Role of trastuzumab emtansine in the treatment of HER2-positive breast cancer

Figures & data

Figure 1 Mechanism of action of T-DM1

Notes: (1) Trastuzumab retains all of its mechanisms of action. It delivers the DM1 chemotherapy directly and specifically to the HER2-positive breast cancer cell. (2) T-DM1 is internalized into the HER2-positive breast cancer cell. (3) DM1 is released once inside the cell. DM1 is a very potent chemotherapy agent that inhibits tubulin development of the mitotic spindle and cell division.
Abbreviations: DM1, emtansine; HER2, human epidermal growth factor receptor 2; T-DM1, trastuzumab emtansine.

Table 1 Summary of Phase I clinical trials

Authors	Year	Number of patients	Study design	Dose escalation	Dosing frequency	Grade 3 or 4 adverse events	Maximum tolerated dose
Krop et al^Citation38	2010	24	Phase I single-arm	0.3–4.8 mg/kg	Every 3 weeks	Thrombocytopenia, pulmonary hypertension	3.6 mg/kg every 3 weeks
Beeram et al^Citation39	2012	28	Phase I single-arm with additional patients added later at maximum dose	1.2–2.9 mg/kg	Weekly	Thrombocytopenia	2.4 mg/kg weekly

Table 2 Summary of Phase II clinical trials

Author	Year	Number of patients	Study design	Study population	Objective response rate	Progression-free survival	Grade 3 adverse events
Burris et al^Citation40	2010	112	Phase II single-arm	HER2-positive MBC who had tumor progression after prior HER2-directed therapy or received prior chemotherapy	25.90%	4.6 months	Hypokalemia (8.9%), thrombocytopenia (8.0%), and fatigue (4.5%)
Krop et al^Citation41	2012	110	Phase II single-arm	HER2-positive MBC who had prior treatment with trastuzumab, lapatinib, an anthracycline, a taxane, and capecitabine	34.50%	7.3 months	Thrombocytopenia (9.1%), fatigue (4.5%), and cellulitis (3.6%)
Hurvitz et al^Citation42	2013	137	Phase II randomized to:	HER2-positive MBC or recurrent locally advanced breast cancer
			T-DM1 versus trastuzumab plus docetaxel	First-line treatment	64.20%	14.2 months	46.40%
				First-line treatment	58.00%	9.2 months	90.90%

Abbreviations: HER2, human epidermal growth factor receptor 2; MBC, metastatic breast cancer; T-DM1, trastuzumab emtansine.

Table 3 Summary of clinical trials currently underway

ClinicalTrials.gov identifier	Phase	Name	Status	Sponsor	Number of patients	Study design
NCT01816035	I	N/A	Not open yet	University of Washington	20 (estimated)	HER2-positive MBC or locally advanced breast cancer that cannot be removed by surgery.
NCT02038010	I	N/A	Currently recruiting	Northwestern University	28 (estimated)	To assess combination of T-DM1 and BYL719 for safety and efficacy in treating MBC.
NCT01513083	I	N/A	Currently recruiting	Hoffmann-La Roche	30 (estimated)	HER2-positive MBC with normal or reduced hepatic function.
NCT00934856	I	N/A	Completed	Hoffmann-La Roche	99	Adding T-DM1 to docetaxel in patients with locally advanced or HER2-positive MBC. For patients with locally advanced breast cancer, pertuzumab may be added to T-DM1 and docetaxel.
NCT00928330	I	N/A	Completed	Genentech	57	Oral GDC 0941 administered in combination with either IV infusion of T-DM1 or IV infusion of trastuzumab.
NCT01513083	I	N/A	Currently recruiting	Hoffmann-La Roche	30 (estimated)	Evaluate the pharmacokinetics and safety of T-DM1 in patients with HER2-positive MBC and normal or reduced hepatic function.
NCT02073916	I	STELA	Currently recruiting	The Methodist Hospital System	18 (estimated)	Assess the safety and tolerability of combining T-DM1 with lapatinib and abraxane in patients with HER2-positive MBC.
NCT01983501	Ib	N/A	Currently recruiting	Oncothyreon Inc.	48 (estimated)	Determine the maximum tolerated dose or recommended dose and assess the safety and tolerability of ONT-380 combined with T-DM1 in patients with HER2-positive breast cancer.
NCT01976169	Ib	N/A	Not yet open	University of Texas Southwestern Medical Center	17 (estimated)	Phase 1b inter-patient dose-escalation study of PD-0332991 in combination with T-DM1 in patients with recurrent or metastatic HER2-positive breast cancer after prior trastuzumab or other HER2-directed therapies.
NCT00951665	Ib-IIa	N/A	Completed	Genentech	107	T-DM1, paclitaxel, and pertuzumab in patients with HER2-positive locally advanced breast cancer or MBC.
NCT01702558	I and II	N/A	Currently recruiting	Hoffmann-La Roche	240 (estimated)	Maximum tolerated dose of capecitabine in combination with T-DM1 in patients with HER2-positive MBC or locally advanced or metastatic gastric cancer using a Phase I design, followed by a Phase II single-arm study to explore the efficacy of the combination in MBC patients.
NCT02070094	I and II	N/A	Currently recruiting	Ukrainian Antitumor Center	80 (estimated)	A Phase I/II study of T-DM1 plus ABT-737 in treating patients with HER2-positive breast cancer.
NCT01196052	II	N/A	Ongoing, not recruiting anymore	Hoffmann-La Roche	153	T-DM1 after the completion of anthracycline-based adjuvant/neoadjuvant chemotherapy in patients with early HER2-positive breast cancer.
NCT01975142	II	N/A	Currently recruiting	Institut Curie	480 (estimated)	Patients with MBC considered HER2-negative are screened for HER2-amplified circulating tumor cells. If HER2-amplifed circulating tumor cells are detected, patients are treated with T-DM1.
NCT01853748	II	ATEMPT	Currently recruiting	Dana-Farber Cancer Institute	500 (estimated)	T-DM1 (×17) versus paclitaxel (weekly ×12)/trastuzumab (every 3 weeks ×13) for stage I (small) HER2-positive breast cancer.^Citation50
NCT01745965	II	N/A	Currently recruiting	West German Study Group	380 (estimated)	Preoperative T-DM1 with or without standard endocrine therapy versus trastuzumab with standard endocrine therapy given for 12 weeks in patients with operable HER2-positive/HR+ breast cancer within the ADAPT protocol.
NCT00781612	II	N/A	Enrolling participants by invitation only	Genentech	720 (estimated)	Patients receiving single-agent T-DM1 or combination T-DM1 administered in combination with paclitaxel or with pertuzumab ± paclitaxel.
NCT01835236	II	N/A	Currently recruiting	Swiss Group for Clinical Cancer Research	208 (estimated)	Trastuzumab and pertuzumab followed by T-DM1 in MBC.
NCT01597414	II	N/A	Currently recruiting	EORTC	80 (estimated)	Elderly MBC: pertuzumab–Herceptin versus pertuzumab–Herceptin–metronomic chemotherapy, followed by T-DM1.
NCT02073487	II	N/A	Currently recruiting	The Methodist Hospital System	30 (estimated)	Evaluate the pathological CR when T-DM1 and lapatinib and abraxane are combined in newly diagnosed HER2-positive breast cancer.
NCT01565200	II	ZEPHIR	Ongoing, not recruiting anymore	Jules Bordet Institute	60 (estimated)	HER2 imaging study to identify HER2-positive MBC patients unlikely to benefit from T-DM1.
NCT01904903	II	SAFE-HEaRt	Currently recruiting	Washington Hospital Center	33 (estimated)	Cardiac safety study in patients with HER2-positive breast cancer.
NCT01702571	III	N/A	Currently recruiting	Hoffmann-La Roche	2,220 (estimated)	T-DM1 in patients with HER2-positive locally advanced breast cancer or MBC who have received prior anti-HER2 and chemotherapy-based treatment. Patients will receive 3.6 mg/kg T-DM1 intravenously every 3 weeks until unacceptable toxicity, withdrawal of consent, or disease progression.^Citation51
NCT01772472	III	KATHERINE	Currently recruiting	Hoffmann-La Roche	1,484 (estimated)	T-DM1 versus trastuzumab as adjuvant therapy in patients with HER2-positive breast cancer who have residual tumor present in the breast or axillary lymph nodes following preoperative therapy. Radiotherapy and/or hormone therapy will be given in addition if indicated.^Citation49
NCT01120184	III	MARIANNE	Ongoing, not recruiting anymore	Hoffmann-La Roche	1,095	T-DM1 with pertuzumab or T-DM1 with pertuzumab–placebo (blinded for pertuzumab), versus the combination of trastuzumab plus taxane (docetaxel or paclitaxel) in patients with HER2-positive progressive or recurrent locally advanced or previously untreated MBC.^Citation48
NCT01419197	III	TH3RESA	Ongoing, not recruiting anymore	Hoffmann-La Roche	604	T-DM1 in comparison with treatment of the physician’s choice in patients with metastatic or unresectable locally advanced/recurrent HER2-positive breast cancer.^Citation9
NCT01966471	III	KAITLIN	Currently recruiting	Hoffmann-La Roche	2,500 (estimated)	Evaluate the efficacy and safety of T-DM1 plus pertuzumab versus trastuzumab plus pertuzumab and taxane as adjuvant therapy in patients with HER2-positive primary invasive breast cancer following surgery and anthracycline-based chemotherapy.^Citation52
NCT00833963	IV	MotHER	Currently recruiting	Genentech	100 (estimated)	The MotHER Pregnancy Registry is a cohort study in women with breast cancer who have been or are being treated with a trastuzumab-containing regimen with or without pertuzumab, or ado-trastuzumab emtansine, during pregnancy or within 6 months prior to conception.

Abbreviations: HER2, human epidermal growth factor receptor 2; IV, intravenous; MBC, metastatic breast cancer; N/A, not applicable; T-DM1, trastuzumab emtansine; EORTC, European Organisation for Research and Treatment of Cancer; CR, complete remission.

KropIEBeeramMModiSPhase I study of trastuzumab-DM1, an HER2 antibody-drug conjugate, given every 3 weeks to patients with HER2-positive metastatic breast cancerJ Clin Oncol201028162698270420421541

 PubMed Web of Science ®Google Scholar

BeeramMKropIEBurrisHAA phase 1 study of weekly dosing of trastuzumab emtansine (T-DM1) in patients with advanced human epidermal growth factor 2-positive breast cancerCancer2012118235733574022648179

 PubMed Web of Science ®Google Scholar

BurrisHA3rdRugoHSVukeljaSJPhase II study of the antibody drug conjugate trastuzumab-DM1 for the treatment of human epidermal growth factor receptor 2 (HER2) –positive breast cancer after prior HER2-directed therapyJ Clin Oncol201129439840521172893

 PubMed Web of Science ®Google Scholar

KropIELoRussoPMillerKDA phase II study of trastuzumab emtansine in patients with human epidermal growth factor receptor 2 –positive metastatic breast cancer who were previously treated with trastuzumab, lapatinib, an anthracycline, a taxane, and capecitabineJ Clin Oncol201230263234324122649126

 PubMed Web of Science ®Google Scholar

HurvitzSADirixLKocsisJPhase II randomized study of trastuzumab emtansine versus trastuzumab plus docetaxel in patients with human epidermal growth factor receptor 2-positive metastatic breast cancerJ Clin Oncol20133191157116323382472

 PubMed Web of Science ®Google Scholar

Dana-Farber Cancer InstituteT-DM1 vs paclitaxel/trastuzumab for Breast (ATEMPT Trial) Available from: http://clinicaltrials.gov/show/NCT01853748. NLM identifier: NCT01853748Accessed April 30, 2014

 Google Scholar

Hoffmann-La RocheA study of Kadcyla (trastuzumab emtansine) in patients with HER2 positive breast cancer who have received prior anti-HER2 and chemotherapy-based treatment Available from: http://clinicaltrials.gov/show/NCT01702571. NLM identifier: NCT01772472Accessed June 10, 2013

 Google Scholar

Hoffmann-La RocheA study of trastuzumab emtansine versus trastuzumab as adjuvant therapy in patients with HER2-positive breast cancer who have residual tumor in the breast or axillary lymph nodes following preoperative therapy (KATHERINE) Available from: http://clinicaltrials.gov/show/NCT01772472. NLM identifier: NCT01772472Accessed June 10, 2013

 Google Scholar

EllisPABarriosCHImYMARIANNE: A phase III, randomized study of trastuzumab-DM1 (T-DM1) with or without pertuzumab (P) compared with trastuzumab (H) plus taxane for first-line treatment of HER2-positive, progressive, or recurrent locally advanced or metastatic breast cancer (MBC)J Clin Oncol201129Suppl 15TPS 102

 Web of Science ®Google Scholar

Hoffmann-La RocheA study of trastuzumab emtansine in comparison with treatment of physician’s choice in patients with HER2-positive breast cancer who have received at least two prior regimens of HER2-directed therapy (TH3RESA) Available from: http://clinicaltrials.gov/show/NCT01419197. NLM identifier: NCT01419197Accessed June 18, 2014

 Google Scholar

Hoffmann-La RocheA study of kadcyla (trastuzumab emtansine) plus perjeta (pertuzumab) following anthracyclines in comparison with herceptin (trastuzumab) plus perjeta and a taxane following anthracyclines as adjuvant therapy in patients with operable HER2-positive primary breast cancer Available from: http://clinicaltrials.gov/show/NCT01966471. NLM identifier: NCT01966471Accessed April 30, 2014

 Google Scholar