. 2021 May 20;7:56. doi: 10.1038/s41523-021-00265-1

Table 3.

Ongoing key phase 2–3 trials investigating HER-2-targeted tyrosine kinase inhibitors in breast cancer.

Trial information	Description (sample size)	Endpoints
Early stage
NCT01042379 (I-SPY 2) phase 2	Neoadjuvant tucatinib + trastuzumab + pertuzumab + paclitaxel → doxorubicin + cyclophosphamide	pCR RBC, relapse free survival, OS, safety
NCT03101748 phase 1b/2	Neoadjuvant neratinib + paclitaxel + trastuzumab + pertuzumab → doxorubicin + cyclophosphamide vs neratinib + paclitaxel → doxorubicin + cyclophosphamide (n = 99)	pCR Maximum tolerated dose of neratinib, PFS, safety
NCT04457596 (compassHER RD) phase 3	Adjuvant tucatinib + ado-trastuzumab emtansine vs ado-trastuzumab emtansine in patients with residual disease after neoadjuvant therapy (n = 1031)	Invasive DFS distant DFS, CNS metastases DFS, OS
NCT03085368 phase 3	Adjuvant epirubicin + cyclophosphamide → docetaxel + lapatinib vs epirubicin + docetaxel + lapatinib vs epirubicin + cyclophosphamide → docetaxel + trastuzumab vs epirubicin + docetaxel + trastuzumab (n = 482)	DFS OS
Advanced/metastatic disease
NCT01670877 phase 2	Neratinib in HER2 mutant (not amplified) mBC or neratinib + fulvestrant in HR +/HER2 mutant mBC (n = 80)	ORR PFS, safety
NCT03975647 (HER2CLIMB02) phase 3	Tucatinib + ado-trastuzumab emtansine vs placebo + ado-trastuzumab emtansine vs placebo (n = 460)	PFS OS, PFS per RECIST, ORR, DOR, clinical benefit, adverse events
NCT04539938 (HER2CLIMB04) phase 2	Tucatinib + ado-trastuzumab deruxtecan (n = 70)	ORR DOR, PFS, disease control rate, OS, adverse events
NCT03054363 phase 1b/2	Tucatinib + palbociclib + letrozole in ER + /HER2 + mBC (n = 25)	Tolerability PFS
Advanced/metastatic disease with CNS involvement
NCT01494662 phase 2	HER2 + mBC and CNS metastases: neratinib vs neratinib + surgical resection vs capecitabine (in patients previously treated with/without lapatinib) vs neratinib + ado-trastuzumab emtansine (n = 168)	ORR PFS, OS, CNS response, site of progression, safety and tolerability, clinical outcomes
NCT04334330 phase 2	HR + HER2 + mBC with CNS metastases: palbociclib, fulvestrant, trastuzumab, and lapatinib (n = 48)	CNS response rate Safety, OS, PFS, ORR, time to CNS progression, time to radiotherapy
NCT03501979 phase 2	HER2 + mBC with leptomeningeal disease: tucatinib + trastuzumab + capecitabine (n = 30)	OS Safety, PFS, CNS ORR, clinical benefit, symptom burden, quality of life
NCT04512261 (TOPAZ) phase 1/2	HER2 + mBC with CNS metastases: tucatinib in combination with pembrolizumab and trastuzumab (n = 33)	CNS disease control rate. Recommended dose of tucatinib. CNS ORR, systemic ORR, PFS, OS, toxicity profile

Trial information

Description (sample size)

Endpoints

Early stage

NCT01042379 (I-SPY 2)

phase 2

Neoadjuvant tucatinib + trastuzumab + pertuzumab + paclitaxel → doxorubicin + cyclophosphamide

pCR

RBC, relapse free survival, OS, safety

NCT03101748

phase 1b/2

Neoadjuvant neratinib + paclitaxel + trastuzumab + pertuzumab → doxorubicin + cyclophosphamide vs neratinib + paclitaxel → doxorubicin + cyclophosphamide (n = 99)

pCR

Maximum tolerated dose of neratinib, PFS, safety

NCT04457596 (compassHER RD)

phase 3

Adjuvant tucatinib + ado-trastuzumab emtansine vs ado-trastuzumab emtansine in patients with residual disease after neoadjuvant therapy (n = 1031)

Invasive DFS

distant DFS, CNS metastases DFS, OS

NCT03085368

phase 3

Adjuvant epirubicin + cyclophosphamide → docetaxel + lapatinib vs epirubicin + docetaxel + lapatinib vs epirubicin + cyclophosphamide → docetaxel + trastuzumab vs epirubicin + docetaxel + trastuzumab (n = 482)

DFS

Advanced/metastatic disease

NCT01670877

phase 2

Neratinib in HER2 mutant (not amplified) mBC or neratinib + fulvestrant in HR +/HER2 mutant mBC (n = 80)

ORR

PFS, safety

NCT03975647 (HER2CLIMB02)

phase 3

Tucatinib + ado-trastuzumab emtansine vs placebo + ado-trastuzumab emtansine vs placebo (n = 460)

PFS

OS, PFS per RECIST, ORR, DOR, clinical benefit, adverse events

NCT04539938 (HER2CLIMB04)

phase 2

Tucatinib + ado-trastuzumab deruxtecan (n = 70)

ORR

DOR, PFS, disease control rate, OS, adverse events

NCT03054363

phase 1b/2

Tucatinib + palbociclib + letrozole in ER + /HER2 + mBC (n = 25)

Tolerability

PFS

Advanced/metastatic disease with CNS involvement

NCT01494662

phase 2

HER2 + mBC and CNS metastases: neratinib vs neratinib + surgical resection vs capecitabine (in patients previously treated with/without lapatinib) vs neratinib + ado-trastuzumab emtansine (n = 168)

ORR

PFS, OS, CNS response, site of progression, safety and tolerability, clinical outcomes

NCT04334330

phase 2

HR + HER2 + mBC with CNS metastases: palbociclib, fulvestrant, trastuzumab, and lapatinib (n = 48)

CNS response rate

Safety, OS, PFS, ORR, time to CNS progression, time to radiotherapy

NCT03501979

phase 2

HER2 + mBC with leptomeningeal disease: tucatinib + trastuzumab + capecitabine (n = 30)

Safety, PFS, CNS ORR, clinical benefit, symptom burden, quality of life

NCT04512261 (TOPAZ)

phase 1/2

HER2 + mBC with CNS metastases: tucatinib in combination with pembrolizumab and trastuzumab (n = 33)

CNS disease control rate. Recommended dose of tucatinib.

CNS ORR, systemic ORR, PFS, OS, toxicity profile

pCR pathologic complete response, RCB residual cancer burden; PFS progression-free survival, OS overall survival, ORR objective response rate, TTP time to progression, DOR duration of response, CNS central nervous system, mBC metastatic BC, ER hormone receptor.