Can Patients with HER2-Low Breast Cancer Benefit from Anti-HER2 Therapies? A Review

Figures & data

Table 1 The ADCs and Their Trials for the Treatment of HER2-Low BC

Drug	Study (NCT Number)	Phase	Number	Population and Setting	Experimental Arm	Control Arm	Efficacy	Adverse Events Grade≥3
T-DXd	-, NCT02564900^Citation36	I	292 (HER2-low: 54)	HER2-low ABC; Disease is refractory to or intolerable with standard treatment, or for which no standard treatment is available	T-DXd	-	cORR: 37.0% cDCR: 87.0% DOR: 10.4 months TTR: 2.7 months PFS: 11.1 months	63.0%: decreases in neutrophil, platelet, WBC counts, anemia, hypokalemia, AST increase, decreased appetite, diarrhea, interstitial lung disease, pneumonitis
	DEBBRAH, NCT04420598^Citation41	II	41 (HER2-low: Unknown)	HER2-low ABC with progressing BM after local treatment	T-DXd	-	ORR: Unupdated CBR: Unupdated TTR: Unupdated DOR: Unupdated OS: Unupdated	Unupdated
	DESTINY-Breast 04, NCT03734029^Citation38	III	557 (373; 184)	HER2-low MBC; Prior 1 to 2 lines of chemotherapy/adjuvant in the metastatic setting	T-DXd	TPC (capecitabine, eribulin, gemcitabine, paclitaxel, or nab-paclitaxel)	mPFS: HR (+): 10.1 vs 5.4 months; HR (-): 8.5 vs 2.9 months mOS: HR (+): 23.9 vs 17.5 months; HR (-): 18.2 vs 8.3 months	52.6%: interstitial lung disease, pneumonitis, others are unknown
	DESTINY-Breast06, NCT04494425^Citation42	III	850	HER2-low MBC; Prior ≥2 lines of endocrine therapies or an endocrine therapy combined with a CDK4/6 inhibitor.	T-DXd	TPC (paclitaxel, nab-paclitaxel or capecitabine)	OS: Ongoing PFS: Ongoing ORR: Ongoing DOR: Ongoing	Ongoing
	DESTINY-Breast08, NCT04556773^Citation43	Ib	182	Module 1 (HR+ or HR-): HR-, only 1 prior line of chemotherapy for mBC; HR+, only 1 prior line of endocrine therapy but no prior chemotherapy for mBC; Module 2 (HR-): no prior chemotherapy for mBC; Module 3 (HR-): only 1 prior line of chemotherapy for mBC; Module 4 and 5 (HR+): only 1 prior line of endocrine therapy but no prior chemotherapy for mBC	Module 1: T-DXd + capecitabine Module 2: T-DXd + durvalumab + paclitaxel Module 3: T-DXd + capivasertib Module 4: T-DXd + anastrozole Module 5: T-DXd + fulvestrant	-	ORR: Ongoing PFS: Ongoing DOR: Ongoing OS: Ongoing	Ongoing
	TALENT, NCT04553770^Citation44	II	88	HR+, HER2-low BC; Previously untreated operable invasive carcinoma of the breast greater than 2.0 cm	A: T-DXd B: T-DXd + anastrozole	-	pCR: Ongoing COR: Ongoing	Ongoing
SYD985	-, NCT02277717^Citation48	I	99 (HER2+: 50, HER2-low and HR+: 32, HER2-low and HR-: 17)	HER2+ or HER2-low, HR± ABC/ MBC; Rogressed on standard therapy or no standard therapy exists	SYD985	-	ORR (HER2+): 33% ORR (HER2-low and HR+): 27% ORR (HER2-low and HR-): 40%	10%: neutropenia, conjunctivitis
MRG002	-, NCT04742153^Citation50	II	66	HER2-low ABC/ MBC; Prior at least first-line standard treatment for recurrent or metastatic breast cancer	MRG002	-	ORR: 34.7% ORR (HER2 IHC 1+): 34.1% ORR (HER2 IHC 2+): 37.5% ORR (TNBC): 37.5% DCR: 75.5% DCR (TNBC): 62.5%	-: neutrophil count decreased
A66	-, NCT03602079^Citation51	I–II	49 (HER2-low BC: unknown)	HER2 expression (≥ 1+ determined by IHC) MBC;-	A66	-	Ongoing	Ongoing
PF-06804103	-, NCT03284723^Citation53	I	95 (HER2-low BC: unknown)	HER2-low (1+) TNBC;-	PF-06804103	PF-06804103 + palbociclib +letrozole	DOR: Ongoing PFS: Ongoing TTP: Ongoing	Ongoing
RC48-ADC	C001 CANCER, NCT02881138; C003 CANCER, NCT03052634^Citation54	I/Ib	118 (HER2+: 70, HER2-low: 48)	HER2+/HER2-low MBC; Prior ≥2 lines of chemotherapy for MBC	RC48-ADC	-	ORR (HER2-low): 39.6% mPFS (HER2-low): 5.7 months ORR (IHC2+/FISH-): 42.9% mPFS (IHC2+/FISH-): 6.6 months ORR (IHC1+): 30.8% mPFS (IHC1+): 5.5 months	41.5%: neutrophil count decreased, GGT increased, fatigue
	-, NCT04400695z	III	366	HER2-low MBC; Prior anthracycline and 1 or 2 systemic chemotherapy after relapse / metastasis	RC48-ADC	TPC (paclitaxel injection, docetaxel injection, vinorelbine tartrate injection, capecitabine tablets)	PFS: Ongoing ORR: Ongoing DOR: Ongoing DCR: Ongoing TTP: Ongoing OS: Ongoing	Ongoing

Abbreviations: (A) (M) BC, (advanced) (metastatic) breast cancer; TNBC, triple-negative breast cancer; BM, brain metastases; (c)ORR, (confirmed) overall response rate; DCR, disease control rate; DOR, duration of response; TTR, time to response; (m) PFS, (median) progression-free survival; WBC, white blood cells; AST, aspartate transaminase; CBR, clinical benefit rate; (m) OS, (median) overall survival; TPC, the physician’s choice; pCR, pathologic complete response; COR, clinical objective response; GTT, gamma-glutamyl transferase.

Table 2 Trials of ICIs in Combination with Other Drugs

Study (NCT Number)	Phase	Target	Number	Population and Setting	Experimental Arm	Control Arm	Efficacy	Adverse Events Grade≥3
-, NCT03523572^Citation78	Ib	PD-1	48 (HER2+: 32, HER2-low: 16)	HER2-low MBC; Prior received all clinically meaningful treatments	T-DXd + nivolumab	-	cORR (HER2+): 65.6% cORR (HER2-low): 50% mPFS (HER2+): 11.6 months mPFS (HER2-low): 7.0 months mDOR (HER2+): NE mDOR (HER2-low): 5.5 momths	50%: nausea, drug-related interstitial lung disease
-, NCT04042701^Citation79	Ib	PD-1	115 (HER2-low BC: unknown)	HER2-low MBC; Prior received all clinically meaningful treatments	T-DXd + pembrolizumab	-	ORR: Ongoing DOR: Ongoing DCR: Ongoing PFS: Ongoing TTR: Ongoing OS: Ongoing	Ongoing
BEGONIA, NCT03742102^Citation81	Ib/II	PD-L1	210 (HER2-low BC: unknown)	Advanced/unresectable or metastatic TNBC with HER2 low; Unknown	T-DXd + durvalumab + paclitaxel	-	cORR: 100% (4/4)	Ongoing
DESTINY-Breast08, NCT04556773^Citation43	Ib	PD-L1	182	As listed in Table 1	As listed in Table 1	As listed in Table 1	As listed in Table 1	As listed in Table 1

Abbreviations: (c) ORR, (confirmed) overall response rate; (m) PFS, (median) progression-free survival; (m) DOR, (median) duration of response; DCR, disease control rate; PFS, progression-free survival; TTR, time to response; OS, overall survival.

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