Use of mTOR inhibitors in the treatment of breast cancer: an evaluation of factors that influence patient outcomes

Figures & data

Table 1 Results of key clinical trials

Study	Study design	Patients	Treatments	Primary endpoint	Secondary endpoints
ER-positive, HER2-negative advanced BC
Wolff et al^Citation14 (HORIZON)	Placebo-controlled, randomized, Phase III	Postmenopausal AI-naïve, ER-positive, advanced BC, first-line (n=1,112)	Letrozole 2.5 mg daily, temsirolimus 30 mg daily, 5 days every 2 weeks or letrozole 2.5 mg daily + placebo	Median PFS 9 versus 8.9 months (comparable)	Median OS not reached (comparable) ORR 27% versus 27% SD at least 24 weeks 17% versus 19%
Bachelot et al^Citation16 (TAMRAD)	Randomized, open, Phase II	Postmenopausal AI-resistant, ER-positive, HER2-negative, metastatic BC (n=111)	Tamoxifen 20 mg daily + everolimus 10 mg daily or tamoxifen 20 mg daily	6 month CBR 61% versus 42% (exploratory analysis)	TTP 8.6 versus 4.5 months Risk of death HR 0.45
Yardley et al^Citation19 (BOLERO-2)	Placebo-controlled, randomized Phase III	Postmenopausal NSAI-resistant, ER-positive, HER2-negative, advanced BC (n=724)	Exemestane 25 mg daily + everolimus 10 mg daily or exemestane 25 mg daily + placebo	Median PFS 7.8 versus 3.2 months investigator review difference statistically significant	Median PFS 11 versus 4.1 months central review OS events 25.4% versus 32.2% ORR 12.6% versus 2.1% CBR 49.9% versus 22.2%
HER2-positive advanced BC
O’Regan et al^Citation28 BOLERO-3	Placebo-controlled, randomized Phase III	HER2-positive advanced BC, prior taxane required, trastuzumab-resistant (n=569)	Vinorelbine 25 mg/m^2 weekly + trastuzumab 2 mg/kg/week + everolimus 5 mg daily or vinorelbine 25 mg/m^2 weekly + trastuzumab 2 mg/kg/week + placebo	Median PFS 7 versus 5.78 months (difference statistically significant)	ORR 40.8% versus 37.2% CBR 59.2% versus 53.3% OS events 36.3% versus 41.1%
ER-positive BC : neoadjuvant therapy
Baselga et al^Citation15	Placebo-controlled, randomized Phase II	Postmenopausal operable ER-positive (n=270)	Letrozole 2.5 mg daily + everolimus 10 mg daily or letrozole 2.5 mg daily + placebo (4 months)	Clinical RR 68.1% versus 59.1% (difference statistically significant)	Antiproliferative response day 15 (downregulation of Ki67 expression) 57% versus 30% RR 58% versus 47% (ultrasound) RR 36.2% versus 39.4% (mammography)

Abbreviations: ER, estrogen receptor; BC, breast cancer; RR, response rate; HER2, human epidermal growth factor 2 receptor; AI, aromatase inhibitor; PFS, progression-free survival; OS, overall survival; CBR, clinical benefit rate; TTP, time to progression; HR, hazard ratio; NSAI, non-steroidal aromatase inhibitor; ORR, overall response rate; SD, stable disease.

Table 2 Side effects observed in key trials involving everolimus and temsirolimus

	Neoadjuvant letrozole ± everolimus 10 mg daily (Baselga et al ^Citation15)		TAMRAD tamoxifen ± everolimus 10 mg daily (Bachelot et al ^Citation16)		BOLERO-2 exemestane ± everolimus 10 mg daily (Yardley et al ^Citation19)		BOLERO-3 trastuzumab ± vinorelbine ± everolimus 5 mg daily (O’Regan et al ^Citation28)		HORIZON Letrozole ± temsirolimus 5/14 days (Wolff et al ^Citation14)
	EVE	Placebo	EVE	Placebo	EVE	Placebo	EVE	Placebo	EVE	Placebo
Stomatitis/mucositis
All grade	36.5	6.1	56	7	59	12	63	28	26	4
Grade 3–4	2.2	0	11	0	8	0	13	2	1	<1
Rash
All grade	20.4	7.6	44	7	39	7	25	18	15	4
Grade 3–4	0.7	0	4	0	1	0	0	1	1	<1
Fatigue/asthenia
All grade	29.9	13.3	72	53	37	27	43	42	27	21
Grade 3–4	1.5	0.8	6	11	4	1	12	4	3	2
Diarrhea
All grade	NR		39	11	34	19	38	31	21	9
Grade 3–4			2	0	2	<1	4	1	2	1
Nausea
All grade	NR		35	35	31	29	35	37	16	16
Grade 3–4			4	0	<1	1	3	1	1	1
Decreased appetite/anorexia
All grade	12.4	3.8	43	18	31	13	33	17	15	7
Grade 3–4	0	0	7	4	1	<1	1	1	1	1
Pyrexia
All grade	NR		NR		16	7	39	23	14	7
Grade 3–4							3	1	1	1
Weight decreased
All grade	NR		NR		28	7	NR		NR
Grade 3–4					1	0
Cough
All grade	NR		NR		26	12	NR		15	10
Grade 3–4					<1	0			<1	<1
Dysgeusia
All grade	NR		NR		22	6	NR		NR
Grade 3–4					0	0
Dyspnea
All grade	7.3	1.5	NR		22	11	NR		13	10
Grade 3–4	0.7	0			5	<1			3	3
Peripheral edema
All grade	NR		NR		21	6	NR		15	6
Grade 3–4					1	<1			0	0
Epistaxis
All grade	NR		NR		17	1	NR		NR
Grade 3–4					0	0
Hyperglycemia
All grade	13.1	3	NR		14	2	9	5	13	5
Grade 3–4	5.1	0			5	<1	6	3	4	1
Pneumonitis
All grade	2.9	0	17	4	16	0	6	3	NR
Grade 3–4	2.2	0	2	4	3	0	<1	1

Abbreviations: EVE, everolimus; NR, not reported.

Table 3 Key messages concerning the BOLERO-2 trial

Compared with exemestane alone, everolimus + exemestane improves median progression-free survival (3.2 months versus 7.8 months) in the treatment of estrogen receptor-positive, HER2-negative advanced breast cancer resistant to nonsteroidal aromatase inhibitor therapy

The benefit is consistent among all prespecified clinical subgroups

Side effects are manageable. Patient education and appropriate dose modification according to existing guidelines are indicated

The most frequent clinically significant side effect is stomatitis. The most medically important side effect is noninfectious pneumonitis

Abbreviations: BOLERO, Breast cancer trials of OraL EveROlimus; HER2, human epidermal growth factor receptor 2.

Table 4 Key messages concerning the BOLERO-3 trial

The trial met its primary endpoint: median progression-free survival is increased when everolimus is added to trastuzumab and vinorelbine compared with placebo, trastuzumab, and vinorelbine

The average benefit in median progression-free survival is only 5 weeks, indicating the need to identify patients who benefit most

The benefit is more pronounced in estrogen receptor-negative tumors (hazards ratio 0.65)

New treatment approaches are needed for HER2-positive, estrogen receptor-positive tumors. In particular, a treatment strategy including an endocrine agent should also be evaluated

Abbreviations: BOLERO, Breast cancer trials of OraL EveROlimus; HER2, human epidermal growth factor receptor 2.

Table 5 Ongoing trials with everolimus in triple-negative breast cancer

Study title	ClinicalTrials.gov identifier
Phase Ib/II trials of RAD001 in triple-negative metastatic breast cancer	NCT01939418
A study of lapatinib in combination with everolimus in patients with advanced, triple-negative breast cancer	NCT01272141
NECTAR: everolimus plus cisplatin in triple-negative breast cancer	NCT01931163
Temsirolimus plus neratinib for patients with metastatic HER2-amplified or triple-negative breast cancer	NCT01111825
Study of temsirolimus, erlotinib, and cisplatin in solid tumors	NCT00998036
Cisplatin and paclitaxel with or without everolimus in treating patients with stage II or stage III breast cancer	NCT00930930
RAD001 plus carboplatin in breast cancer patients	NCT01127763
Cisplatin, paclitaxel, and everolimus in treating patients with metastatic breast cancer	NCT01031446
Trial of RAD001 in triple-negative metastatic breast cancer	NCT00827567
Phase I/II study of weekly nab-paclitaxel and RAD001 in women with locally advanced or metastatic breast cancer	NCT00934895
Study to compare vinorelbine in combination with the mTOR inhibitor everolimus versus vinorelbine monotherapy for second-line treatment in advanced breast cancer	NCT01520103
Trial of paclitaxel/bevacizumab ± everolimus for patients with HER2-negative metastatic breast cancer	NCT00915603
Efficacy of RAD001 in breast cancer patients with bone metastases	NCT00466102
Paclitaxel followed by FEC versus paclitaxel and RAD001 followed by FEC in women with breast cancer	NCT00499603

Abbreviations: FEC, fluorouracil, epirubicin, and cyclophosphamide; HER2, human epidermal growth factor receptor 2.

Figure 1 Mechanism of action of different classes of mTOR inhibitors (rapalogs) already approved or under development.

Abbreviations: IRS-1, insulin receptor substrate 1; PI3K, phosphatidylinositol-3-kinase; AKT, protein kinase B; mTOR, mammalian target of rapamycin; PTEN, phosphatase and tensin homologue; S6K1, S6 kinase 1; 4E-BP1, eIF4E-binding protein 1.

Table 6 Key questions in ongoing clinical trials

Will the BOLERO-2 trial show an overall survival benefit favoring patients receiving everolimus combined with exemestane?

Is there a role for everolimus in the first-line treatment of estrogen receptor-positive HER2-negative advanced breast cancer not previously exposed to any endocrine therapy?

Should everolimus or a drug targeting the PI3K-AKT-mTOR pathway be part of the next or later line of treatment for tumors progressing while receiving a regimen containing an mTOR inhibitor?

Is there any role for everolimus in the adjuvant treatment of high-risk, early-stage estrogen receptor-positive, HER2-negative breast cancer?

Is there any overall survival benefit in the BOLERO-3 trial comparing trastuzumab, vinorelbine, and everolimus with trastuzumab, vinorelbine, and placebo in heavily pretreated HER2-positive advanced breast cancer?

Do we see a more pronounced absolute benefit in HER2-positive advanced breast cancer when everolimus is added to standard therapy in less heavily pretreated patients (BOLERO-1) compared with the outcome observed in the BOLERO-3 trial?

Will we see improved outcome compared with everolimus-based therapy using second-generation mTOR inhibitors?

Abbreviations: BOLERO, Breast cancer trials of OraL EveROlimus; HER2, human epidermal growth factor receptor 2; PI3K-AKT-mTOR, phosphatidylinositol-3-kinase/protein kinase B/mammalian target of rapamycin.

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