Profile of neratinib and its potential in the treatment of breast cancer

Figures & data

Figure 1 HER member family and activation.

Abbreviations: ADAMs, A disintegrin and metalloproteinases; EGF, epidermal growth factor; TGF, tumor growth factor; AREG, amphiregulin; EPG, epigen; HB-EGF, heparin-binding EGF-like growth factor; BTC, betacellulin; EPR, epiregulin; NRG, neuregulin; PI3K, phosphatidylinositide 3-kinase; PTEN, phosphatase and tensin homolog; PKC, protein kinase C; STAT, signal transducer and activator of transcription; JAK, Janus kinase.

Figure 2 Chemical structure of tyrosine kinase inhibitors.

Note: Adapted Data from PubChem.^16–21

Table 1 Comparison of various tyrosine kinase inhibitors

Compound	Binding	IC50 (nM)
		EGFR	HER2	HER4
Gefitinib	Reversible	27–33^Citation12,*	≥3,700^Citation12,*
		0.4–4.7^Citation13,**	416–1,830^Citation13,**	293–323^Citation13,**
Erlotinib	Reversible	2^Citation12,*	>1,000^Citation12,*
		0.9–1.7^Citation13,**	238–698^Citation13,**	579–756^Citation13,**
Lapatinib	Reversible	11^Citation12,*	9^Citation12,*	367^Citation12,*
		0.3–17	6–25	18–30
Neratinib	Irreversible	92^Citation14,***	59^Citation14,***
Afatinib	Irreversible	0.2–0.7^Citation13,**	7–25^Citation13,**	0.7–1.7^Citation13,**
Canertinib	Irreversible	0.8^Citation12,*	19^Citation12,*	7^Citation12,*
		0.3–1.7^Citation13,**	22–72^Citation13,**	0.8–10^Citation13,**
Dacomitinib	Irreversible	6^Citation15,#	46^Citation15,#	74^Citation15,#

Notes: Measuring IC₅₀ values is highly dependent on the assay set-up; please refer to individual references for more information on exact methods.

* Purified enzyme kinases were used to calculate in vitro IC₅₀ values (please refer to review);

** purified cytoplasmic tyrosine kinase domains were used in in vitro kinase assays (non-radioactive for EGFR and HER2 and radioactive for HER4);

*** purified cytoplasmic domains were used to measure autophosphorylation using a time-resolved fluorometry assay;

# purified catalytic domains were used in in vitro enzyme-linked immunosorbent-based kinase assays.

Abbreviations: EGFR, epidermal growth factor receptor; TKR, tyrosine kinase receptor.

Figure 3 Sites of interaction of trastuzumab and neratinib with HER receptors.

Abbreviations: ADAMs, A disintegrin and metalloproteinases; TKIs, tyrosine kinase inhibitors; EGFR, epidermal growth factor receptor.

Table 2 Clinical trials involving neratinib in breast cancer

NCT identifier	Title	Study participants	Study design	Patients (n)	Objectives	Status	Reference
NCT01423123	Combination of weekly paclitaxel with neratinib and trastuzumab in women with metastatic HER2-positive breast cancer	Women ≥18 years with metastatic HER2-positive BC	Open-label, non-randomized, single arm, Phase I	21	Safety/tolerability of neratinib + trastuzumab + paclitaxel	Completed	^Citation82
NCT00708903	Study to examine the effect of HKI-272 on rhythms of the heart (cardiac repolarization)	Healthy participants aged 18–50 years	Double-blind, randomized, Phase I	60	Pharmacokinetic/dynamic comparison of neratinib vs placebo vs moxifloxacin	Completed	^Citation85
NCT00146172	Study evaluating HKI-272 in tumors	Patients aged ≥18 years with HER2/EGFR-overexpressing tumors	Open-label, non- randomized, Phase I	72	Safety (see title)	Completed	^Citation78
NCT00398567	Phase I/II study of HKI-272 (neratinib) in combination with trastuzumab (Herceptin^®) in subjects with advanced breast cancer	Patients aged ≥18 years with advanced HER2-positive BC that is not curable by available therapy and who progressed following at least one trastuzumab- containing cytotoxic chemotherapy regimen	Open-label, non-randomized, Phase I/II	45	Safety/efficacy (see title)	Ongoing, not recruiting
NCT00445458	Phase I/II study of HKI-272 (neratinib) in combination with paclitaxel (Taxol^®) in subjects with solid tumors and breast cancer	Patients aged ≥18 years with a pathologically confirmed solid tumor not curable with available standard therapy (Part 1) or HER2-positive pathologically confirmed BC with prior trastuzumab treatment	Open-label, randomized, Phase I/II	115	Safety/efficacy (see title)	Ongoing, not recruiting	^Citation81
NCT00777101	Study evaluating neratinib vs lapatinib + capecitabine for ErbB2-positive advanced breast cancer	Women aged ≥18 years with locally advanced or metastatic HER2-positive BC with prior trastuzumab + taxane	Open-label, randomized, Phase II	233	Safety/efficacy (see title)	Ongoing, not recruiting	^Citation86
NCT02236000	A dose-escalation study evaluating the combination of trastuzumab emtansine (T-DM1) with neratinib in women with metastatic HER2-positive breast cancer	Women aged ≥18 years with metastatic HER2-positive BC with one (and only one) prior regimen of anti-HER2-based therapy for metastatic disease	Open-label, single arm, Phase I/II	63	Safety/efficacy (see title)	Ongoing, not recruiting
NCT00878709 ExteNET	Study evaluating the effects of neratinib after adjuvant trastuzumab in women with early stage breast cancer	Women aged ≥18 years with early stage HER2-positive BC with prior trastuzumab	Double-blind, randomized, Phase III	2,821	Efficacy (see title)	Ongoing, not recruiting
NCT00741260	Study evaluating the combination of neratinib and capecitabine in solid tumors and breast cancer	Women aged ≥18 years with confirmed pathologic diagnosis of a solid tumor not curable with available therapies for which neratinib + capecitabine is a reasonable treatment option (Part 1) and with HER2- positive metastatic or locally advanced BC that progressed on or following a trastuzumab containing treatment	Open-label, non-randomized, Phase I/II	105	Safety/efficacy (see title)	Ongoing, not recruiting
NCT00915018 NEFERTT	Study evaluating neratinib + paclitaxel vs trastuzumab + paclitaxel in ErbB2-positive advanced breast cancer	Women aged ≥18 years with HER2-positive locally recurrent or metastatic BC without prior systemic anticancer therapy other than endocrine therapy for locally recurrent or metastatic disease and no prior HER2 inhibitor other than trastuzumab or lapatinib in the neoadjuvant or adjuvant setting	Open-label, randomized, Phase II	480	Safety/efficacy, comparison of neratinib + paclitaxel vs trastuzumab + paclitaxel	Ongoing, not recruiting
NCT00706030	Study evaluating neratinib (HKI-272) in combination with vinorelbine in subjects with solid tumors and metastatic breast cancer	Women aged ≥18 years with confirmed pathologic diagnosis of a solid tumor that is not curable with available therapies (Part 1) or confirmed pathologic diagnosis of HER2- positive BC (current stage IV, Part 2) for which vinorelbine + neratinib is a reasonable treatment option and who had at least one prior antineoplastic chemotherapy for metastatic disease and at least one prior treatment with a trastuzumab-containing regimen or who relapsed under adjuvant treatment (Part 2 only)	Open-label, non-randomized, Phase I/II	92	Safety/efficacy of neratinib + vinorelbine, in Part 2 patients with or without prior lapatinib were included	Ongoing, not recruiting	^Citation80
NCT00300781	Study evaluating HKI-272 (neratinib) in subjects with advanced breast cancer	Women aged ≥18 years with advanced HER2-positive BC	Open-label, randomized, Phase II	137	Efficacy, cohort 1 patients that progressed on trastuzumab, cohort 2 patients with no prior trastuzumab	Ongoing, not recruiting	^Citation79
NCT01008150	Phase II randomized trial evaluating neoadjuvant therapy with neratinib and/ or trastuzumab followed by postoperative trastuzumab in women with locally advanced HER2-positive breast cancer	Women aged ≥18 years with locally advanced HER2-positive BC without previous therapy with anthracyclines, taxanes, cyclophosphamide, trastuzumab, or neratinib for any malignancy	Open-label, randomized, Phase II	126	Safety/efficacy (Three arms: neratinib + paclitaxel ± trastuzumab then doxorubicin and cyclophosphamide or paclitaxel + trastuzumab then doxorubicin and cyclophosphamide)	Recruiting
NCT01494662	HKI-272 for HER2-positive breast cancer and brain metastases	Patients aged ≥18 years with HER2-positive metastatic invasive BC who are not receiving other investigational agents, enzyme-inducing antiepileptic drugs, or any cancer-directed concurrent therapy Cohort 1: patients with new or progressive measurable CNS lesions Cohort 2: patients with CNS disease that is operable Cohort 3: patients with measurable CNS disease who a) had no prior lapatinib or b) had prior lapatinib	Open-label, non-randomized, Phase II	105	Efficacy (see patient cohorts)	Recruiting
NCT01670877	Neratinib in metastatic HER2- non-amplified but HER2-mutant breast cancer	Patients aged ≥18 years with stage IV, HER2- negative BC carrying a HER2 mutation with disease progression and not receiving any other investigational agents or systemic cancer therapy	Open-label, Phase II	29	Efficacy study (see title)	Recruiting
NCT01808573	A study of neratinib + capecitabine vs lapatinib + capecitabine in patients with HER2-positive metastatic breast cancer who have received two or more prior HER2-directed regimens in the metastatic setting	Patients aged ≥18 years with confirmed HER2-positive metastatic BC, stage IV, with prior treatment with at least two (2) HER2-directed regimens for metastatic BC (except HER2-targeting TKIs)	Open-label, randomized, Phase III	600	Safety/efficacy (see title)	Recruiting
NCT01111825	Temsirolimus + neratinib for patients with metastatic HER2-amplified or triple negative breast cancer	Patients aged ≥18 years with metastatic HER2-positive BC progressed on trastuzumab or lapatinib or metastatic triple negative invasive adenocarcinoma who do not receive any concurrent anticancer therapy or investigational agents	Open-label, non-randomized, Phase I/II	65	Safety/efficacy	Recruiting

Note: ClinicalTrials.gov entries as of December 2014 are listed.

Abbreviations: BC, breast cancer; CNS, central nervous system; EGFR, epidermal growth factor receptor; TKIs, tyrosine kinase inhibitors; vs, versus.

Table 3 Clinical trials involving neratinib in other cancers

NCT identifier	Title	Study subjects	Study design	Patients (n)	Objective	Status	Reference
NCT01142063	A single dose bioequivalence study of neratinib in healthy subjects	Healthy patients, aged 18–55 years	Phase I	28	Plasma concentration and half-life for neratinib, testing of bioequivalence of the two formulations	Completed
NCT00860223	Study evaluating the potential effect of multiple doses of neratinib on the pharmacokinetics of a single dose of digoxin	Healthy patients, aged 18–50 years	Open-label, non-randomized, Phase I	27	Pharmacokinetics study (see title)	Completed
NCT00380328	HKI-272 ketoconazole drug interaction study	Healthy subjects, aged 18–50 years	Open-label, randomized, Phase I	24	Pharmacokinetics, safety and tolerability	Completed
NCT00498745	Study comparing 2 new formulations of HKI-272 in healthy adult subjects	Healthy subjects, aged 18–50 years	Open-label, randomized, Phase I	36	(see title)	Completed
NCT00550212	Study evaluating oral administrations of HKI-272 in healthy male subjects	Healthy male subjects, aged 18–50 years	Open-label, non-randomized, Phase I	6	Pharmacokinetics (see title)	Completed
NCT00366600	Study evaluating HKI-272 administered to healthy subjects	Healthy subjects, aged 18–50 years	Double-blind, randomized, Phase I	56	Pharmacokinetics; safety and tolerability; influence of food	Completed
NCT00864487	Study evaluating the potential effect of rifampin on the pharmacokinetics of neratinib	Healthy subjects, aged 18–50 years	Open-label, non-randomized, Phase I	24	Pharmacokinetics (see title)	Completed
NCT00814060	Study evaluating two tablet formulations of neratinib (HKI-272)	Healthy subjects, aged 18–50 years	Open-label, randomized, Phase I	24	Pharmacokinetics (see title)	Completed
NCT00757809	Study evaluating the tolerability of multiple doses of HKI-272	Healthy subjects, aged 18–50 years	Double-blind, randomized, Phase I	50	Safety, occurrence of diarrhea (see title)	Completed	^Citation84
NCT00781430	Study evaluating the PK and safety of neratinib in healthy subjects and subjects with chronic liver disease	Healthy subjects, aged 18–65 years	Open-label, non-randomized, Phase I	27	Pharmacokinetics of neratinib in healthy subjects vs hepatically impaired patients/safety	Completed
NCT00958724	Study evaluating neratinib in combination with vinorelbine in subjects with advanced or metastatic solid tumors	Patients aged ≥20 years with a solid tumor that is not curable with available therapies for which neratinib + vinorelbine is a reasonable treatment option	Open-label, non-randomized, Phase I	6	Safety/pharmacokinetics/activity	Completed
NCT00768469	Study evaluating safety and tolerability, solid tumor	Patients aged ≥20 years with confirmed pathologic diagnosis of a solid tumor that is not curable with available therapy for which HKI-272 + paclitaxel is a reasonable treatment option	Open-label, Phase I	10	Safety and tolerability of neratinib + paclitaxel; pharmacokinetics and activity	Completed
NCT00266877	Study evaluating the safety of HKI-272 (neratinib) in subjects with advanced NSCLC	Patients aged ≥18 years with pathologic diagnosis of advanced NSCLC, not curable with conventional therapy	Open-label, non-randomized, Phase II	172	Efficacy: three arms A, B: patients with or without an EGFR mutation that have progressed on erlotinib or gefitinib C: previous smokers without prior EGFR TKI treatment	Completed
NCT00838539	Study evaluating neratinib in combination with temsirolimus in subjects with solid tumors	Patients aged ≥18 years with pathologic diagnosis of incurable advanced or metastatic solid tumor who progressed on at least one conventional or standard therapy	Open-label, non-randomized, Phase I	63	Safety/pharmacokinetics and dosing of combination (see title)	Completed	^Citation83
NCT00397046	A study of the safety and tolerability of HKI-272 administered orally to Japanese subjects with advanced solid tumors	Patients aged ≥20 years with metastatic or advanced cancer that has failed standard therapy	Open-label, non-randomized, Phase I	21	Safety/efficacy (see title)	Completed	^Citation89
NCT01956253	Single subject neratinib in bladder cancer	One patient with metastatic bladder cancer harboring a HER2-GRB7 gene fusion	Open-label, non-randomized	1	Response	Ongoing, not recruiting
NCT01827267	Neratinib with and without temsirolimus for patients with HER2-activating mutations in NSCLC	Patients aged ≥18 years with histologically confirmed advanced or metastatic HER2- mutant NSCLC without prior treatment with any investigational agent or neratinib or mTOR inhibitor	Open-label, randomized, Phase II	104	Safety/efficacy	Ongoing, not recruiting
NCT01960023	Safety and efficacy study of neratinib and cetuximab to treat patients with quadruple wild-type metastatic colorectal cancer	Patients aged ≥18 years with KRAS, NRAS, BRAF, PIK3CA wild-type	Open-label, Phase I/II	70	Safety/efficacy (see title)	Recruiting
NCT01953926 Basket	An open-label, Phase II study of neratinib in patients with solid tumors with somatic human epidermal growth factor receptor (EGFR, HER2, HER3) mutations or EGFR gene amplification	Patients aged ≥18 years with solid tumors with activating HER2, HER3 or EGFR mutations or with EGFR gene amplification without prior treatment with any pan-HER TKI	Open-label, non-randomized, Phase II	180	Safety/efficacy (see title)	Recruiting

Note: ClinicalTrials.gov entries as of December 2014 are listed.

Abbreviations: EGFR, epidermal growth factor receptor; mTOR, mammalian target of rapamycin; NSCLC, non-small cell lung cancer; TKI, tyrosine kinase inhibitor; vs, versus.

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