Therapy for Hormone Receptor-Positive, Human Epidermal Growth Receptor 2-Negative Metastatic Breast Cancer Following Treatment Progression via CDK4/6 Inhibitors: A Literature Review

Figures & data

Figure 1 The key mechanisms for the resistance to CDK4/6 inhibitors.

Table 1 Clinical Trials or Retrospective Studies Targeting cyclinD1-CDK4/6 Complex

Study ID	Phase	Population	Size	Intervention	Result
Retrospective study	NA	HR+ HER2- mBC prior progression on a CDK4/6 inhibitors	308	The same CDK4/6i in 75% patients, different in 25% patients	mPFS =8.25 months
Retrospective study	NA	HR+ HER2- mBC prior progression on palbociclib plus AI	30	Palbociclib+fulvestrant	mPFS =10.3 months
Retrospective study	NA	HR+ HER2- mBC prior progression on palbociclib plus AI	87	Abemaciclib monotherapy	mPFS =5.3 months mOS=17.2 months
MAINTAIN (NCT02632045)	II	HR+ HER2- mBC prior progression on palbociclib plus or ribociclib, ≤1 line prior chemotherapy	132	Ribociclib plus fulvestrant or exemestane	mPFS = 5.29 months CBR=43%
PACE NCT03147287	II	ABC HR+ HER2- progression on AI+CDK4/6 inhibitors	220	Ful vs Ful+Palbociclib vs Ful+Palbociclib +avelumab	mPFS =4.89 (F) vs 4.6 (F+P) vs 8.1 (F+P+A) months; mOS=27.5 (F) vs 24.6 (F+P) vs 42.5 months (F+P+A)
BioPAR NCT03184090	II	Prior ET 1–2 lines, prior Palbociclib, ≤1 line prior chemotherapy	33	Palbociclib + Physician’s choice ET	mPFS =2.6 months mOS=23.9 months CBR=34%
NCT03809988 (PALMIRA)	II	HR+ HER2- ABC prior progression on Pal+AI/Ful	198	Palbociclib +AI/Ful vs AI/Ful	NA
NCT02738866	II	HR+ HER2- ABC prior progression on Pal+AI	100	Palbociclib +Ful	NA
NCT04318223	II	HR+ HER2- mBC prior progression on CDK4/6i plus endocrine therapy	168	Palbociclib Plus Fulvestrant	NA
NCT03809988 (PALMIRA)	II	HR+ HER2- ABC prior progression on Pal+AI/Ful	198	Palbociclib +AI/Ful vs AI/Ful	NA
NCT02738866	II	HR+ HER2- ABC prior progression on Pal+AI	100	Palbociclib +Ful	NA
NCT03519178	I/II	HR+ HER2- ABC prior progression on a CDK4/6 inhibitors	?/157	PF-06873600 vs PF-06873600+ Endocrine Therapy	NA
TRINITI-1 NCT02732119	I/II	HR+ HER2- ABC prior progression on a CDK4/6 inhibitors≥ 4 months	95	Ribociclib+EVE+EXE	mPFS =5.7 months CBR at 24 weeks: 41% ORR:8.4%

Abbreviations: HR, hormone-receptor; HER2, human epidermal growth factor receptor 2; ABC, advanced breast cancer; mBC, metastatic breast cancer; CDK, Cyclin-dependent kinase; AI, aromatase inhibitor; Ful, fulvestrant; NA, not available; mPFS, median progression-free survival; mOS, median overall survival; CBR, clinical benefit rate.

Table 2 Clinical Trials or Retrospective Studies of Targeting PI3K-AKT-mTOR Pathway

Study ID	Phase	Population	Size	Intervention	Result
SOLAR-1 NCT02437318	III	HR+ HER2- ABC	20	Alpelisib+Ful vs Placebo+Ful	mPFS: 5.5 vs 1.8 months HR 0.48 (95% CI 0.17–1.36)
BYLieve NCT03056755 (cohort A)	II	HR+ HER2- ABC with PIK3CA mutation progression on AI +CDK4/6 inhibitors	121	Alpelisib+Ful	50.4% patients were progression free at 6month mPFS=7.3 months
TAKTIC NCT03959891	I	HR+ ABC with PIK3CA mutation, with or without prior use of CDK4/6 inhibitors	60	Ipatasertib+Ful vs Ipatasertib+AI vs Ipatasertib + Ful+Pal	NA
FINER NCT04650581	III	HR+ ABC with PIK3CA mutation with prior use of CDK4/6 inhibitors	250	Ipatasertib+Ful vs Ful	NA
CAPItello-291 NCT04305496	III	HR+ HER2- ABC progression on AI +CDK4/6 inhibitors	489/ 708	Capivasertib + Fulvestrant vs Ful	mPFS=7.2 vs 3.6 months HR=0.60, p<0.001
Retrospective study	NA	HR+ ABC with or without prior use of CDK4/6 inhibitors	43	EVE+EXE	mPFS=3.6 months mOS=15.6 months
Retrospective study	NA	HR+ mBC with or without prior use of CDK4/6 inhibitors	192	EVE + prior CDK4/6 i or another inhibitor	mPFS: 3.8 vs 5.4 months HR:1.46 (95% CI: 1.08 to 1.97, P = 0.013)

Abbreviations: HR, hormone-receptor; HER2, human epidermal growth factor receptor 2; ABC, advanced breast cancer; mBC, metastatic breast cancer; CDK, Cyclin-dependent kinase; AI, aromatase inhibitor; Ful, fulvestrant; Pal, Palbociclib; EVE, everolimus; EXE, Exemestane; NA, not available; HR, hazard ratio; mPFS, median progression-free survival; mOS, median overall survival.

Table 3 Other Clinical Trials on CDK4 Inhibitors Progression

Study ID	Phase	Population	Size	Intervention	Result
TROPICS-02 (NCT00034723)	III	HR+ HER2- mBC prior progression on a CDK4/6I (98%) and received 2–4 lines of chemotherapy	273	Sacituzumab govitecan	mPFS= 5.5 (4.2–7.0) months mOS=14.4 (13.0–15.7) months
DESTINY-Breast04 (NCT03734029)	III	HR+ HER2-low mBC prior progression on a CDK4/6I (70%) and received 1–2 lines of chemotherapy	480	Trastuzumab deruxtecan	mPFS=10.1 months mOS=23.9 months ORR=52.6%
TBCRC 048 (NCT02032823)	II	HR+ HER2-low mBC prior progression on a CDK4/6I (70%) and received 1–2 lines of chemotherapy	41	Olaparib	ORR: 82% and 50% in Germline PALB2 mutations somatic BRCA1/2 mutations
NCT03134638	I	HR+ HER2- mBC prior progression on a CDK4/6iI	12	SY-1365 plus fulvestrant	Terminated for business reason
NCT04247126	I	HR+ HER2- mBC prior progression on a CDK4/6iI	?/80	SY-5609 plus fulvestrant	NA
NCT04726332	I	HR+ HER2- mBC prior progression on a CDK4/6iI	12	XL102 plus fulvestrant	NA
Veronica NCT03584009	II	HR+ HER2- ABC prior progression on a CDK4/6 inhibitors≥ 8 weeks	103	Venetoclax+Ful vs Ful	mPFS: 2.69 vs 1.94 months; CBR: 11.8% vs 13.7%
SMILE study NCT04738292	II	ABC HR+ HER2- progression on AI+CDK4/6 inhibitors	39	Onapristone+Ful	NA
TATEN NCT04251169	II	HR+ HER2- ABC prior progression on a CDK4/6 inhibitors	46	Pembrolizumab+ Paclitaxel	NA
EMERALD NCT03778931	III	HR+ HER2- ABC prior progression on a CDK4/6 inhibitors	466	Lacestrant vs Ful vs AI	mPFS: 2.8 vs 1.9 months, p=0.002
SERENA-2 NCT04214288	II	HR+ HER2- ABC prior progression on a CDK4/6 inhibitors	112/ 220	Camizestrant 75mg vs camizestrant 150mg vs Ful	mPFS: 5.5, 3.8 and 2.1 months
AMEERA-3 NCT04059484	II	Prior ET 1–2 lines, prior CDK4/6i (80%), ≤1 line prior chemotherapy or targeted agent	290	Amcenestrant (oral SERD) vs TPC	mPFS: 3.6 vs 3.7 months
acelERA NCT04576455	II	1–2 lines prior systemic therapy (≤1 line chemotherapy, ≤1 line targeted therapy)	303	Giredestrant (oral SERD) vs TPC	mPFS: 5.6 vs 5.4 months
NCT03955939	I	HR+ HER2- ABC prior progression on a CDK4/6 inhibitors	5	LY3295668 Erbumine ±Endocrine therapy	NA
NCT04553133	I/II	HR+ HER2- ABC prior progression on a CDK4/6 inhibitors	?/240	PF-07104091 vs PF-07104091 + endocrine therapy	NA
NCT03519178	I/IIa	Advanced solid tumors including ER+/HER2- breast cancer; prior ET + CDK4/6 inhibitors	?/155	PF-06873600 vs PF-06873600 + endocrine therapy	NA
VELA NCT05252416	I/II	Advanced solid tumors including ER+/HER2- breast cancer; prior ET + CDK4/6 inhibitors	?/360	BLU-222 monotherapy BLU-222 + Carboplatin BLU-222 + Ribociclib + Fulvestrant BLU-222 + Fulvestrant	NA
NCT05262400	Ib/II	Advanced solid tumors including ER+/HER2- breast cancer; prior ET + CDK4/6 inhibitors	?/144	PF-07220060 + PF-07104091 vs PF-07220060 + PF-07104091 + endocrine therapy	NA
NCT04134884	I	HR+ HER2- ABC prior progression on a CDK4/6 inhibitors	?/32	STX727+talazoparib	NA

Abbreviations: HR, hormone-receptor; HER2, human epidermal growth factor receptor 2; ABC, advanced breast cancer; CDK, Cyclin-dependent kinase; TAM, tamoxifen; LHRHa, luteinizing Hormone Releasing Hormone analogues; RIB, ribociclib; ER, estrogen receptor; AI, aromatase inhibitor; Ful, fulvestrant; Pal, palbociclib; NA, not available; Onapristone, a progesterone antagonist; Venetoclax, BCL-2 inhibitor; Ipatasertib, AKT inhibitor; LY3295668 Erbumine, Aurora kinase A inhibitor; Copanlisib, PIK inhibitor; SY-5609, CDK7 inhibitor; PF-07104091, CDK2 inhibitor; PF-06873600, CDK2/4/6 inhibitor; IMMU-132, Trop-2 directed antibody–drug conjugate; ASTX727, cedazuridine +decitabine.

Table 4 Clinical Trials on Oral SERDs After CDK4/6i Progression

Drug	Elacestrant	Camizestrant	Amcenestrant	Giredestrant
MOA	Oral SERD	Oral SERD	Oral SERD	Oral SERD
Study name	EMERALD^Citation65	SERENA-2^Citation66	AMEERA-3^Citation67	aceIERA^Citation68
Phase	III	II	II	II
n	466	220	290	303
Prior CDK4/6i	100%	50%	80%	40%
Adverse Effects (>10%)	Nausea (35%) Fatigue (19%) Vomiting (19%) Decreased Appetite (14.8%) Arthralgia (14.3%) Diarrhea (13.9%) Back pain (13.9%) AST increased (13.1%) Constipation (12.2%) Headache (12.2%) Hot flashes (11.4%) Dyspepsia (10.1%)	Photopsia (24.7%) Bradycardia (26%) Fatigue (17.8%) Anemia (15.1%) Asthenia (15.1%) Arthralgias (12.3%)	Nausea (20.3%) Vomiting (19.6%) Arthralgia (14.0%) Back pain (13.3%) Headache (12.6%) Fatigue (11.2%) Diarrhea (10.5%)	Hepatotoxity (23.6%) Muscoluskeletal (15.0%) Arthralgias (12.1%) Fatigue (13.9%) Nausea (10.1%)

Abbreviations: MOA, mechanism of action; SERD, selective estrogen receptor degrader.

Table 5 Clinical Trials of ADCs and Inhibitors Targeting PI3K-AKT-mTOR

Drug	Alpelisib-FUL	Capivasertib-FUL	Everolimus-EXE	Trastuzumab deruxtecan	Sacituzumab Govitecan
MOA	PI3K inhibitor	AKT inhibitor	mTOR inhibitor	ADC	ADC
Study	SOLAR-1^Citation42	FACTION^Citation49	BOLERO-2^Citation44	DESTINY-Breast04^Citation62	TROPICS-02^Citation60
Phase	II	II	III	III	III
Adverse Effects (>10%)	Hyperglycemia (63.7%) Diarrhea (57.7%) Nausea (44.7%) Decreased appetite (35.6%) Rash (35.6%) Vomiting (27.1%) Weight loss (26.8%) Stomatitis (24.6%) Fatigue (24.1%) Asthenia (20.4%) Alopecia (19.7%) Mucosal inflammation (18.3%) Pruritus (18.0%) Headache (17.6%) Dysgeusis (16.5%) Arthralgias (11.2%)	Hypertension (91%) Diarrhoea (81%) Fatigue (58%) Nausea (55%) Hyperlipidemia (53%) Rash (52%) Hyperglycaemia (42%) Vomiting (40%) Proteinuria (38%) Infection (37%) Back pain (24%) Urea (high) (18%) Creatinine increased (16%) Abdominal pain (15%) Hot flashes (15%)	Stomatitis (62%) Rash (42%) Fatigue (37%) Diarrhea (34%) Nausea (30%) Appetite decrease (29%) Weight loss (27%) Headache (26%) Cough (25%) Dysgeusia (23%) Arthralgia (21%) Peripheral edema (21%) Dyspnea (20%) Vomiting (18%) Anemia (17%) Pyrexia (17%) Pneumonitis (17%) Back pain (15%) Insomnia (15%) Thrombocytopenia (12%)	Nausea (73%) Fatigue (47.7%) Alopecia (37.7%) Vomiting (34%) Neutropenia (33.2%) Anemia (33.2%) Decreased appetite (28.0%) Thrombocyopenia (23.7%) Increased ALT (23.5%) Leukopenia (23.2%) Diarrhea (22.4%) Constipation (21.3%) Increased ALT (23.5%) Interstitial lung disease (12.1%) LVEF (11.9%)	Neutropenia (70%) Diarrhea (57%) Nausea (55%) Alopecia (46%) Fatigue (37%) Anemia (34%) Asthenia (20%) Vomiting (19%) Constipation (18%) Decreased appetite (15%) Leukopenia (14%) Abdominal pain (13%) Lymphopenia (12%)

Abbreviations: Exe, exemestane; ALT, amino transaminases; LVEF, left ventricular ejection fraction.

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