Clinical utility of fulvestrant in the treatment of breast cancer: a report on the emerging clinical evidence

Figures & data

Table 1 Main randomized clinical trials in postmenopausal women with hormone receptor-positive, HER2-negative advanced breast cancer

Study acronyms	Study	Single-agent fulvestrant
		Design	n	Menopausal status*	Treatment	ET line**	PD to prior ET***	Primary end point	CBR (%)	Median TTP/PFS (months)	HR (95% CI)	Median OS	HR (95% CI)
0020	Howell et al^Citation59	OL Phase III	451	Post	Fulvestrant IAD vs anastrozole	1st–2nd	Yes	TTP	43.5 vs 40.9 (P=0.51)	5.5 vs 4.1	0.95 (0.82–1.10), P=0.48	NA	NA
0021	Osborne et al^Citation60	DB Phase III	400	Post	Fulvestrant IAD vs anastrozole	1st–2nd	Yes	TTP
0025	Howell et al^Citation64	DB Phase III	587 (HR^+/unknown) 459 HR^+	Post	Fulvestrant IAD vs tamoxifen	1st	No	TTP	54 vs 62 57 vs 63	6.8 vs 8.3 8.2 vs 8.3	1.18 (0.98–1.44), P=0.088 1.10 (0.89–1.36), P=0.39	36.9 vs 38.7 39.3 vs 40.7	1.29 (1.01–1.64), P=0.04 1.16 (0.88–1.54), P=0.30
CONFIRM	Di Leo et al^Citation65,Citation66	DB Phase III	736	Post	Fulvestrant HD vs fulvestrant IAD	1st–2nd	Yes	PFS	45.6 vs 39.6	5.5 vs 6.5	0.80 (0.68–0.94), P=0.006	26.4 vs 22.3	0.81 (0.69–0.96), P=0.02
EFECT	Chia et al^Citation51	DB Phase III	693	Post	Fulvestrant LD vs exemestane	1st–2nd	Yes	TTP	32.2 vs 31.5	3.7 vs 3.7	0.93 (0.819–1.133), P=0.65	NA	NA
FIRST	Robertson et al^Citation69^–^Citation71	OL Phase II	205	Post	Fulvestrant HD vs anastrozole	1st	No	CBR	72.5 vs 67.0 (P=0.386)	23.4 vs 13.1	0.66 (0.47–0.92), P=0.01	54.1 vs 48.4	0.70 (0.50–0.98), P=0.04
FALCON	Robertson et al^Citation72	DB Phase III	462	Post	Fulvestrant HD vs anastrozole	1st	No	PFS	78 vs 74 (P=0.3045)	16.6 vs 13.8	0.797 (0.637–0.999), P=0.0486	NA	NA
		Fulvestrant + other endocrine agents
FACT	Bergh et al^Citation78	OL Phase III	514	Pre/post	Fulvestrant LD + anastrozole vs anastrozole	1st	Yes/no	TTP	55.0 vs 55.1 (P=0.99)	10.8 vs 10.2	0.99 (0.81–1.20), P=0.91	37.8 vs 38.2	1.0 (0.76–1.32), P=1.00
SWOG 0226	Mehta et al^Citation79	OL Phase III	694	Post	Fulvestrant LD + anastrozole vs anastrozole	1st	No	PFS	73 vs 70	15.0 vs 13.5	0.80 (0.68–0.94), P=0.007	47.7 vs 41.3	0.81 (0.65–1.00), P=0.05
SoFEA	Johnston et al^Citation80	DB Phase III	723	Post	Fulvestrant LD + anastrozole vs fulvestrant LD + placebo Fulvestrant LD + placebo vs exemestane	1st–2nd	Yes	PFS	34 vs 32 (P=0.75) 32 vs 27 (P=0.27)	4.4 vs 4.8 4.8 vs 3.4	1.00 (0.83–1.21), P=0.98 0.95 (0.79–1.14), P=0.56	20.2 vs 19.4 19.4 vs 21.6	0.95 (0.76–1.17), P=0.61 1·05 (0.84–1.29), P=0.68
		Fulvestrant + inhibitors of growth-factor-receptor pathways
CALGB 40302/ALLIANCE	Burstein et al^Citation87	DB Phase III	295	Post	Fulvestrant HD + lapatinib vs fulvestrant HD + placebo	1st–2nd	Yes	PFS	NA	4.7 vs 3.8	1.04 (0.82–1.33), P=0.37	30.0 vs 26.4	0.91 (0.68–1.21), P=0.25
		Fulvestrant + inhibitors of MAPK–ERK1/2 and PI3K–mTOR pathways
SAKK 21/08	Zaman et al^Citation90	DB Phase II	46	Post	Fulvestrant HD + selumetinib vs fulvestrant HD + placebo	1st–2nd	Yes	DCR	NA	3.7 vs 5.6	NA	22.9 vs 19.4	NA
BELLE 2	Baselga et al^Citation95	DB Phase III	1,147	Post	Fulvestrant HD + buparlisib vs fulvestrant HD + placebo	1st–2nd	Yes	PFS	43.8 vs 42.0	6.9 vs 5.0	0.78 (0.67–0.89), P=0.00021	NA	NA
BELLE 3	Di Leo et al^Citation96	DB Phase III	432 (2:1)	Post	Fulvestrant HD + buparlisib vs fulvestrant HD + placebo	2nd–4th	Yes	PFS	25 vs 15	3.9 vs 1.8	0.67 (0.53–0.84), P=0.0003	NA	NA
FERGI	Krop et al^Citation98	DB Phase II	168	Post	Fulvestrant HD + pictilisib vs fulvestrant HD + placebo	1st–4th	Yes	PFS	24.7 vs 17.7 (P=0.27)	6.6 vs 5.1	0.74 (0.52–1.06), P=0.096	NA	NA
PrECOG 0102	Kornblum et al^Citation102	DB Phase II	131	Post	Fulvestrant HD + everolimus vs fulvestrant HD + placebo	1st–3rd	Yes	PFS	NA	10.4 vs 5.1	0.60 (0.40–0.92), P=0.02	NA	NA
		Fulvestrant + CDK4/6 inhibitors
PALOMA 3	Turner et al^Citation104^–^Citation109	DB Phase III	521 (2:1)	Pre/post	Fulvestrant HD + palbociclib vs fulvestrant HD + placebo	1st–3rd	Yes	PFS	67 vs 40 (P<0.0001)	9.5 vs 4.6	0.46 (0.36–0.59), P<0.0001	NA	NA
MONARCH 2	Sledge et al^Citation111	DB Phase III	669 (2:1)	Pre/post	Fulvestrant HD + abemaciclib vs fulvestrant HD + placebo	1st–2nd	Yes	PFS	72.2 vs 56.1 (P<0.001)	16.4 vs 9.3	0.553 (0.449–0.681), P<0.001	NA	NA
		Fulvestrant + angiogenesis inhibitors and multitargeting tyrosine-kinase inhibitors
LEA	Martín et al^Citation117	OL Phase III	380	Post	Fulvestrant HD or letrozole vs fulvestrant HD or letrozole + bevacizumab	1st	Yes/no	PFS	67 vs 77 (P=0.041)	14.4 vs 19.3	0.83 (0.65–1.06), P=0.126	51.8 vs 52.1	0.87 (0.58–1.32), P=0.518
CTK1258A2210	Musolino et al^Citation119	DB Phase II	97	Post	Fulvestrant HD + dovitinib vs fulvestrant HD + placebo	1st–2nd	Yes	PFS	NA	5.5 vs 5.5	0.68 (0.41–1.14), NS	NA	NA

Notes:

* Premenopausal patients also received a GnRH analog;

** for advanced disease;

*** disease progression while on or ≤12 months after the end of adjuvant endocrine therapy or ≤1 month after the end of endocrine therapy for advanced disease.

Abbreviations: ET, endocrine therapy; CBR, clinical benefit rate; PFS, progression-free survival; TTP, time to progression; OS, overall survival; DCR, disease-control rate; DB, double-blind; OL, open-label; IAD, initially approved dose; LD, loading dose; HD, high dose; MAPK, mitogen activated protein kinase; HER2, human epidermal growth factor receptor 2; GnRH, gonadotropin-releasing hormone; PI3K, phosphatidylinositol 3-kinase; mTOR, mammalian target of rapamycin; NA, not assessed; ERK, extracellular signal-regulated kinase; NS, not significant.

Table 2 Selected ongoing clinical trials with fulvestrant in breast cancer

ClinicalTrials.gov ID (other ID)	Main inclusion criteria	Design	Treatment
Neoadjuvant setting
NCT02955394 (16-1042.cc)	HER2^−/ER^+/AR^+ postmenopausal LABC	Phase II, randomized (2 arms), open-label	Enzalutamide + fulvestrant	Fulvestrant
NCT03236974 (D6090C00002)	HER2^−/ER^+ postmenopausal EBC	Phase I, randomized (2 arms), open-label	Fulvestrant	AZD9496
NCT02760030 (OSU-15266)	HER2^−/HR^+ vulnerable or frail EBC	Phase II, single arm, open-label	Palbociclib + fulvestrant
NCT03447132 (ICRG1201; SAFIA)	HER2^−/HR^+ EBC	Phase III, randomized (2 arms), double-blind	Palbociclib + fulvestrant	Placebo + fulvestrant
Metastatic setting
NCT02953860 (16-1001.cc)	HER2^−/HR^+ MBC	Phase II, single arm, open-label	Enzalutamide + fulvestrant
NCT03393845 (BTCRC-BRE16-042)	HER2^−/HR^+ LABC or MBC	Phase II, single arm, open-label	Pembrolizumab + fulvestrant
NCT03056755 (CBYL719X2402)	HER2^−/HR^+ MBC progressed on CDK4/6 inhibitor	Phase II, nonrandomized (2 cohorts), open-label	Alpelisib + fulvestrant	Alpelisib + letrozole
NCT03294694 (17-285)	HER2^−/HR^+ MBC	Phase I, nonrandomized (2 cohorts), open-label	PDR001 + ribociclib	PDR001 + ribociclib + fulvestrant
NCT03344536 (17-379)	HER2^−/HR^+ MBC with FGFR amplifications	Phase IB–II, single-group assignment, open-label	Debio 1347 + fulvestrant
NCT03238196 (VICC BRE 16126)	HER2^−/HR^+ FGFR amplified postmenopausal MBC	Phase IB, single-arm, open-label	Erdafitinib + palbociclib + fulvestrant
NCT03241810 (MM-121-02-02-10; SHERBOC)	HER2^−/HR^+ heregulin positive postmenopausal MBC	Phase II, randomized (2 arms), double- blind	Seribantumab + fulvestrant	Placebo + fulvestrant
NCT02964507 (201973)	HER2^−/HR^+ MBC	Phase I–II, single-arm open-label (Phase I) followed by randomized (2 arms) double-blind (Phase II)	GSK525762 + fulvestrant (Phase I)	GSK525762 + fulvestrant (Phase II) Placebo + fulvestrant (Phase II)
NCT02049957 (C31001)	HER2^−/ER^+ postmenopausal MBC	Phase IB–II, nonrandomized (2 arms), open-label	MLN0128 + exemestane	MLN0128 + fulvestrant
NCT03425838 (BOOG 2017-03; SONIA)	HER2^−/HR^+ LRBC or MBC	Phase III, randomized (2 arms), open- label	NSAI + CDK4/6 inhibitor (first line) followed by fulvestrant (second line)	NSAI (first line) followed by fulvestrant + CDK4/6 inhibitor (second line)
NCT02763566 (I3Y-CR-JPBQ; MONARCH plus)	HER2^−/HR^+ postmenopausal LRBC or MBC	Phase III, randomized (4 arms), double- blind	Abemaciclib + NSAI Placebo + NSAI	Abemaciclib + fulvestrant Placebo + fulvestrant
NCT03289039 (17-318)	HER2^+/ER^+ MBC	Phase II, randomized (2 arms), open- label	Neratinib + fulvestrant	Neratinib
NCT02983071 (G1T38-02)	HER2^−/HR^+ LABC or MBC after endocrine failure	Phase I–II, nonrandomized (2 dosing cohorts), open-label open-label	G1T38 (CDK4/6 inhibitor) + fulvestrant
NCT02684032 (B2151009)	HER2^−/ER^+ MBC	Phase IB, nonrandomized (2 cohorts), open-label	Gedatolisib + palbociclib + letrozole	Gedatolisib + palbociclib + fulvestrant
NCT03322215 (PASIPHAE)	HER2^−/HR^+ postmenopausal endocrine- resistant LABC or MBC	Phase II, randomized (2 arms), open-label	Palbociclib + fulvestrant	Capecitabine
NCT02756364 (C31006)	HER2^−/HR^+ MBC progressed on AI	Phase II, single-arm, open-label	MLN0128 + fulvestrant
NCT02028507 (PEARL)	HER2^−/ER^+ postmenopausal MBC	Phase III, randomized (2 cohorts), open-label	Exemestane + palbociclib (cohort I) Fulvestrant + palbociclib (cohort II)	Capecitabine (cohort I) Capecitabine (cohort II)
NCT02028507 (GEICAM/2013-02; PEARL)	HER2^−/HR^+ postmenopausal AI-resistant MBC	Phase III, randomized (2 cohorts), open-label	Palbociclib + exemestane (cohort I) Palbociclib + fulvestrant (cohort II)	Capecitabine (cohort I) Capecitabine (cohort II)
NCT03007979 (201612098)	HER2^−/HR^+ MBC	Phase II, nonrandomized (2 arms), open-label	Palbociclib (with alternative dosing schedule) + letrozole	Palbociclib (with alternative dosing schedule) + fulvestrant
NCT02530411 (2014/VCC/0013; FURVA)	HER2^−/ER^+ postmenopausal AI-resistant MBC	Phase II, randomized (2 arms), double-blind	Vandetanib + fulvestrant	Fulvestrant
NCT03280563 (CO39611; MORPHEUS)	HER2^−/HR^+ postmenopausal LABC or MBC	Phase IB–II, randomized (4 arms) open-label (stage 1), single-arm, open-label (stage 2)	Fulvestrant (stage 1) Atezolizumab + cobimetinib (stage 1) Atezolizumab + ipatasertib + fulvestrant (stage 1)	Atezolizumab + fulvestrant (stage 1) Atezolizumab + bevacizumab + fulvestrant or other endocrine therapy (stage 2)
NCT02057133 (I3Y-MC-JPBH)	MBC	Phase IB, nonrandomized (different groups), open-label	Abemaciclib + letrozole or anastrozole or tamoxifen or exemestane or exemestane + everolimus or trastuzumab or LY3023414 + fulvestrant
NCT02947685 (AFT-38; PATINA)	HER2^+/HR^+ MBC	Phase III, randomized (2 arms), open-label	Palbociclib + trastuzumab/pertuzumab + letrozole or anastrozole or exemestane or fulvestrant	Trastuzumab/pertuzumab + letrozole or anastrozole or exemestane or fulvestrant
NCT02384746 (D13036)	HER2^−/ER^+ postmenopausal LABC or MBC progressed on fulvestrant	Phase I, single-arm, open-label	MLN9708 + fulvestrant
NCT02860000 (MC1431)	HER2^−/ER^+ postmenopausal endocrine-resistant LABC or MBC	Phase II, randomized (2 arms), open-label	Alisertib + fulvestrant	Alisertib
NCT03377101 (10194)	HER2^−/HR^+ endocrine-resistant MBC	Phase II, randomized (2 arms), open-label	Copanlisib + palbociclib + fulvestrant	Palbociclib + fulvestrant
NCT02970682 (EVG001BC)	HER2^−/ER^+ MBC	Phase II, nonrandomized (3 cohorts), open-label	SFX01 + AI or tamoxifen or fulvestrant
NCT03147287 (17-101; PACE)	HER2^−/HR^+ LRBC or MBC previously exposed to CDK4/6 ^+ endocrine therapy	Phase II, randomized (3 arms), open-label	Palbociclib + fulvestrant Palbociclib + avelumab + fulvestrant	Fulvestrant
NCT03182634 (ICR-CTSU/2015/10056; plasma MATCH)	LRBC or MBC where the targetable mutation is identified through ctDNA	Phase II, nonrandomized (4 cohorts), open-label	Fulvestrant Neratinib + fulvestrant	AZD5363 AZD5363 + fulvestrant
NCT03430466 (kbcrnb001)	HER2^−/HR^+ menopausal EBC	Phase II, single arm, open-label	Durvalumab + tremelimumab + fulvestrant

Notes: When not specified, studies enrolled pre-, peri- (with ovarian suppression), and post-menopausal patients. New drug classes: alisertib, aurora A kinase inhibitor; AZD5363, pan-Akt inhibitor; AZD9496, nonsteroidal oral SERD; copanlisib, pan-class I PI3K inhibitor; Debio 1347, pan-FGFR inhibitor; erdafitinib, pan-FGFR inhibitor; G1T38, CDK4/6 inhibitor; gedatolisib, PI3K/mTOR inhibitor; GSK525762, BET inhibitor; ipatasertib, pan-Akt inhibitor; LY3023414, PI3K/mTOR inhibitor; MLN0128, mTORC1/2 inhibitor; MLN9708 (ixazomib), proteasome inhibitor; PDR001, anti-PD-1 antibody; seribantumab, anti-ErbB3 antibody; SFX01, antioxidant; vandetanib, inhibitor of VEGFR, EGFR and RET.

Abbreviations: EBC, early breast cancer; LABC, locally advanced BC; LRBC, locoregionally recurrent BC; MBC, metastatic breast cancer; AI, aromatase inhibitor; NSAI, nonsteroidal aromatase inhibitor; ER, estrogen receptor; FGFR, fibroblast growth factor receptor; ctDNA, circulating tumor DNA; HER2, human epidermal growth factor receptor 2; AR, androgen receptor.

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