 mo; hazard ratio: 0.61, P = 0.02	[84]
Alpelisib	Class I PI3K p110α	SOLAR-1 NCT02437318	III	HR⁺/HER2^– postmenopausal advanced BC	First or second line	Alpelisib + FULV vs. placebo + FULV	mPFS: 11.0 mo vs. 5.7 mo; hazard ratio: 0.65, P < 0.001 ORR: 26.6% vs. 12.8%; PIK3CA- mutant subset mOS: 39.3 mo vs. 31.4 mo; hazard ratio: 0.86, P = 0.15	[71, 85]

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mo: months; mOS: median overall survival; mPFS: median PFS; mTOR: mammalian target of rapamycin; n.r.: not reached; ORR: overall response rate; PIK3CA: phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha