Treating Advanced Unresectable or Metastatic HER2-Positive Breast Cancer: A Spotlight on Tucatinib

Figures & data

Figure 1 The HER2 receptor and its drug targets.

Abbreviations: ADCs, antibody-drug conjugates; TKIs, tyrosine kinase inhibitors; ATP, adenosine triphosphate.

Table 1 Randomised Trials of Anti-HER2 Tyrosine Kinase Inhibitors in Advanced HER2-Positive Breast Cancer

Trial	Phase	Setting	Arms	Previous Treatment	N	ORR (%)	Median PFS (Months)	Median OS (Months)	Safety Profile
NCIC CTG MA.31, GELMON ET AL (2015)^Citation47	III	1st line	Trastuzumab + taxane	Nil	537	75.9	13.6	NR	1% vs 19% G3/4 diarrhoea, 0 vs 8% G3/4 rash
			Lapatinib + taxane			75.8	9.1*	NR
GUAN ET AL (2013)^Citation46	III	1st line	Lapatinib + taxane	Nil	444	69	9.7	27.8	23% vs <1% G3 diarrhoea
			Placebo + taxane			50*	6.5*	20.5*
NEfERT, AWADA ET AL (2016)^Citation74	II	1st line	Neratinib + taxane	Nil	479	74.8	12.9	NR	30.4% vs 3.8% G3 diarrhoea
			Trastuzumab + taxane			77.6	12.9	NR	No loperamide prophylaxis allowed
EGF100151, GEYER ET AL (2006)^Citation48	III	≥2nd line	Lapatinib + capecitabine	Trastuzumab, anthracycline + taxane	324	22	8.4	75.0 weeks	12% vs 11% G3 diarrhoea, 7 vs 11% G3 PPE
			Capecitabine			14*	4.1*	64.7 weeks
MARTIN ET AL (2013)^Citation66	II	≥2nd line	Neratinib	100% previous taxane (neo (adj) or met)	233	29	4.4	19.7	28% vs 10% G3/4 diarrhoea
			Lapatinib + capecitabine	1–2 lines previous trastuzumab		41*	6.8	23.6	No neratinib-associated LVEF drop
SAURA ET AL (2014)^Citation69	II	≥2nd line	Neratinib + capecitabine (lapatinib naïve)	100% previous taxane (neo (adj) or met)	105	64	40.3 weeks	NR	23% G3 diarrhoea (88% all grades) No loperamide prophylaxis allowed
			Neratinib + capecitabine (lapatinib exposed)	At least 1 prior trastuzumab-containing regimen		57	35.9 weeks	NR	12% experienced G3 PPE
EMILIA, VERMA ET AL (2012)^Citation39	III	2nd line	T-DM1	100% prior trastuzumab + taxane	991	44	9.6	30.9	41% vs 57% all G3/4 toxicities
			Lapatinib + capecitabine (lap/cape)	No pertuzumab		31*	6.4*	25.1*	T-DM1 higher risk of thrombocytopenia + abnormal LFTs
LUX-BREAST 1, HARBECK ET AL (2016)^Citation28	III	≥2nd line	Afatinib + vinorelbine	Prior trastuzumab in the adjuvant or 1st line metastatic setting	508	46	5.5	20.5	Recruitment stopped early due to safety concerns with afatinib + vinorelbine
			Trastuzumab + vinorelbine			47	5.6	28.6*
NALA, SAURA ET AL (2020)^Citation70	III	3rd line	Neratinib + capecitabine	75% previous T-DM1	621	32.8	5.6	21	24% vs 12.5% G3 diarrhoea despite loperamide prophylaxis
			Lapatinib + capecitabine	42.5% trastuzumab + pertuzumab		26.7	5.5*	18.7
HER2CLIMB, MURTHY ET AL (2020)^Citation83	II	3rd line	Trastuzumab + capecitabine + tucatinib	100% previous T-DM1 + trastuzumab/ pertuzumab	612	40.6	7.8	21.9	12.9% vs 8.5% G3 diarrhoea with no loperamide prophylaxis
			Trastuzumab + capecitabine + placebo			22.8*	5.68*	17.4*	5% vs 0.5% G3 transaminitis
MA ET AL (2019)^Citation103	II	3rd line	Pyrotinib + capecitabine	Only 29.7% received prior anti-HER2 therapy	128	78.5	18.1	NR	24.6% vs 20.6% G3 PPE
			Lapatinib + capecitabine			57.1*	7*	NR	15.4% vs 4.8% G3 diarrhoea
PHOEBE, XU ET AL (2020 INTERIM)^Citation104	III	3rd line	Pyrotinib + capecitabine	100% received trastuzumab + taxane	267	67.2	12.5	Not reached	30.6% vs 8.3% G3 diarrhoea
			Lapatinib + capecitabine	Maximum 2 lines of chemo		51.5*	6.8*	Not reached
EFG104900, BLACKWELL ET AL (2010)^Citation44	III	>3rd line	Lapatinib + trastuzumab	100% prior trastuzumab	296	10.3	12.1 weeks	14	Asymptomatic cardiac events: 3.4% vs 1.4%
			Lapatinib	No T-DM1 or pertuzumab		6.9	8.1* weeks	9.5*	Symptomatic: 2% vs 0.7%

Notes: Emboldened arm includes tyrosine kinase inhibitor, *Indicates statistical significance.

Abbreviations: G3/G4, grade 3/grade 4; LFT, liver function test; LVEF, left ventricular ejection fraction; N, number of patients; NR, not reported; ORR, overall response rate; PFS, progression-free survival; OS, overall survival; PPE, palmo-plantar erythrodysesthesia.

Table 2 Studies of Tyrosine Kinase Inhibitors in Advanced HER2-Positive Breast Cancer Patients with Brain Metastases

Trial	Phase	Arms	Previous treatment of brain metastases	Previous Systemic Treatment	N with CNS Disease	CNS ORR (%)	CNS Median PFS (Months)	CNS Median OS (Months)	Comments
LAPATINIB
EGF105084, LIN ET AL (2009)^Citation57	II(two phases)	Lapatinib	100% prior cranial radiotherapy	100% trastuzumab	240	6	2.4	6.37	Only 8% expansion group experienced G3 PPE
		Lapatinib + capecitabine (expansion phase)			50	20	3.65	NR
EGF107671, LIN ET AL (2011)^Citation58	II	Lapatinib + capecitabine	100% prior cranial radiotherapy	100% trastuzumab	22	38	NR	NR	Stopped prematurely due to lack of efficacy with topotecan arm. Small sample size.
		Lapatinib + topotecan				0	NR	NR
EMILIA, VERMA ET AL (2013)^Citation39	III	T-DM1	100% prior cranial radiotherapy	100% trastuzumab and taxane chemotherapy	95 (AS)	NR	5.9	26.8	Exploratory analysis therefore under-powered
		Lapatinib + capecitabine
						NR	5.7	12.9*
LANDSCAPE, BACHELOT ET AL (2013)^Citation59	II (single arm)	Lapatinib + capecitabine	Nil	93% trastuzumab-based chemotherapy	45	65.9	5.5	17	49% suffered G3/G4 toxicity
AFATINIB
LUX-BREAST 1, HARBECK ET AL (2016)^Citation28	II	Afatinib	75% prior cranial radiotherapy	100% trastuzumab	111	0	11.9	57.7 weeks	57% G3 toxicity in afatinib + vinorelbine group
		Afatinib + vinorelbine		80% previous lapatinib		8	12.3	37.3 weeks
						14	18.4	52.1 weeks
		TPC
NERATINIB
TBCRC 022, FREEDMAN ET AL (2019)^Citation75	II (single arm)	Neratinib + capecitabine	92% prior neurosurgery ± radiotherapy	Cohort A: 50% exposed to lapatinib	49	49	5.5	13.3	Cohort B closed early due to slow accrual
				Cohort B: 50% lapatinib naïve		33	3.1	15.1
TUCATINIB
HER2CLIMB, MURTHY ET AL (2020)^Citation83	II	Tucatinib + capecitabine + trastuzumab	43% prior cranial radiotherapy	100% trastuzumab, pertuzumab and T-DM1	291	47.3	9.9	18.1	First TKI to demonstrate significant OS benefit in patients with CNS HER2+ disease
		Placebo + capecitabine + trastuzumab				20*	4.2*	12*

Note: *Indicates statistical significance.

Abbreviations: AS, asymptomatic; CNS ORR, central nervous system overall response rate; CNS median OS, central nervous system median overall survival; CNS median PFS, central nervous system median progression-free survival; G3/G4, grade 3/grade 4; N, number of patients; NR, not reported; TPC, treatment of physician’s choice.

Table 3 Current Clinical Trials Looking at Tyrosine Kinase Inhibitors in Advanced HER2-Positive Breast Cancer

Trial Identifier	Phase	Treatment Setting	Population	Planned Sample Size	Treatment Arms	Primary Endpoint	Study Status
TUCATINIB
NCT03975647 (HER2CLIMB-02)	III (RCT double blind)	2nd line	HER2+ MBC	460	Tucatinib + T-DM1 vs Placebo and T-DM1	PFS	Recruiting
NCT04539938 (HER2CLIMB-04)	II (single arm)	3rd line	HER2+ MBC	70	Tucatinib + T-Dxd	ORR	Recruiting
NCT03054363	1b/II (single arm)	≥3rd line	HR+ HER2+ MBC	42	Tucatinib, palbociclib + letrozole	Phase 1b: incidence of toxicity	Active, not recruiting
						Phase II: PFS
NCT03501979	II (single arm)	No previous LMD specific therapy	HER2+ MBC with leptomeningeal disease	30	Tucatinib, trastuzumab + capecitabine	OS	Recruiting
NCT04512261 (TOPAZ)	Ib/II (single arm)	≥1st line	HER2+ MBC with brain metastases (new or progression)	33	Tucatinib, pembrolizumab + trastuzumab	Phase Ib: MTD tucatinib (with pembrolizumab and trastuzumab)	Not yet recruiting
						Phase II: 24-week CNS DCR
NCT04760431 (HER2BRAIN)	II (RCT double blind)	2nd line (progression on/after trastuzumab)	HER2+ MBC with active brain metastases	120	Trastuzumab, taxane + pertuzumab vs trastuzumab, taxane + TKI (Tucatinib, pyrotinib or neratinib)	CNS ORR	Not yet recruiting
NCT04538742 (DESTINY-BREAST07)	1b/II	1st line	HER2+ MBC including those with active brain metastases	350	7 cohorts combining T-DXd with: 1) Durvalumab 2) Pertuzumab 3) Paclitaxel 4)Durvalumab/paclitaxel 5) T-DXd alone 6) Tucatinib 7) Tucatinib in active brain mets 8) T-DXd alone in active brain mets	Phase 1b/II: incidence of toxicity	Recruiting
NERATINIB
NCT02673398	II (Single arm)	≥2nd line	HER2+ MBC in patients >60	40	Neratinib monotherapy	Incidence of G2+ toxicity	Active, not recruiting
NCT02236000	Ib dose escalation + II	2nd line	HER2+ MBC	63	Neratinib + T-DM1	Phase Ib: MTD	Active, not recruiting
						Phase II: ORR
NCT03377387	1b/II	1b: any line	HER2+ MBC	48	Capecitabine 7/7 + neratinib	Phase Ib: MTD	Recruiting
		II: ≥2nd line
NCT03289039	II	3rd line (must have had prior trastuzumab, pertuzumab + T-DM1)	HR+ HER2+ MBC	21	Neratinib vs neratinib + fulvestrant	PFS	Active, not recruiting
NCT01494662	II (4 cohorts, non-randomised)	Varied	HER2+ MBC with brain metastases	168	1) Neratinib 2) Neratinib + surgical resection 3) Neratinib + capecitabine 4) Neratinib + T-DM1	CNS ORR	Recruiting
PYROTINIB
NCT03080805 (PHOEBE)	III (RCT)	≥2nd line (must have had prior trastuzumab + taxane)	HER2+ MBC	240	Pyrotinib + capecitabine vs Lapatinib + capecitabine	PFS	Active, not recruiting
NCT02422199	II	≥2nd line (must have had prior trastuzumab + taxane, anthracycline)	HER2+ MBC	128	Pyrotinib + capecitabine vs Lapatinib + capecitabine	Safety and ORR	Unknown
NCT04246502	II (randomised)	1st line	HER2+ MBC	200	Pyrotinib + capecitabine vs Capecitabine + trastuzumab + pertuzumab	PFS	Not yet recruiting
NCT03876587	II (single arm)	1st line	HER2+ MBC	79	Pyrotinib + docetaxel	ORR	Not yet recruiting
NCT03997539	Ib dose escalation + II (randomised)	≥2nd line (must have had prior trastuzumab + taxane)	HER2+ MBC	256	Pyrotinib + vinorelbine vs TPC	Phase 1b: MTD	Not yet recruiting
						Phase II: PFS
NCT04001621	II (single arm)	≥2nd line (trastuzumab resistance)	HER2+ MBC	100	Pyrotinib + capecitabine	PFS	Recruiting
NCT04605575	Ib dose escalation + II (single arm)	≥2nd line (must have had prior trastuzumab + taxane)	HER2+ MBC	208	Pyrotinib + vinorelbine	Phase Ib: MTD	Recruiting
						Phase II: PFS
NCT03863223	III (RCT, double blind)	1st line	HER2+ MBC	590	Pyrotinib, trastuzumab + docetaxel vs Placebo, trastuzumab + docetaxel	PFS	Recruiting
NCT03923179	II (single arm)	≥2nd line (must have had prior trastuzumab)	HER2+ MBC	32	Pyrotinib + etoposide	ORR	Recruiting
NCT04095390 (INPHASE)	II (randomised)	≥1st line (must have had prior trastuzumab)	HR+ HER2+ and HR- HER2+ MBC	60	HR+ HER2+ = pyrotinib, SHR6390, letrozole	ORR	Recruiting
					HR- HER2+ = pyrotinib, SHR6390, capecitabine
NCT04033172	II (single arm)	1st line	HR+ HER2+ MBC	40	Pyrotinib + fulvestrant	PFS	Recruiting
NCT04646759	III (randomised)	≥2nd line	HR+ HER2+ MBC	516	Pyrotinib + capecitabine vs pyrotinib + fulvestrant	PFS + incidence of G3 PPE	Recruiting
NCT03910712	II (randomised)	1st line	HR+ HER2+ MBC	250	Pyrotinib + trastuzumab + AI vs trastuzumab + AI	PFS	Not yet recruiting
NCT03691051	II (single arm)	Any line	HER2+ MBC with brain metastases	102	Pyrotinib + capecitabine	CNS ORR	Not yet recruiting
NCT03933982	II (single arm)	≥2nd line (must have had prior taxane and anthracycline)	HER2+ MBC with brain metastases	30	Pyrotinib + vinorelbine	CNS ORR	Recruiting
NCT04582968	1b/II	Any line	HER2+ MBC with brain metastases	47	Pyrotinib + capecitabine + brain radiotherapy	Phase 1b: incidence of toxicity	Recruiting
						Phase II: intracranial progression
NCT04639271	II (single arm)	Any line	HER2+ MBC with brain metastases	100	Pyrotinib + trastuzumab + abraxane	CNS ORR	Not yet recruiting
POZIOTINIB
NCT02659514	II (single arm)	3rd line (must have had previous trastuzumab and T-DM1)	HER2+ MBC	67	Poziotinib monotherapy	ORR	Active, not recruiting
LAPATINIB
NCT01526369	III (RCT)	1st line	HER2+ MBC	75	Lapatinib, trastuzumab + paclitaxel vs Trastuzumab + paclitaxel	PFS	Active, not recruiting
NCT01873833	II (single arm)	≥2nd line (must have had prior trastuzumab)	HER2+ MBC	10	Capecitabine, cyclophosphamide (PO), lapatinib + trastuzumab	PFS	Active, not recruiting
NCT03500380	II (randomised)	≥2nd line (must have had prior trastuzumab + taxane)	HER2+ MBC	228	RC48-ADC vs lapatinib + capecitabine	PFS	Recruiting
NCT00470704	II (2 cohorts)	Cohort 1: 1st line	HER2+ MBC	116	Lapatinib + trastuzumab	ORR	Active, not recruiting
		Cohort 2: 2nd and 3rd line
NCT01273610	II (single arm)	Any line	HER2+ MBC patients >60	40	Lapatinib + trastuzumab	Incidence of G3+ toxicity +symptomatic heart failure	Active, not recruiting
NCT00667251	III (randomised)	1st line	HER2+ MBC	649	Lapatinib + taxane vs trastuzumab + taxane	PFS	Active, not recruiting
NCT01622868	II (randomised)	No previous cranial radiotherapy	HER2+ MBC with brain metastases	143	WBRT or SRS vs WBRT or SRS and lapatinib for 6 weeks	CNS CR over 12 weeks	Active, not recruiting

Abbreviations: ADC, antibody–drug conjugate; AI, aromatase inhibitor; CR, complete response; DCR, disease control rate; G3, grade 3; HR+, hormone receptor positive; LMD, leptomeningeal disease; MBC, metastatic breast cancer; MTD, maximum tolerated dose; ORR, overall response rate; PFS, progression-free survival; PPE, palmo-plantar erythrodysesthesia; PO, oral; RCT, randomised controlled trial; SRS, stereotactic radiosurgery; TPC, treatment of physician’s choice; WBRT, whole brain radiotherapy.

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