Evolving landscape of human epidermal growth factor receptor 2-positive breast cancer treatment and the future of biosimilars

Abstract

Human epidermal growth factor receptor 2-positive (HER2+) breast cancer comprises approximately 15%–20% of all breast cancers and is associated with a poor prognosis. The introduction of anti-HER2 therapy has significantly improved clinical outcomes for patients with HER2+ breast cancer, and multiple HER2-directed agents (ie, trastuzumab, pertuzumab, lapatinib, and ado-trastuzumab emtansine [T-DM1]) are approved for clinical use in various settings. The treatment landscape for patients with HER2+ breast cancer is continuing to evolve. While novel agents and therapeutic strategies are emerging, biologic therapies, particularly trastuzumab, are likely to remain a mainstay of treatment. However, access issues create barriers to the use of biologics, and there is evidence for underuse of trastuzumab worldwide. A biosimilar is a biologic product that is highly similar to a licensed biologic in terms of product safety and effectiveness. Biosimilars of trastuzumab are in development and may soon become available. The introduction of biosimilars may improve access to anti-HER2 therapies by providing additional treatment options and lower-cost alternatives. Because HER2-targeted drugs may be administered for extended periods of time and in combination with other systemic therapies, biosimilars have the potential to result in significant savings for healthcare systems. Herein we review current and emerging treatment options for, and discuss the possible role of biosimilars in, treating patients with HER2+ breast cancer.

1. Introduction

Breast cancer is the most common cancer among women worldwide, with an estimated 231,840 new cases diagnosed in the United States and 471,724 in Europe in 2015 [1,2]. Approximately 1.7 million new cases of breast cancer were diagnosed in 2012 worldwide [3] and the global incidence is projected to be over 1.9 million in 2020 [2]. Breast cancer comprises many distinct histological subtypes and is further classified based on the expression of biological markers [4,5].

Approximately 15%–20% of all invasive breast cancers overexpress human epidermal growth factor receptor 2 (HER2) [6–10], a key mediator of cell growth, differentiation, and survival [11]. HER2-positive (HER2+) tumors tend to be of higher histological grade and are more likely to invade axillary lymph nodes (node-positive) than other tumor subtypes [4,5]. These histopathological features give rise to an aggressive tumor subtype that historically was associated with shortened survival and an increased risk of disease recurrence and metastasis [12–14]. However, patients with HER2+ breast cancer are sensitive to and derive significant clinical benefit from HER2-directed agents [15–32]. Therefore, HER2-overexpressing tumors can be targeted directly. Currently, four HER2-directed agents are approved for the treatment of patients with HER2+ breast cancer: trastuzumab, pertuzumab, lapatinib, and ado-trastuzumab emtansine (T-DM1) [33–40]. However, access issues have been reported as a barrier to the use of biologics [41–43], and there is evidence for underuse of trastuzumab worldwide [9,44–53].

The treatment landscape for HER2+ breast cancer is evolving. Novel agents and therapeutic strategies are emerging, but treatment regimens remain focused on targeted therapy with biologics, particularly trastuzumab. Patents for many biologics have expired or will expire within the next few years [54], allowing for the development of biosimilar agents. A biosimilar is highly similar to and has no clinically meaningful differences in safety and effectiveness from a licensed biologic product (ie, reference or originator) [55–57].

The availability of safe and effective biosimilars for HER2-directed biologics may improve access to these critical therapies. For example, trastuzumab biosimilars are in development and may soon become available to patients with HER2+ breast cancer. This review summarizes current standard treatment options and the evolving landscape for patients with HER2+ breast cancer as well as the possible role of biosimilars in treating this disease.

2. HER2+ breast cancer: current treatment options

Current treatments for patients with HER2+ breast cancer include different strategies for inhibiting the HER2 pathway. Trastuzumab and pertuzumab are recombinant humanized monoclonal antibodies that target different epitopes of the HER2 extracellular domain [33–35,39]. Binding of trastuzumab to HER2 inhibits ligand-independent signaling by preventing the formation of HER2 homodimers [33,58]. By contrast, pertuzumab inhibits ligand-dependent signaling by preventing heterodimerization of HER2 with other members of the HER family [35,39,58]. Lapatinib, a small-molecule tyrosine kinase inhibitor (TKI), binds HER1 and HER2 intracellular domains to block activation of their downstream signaling pathways [37,38]. Finally, the antibody-drug conjugate T-DM1 links trastuzumab to the cytotoxin emtansine to inhibit HER2 signaling and to optimize the delivery of chemotherapy [36,40].

The American Society of Clinical Oncology (ASCO), the European Society for Medical Oncology (ESMO), and the National Comprehensive Cancer Network (NCCN) treatment guidelines for breast cancer recommend the addition of HER2-directed agents to systemic chemotherapy or endocrine therapy for the treatment of patients with early, advanced, and metastatic HER2+ breast cancer (Table 1) [59–63].

Table 1.

Summary of American Society of Clinical Oncology, European Society for Medical Oncology, and National Comprehensive Cancer Network treatment guidelines for patients with HER2+ breast cancer.

Setting	ASCO [62,63]	ESMO [59,61]	NCCN [60]
Neoadjuvant/adjuvant	Dox + Cy → Pac (or Doc) + Trast	Dox + Cy → Taxane + Trast ± Perta	Dox + Cy → Pac (or Doc) + Trast ± Perta,b
	Doc + Carb + Trast		Doc + Carb + Trast ± Perta,b
	Fluor + Epi + Cy → Doc + Trast		Fluor + Epi + Cy → Pac (or Doc) + Trast + Perta,b
	Dose-dense Dox + Cy → Pac + Trast		Pac (or Doc) + Trast + Pert → Fluor + Epi + Cya,b
	Pac + Trastc		Pac + Trastc
	Doc + Cy + Trastc		Doc + Cy + Trast
Metastatic
First line	Trast + Pert + Pac (or Doc)	Trast + Pert + Pac (or Doc)	Trast + Pert + Pac (or Doc)
Second or later line	T-DM1	T-DM1	T-DM1
	Trast + Pert ± Chtd	Trast + Pert ± Chtd	Trast + Pert ± Chtd
	Lap + Cap		Trast + Pac ± Carb
	Lap + Trast		Trast + Doc
			Trast + Vin
			Trast + Cap
			Lap + Cap
			Lap + Trast

ASCO, American Society of Clinical Oncology; Cap, capecitabine; Carb, carboplatin; Cht, chemotherapy; Cy, cyclophosphamide; Doc, docetaxel; Dox, doxorubicin; Epi, epirubicin, ESMO, European Society for Medical Oncology; Fluor, fluorouracil; HER2, human epidermal growth factor receptor 2; Lap, lapatinib; NCCN, National Comprehensive Cancer Network; Pac, paclitaxel; Pert, pertuzumab; Trast, trastuzumab; T-DM1, ado-trastuzumab emtansine; Vin, vinorelbine.

^aThe addition of pertuzumab to adjuvant systemic therapy is recommended as a possible treatment for patients who have not received a pertuzumab-containing regimen as neoadjuvant therapy.

^bA pertuzumab-containing regimen is recommended by NCCN as neoadjuvant treatment for patients with locally advanced HER2+ breast cancer and for some patients (node-positive or tumor ≥2 cm) with early-stage disease.

^cMay be considered for patients with small (≤1 cm), node-negative HER2+ breast cancer.

^dA line of therapy containing trastuzumab and pertuzumab with or without cytotoxic chemotherapy may be considered for patients whose disease progressed following prior trastuzumab-based therapy that did not include pertuzumab in the metastatic setting.

2.1. Early and operable HER2+ breast cancer

For patients with early (clinical stage I or II) or operable (clinical stage IIIA; T3, N1, M0) locally advanced HER2+ and node-positive or high-risk (ie, hormone receptor-negative [HR−], primary tumor >1 cm, <35 years of age, or histologic and/or nuclear grade 2 or 3) node-negative breast cancer, guidelines recommend adjuvant chemotherapy with trastuzumab (Table 1) [60–62]. The addition of trastuzumab either starting with or after the completion of chemotherapy reduces the risk of recurrence (Table 2) [17,18,29,64]. However, trastuzumab may provide greater benefit when administered concurrently with chemotherapy rather than after, and this has become the standard approach [29,60–62].

Table 2.

Clinical trials of adjuvant HER2-targeting therapy.

Study name or NCT no.	Patient population	Treatments	DFS rate, % (95% CI)	OS rate, % (95% CI)	Safety
Cht + Trast (1 yr) vs Cht alone
BCIRG-006 [18]	Early or operable HER2+ BC (N+ or N0 with tumors >2 cm)	Dox + Cy → Pac	5 yr: 75	87	Fewer acute toxic AEs and lower risk of cardiotoxicity with Doc + Carb + Trast vs Dox + Cy → Pac + Trast
		Dox + Cy → Pac + Trast	5 yr: 84 HR = 0.64; P < 0.001a	92 HR = 0.63; P < 0.001a
		Doc + Carb + Trast	5 yr: 81 HR = 0.75; P = 0.04a	91 HR = 0.77; P = 0.04a
Joint analysis of NCCTG N9831 and NSABP B-31b [17]	Early or operable HER2+ BC (N+ or N0 with HR+ tumors >2 cm or HR-tumors >1 cm)	Dox + Cy → Pac	10 yr: 62.2	75.2	Higher incidence of cardiac-related deaths with Trast vs Cht alone
		Dox + Cy → Pac + Trast	10 yr: 73.7 HR (95% CI) = 0.60 (0.53–0.68); P < 0.001a	84 HR (95% CI) = 0.63 (0.54–0.73); P < 0.001a
Sequential vs concurrent Trast
NCCTG N9831 [29]	Early or operable HER2+ BC (N+ or N0 with HR+ tumors >2 cm or HR-tumors >1 cm)	Dox + Cy → Pac	5 yr: 71.8 (68.6–75.1)	88.4 (86.1–90.7)	Safety profile of concurrent Trast, including cardiac safety, similar to sequential Trast
		Dox + Cy → Pac → Trast	5 yr: 80.1 (77.3–83) HR (95% CI) = 0.69 (0.57–0.85); P < 0.001a, vs Cht alone	89.3 (87.1–91.5) HR (95% CI) = 0.88 (0.67–1.15); P = 0.343, vs Cht alone
		Dox + Cy → Pac + Trast → Trast	5 yr: 84.5 (82.0–86.5) HR (95% CI) = 0.77 (0.53–1.11); P = 0.022, vs sequential Trast	91.9 (90.0–93.7) HR (95% CI) = 0.78 (0.58–1.05); P = 0.102, vs sequential Trast
Trast (1 yr) vs Lap
ALTTO [78]	Early or operable HER2+ BC (N+ or N0 with tumors ≥1 cm)	Trastc	4 yr: 86	N/A	Higher incidence of diarrhea, rash, and hepatobiliary AEs with Lap + Trast vs Trast; Low incidence of cardiac events in all arms
		Lap + Trastc	4 yr: 88 HR (97.5% CI) = 0.84 (0.70–1.02); P = 0.048, superiority vs Trast	N/A
		Trast → Lapc	4 yr: 87 HR (97.5% CI) = 0.93 (0.76–1.13); P = 0.044, noninferiority vs Trast	N/A
		Lapc	N/A	N/A
1 yr vs 2 yr or 6 mo Trast; 9 wk Trast
HERA [67]	Early or operable HER2+ BC (N+ or N0 with tumors >1 cm)	Cht → Trast (1 yr)	8 yr: 76	87.6	Higher incidence of grade 3/4 AEs and cardiac events with 2 yr vs 1 yr of Trast
		Cht → Trast (2 yrs)	8 yr: 75.8 HR (95% CI) = 0.99 (0.85–1.14); P = 0.86	86.4 HR (95% CI) = 1.05 (0.86–1.28); P = 0.63
NCT00615602 [69]	Early or operable HER2+ BC (N+ or high-risk N0)	Dose-dense Fluor + Epi + Cy → Dose-dense Doc + Trast (1 yr)	3 yr: 95.7	N/A	No difference in rates of cardiac toxicity with 1 yr vs 6 mo of Trast
		Dose-dense Fluor + Epi + Cy → Dose-dense Doc + Trast (6 mo)	3 yr: 93.3 HR (95% CI) = 1.57 (0.86–2.10); P = 0.137	N/A HR (95% CI) = 1.45 (0.57–3.67); P = 0.438
PHARE [70]	Early or operable HER2+ BC (N+ or N0; tumors ≥1 cm)	Cht → Trast (1 yr)	2 yr: 93.8 (92.6–94.9)	N/A	Higher incidence of cardiac events with 1 yr vs 6 mo of Trast
		Cht → Trast (6 mo)	2 yr: 91.1 (89.7–92.4) HR (95% CI) = 1.28 (1.05–1.56); P = 0.29	N/A HR (95% CI) = 1.46 (1.06–2.01)d
FinHER [16,68]	Early, operable or inoperable locally advanced HER2 + BC (N+ or N0 with tumors ≥2 cm and HR−)	Doc → Fluor + Epi + Cy	5 yr DDFS: 74.1 [16]	82.0 [16]	Low incidence of cardiac toxicity and improved LVEF with Trast vs Cht alone; higher incidence of AEs with Doc vs Vin [16,68]
		Doc + Trast (9 wks) → Fluor Epi + Cy	5 yr DDFS: 92.5 HR (95% CI) = 0.32 (0.12–0.89); P = 0.029a	94.4 HR (95% CI) = 0.42 (0.13–1.33); P = 0.14
		Vin → Fluor + Epi + Cy	5 yr DDFS: 72	82.8
		Vin + Trast (9 wks) → Fluor Epi + Cy	5 yr DDFS: 75.2 HR (95% CI) = 0.92 (0.47–1.83); P = 0.82	88.4 HR (95% CI) = 0.64 (0.26–1.60); P = 0.35

AE, adverse event; BC, breast cancer; Carb, carboplatin; Cht, chemotherapy; CI, confidence interval; Cy, cyclophosphamide; DDFS, distant disease-free survival; DFS, disease-free survival; Doc, docetaxel; Dox, doxorubicin; Epi, epirubicin; Fluor, fluorouracil; HER2, human epidermal growth factor receptor 2; HR, hazard ratio; HR+, hormone receptor-positive; HR−, hormone receptor-negative; Lap, lapatinib; LVEF, left ventricular ejection fraction; N+, node-positive; N0, node-negative; N/A, not reported; NCT, National Clinical Trial; OS, overall survival; Pac, paclitaxel; Trast, trastuzumab; Vin, vinorelbine.

^aStatistically significant.

^bPatients with N0 disease were enrolled into the NCCTG N9831 trial only. Sequential Dox + Cy followed by Pac and then Trast was evaluated in the NCCTG N9831 trial only.

^cAnti-HER2 therapy was started following the completion of Cht, concurrently with taxane Cht after anthracycline Cht, or concurrently with non-anthracycline, platinum-based Cht. Data for Lap only not reported because arm was closed in August 2011 for futility.

^dTest of proportional hazards was significant (P = 0.03). Longer follow-up required to provide mature data for OS analysis.

Trastuzumab is safely combined with non-anthracycline chemotherapy (eg, paclitaxel, docetaxel, carboplatin, or cyclophosphamide) and may be given concurrently with taxane chemotherapy that precedes or follows anthracycline-containing regimens [18,60,64–66]. However, concurrent use of anthracyclines (ie, doxorubicin or epirubicin) and trastuzumab is not recommended because of an increased risk for cardiac toxicity [19,60–62]. Sequential doxorubicin plus cyclophosphamide followed by concomitant paclitaxel or docetaxel and trastuzumab is recommended for most patients [60–62]. Guidelines also recommend trastuzumab in combination with paclitaxel, docetaxel and carboplatin, or docetaxel and cyclophosphamide, particularly for patients with increased risk for cardiac toxicity or those with small (≤1 cm), node-negative HER2+ tumors [60–62].

In terms of treatment duration, guidelines recommend up to 1 year of adjuvant trastuzumab [60–62] as there is no evidence of better outcome with longer-term therapy (Table 2) [67]. Shorter courses (9 weeks or 6 months) of trastuzumab are safe and effective [16,68–70]; however, comparative studies failed to demonstrate noninferiority for 6 months versus 1 year of trastuzumab treatment [69,70].

2.2. Inoperable locally advanced HER2+ breast cancer

Neoadjuvant chemotherapy with trastuzumab is associated with higher rates of pathologic complete response (pCR) than chemotherapy alone or in combination with lapatinib (Table 3) [21,24,71–73] and trastuzumab-based neoadjuvant chemotherapy is recommended as initial treatment for patients with inoperable (clinical stage IIIA [anyT, N2, M0], IIIB, or IIIC) locally advanced HER2+ breast cancer [59,60]. A subcutaneous (SC) formulation of trastuzumab, which offers a more convenient alternative and flexibility for patients and may optimize the use of medical resources, is available for all indications of breast cancer in Europe and other areas outside of the United States [34,74,75]. In a study of neoadjuvant chemotherapy in combination with intravenous (IV) versus SC trastuzumab in patients with early or operable locally advanced HER2+ breast cancer (HannaH), the pharmacokinetic (PK) profile and efficacy of SC trastuzumab were non-inferior to IV administration and overall safety was similar although a slightly higher incidence of serious adverse events due to infection was noted for SC trastuzumab [76].

Table 3.

Clinical trials of neoadjuvant HER2-targeting therapy.

Study name or NCT no.	Patient population	Treatments	pCR, % (CI)	Safety
Cht + Trast vs Cht alone
MDACC [71]	Stages II or IIIA operable HER2+ BC	Pac → Fluor + Epi + Cy	26.3 (95% CI: 9.1–51.2)	Higher incidence of grade 4 neutropenia with Trast vs Cht alone; no differences in cardiac toxicity and no clinical congestive heart failure reported
		Pac + Trast → Fluor + Epi + Cy + Trast	65.2 (95% CI: 43–84) P = 0.016a
NOAH [24,72]	Locally advanced or inflammatory HER2+ BC	Dox + Pac → Pac → Cy + Metho + Fluor	19% [24]	Safety profiles similar, though slightly higher incidence of decline in LVEF with Trast vs Cht alone [24,72]
		Dox + Pac → Pac → Cy + Metho + Fluor + Trast	38% P = 0.001a
SC vs IV formulation
HannaHb [76]	Operable, locally advanced, or inflammatory BC (neoadjuvant)	Doc + Fluro + Epi + Cy + Trast-IV	40.7%	Incidence of grade 3 + AEs similar between groups; incidence of serious AEs higher with Trast-SC vs Trast-IV
		Doc + Fluro + Epi + Cy + Trast-SC	45.4% Difference in pCR: 4.7% (95% CI: −4.0–13.4); noninferiority margin, −12.5%
Trast vs Pert or Lap
NeoSphere [15,79]	Early stage, locally advanced, or inflammatory HER2+ BC	Doc + Trast	29 (95% CI: 20.6–38.5) [15] 3-yr DFS; PFS: 85%; 86% [79]	Similar safety profiles for Doc + Trast, Doc + Trast + Pert, and Doc + Pert; lower incidence of serious AEs with Trast + Pert vs other groups [15]
		Doc + Trast + Pert	45.8 (95% CI: 36.1–55.7) 3-yr DFS; PFS: 92%; 90% pCR: P = 0.0141a (vs Doc + Trast) DFS: HR (95% CI) = 0.60 (0.28–1.27)c; vs Doc + Trast PFS: HR (95% CI) = 0.69 (0.34–1.40)c; vs Doc + Trast
		Trast + Pert	16.8 (95% CI: 10.3–25.3) 3-yr DFS; PFS: 88%; 81%
		Doc + Pert	24 (95% CI: 15.8–33.7) 3-yr DFS; PFS: 84%; 82%
TRYPHAENAd [77]	Operable, locally advanced, or inflammatory HER2+ BC	Fluor + Epi + Cy + Trast + Pert → Doc + Trast + Pert	61.6	Combination of Trast and Pert concurrent with or sequentially to Cht generally well tolerated; low incidence of symptomatic LVSD and decline in LVEF
		Fluor + Epi + Cy → Doc + Trast + Pert	57.3
		Doc + Carb + Trast + Pert	66.2
CHER-LOB [26]	Stages II or IIIA operable HER2+ BC	Pac + Trast → Fluor + Epi + Cy + Trast	25 (90% CI: 13.1–36.9)	Higher incidence of diarrhea and dermatologic and hepatic toxicities with Lap vs Trast
		Pac + Lap → Fluor + Epi + Cy + Lap	26.3 (90% CI: 14.5–38.1)
		Pac + Trast + Lap → Fluor + Epi + Cy + Trast + Lap	46.7 (90% CI: 34.4–58.9) P = 0.019a (vs Trast alone and Lap alone)
GeparQuinto [73]	Operable or locally advanced HER2+ BC	Epi + Cy + Trast → Doc + Trast	30.3	Higher incidence of edema and dyspnea with Trast vs Lap; higher incidence of diarrhea with Lap vs Trast
		Epi + Cy + Lap → Doc + Lap	22.7 OR = 0.68 (95% CI: 0.47–0.97); P = 0.04a
NeoALTTO [21]	HER2+ BC (tumors >2 cm)	Trast → Pac + Trast	29.5 (95% CI: 22.4–37.5)	Higher incidence of grade 3 diarrhea and liver-enzyme alterations with Lap and Lap + Trast vs Trast alone; no major cardiac dysfunctions reported
		Lap → Pac + Lap	24.7 (95% Cl: 18.1–32.3) Difference (95% Cl): −4.8 (−17.6–8.2); P = 0.34 (vs Trast alone)
		Trast + Lap → Trast + Lap + Pac	51.3 (43.1–59.5) Difference (95% Cl): 21.1 (9.1–34.2); P = 0.0001a (vs Trast alone)

AE, adverse event; BC, breast cancer; Carb, carboplatin; Cht, chemotherapy; CI, confidence interval; Cy, cyclophosphamide; DFS, disease-free survival; Doc, docetaxel; Dox, doxorubicin, Epi, epirubicin; Fluor, fluorouracil; HER2, human epidermal growth factor receptor 2; HR, hazard ratio; Lap, lapatinib; LVEF, left ventricular ejection fraction; LVSD, left ventricular systolic dysfunction; Metho, methotrexate; NCT, National Clinical Trial; OR, odds ratio; Pac, paclitaxel; pCR, pathologic complete response; Pert, pertuzumab; PFS, progression-free survival; Trast, trastuzumab; Trast-IV, intravenous trastuzumab; Trast-SC, subcutaneous trastuzumab.

^aStatistically significant.

^bGeometric mean C_trough (μg/mL; coefficient of variation) was 51.8 (52.5%) for Trast-IV and 69.0 (55.8%) for Trast-SC; geometric mean C_trough Trast-IV/Trast-SC = 1.33 (90% CI: 1.24–1.44), noninferiority margin, 0.80.

^cBased on a pre-planned descriptive intent-to-treat analysis.

^dNo statistical comparisons were made between treatment groups.

The pCR rate following neoadjuvant chemotherapy and HER2 blockade is higher with dual therapy (trastuzumab and lapatinib or trastuzumab and pertuzumab) than with trastuzumab alone [15,21,26,77]. However, the combination of trastuzumab, lapatinib, and chemotherapy is not recommended because it failed to demonstrate noninferiority versus trastuzumab and chemotherapy in the adjuvant setting [78]. By contrast, guidelines recommend the combination of trastuzumab, pertuzumab, and chemotherapy as neoadjuvant treatment for patients with locally advanced HER2+ breast cancer and for some patients (node-positive or tumor ≥2 cm) with early-stage disease [60,61]. Follow-up data from one trial demonstrated that neoadjuvant chemotherapy in combination with pertuzumab and trastuzumab reduced the risk of progression or death by 31% and recurrence or death by 40% versus trastuzumab alone suggesting that the pCR benefit associated with pertuzumab may translate into improvements in long-term outcomes [79]. However, confirmation of clinical benefit for pertuzumab awaits data from an ongoing trial (APHINITY) that is evaluating trastuzumab-based chemotherapy with or without pertuzumab in the adjuvant setting. Patients who achieve clinical response may undergo locoregional treatment followed by adjuvant chemotherapy with up to 1 year of trastuzumab and possibly pertuzumab, if not received as part of neoadjuvant therapy [60].

2.3. HER2+ metastatic or recurrent breast cancer

For patients with stage IV or recurrent HER2+ breast cancer, HER2-targeting regimens may include trastuzumab, pertuzumab, lapatinib, or T-DM1 [59,60,63]. Concurrent chemotherapy and HER2-directed therapy improves survival outcomes over chemotherapy alone (Table 4) [19,25,28] and is considered the standard approach for treating patients with HER2+ metastatic breast cancer (MBC) in the first-line setting [59,60,63]. However, the combination of lapatinib and taxane chemotherapy has inferior progression-free survival (PFS) and greater toxicity than trastuzumab plus taxane chemotherapy [80]. Furthermore, a trial (CEREBEL) comparing lapatinib to trastuzumab (both in combination with capecitabine) demonstrated shorter PFS and overall survival (OS) with lapatinib versus trastuzumab-based chemotherapy [81]. By contrast, dual inhibition of HER2 with trastuzumab and pertuzumab in combination with paclitaxel reduced the risk of death or progression by approximately 40% compared with concurrent trastuzumab and paclitaxel [20,22,30]. Therefore, the combination of trastuzumab, pertuzumab, and taxane chemotherapy is the preferred first-line regimen [59,60,63].

Table 4.

Clinical trials of HER2-targeting therapy in metastatic breast cancer.

Study name or NCT no.	Patient population	Treatments	ORR, % (95% CI)	mTTP or mPFS, mo (95% CI)	mOS, mo (95% CI)	Safety
First line
M77001 [28]	HER2+ MBC (no prior Cht for MBC; no prior taxanes or anti-HER therapy)	Doc	34 (25–45)	mTTP: 6.1	22.7	Higher incidence of certain AEs and cardiac toxicity with Trast vs Doc alone
		Doc + Trast	61 (50–71) P = 0.0002a	11.7 P = 0.0001a	31.2 P = 0.0325a
Multinational clinical trial [19]	HER2+ MBC (no prior Cht for MBC)	Dox or Epi + Cy	42 (34–50)	mTTP: 6.1	21.4	Higher incidence of cardiac toxicity with anthracycline + Trast vs anthracycline alone or Pac ± Trast
		Dox or Epi + Cy + Trast	56 (48–64) P = 0.02a	7.8 RR (95% CI) = 0.62 (0.47–0.81); P < 0.001a	26.8 RR (95% CI) = 0.82 (0.61–1.09); P = 0.16
		Pac	17 (9–24)	3.0	18.4
		Pac + Trast	41 (31–51) P < 0.001a	6.9 RR (95% CI) = 0.38 (0.27–0.53); P < 0.001a	22.1 RR (95% CI) = 0.80 (0.56–1.11); P= 0.17
EGF104535 [25]	HER2+ MBC (no prior treatment for MBC, except HT)	Pac + Placebo	50 (42.8–56.3)	mPFS: 6.5 (5.5–7.3)	20.5 (17.9–24.3)	Higher incidence of diarrhea and rash, and hematologic and cardiac toxicities with Lap vs Pac + placebo
		Pac + Lap	69 (62.9–75.4) OR (95% CI) = 2.3 (1.54–3.47); P< 0.001a	9.7 (9.2–11.1) HR (95% CI) = 0.52 (0.42–0.64); P < 0.001a	27.8 (23.2–32.2) HR (95% CI) = 0.74 (0.58–0.94); P = 0.0124a
NCIC CTG MA.31 [80]	HER2+ MBC (no prior cytotoxics or biologics for recurrent or advanced disease)	Doc or Pac + Trast / Trast	55	mPFS: 11.3	NR	Higher incidence of rash and diarrhea with Lap vs Trast
		Doc or Pac + Lap / Lap	54b	9.0 HR (95% CI) = 1.37 (1.13–1.65); P = 0.001a	NR HR (95% CI) = 1.28 (0.95–1.72); P= 0.11
CLEOPATRA [20,22,30]	HER2+ locally recurrent, unresectable, or MBC (no prior anticancer therapy for MBC, except HT)	Doc + Trast + Placebo	69.3 [30]	mPFS: 12.4 [22]	40.8 (35.8–48.3) [20]	Safety profile generally similar, though slightly higher incidence of certain AEs with Pert + Trast vs Trast alone [22]
		Doc + Trast + Pert	80.2 Difference (95% CI): 10.8 (4.2–17.5); P = 0.001a	18.5 HR (95% CI) = 0.62 (0.51–0.75); P < 0.001a	56.5 (49.3, NR) HR (95% CI) = 0.68 (0.56–0.84); P< 0.001a
Second or later line
NCT00301899 [82]	HER2+ MBC (<3 prior Cht regimens; progression during Trast-based therapy as last treatment for MBC)	Trast + Pert	24.2	mPFS: 5.5 (80% CI: 18–31)		Trast + Pert generally well tolerated; no clinically significant cardiac events were reported
GBG 26/BIG 3-05 [32,85]	HER2+ locally advanced or MBC (>12 wk prior Trast with <6 wk since last cycle; <1 Cht drug for MBC)	Cap	27 (17.4–38.6) [32]	mTTP: 5.6 (4.2–6.3) [32]	20.6 [85]	Similar safety profiles [32]
		Cap + Trast	48.1 (36.5–59.7) OR = 2.5; P = 0.0115a	8.2 (7.3–11.2) HR (95% CI) = 0.69 (0.48–0.97); P = 0.0338a	24.9 HR (95% CI) = 0.94 (0.65–1.35); P= 0.73
PHEREXA [83]	HER2+ MBC (progression during or after first-line Trast-based therapy for MBC; last prior treatment regimen must have contained Trast; prior treatment with taxane-based Cht; no prior Pert or Cap)	Cap + Trast	–	mPFS: 9.0	28.1	Similar safety profiles
		Cap + Trast + Pert	–	11.1 HR (95% CI) = 0.82 (0.65–1.02); P = 0.0735	36.1 HR (95% CI) = 0.68 (0.51–0.90)c
NCT00078572 [23]	HER2+ locally advanced or MBC (progression after treatment that included an anthracycline, a taxane, and Trast)	Cap	13.9 (9.5–19.5)	mTTP: 4.3	15.3	Higher incidence of diarrhea and rash with Lap vs Cap alone
		Cap + Lap	23.7 (18.0–30.3) OR (95% CI) = 1.9 (1.1–3.4); P = 0.017a	6.2 HR (95% CI) = 0.57 (0.43–0.77); P < 0.001a	15.6 HR (95% CI) = 0.78 (0.55–1.12); P = 0.177
EGF104900 [84,125]	HER2+ MBC (progression during most recent regimen which must have contained Trast; prior anthracycline- and taxane-based Cht in adjuvant or metastatic setting)	Lap	6.9 (5.9–16.4) [125]	mPFS (wk): 8.1 [84]	9.5 [84]	Safety profile generally similar, though higher incidence of diarrhea with Lap + Trast vs Lap alone and higher incidence of rash with Lap vs Lap + Trast [84,125]
		Lap + Trast	10.3 (3.4–12.3) OR (95% CI) = 1.5 (0.6–3.9); P = 0.46	11.1 HR (95% CI) = 0.74 (0.58–0.94); P = 0.011a	14 HR (95% CI) = 0.74 (0.57–0.97); P = 0.026a
EMILIA [31]	HER2+ locally advanced, unresectable, or MBC (prior taxane and Trast; progression during or after most recent treatment for locally advanced or MBC, or within 6 mo after treatment for early-stage disease; no prior T-DM1, Lap, or Cap)	Lap + Cap	30.8 (26.3–35.7)	6.4	25.1	Higher incidence of diarrhea, palmarplantar erythrodysesthesia, vomiting, and nausea with Lap + Cap vs T-DM1; higher incidence of thrombocytopenia and elevated aminotransferase levels with T-DM1 vs Lap + Cap
		T-DM1	43.6 (38.6–48.6) Difference (95% CI): 12.7 (6.0–19.4); P < 0.001a	9.6 HR (95% CI) = 0.65 (0.55–0.77); P < 0.001a	30.9 HR (95% CI) = 0.68 (0.55–0.85); P < 0.001a
TH3RESA [27]	HER2+ advanced breast cancer (≥2 HER2-directed regimens in the advanced setting, including Trast and Lap, and prior taxane in any setting)	TPC	9	mPFS: 3.3 (2.89–4.14)	14.9 (11.27–NE)	Lower incidence of grade 3+ AEs with T-DM1 vs TPC; thrombocytopenia more commonly reported with T-DM1 than TPC
		T-DM1	31 Difference (95% CI): 22.7 (16.2–29.2); P < 0.0001a	6.2 (5.59–6.87) HR (95% CI) = 0.528 (0.422–0.661); P < 0.0001a	NE HR (95% CI) = 0.552 (0.369–0.826); P = 0.0034
First or later line
CEREBELd [81]	HER2+ MBC (prior anthracycline and/or taxanes for neoadjuvant, adjuvant, or metastatic disease; prior Trast allowed; no history or presence of CNS metastases at baseline)	Cap + Trast	32 (26.43–37.57)	mPFS: 8.1 (6.1–8.9)	27.3 (23.7–NR)	Most common AEs consistent between treatment arms, except for higher incidence of diarrhea, nausea, rash, and hyperbilirubinemia, with Cap + Lap vs Cap + Trast
		Cap + Lap	27 (21.71–32.29) OR (95% CI) = 0.80 (0.54–1.18); P = 0.2731	6.6 (5.7–8.1) HR (95% Cl) = 1.30 (1.04–1.64); P = 0.021a	22.7 (19.5–NR) HR (95% CI) = 1.34 (0.95–1.90); P = 0.095

AE, adverse event; Cap, capecitabine; Cht, chemotherapy; CI, confidence interval; CNS, central nervous system; Cy, cyclophosphamide; Doc, docetaxel; Dox, doxorubicin; Epi, epirubicin; HER2, human epidermal growth factor receptor 2; HR, hazard ratio; HT, hormone therapy; Lap, lapatinib; MBC, metastatic breast cancer; mOS, median overall survival; mPFS, median progression-free survival; mTTP, median time to disease progression; NCT, National Clinical Trial; NE, not estimable; NR, not reached; OR, odds ratio; ORR, overall response rate; Pac, paclitaxel; Pert, pertuzumab; RR, risk ratio; TPC, treatment of physician’s choice; Trast, trastuzumab; T-DM1, ado-trastuzumab emtansine; –, not included as study endpoint or not reported.

^aStatistically significant.

^bNo statistical comparisons were made between treatment groups.

^cLonger mOS with Pert not considered statistically significant due to hierarchical testing.

^dNo statistically significant difference between groups in primary endpoint of incidence of central nervous system metastases as first site of progression was observed (5% for Cap + Trast vs 3% for Cap + Lap; Difference [95% CI]: −1.6% [−2%–5%]; P = 0.360).

For patients whose disease progresses on first-line trastuzumab-based regimens or those who are diagnosed with MBC after prior exposure to adjuvant trastuzumab, guidelines recommend continuation of HER2 blockade in subsequent lines of therapy [59,60,63]. Single-agent T-DM1 is the preferred regimen, based on findings of prolonged PFS or OS for T-DM1 versus concurrent capecitabine and lapatinib or other treatments of physician’s choice [27,31,59,60,63]. The combination of pertuzumab and trastuzumab has clinical activity and is well tolerated in patients with HER2+ MBC that has progressed on prior trastuzumab-based therapy [82], and guidelines suggest this regimen (with or without a cytotoxic agent) as an option for patients previously treated with trastuzumab-based chemotherapy without pertuzumab in the metastatic setting [59,60]. However, in a trial (PHEREXA) evaluating concurrent trastuzumab and capecitabine with or without pertuzumab as treatment for HER2+ MBC that has progressed during or after one line of trastuzumab-based therapy in the metastatic setting, the combination of pertuzumab, trastuzumab, and capecitabine was not superior to trastuzumab and capectiabine in terms of PFS [83]. Another option is dual HER2 inhibition with lapatinib and trastuzumab without chemotherapy, which was associated with prolonged PFS and OS benefit versus lapatinib monotherapy [59,60,82,84]. Other regimens recommended for the treatment of patients with trastuzumab-exposed HER2+ breast cancer include trastuzumab in combination with selected chemotherapeutics (paclitaxel alone or with carboplatin, docetaxel, vinorelbine, or capecitabine) and lapatinib in combination with capecitabine [23,32,59,60,63,85].

3. The evolving treatment landscape of HER2+ breast cancer

The introduction of HER2-targeted therapy has revolutionized treatment of HER2+ breast cancer. Novel agents and therapeutic strategies that may lead to further improvements in patient outcomes are emerging. These include new HER2-directed antibodies, novel TKIs of the HER family, and drugs with targets downstream from HER activation. In addition, other HER2-targeted drugs approved for MBC are being studied in patients with earlier-stage disease. Finally, other strategies are further investigating SC trastuzumab or exploring the combination of HER2-directed agents and immunotherapy.

3.1. Neoadjuvant and adjuvant settings

The addition of pertuzumab to trastuzumab-based chemotherapy is recommended for some patients, although direct clinical evidence is lacking in the adjuvant setting [59–61]. Therefore, the ongoing APHINITY trial is evaluating concurrent chemotherapy and trastuzumab with or without pertuzumab as adjuvant therapy in patients with nonmetastatic primary invasive HER2+ breast cancer [86]. An ongoing, non-randomized, open-label study (SafeHer) is evaluating safety, efficacy, and patient satisfaction with SC trastuzumab as adjuvant therapy in nonmetastatic HER2+ breast cancer [87]. Other ongoing adjuvant trials are evaluating T-DM1 alone or in combination with pertuzumab versus trastuzumab-containing regimens (Table 5).

Table 5.

Therapeutic strategies under evaluation as treatment for patients with HER2+ breast cancer in the adjuvant or neoadjuvant settings.

Study name (NCT no.)	Patient population (setting)	Treatments	Efficacy, patient reported outcomes	Safety
SC vs IV formulation
SafeHER (NCT01566721) [87]	Early, operable, or inoperable locally advanced HER2+ BC (adjuvant)	Trast-SC (handheld syringe) ± Cht
		Trast-SC (single-use injection device) ± Cht
Trast vs T-DM1, Pert, or Lap (± Cht)
I-SPY II (NCT01042379) [90]	Stages II (tumor ≥2.5 cm) or III HER2+ BC (neoadjuvant)	Pac + Trast → Dox + Cy	pCR (95% CI): 22% (5%–39%)	N/A
		T-DM1 + Pert → Dox + Cy	pCR (95% CI): 52% (36%–68%) Probability T-DM1 + Pert is superior to Pac + Trast → Dox + Cy: 99.5% Predictive probability of success in phase III: 94%
ATEMPT (NCT01853748)	Stage I HER2+ BC (adjuvant)	Pac + Trast T-DM1
TEAL (NCT02073487)	Early, operable, or inoperable locally advanced HER2+ BC (neoadjuvant)	Trast + Pert → Pac
		T-DM1 + Lap → nab-Pac
KRISTINE (NCT02131064) [88]	Stages II or III HER2+ BC (neoadjuvant)	Doc + Carb + Trast + Pert	pCR (95% CI): 55.7% (48.8%–62.3%) Time to ≥10-pt decrease from baseline in HRQoLa: 3.0 mo Time to ≥10-pt decrease from baseline in physical functiona: 2.8 mo	Lower incidence of grade 3+ AEs and serious AEs with T-DM1 + Pert vs Doc + Carb + Trast + Pert
		T-DM1 + Pert	pCR (95% CI): 44.4% (37.8%–51.2%) P = 0.0155b Time to ≥10-pt decrease from baseline in HRQoLa: 4.6 mo Time to ≥10-pt decrease from baseline in physical functiona: 4.9 mo
KATHERINE (NCT01772472)	Early, operable, or inoperable locally advanced HER2+ BC (adjuvant)	Trast
		T-DM1
APHINITY (NCT01358877)	Nonmetastatic operable and N+ HER2+ BC (adjuvant)	Cht + Trast
		Cht + Trast + Pert
KAITLIN (NCT01966471)	Early or operable HER2+ BC (N+ or N0 with tumors >2 cm) (adjuvant)	Chtc → Pac or Doc + Trast + Pert
		Chtc → T-DM1 + Pert
UK EPHOS-B (NCT01104571) [95]	Early or operable HER2+ BC (neoadjuvant)	Controld	Breast pCR: 0% MRD: 0%	–
		Trast	Breast pCR: 0% MRD: 3.1%
		Lap	Breast pCR: 0% MRD: 0%
		Trast + Lap	Breast pCR: 10.6% MRD: 16.7%
Trastuzumab + TKIs
NSABP FB-7 (NCT01008150)	Early, operable, or inoperable locally advanced HER2+ BC (neoadjuvant)	Pac + Trast → Dox + Cy
		Pac + Ner → Dox + Cy
		Pac + Trast + Ner → Dox + Cy
DAFNE (NCT01594177) [91]	Non-metastatic (tumors ≥2 cm or inflammatory) HER2+ BC (neoadjuvant)	Trast + Af → Pac + Trast + Af → Epi + Cy + Trast	pCR (95% Cl): 49.2% (38.5%–60.1%)	Most common grade 3/4 hematologic and nonhematologic toxicities mainly reported during Cht treatment; grade 1/2 liver toxicity was frequent throughout all treatment phases
Anti-HER2 therapy + immune-checkpoint inhibitors
NCT02605915	Locally advanced HER2+ BC (neoadjuvant)	Trast + Pert + Atz → Doc + Carb + Trast + Pert
		T-DM1 + Atz → Doc + Carb + Trast + Pert

AE, adverse event; Af, afatinib; Atz, atezolizumab; BC, breast cancer; Carb, carboplatin; Cht, chemotherapy; CI, confidence interval; Cy, cyclophosphamide; Doc, docetaxel; Dox, doxorubicin; Epi, epimbicin; HER2, human epidermal growth factor receptor 2; HRQoL, health-related quality of life; Lap, lapatinib; MRD, minimal residual disease; N/A, not reported; nab-Pac, albumin bound paclitaxel; NCT, National Clinical Trial; Ner, neratinib; Pac, paclitaxel; pCR, pathologic complete response; Pert, pertuzumab; Trast, trastuzumab; T-DM1, ado-trastuzumab emtansine; Trast-SC, subcutaneous trastuzumab.

^aHRQoL was assessed by the European Organization for Research and Treatment of Cancer quality-of-life questionnaire C30/BR23 [89].

^bStatistically significant.

^cInitial Cht will consist of an anthracycline-containing regimen.

^dPatients in the control group received therapeutic conventional surgery without neoadjuvant or adjuvant systemic therapy. No statistical comparisons were made between treatment groups.

In the neoadjuvant setting, trials are evaluating T-DM1 in combination with other anti-HER2 agents (ie, pertuzumab or lapatinib) or atezolizumab (a programmed death ligand 1-targeting antibody) versus trastuzumab-containing regimens (Table 5). Initial results from some trials show promising efficacy and safety for T-DM1 in combination with pertuzumab [88–90].

Other neoadjuvant trials are evaluating the safety, tolerability, and clinical activity of chemotherapy regimens that include neratinib or afatinib with or without trastuzumab (Table 5) [91]. These irreversible pan-HER TKIs bind HER1, HER2, and HER4 intracellular domains to block activation of their downstream signaling pathways [92–94]. Finally, initial results from a study comparing perioperative trastuzumab and lapatinib to either agent alone or no perioperative treatment suggest that dual HER2 blockade without chemotherapy may be an interesting and effective strategy for some patients [95].

3.2. Metastatic setting

Neratinib alone or in combination with chemotherapy has clinical activity among patients with advanced or metastatic HER2+ breast cancer, and trials are underway to compare neratinib to lapatinib (both given in combination with capecitabine) and to evaluate the combination of neratinib and T-DM1 in patients with HER2+ MBC who previously received anti-HER2 therapy for metastatic disease (Table 6) [96,97]. Afatinib has clinical activity among patients with HER2+ MBC who have progressed on prior treatment with trastuzumab; however, afatinib-containing treatments are less well-tolerated and show no efficacy benefit over concurrent trastuzumab and vinorelbine or investigator’s choice of treatment [98,99].

Table 6.

Therapeutic strategies under evaluation as treatment for patients with HER2+ metastatic breast cancer.

Study name (NCT no.)	Patient population (setting)	Treatments	Efficacy	Safety
Anti-HER2 therapy + TKIs
ONT-380-004 (NCT01983501) [105]	HER2+ MBC with or without CNS progression; prior taxane and Trast; no prior T-DM1 or HER2 TKIs (second or later line)	T-DM1 + ONT-380	2 PRs; 2 SDs	Grade 3 elevated aminotransferase levels reported in 2 patients treated with T-DM1
		Trast	2 SDs
		Trast + Cap	1 PR
ONT-380-005 (NCT02025192) [106]	HER2+ MBC; prior Trast and T-DM1; no prior Cap or HER2 TKIs (third or later line)	Cap + ONT-380		Most AEs were grade 1–2; one grade 3 treatment-related increase in aminotransferase levels (reversible) was reported; 1 DLT of cerebral edema with grade 3 dysarthria and visual field deficit occurred in a patient with known CNS metastases
		Trast + ONT-380 Cap + Trast + ONT-380
NSABP FB-10 (NCT02236000)	HER2+ MBC; prior Trast and Pert; no prior T-DM1 or HER2 TKIs (second or later line)	T-DM1 + Ner
NEfERT-T (NCT00915018) [96]	HER2+ locally recurrent or MBC; no prior anticancer therapy for locally recurrent or metastatic disease; no prior anti-HER2 therapy (except for Trast or Lap) in the neoadjuvant or adjuvant setting (first line)	Pac + Trast	mPFS (95% CI): 12.9 (11.1–14.8) mo	Higher incidence of grade 3 diarrhea with Ner vs Trast
		Pac + Ner	mPFS (95% CI): 12.9 (11.1–14.9) mo HR (95% CI) = 1.02 (0.81–1.27); P = 0.89
B1891003 (NCT00777101) [97]	HER2+ locally advanced or MBC; ≤2 prior Trast regimens and a taxane; no prior Cap; no prior Lap (second or later line)	Cap + Lap	mPFS: 6.8 mOS: 23.6 mo ORR: 41%	Acceptable overall tolerability of Ner
		Ner	mPFS: 4.5 mo HR (95% CI) = 1.19 (0.89–1.60); noninferiority margin, 1.15 mOS: 19.7 mo ORR: 29% P = 0.067a
NALA (NCT01808573)	HER2+ MBC; ≥2 prior HER2-directed regimens for metastatic disease (third or later line)	Cap + Lap
		Cap + Ner
LUX-Breast 1 (NCT01125566) [99]	HER2+ MBC; progression on 1 prior Trast treatment (adjuvant or metastatic regimens); prior anthracycline and/or taxane-based Cht (adjuvant or metastatic regimens); no prior Vin; no prior anti-HER2 therapy except Trast (second line)	Vin + Trast	mPFS (95% Cl): 5.6 (5.3–7.3) mo	Safety profile similar, though higher incidence of diarrhea
		Vin + Af	mPFS (95% CI): 5.5 (5.4–5.6) mo HR (95% CI) = 1.10 (0.86–1.41); P = 0.43
LUX-Breast 3 (NCT01441596) [98]	HER2+ BC with CNS recurrence/progression during or after prior Trast,	TPC	Patient benefit at 12 wk (95% CI):b 41.9% (27.0%–57.9%)	Af-containing treatments less well tolerated vs TPC
	Lap, or both; no prior HER2 TKI other than Lap (second or later line)
		Af	Patient benefit at 12 wk (95% CI):b 30% (16.6%–46.5%) Difference (95% CI), vs TPC: −11.9% (−32.9%–9.7%); P = 0.37
		Vin + Af	Patient benefit at 12 wk (95% CI):b 34.2% (19.6%–51.4%) Difference (95% CI), vs TPC: −7.6% (−28.9%–14.2%); P = 0.63
Anti-HER2 therapy + Ev
J2101 (NCT00426556) [103]	HER2+ advanced BC; progression during or within 3 mo of last Trast dose for advanced disease or recurrence within 12 mo of completing Trast-based neoadjuvant or adjuvant therapy; no prior Cht within 4 wk or prior Lap within 2 wk of study entry; no prior exposure to mTOR inhibitors (second or later line)	Pac + Trast + Ev	ORR (95% CI): 21.8% (11.8%–35.0%) mPFS (95% CI): 5.5 (4.99–7.69) mo mOS (95% CI): 18.1 (12.85–24.11) mo CBR (95% CI): 36.4% (23.8%–50.4%)	Most common grade 3/4 AEs (any causality; ≥5% of patients) were neutropenia, stomatitis, lymphopenia, leukopenia, anemia, thrombocytopenia, diarrhea, vomiting, fatigue, and pneumonia
BOLERO-3 (NCT01007942) [104]	HER2+ locally advanced or MBC; resistance to Trast; prior taxane therapy; no prior mTOR inhibitors or vinca alkaloid agents for treatment of cancer; ≤3 prior Cht lines for advanced disease (second or later line)	Vin + Trast + placebo	mPFS (95% CI): 5.78 (5.49–6.90) mo	Higher incidence of serious AEs with Ev vs placebo
		Vin + Trast + Ev	mPFS (95% CI): 7.00 (6.74–8.18) mo HR (95% CI) = 0.78 (0.65–0.95); P = 0.0067a
Trast + novel HER2-directed antibody-drug conjugate
HERMIONE (NCT02213744) [107]	HER2+ locally advanced or MBC; progression on, or intolerance to, Pert in advanced/metastatic setting, or recurrence within 12 mo of neoadjuvant or adjuvant Pert; progression on, or intolerance to, T-DM1 in advanced/metastatic setting; prior Trast ± Pert in any setting (second or later line)	ICC + Trast
		Trast + MM-302
Anti-HER2 therapy + immune-checkpoint inhibitors
NCT02605915	HER2+ MBC (not specified)	Trast + Pert + Atz T-DM1 + Atz
PANACEA (NCT02129556)	Inoperable locally advanced or MBC; progression on prior Trast, or recurrence on or within 12 mo of completing adjuvant Trast; ≥1 prior lines of anti-HER2 therapy; no prior anti-PD-1, anti-PD-L1, anti-PD-L2, or anti-CTLA4 therapy (second or later line)	Trast + MK-3475

AE, adverse event; Af, afatinib; Atz, atezolizumab; BC, breast cancer; Cap, capecitabine; CBR, clinical benefit rate; Cht, chemotherapy; CI, confidence interval; CNS, central nervous system; CTLA4, Cytotoxic T-lymphocyte–associated antigen 4; DLT, dose-limiting toxicity; Ev, everolimus; HER2, human epidermal growth factor receptor 2; HR, hazard ratio; ICC, investigator’s choice chemotherapy; Lap, lapatinib; MBC, metastatic breast cancer; mOS, median overall survival; mPFS, median progression-free survival; mTOR, mammalian target of rapamycin; NCT, National Clinical Trial; Ner, neratinib; ORR, overall response rate; Pac, paclitaxel; PR, partial response; Pert, pertuzumab; PD-1, programmed death 1; PD-L1, programmed death ligand 1; PD-L2, programmed death ligand 2; SD, stable disease; Trast, trastuzumab; T-DM1, ado-trastuzumab emtansine; TPC, treatment of physician’s choice; TKI, tyrosine kinase inhibitor; Vin, vinorelbine.

^aStatistically significant.

^bPatient benefit at 12 weeks was defined by “an absence of CNS or extra-CNS disease progression, no tumor-related worsening of neurological signs or symptoms, and no increase in corticosteroid dose” [98].

Activation of the phosphoinositide 3-kinase (PI3K) pathway may lead to trastuzumab resistance [100]. Thus, kinase inhibitors that specifically block the PI3K pathway are also being investigated. For example, everolimus inhibits mammalian target of rapamycin, a major downstream effector of the PI3K pathway, and may resensitize tumors to trastuzumab [100–102].

The addition of everolimus to standard treatments for patients with trastuzumab-resistant HER2+ advanced breast cancer produced promising results in preliminary trials [103,104]. However, it was also associated with poor safety outcomes and thus may not be the best approach due to increased toxicity [103,104]. Finally, other trials in HER2+ MBC are evaluating combinations of anti-HER2 therapy and novel TKIs or HER2-directed antibody-drug conjugates, or immune-checkpoint inhibitors (Table 6) [105–107].

4. Rationale for developing biosimilars of trastuzumab

As described, the treatment landscape for HER2+ breast cancer is evolving, but trastuzumab-based regimens and other HER2-targeting biologics are likely to remain a mainstay of treatment. Patients with HER2+ breast cancer should receive anti-HER2 therapy for as long as recommended because of its clinical benefits [59–61]. However, several studies demonstrate that not all patients with HER2+ breast cancer are treated with anti-HER2 therapy. For example, approximately 19%–32% of eligible patients in the United States and Canada and 29%–52% of those in the United Kingdom and the Netherlands do not receive neoadjuvant or adjuvant trastuzumab [9,44–46,48–53]. Similarly, nearly 12% of eligible patients in the United States and 27%–54% of those in France, Germany, Spain, Italy, the United Kingdom, and Sweden do not receive HER2-targeted therapy as first- or later-line treatment for metastatic disease [108–110].

In some cases, this reflects patient comorbidities (eg, cardiac risk factors) and treatment preference [44,46,49–52]. Age, socioeconomic, and racial disparities in trastuzumab use are also noted among women with HER2+ early breast cancer [111,112]. In the United States, approximately 50% of these patients aged 65 years and older do not receive neoadjuvant or adjuvant therapy with trastuzumab, particularly those with lower income [111–113]. Furthermore, black women are 25% less likely than white women to receive trastuzumab-based therapy within 1 year of diagnosis [111].

Physicians worldwide encounter various barriers to prescribing biologic agents [41–43] that also may contribute to underuse of anti-HER2 therapy. For example, an international physician survey showed that 94% of respondents from low-income and 63% from middle-income countries cited drug costs as a barrier to prescribing trastuzumab as adjuvant treatment for patients with HER2+ breast cancer [47]. In a survey of oncologists in the United States and emerging markets (Brazil, Mexico, Turkey, and Russia), 37%–49% of respondents who reported not frequently prescribing trastuzumab as treatment for HER2+ breast cancer cited lack of insurance coverage, and 37%–44% cited lack of drug availability, as common barriers to using trastuzumab across all clinical settings [43]. Lack of drug availability was more often cited by physicians in Russia versus those from other countries as a barrier to prescribing trastuzumab, particularly in the adjuvant and metastatic settings (65% of respondents) [43]. Many physicians also considered “high out-of-pocket treatment cost for patient” as a barrier to using trastuzumab in the neoadjuvant or adjuvant settings [43]. Furthermore, issues related to treatment costs, drug funding, and reimbursement led to canceled or delayed treatment with trastuzumab [43].

Disparities in the availability of and access to HER2-targeted agents have also been reported across Europe [42]. For example, while trastuzumab is widely available (on formulary) for breast cancer in all Western and most Eastern European countries, it is less often accessible (actual availability) to patients in Eastern versus Western Europe [42]. Compared with trastuzumab, pertuzumab, T-DM1, and lapatinib are less often on formulary [42]. Furthermore, in many countries where pertuzumab, T-DM1, and lapatinib are available, these agents are often not accessible, particularly in Eastern Europe [42]. Out-of-pocket treatment costs also vary, with patients in some Western and many Eastern European countries responsible for the full cost of treatment or >50% after reimbursement, particularly for pertuzumab, T-DM1, and lapatinib [42].

Patents for several biologic drugs, including trastuzumab, have recently expired or will soon expire, allowing for the development of biosimilar agents [54]. A biosimilar is a biologic product that is highly similar to the originator biologic product in terms of safety and effectiveness [55–57]. The availability of trastuzumab biosimilars may improve access to HER2-directed therapy by providing additional treatment options. Biosimilars also have the potential to provide cost savings, which may allow for expanded access to other biologic therapies and for the development of innovative drugs.

5. Overview of biosimilar development and the future of biosimilars in caring for patients with HER2+ breast cancer

Biologics, such as trastuzumab, are therapeutic proteins produced in living systems. These structurally complex molecules are ~100–1000-fold larger and more difficult to fully characterize than chemically synthesized small-molecule drugs [114,115]. Moreover, the biological processes through which these agents are produced are inherently variable and highly sensitive to manufacturing and environmental conditions [114]. Changes to any step of the production process may alter protein structure and, consequently, the biological activity, safety, and effectiveness of the product. For example, variations in cell growth conditions (eg, pH, availability of precursors and nutrients, etc.) can affect the extent of glycosylation, which may influence protein half-life or effector functions (eg, antibody-dependent cellular cytotoxicity) [115]. Proteins may also undergo oxidation or deamidation reactions that result in the formation of protein aggregates that exhibit little or no drug activity and can increase the potential for immunogenicity [115,116]. For these reasons, and because biosimilar manufacturers do not have access to the manufacturing processes of originator products, biologics cannot be exactly replicated. Thus, a biosimilar is not identical to its originator and the degree of similarity between a proposed biosimilar and reference product must be evaluated when seeking regulatory approval [55–57].

The European Medicines Agency (EMA), the US Food and Drug Administration, and the World Health Organization have issued guidelines for the development and approval of biosimilars [55–57]. To receive biosimilar approval, a proposed biosimilar must demonstrate biosimilarity to the originator product, which confirms that it is highly similar to and has no clinically meaningful differences from the originator product in terms of safety, purity, and potency [55–57]. A determination of biosimilarity is based on the totality of the data collected through a rigorous step-wise comparison of the two products in terms of their analytical, functional, and clinical profiles [55–57]. At each step, studies should be designed to detect potentially clinically relevant differences between the proposed biosimilar and originator products. The type and extent of testing will depend on the degree of residual uncertainty about biosimilarity based on evidence from preceding steps [55–57].

Analytical and functional similarity form the foundation of biosimilarity and provide the rationale for a selected and targeted approach to nonclinical in vivo and clinical testing [55–57]. Analytical assessments must demonstrate that the proposed biosimilar has the same primary amino acid sequence as the originator and that the two products are similar in terms of higher-order structures and other quality attributes (eg, posttranslational modifications) [55–57]. Functional assessments should demonstrate that the proposed biosimilar has biologic activity that is similar to and dependent on the same mechanism(s) of action as the originator [55–57]. Finally, comparative clinical studies should be conducted using appropriate and sensitive study populations and endpoints to demonstrate similarity between the proposed biosimilar and originator products in terms of their safety, immunogenicity, and efficacy profiles [55–57].

Several potential biosimilars of trastuzumab are in development and may soon become available (Table 7). For example, the proposed trastuzumab biosimilar ABP 980 demonstrated non-inferior efficacy and similar safety and immunogenicity profiles versus originator trastuzumab [117]. Preliminary results from a comparative safety and efficacy study in first-line patients with HER2+ MBC demonstrated equivalence in the primary endpoint of ORR of the proposed trastuzumab biosimilar PF-05280014 versus originator trastuzumab (both in combination with paclitaxel) [118]. A separate comparative PK trial of PF-05280014 versus originator trastuzumab in patients with HER2+ early breast cancer also met its primary endpoint of steady-state C_trough concentrations [118]. Published data from a trial comparing the proposed trastuzumab biosimilar Myl-1401O to originator trastuzumab (both in combination with paclitaxel) demonstrated equivalence in efficacy and comparable safety in first-line patients with HER2+ MBC [119]. An application for marketing authorization for Myl-1401O is under review by the EMA, and another was submitted to the US Food and Drug Administration [120,121]. A marketing application for the potential trastuzumab biosimilar SB3 is under evaluation by the EMA [122].

Table 7.

Proposed trastuzumab biosimilars in development with registered comparative clinical trials.

Biosimilar (manufacturer)	Patient population (setting)	Interventions	NCT no.
ABP 980 (Amgen)	HER2+ EBC (neoadjuvant)	Epi + Cy → ABP 980 + Pac Epi + Cy → Trastuzumab + Pac	NCT01901146
BCD-022 (Biocad)	HER2+ MBC (first line)	BCD-022 + Pac Trastuzumab-EU + Pac	NCT01764022
CT-P6 (Celltrion)	HER2+ EBC (neoadjuvant)	CT-P6 Trastuzumab	NCT02162667
	HER2+ MBC	CT-P6 + Pac Trastuzumab + Pac	NCT01084876
Hercules/Myl1401O (Mylan GmbH)	HER2+ MBC (first line)	Hercules + Taxane Trastuzumab + Taxane	NCT02472964
PF-05280014 (Pfizer)	HER2+ MBC (first line)	PF-05280014 + Pac Trastuzumab-EU + Pac	NCT01989676
	HER2+ EBC (neoadjuvant)	PF-05280014 + Doc + Carb Trastuzumab-EU + Doc + Carb	NCT02187744
SB3-G31-BC (Samsung Bioepis)	HER2+ BC (neoadjuvant)	SB3 Trastuzumab	NCT02149524

BC, breast cancer; Carb, carboplatin; Cy, cyclophosphamide; Doc, docetaxel; EBC, early breast cancer; Epi, epirubicin; HER2, human epidermal growth factor receptor 2; MBC, metastatic breast cancer; NCT, National Clinical Trial; Pac, paclitaxel; Trastuzumab-EU, trastuzumab sourced from the European Union.

An approved biosimilar of trastuzumab is expected to have the same clinical efficacy and safety as the originator. Thus, all patients who are eligible for trastuzumab treatment are potential candidates for using a biosimilar. The introduction of trastuzumab biosimilars and biosimilars of other HER2-targeted biologics, like pertuzumab or T-DM1, may improve access to anti-HER2 therapies by providing additional options.

Biosimilars may also offer a lower-cost alternative and therefore have the potential to provide savings for healthcare systems, especially in countries where trastuzumab and other cancer drugs are less affordable [123,124]. Since HER2-targeted drugs may be administered for extended periods of time and, in many cases, treatment guidelines indicate the optimal duration of treatment is unknown [59,60], this is particularly relevant for patients with HER2+ MBC continuing to receive trastuzumab after disease progression. Additionally, current and emerging treatment strategies are focused on dual HER2 blockade (eg, trastuzumab plus pertuzumab) and administering HER2-directed agents in combination with other therapies. Thus, availability of biosimilars to any or all of these drugs is relevant in all clinical settings.

6. Conclusions

While new therapeutic options are emerging for patients with HER2+ breast cancer, HER2-targeting biologic therapies, particularly trastuzumab, are likely to remain a mainstay of treatment. Patients with HER2+ breast cancer derive significant clinical benefit from anti-HER2 therapy; thus, all eligible patients should be treated with HER2-directed therapy and continue treatment for as long as recommended. Unfortunately, not all patients with HER2+ breast cancer receive anti-HER2 therapy. Trastuzumab biosimilars are in development and may soon become available. These agents could improve patient access to anti-HER2 therapies worldwide. In addition, they may generate savings for healthcare systems, particularly because HER2-targeted drugs may be administered for extended periods of time and in combination with other systemic therapies. The availability of safe and effective biosimilars may address the unmet needs of patients and physicians.