Fulvestrant in Combination with CDK4/6 Inhibitors for HER2- Metastatic Breast Cancers: Current Perspectives

Figures & data

Figure 1 The molecular mechanism of action for Fulvestrant. Fulvestrant, being a pure steroidal ERα antagonist, inhibits the dimerization of the estrogen receptor and blocks the nuclear localization of the receptor itself. The binding of fulvestrant with ER also leads to a rapid degradation of the fulvestrant-ER complex and makes the receptor unavailable to estrogens, so the ability of ER to promote gene transcription is attenuated.

Table 1 Studies of CDK 4/6 Inhibitors with Fulvestrant in the ABC HR+/HER2- Population

Study	Population	Phase	n	Setting	Treatment	Most Recent ET		Prior CT	Postmenop. at Study Entry		Results
						De novo	ADJ/neo	ABC
Palbociclib
PALOMA-3	Pre- and Postmenopausal women, progressed on/or ≤ 12 months from prior adj therapy with AI/TAM	III	521	2nd-line or greater	Fulvestrant^a plus palbociclib or placebo	–	114 (22%)	406 (78%)	34% (1 prior line)	413 (79%)	PFS 11.2 vs 4.6 mos HR 0.50; p < 0.0001
Ribociclib
MONALEESA-3	Men and postmenopausal women in first-line treatment (treatment naive for ABC) or in second line + early relapsers	III	726	≤ 1st line of prior ET for ABC	Fulvestrant plus Ribociclib or placebo	139 (20%)	431 (60%)	150 (20%)	No	726 (100%)	PFS 20.6 vs 12.8 mos HR 0.60; p < 0.001 OS NR vs 40 mos HR 0.724; p=0.00455
Abemaciclib
MONARCH 2	Pre – and Postmenopausal women relapsed on neoajuvant or on/within 12 months of ET or progressed on first-line therapy	III	669	Failed ET in localized or 1st-line for ABC	Fulvestrant^a plus abemaciclib or placebo	–	396* (60%)	256* (38%)	No	552 (82%)	PFS 16.4 vs 9.3 mos HR 0.55; p < 0.001 OS 46.7 vs 37.3 mos HR 0.757; p=0.01

Notes:^aGoserelin (luteinizing hormone-releasing hormone analog) is coadministered with fulvestrant to premenopausal women in PALOMA-3, MONARCH-2. *ET history was not available for 17 patients.

Abbreviations: ABC, advanced breast cancer; HER2, human epidermal growth factor receptor 2; HR+, hormone receptor-positive; PFS, progression-free survival; OS, overall survival; NR, not reached; ET, endocrine treatment; ADJ adjuvant setting; AI aromatase inhibitor; TAM tamoxifen.

Table 2 Toxicity Profile of Cycline Inhibitors with Fulvestrant or with Letrozole

Palbociclib			Ribociclib			Abemaciclib
Monotherapy^Citation42	+letrozole PALOMA-2^Citation14	+fulvestrant PALOMA-3^Citation6	Monotherapy^Citation43	+letrozole MONALEESA-2^Citation11	+fulvestrant MONALEESA-3^Citation28	Monotherapy MONARCH-1^Citation33	+fulvestrant MONARCH-2^Citation26	+letrozole/anastrozole MONARCH-3^Citation12
Adverse events any grade
Neutropenia (92%) Leukopenia (100%) Thrombocytopenia (76%) Anemia (70%) Lymphopenia (65%)	Neutropenia (80%) Leukopenia (40%) Nausea (35%) Fatigue (35%) Arthralgia (33%) Alopecia (33%)	Neutropenia (80%) Leukopenia (50%) Infections (42%) Fatigue (40%) Nausea (32%)	Neutropenia (46%) Leukopenia (43%) Thrombocytopenia (30%) Fatigue (45%) Nausea (42%)	Neutropenia (75%) Leukopenia (33%) Nausea (50%) Infections (50%) Fatigue (37%) Diarrhea (35%) Alopecia (33%)	Neutropenia (70%) Nausea (45%) Fatigue (32%) Diarrhea (29%) Leukopenia (28%) Vomiting (27%) Constipation (25%) Arthralgia (24%) Cough (22%) Headache (22%) Alopecia (19%) Rash (18%) Anemia (17%)	Neutropenia (85%) Leukopenia (90%) Thrombocytopenia (76%) Anemia (69%) Diarrhea (90%) Fatigue (65%) Nausea (65%) Decreased appetite (45%) Abdominal pain (40%) Vomiting (35%)	Neutropenia (46%) Diarrhea (86%) Nausea (45%) Fatigue (40%) Abdominal pain (35%)	Neutropenia (41%) Diarrhea (81%) Nausea (39%) Fatigue (40%) Infections (39%)
Adverse events grade 3–4
Neutropenia (54%) Leukopenia (51%) Lymphopenia (30%)	Neutropenia (66%) Leukopenia (25%)	Neutropenia (65%) Leukopenia (28%)	Neutropenia (27%) Leukopenia (17%) Fatigue (2%) Nausea (2%)	Neutropenia (59%) Leukopenia (21%)	Neutropenia (53%) Leukopenia (14%) Anemia (3%) Fatigue (2%) Back Pain (2%) Nausea (1%) Constipation (1%) Headache (1%)	Neutropenia (27%) Leukopenia (28%) Diarrhea (20%)	Neutropenia (24%)	Neutropenia (21%)

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