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HER2-positive advanced breast cancer treatment in 2020

      Highlights

      • Treatment of HER2-positive breast cancer has remained largely unchanged since 2012.
      • Several pivotal studies have been presented in 2019 which should change this situation.
      • Integrating these large datasets and 2 new approved regimens is a challenge to experts.
      • Lack of clinically validated biomarkers remains a big problem.

      Abstract

      HER2-positive breast cancer is an aggressive subtype identified in the 1980s. The development of therapies targeting the HER2 has improved outcomes. The current standard of care, established in 2012 is dual blockade with trastuzumab + pertuzumab as first-line followed by TDM-1 as second-line. Several suboptimal choices are available in third-line or more. In 2019 the presentation of several trials evaluating new drugs and regimens in third-line has re-opened questions about sequencing, treatment of triple positive disease and treatment choice after exposure to TDM-1. These include tucatinib, neratinib and trastuzumab-deruxtecan. Other agents – including other antibody drug conjugates and bispecific antibodies as well as combinations - will lead to further changes in coming years. Additionally, should the numerous putative biomarkers thus identified ever come into use at the clinic, choice of treatment and response evaluation may be substantially changed.

      Keywords

      Introduction

      Approximately 15–20% of breast cancers are human epidermal growth factor receptor-positive (HER2-positive), which is associated with worse survival outcomes as compared to estrogen receptor (ER) positive, HER2-negative breast cancer. Over the last 30 years, the development of a number of anti-HER2 agents improved outcomes in both early and advanced HER2-positive breast cancer [
      • Loibl S.
      • Gianni L.
      HER2-positive breast cancer.
      ]. Despite continuous efforts to develop innovative approaches and to improve patient care, management guidelines have nevertheless remained largely unchanged since 2012. Since 2019, however, a large number of trials were presented and 3 new drugs were approved, changing this situation.
      This narrative review is focused on presenting current aspects of advanced HER2-positive breast cancer management, including current practices, new treatment options, and open research questions, with a particular focus on how to integrate trastuzumab-deruxtecan, tucatinib and neratinib into current guidelines based on the available evidence [
      • Pondé N.
      • Brandão M.
      • El-Hachem G.
      • Werbrouck E.
      • Piccart M.
      Treatment of advanced HER2-positive breast cancer: 2018 and beyond.
      ].

      Current management of HER2-positive advanced breast cancer

      Decision-making in HER2-positive advanced breast cancer depends essentially on 2 factors: (1) whether the patient has received trastuzumab previously; (2) time elapsed since the last dose of trastuzumab. This is a consequence of the inclusion criteria used in the CLEOPATRA and EMILIA trials [
      • Giordano S.H.
      • Temin S.
      • Kirshner J.J.
      • et al.
      Systemic therapy for patients with advanced human epidermal growth factor receptor 2–positive breast cancer: American society of clinical oncology clinical practice guideline.
      ,
      • Giordano S.H.
      • Temin S.
      • Chandarlapaty S.
      • et al.
      Systemic therapy for patients with advanced human epidermal growth factor receptor 2–positive breast cancer: ASCO clinical practice guideline update.
      ,
      • Baselga J.
      • Cortés J.
      • Kim S.-B.
      • et al.
      Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer.
      ,
      • Verma S.
      • Miles D.
      • Gianni L.
      • et al.
      Trastuzumab emtansine for HER2-positive advanced breast cancer.
      ]. It is important to highlight, however, that currently many patients diagnosed with advanced disease have been previously exposed to dual anti-HER2 blockade in the early settings based on data from the NeoSphere and APHINITY studies, among others [
      • Cardoso F.
      • Kyriakides S.
      • Ohno S.
      • et al.
      Early breast cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.
      ,
      • Gianni L.
      • Pienkowski T.
      • Im Y.-H.
      • et al.
      Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere): a randomised multicentre, open-label, phase 2 trial.
      ,
      • von Minckwitz G.
      • Procter M.
      • de Azambuja E.
      • et al.
      Adjuvant pertuzumab and trastuzumab in early HER2-positive breast cancer.
      ]. Additionally, following KATHERINE study results, many patients receive T-DM1 in the early setting, further complicating decision-making. Table 1 summarizes the main findings of all pivotal trials for approved anti-HER2 agents in the advanced setting.
      Table 1Clinical practice determinant trials in advanced/metastatic HER2+ disease.
      PhaseComparisonScenarioResults
      PFSOSRR
      CLEOPATRA
      • Baselga J.
      • Cortés J.
      • Kim S.-B.
      • et al.
      Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer.
      ,
      • Swain S.M.
      • Baselga J.
      • Kim S.-B.
      • et al.
      Pertuzumab, trastuzumab, and docetaxel in HER2-positive metastatic breast cancer.
      ,

      Swain SM, Miles D, Kim S-B, et al. End-of-study analysis from the phase III, randomized, double-blind, placebo (Pla)-controlled CLEOPATRA study of first-line (1L) pertuzumab (P), trastuzumab (H), and docetaxel (D) in patients (pts) with HER2-positive metastatic breast cancer (MBC). J Clin Oncol 2019;37(15_suppl):1020–1020.

      IIIDocetaxel + H + Pert

      Docetaxel + H + Pla
      1st line18.7 m vs 12.4 m

      HR 0.68

      (95%CI 0.58–0.80)
      57.1 m vs 40.8 m

      HR 0.69

      (95%CI 0.58–0.82)
      80.2%

      vs 69.3%
      EMILIA
      • Verma S.
      • Miles D.
      • Gianni L.
      • et al.
      Trastuzumab emtansine for HER2-positive advanced breast cancer.
      ,
      • Diéras V.
      • Miles D.
      • Verma S.
      • et al.
      Trastuzumab emtansine versus capecitabine plus lapatinib in patients with previously treated HER2-positive advanced breast cancer (EMILIA): a descriptive analysis of final overall survival results from a randomised, open-label, phase 3 trial.
      IIITDM-1

      Cap + lapatinib
      2nd line

      (100% previous H + taxane; no previous Pert)
      9.6 m vs 6.4 m

      HR 0.65

      (95%CI 0.55–0.77)
      29.9 m vs 25.9 m

      HR 0.75

      (95%CI 0.64–0.88)
      46.3%

      vs

      30.8%
      DESTINY-Breast01
      • Modi Shanu
      • Saura Cristina
      • Yamashita Toshinari
      • et al.
      DESTINY-Breast01 Investigators. Trastuzumab Deruxtecan in Previously Treated HER2-Positive Breast Cancer.
      IISingle arm: Trastuzumab deruxtecan>2nd line

      (100% previous TDM-1; 65.8% previous Pert)
      16.4 mMedian OS: NR

      6 m-OS: 93.9%

      12 m-OS: 86.2%
      60.9%
      HER2CLIMB
      • Murthy R.K.
      • Loi S.
      • Okines A.
      • et al.
      Tucatinib, trastuzumab, and capecitabine for HER2-positive metastatic breast cancer.
      IIITucatinib + H + Cap

      Pla + H + Cap
      >2nd line

      (100% previous TDM-1 and H + Pert)
      7.8 m vs 5.6 m

      HR 0.54

      (95%CI 0.42–0.71)
      21.9 m vs 17.4 m

      HR 0.66

      (95%CI 0.50–0.88)
      40.6%

      vs

      22.8%
      NALA

      Saura C, Oliveira M, Feng Y-H, et al. Neratinib + capecitabine versus lapatinib + capecitabine in patients with HER2+ metastatic breast cancer previously treated with ≥2 HER2-directed regimens: Findings from the multinational, randomized, phase III NALA trial. J Clin Oncol 2019;37(15_suppl):1002–1002.

      IIINeratinib + Cap

      Lapatinib + Cap
      >2nd line

      (75% previous TDM-1; 42.5% previous H + Pert)
      5.6 m vs 5.6 m

      HR 0.76

      (95%CI 0.63–0.93)
      21 m vs 18.7 m

      HR 0.88

      (95%CI 0.72–1.07)
      32.8%

      vs

      26.7%
      SOPHIA

      Rugo HS, Im S-A, Wright GLS, et al. SOPHIA primary analysis: A phase 3 (P3) study of margetuximab (M) + chemotherapy (C) versus trastuzumab (T) + C in patients (pts) with HER2+ metastatic (met) breast cancer (MBC) after prior anti-HER2 therapies (Tx). J Clin Oncol 2019;37(15_suppl):1000–1000.

      ,

      Hope H. SOPHIA: Second interim OS analysis of margetuximab + CT vs trastuzumab + CT for HER2+ MBC after previous HER2 therapy.

      IIIMargetuximab + chemo

      H + chemo
      ≥ 2nd line

      (90% previous TDM-1;

      100% previous H + Pert)
      5.8 m vs 4.9 m

      HR 0.76

      (95%CI 0.59–0.98)
      21.6 m vs 19.2 m

      HR 0.89

      (95%CI 0.69–1.13)
      25.2%

      vs

      13.7%
      TH3RESA
      • Krop I.E.
      • Kim S.-B.
      • González-Martín A.
      • et al.
      Trastuzumab emtansine versus treatment of physician’s choice for pretreated HER2-positive advanced breast cancer (TH3RESA): a randomised, open-label, phase 3 trial.
      ,
      • Krop I.E.
      • Kim S.-B.
      • Martin A.G.
      • et al.
      Trastuzumab emtansine versus treatment of physician’s choice in patients with previously treated HER2-positive metastatic breast cancer (TH3RESA): final overall survival results from a randomised open-label phase 3 trial.
      IIITDM-1

      Physician’s choice
      >2nd line

      (100% previous H and lapatinib; no previous Pert)
      6.2 m vs 3.3 m

      HR 0.53

      (95%CI 0.42–0.66)
      22.7 m vs 15.8 m

      HR 0.68

      (95%CI 0.54–0.85)
      31%

      vs

      9%
      EFG100151
      • Cameron D.
      • Casey M.
      • Oliva C.
      • Newstat B.
      • Imwalle B.
      • Geyer C.E.
      Lapatinib plus capecitabine in women with HER-2-positive advanced breast cancer: final survival analysis of a phase III randomized trial.
      ,
      • Geyer C.E.
      • Forster J.
      • Lindquist D.
      • et al.
      Lapatinib plus capecitabine for HER2-positive advanced breast cancer.
      IIICap + lapatinib

      Cap
      ≥ 2nd line

      (97% previous H, taxane,

      and antracicline;

      no previous TDM-1 or Pert)
      6.2 m vs 4.3 m

      HR 0.57

      (95%CI 0.43–0.77)
      18.7 m vs 16.2 m

      HR 0.87

      (95%CI 0.70–1.08)
      24%

      vs

      14%
      EGF104900
      • Blackwell K.L.
      • Burstein H.J.
      • Storniolo A.M.
      • et al.
      Randomized study of lapatinib alone or in combination with trastuzumab in women with ErbB2-positive, trastuzumab-refractory metastatic breast cancer.
      ,
      • Blackwell K.L.
      • Burstein H.J.
      • Storniolo A.M.
      • et al.
      Overall survival benefit with lapatinib in combination with trastuzumab for patients with human epidermal growth factor receptor 2–positive metastatic breast cancer: final results from the EGF104900 study.
      IIILapatinib + H

      Lapatinib
      ≥ 2nd line

      (100% previous H;

      no previous TDM-1 or Pert)
      2.8 m vs 2.0 m

      HR 0.74

      (95%CI 0.58–0.94)
      14 m vs 9.5 m

      HR 0.74

      (95%CI 0.57–0.97)
      10.3%

      vs

      6.9%
      PFS: median progression-free survival; OS: median overall survival; RR: objective response rate; H: trastuzumab; Pert: pertuzumab; Pla: placebo;
      m: months; Cap: capecitabine; TDM-1: trastuzumab-emtansine; chemo: chemotherapy.
      Briefly, “de novo” metastatic patients or those who develop metastatic disease after 6 months since the last dose of trastuzumab are candidates for first-line treatment with a taxane, trastuzumab and pertuzumab [
      • Baselga J.
      • Cortés J.
      • Kim S.-B.
      • et al.
      Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer.
      ,
      • Swain S.M.
      • Baselga J.
      • Kim S.-B.
      • et al.
      Pertuzumab, trastuzumab, and docetaxel in HER2-positive metastatic breast cancer.
      ,

      Swain SM, Miles D, Kim S-B, et al. End-of-study analysis from the phase III, randomized, double-blind, placebo (Pla)-controlled CLEOPATRA study of first-line (1L) pertuzumab (P), trastuzumab (H), and docetaxel (D) in patients (pts) with HER2-positive metastatic breast cancer (MBC). J Clin Oncol 2019;37(15_suppl):1020–1020.

      ]. The results of the PERUSE clinical trial suggest that paclitaxel is no less effective than docetaxel, and that it may be less toxic. This has led geriatric oncologists to suggest that paclitaxel should be favored in older patients [

      Brain E, Caillet P, de Glas N, et al. HER2-targeted treatment for older patients with breast cancer: An expert position paper from the International Society of Geriatric Oncology. J Geriatr Oncol 2019;S187940681830479X.

      ,
      • Bachelot T.
      • Ciruelos E.
      • Schneeweiss A.
      • et al.
      Preliminary safety and efficacy of first-line pertuzumab combined with trastuzumab and taxane therapy for HER2-positive locally recurrent or metastatic breast cancer (PERUSE).
      ]. Patients who have progressed while on (neo)adjuvant trastuzumab or less than 6 months after its use or, alternatively, who progressed after receiving first-line with the CLEOPATRA regimen, should receive TDM-1 [
      • Verma S.
      • Miles D.
      • Gianni L.
      • et al.
      Trastuzumab emtansine for HER2-positive advanced breast cancer.
      ,
      • Diéras V.
      • Miles D.
      • Verma S.
      • et al.
      Trastuzumab emtansine versus capecitabine plus lapatinib in patients with previously treated HER2-positive advanced breast cancer (EMILIA): a descriptive analysis of final overall survival results from a randomised, open-label, phase 3 trial.
      ]. Patients who did not receive TDM-1 previously can receive it on subsequent lines [
      • Krop I.E.
      • Kim S.-B.
      • González-Martín A.
      • et al.
      Trastuzumab emtansine versus treatment of physician’s choice for pretreated HER2-positive advanced breast cancer (TH3RESA): a randomised, open-label, phase 3 trial.
      ,
      • Krop I.E.
      • Kim S.-B.
      • Martin A.G.
      • et al.
      Trastuzumab emtansine versus treatment of physician’s choice in patients with previously treated HER2-positive metastatic breast cancer (TH3RESA): final overall survival results from a randomised open-label phase 3 trial.
      ]. Following the use of TDM-1, trastuzumab-based combinations with other cytotoxic agents or with lapatinib are common options, though sequencing and expected benefit remain unclear as these regimens were developed before the use of pertuzumab and T-DM1 [
      • Blackwell K.L.
      • Burstein H.J.
      • Storniolo A.M.
      • et al.
      Randomized study of lapatinib alone or in combination with trastuzumab in women with ErbB2-positive, trastuzumab-refractory metastatic breast cancer.
      ,
      • Blackwell K.L.
      • Burstein H.J.
      • Storniolo A.M.
      • et al.
      Overall survival benefit with lapatinib in combination with trastuzumab for patients with human epidermal growth factor receptor 2–positive metastatic breast cancer: final results from the EGF104900 study.
      ,
      • Cameron D.
      • Casey M.
      • Oliva C.
      • Newstat B.
      • Imwalle B.
      • Geyer C.E.
      Lapatinib plus capecitabine in women with HER-2-positive advanced breast cancer: final survival analysis of a phase III randomized trial.
      ,
      • Geyer C.E.
      • Forster J.
      • Lindquist D.
      • et al.
      Lapatinib plus capecitabine for HER2-positive advanced breast cancer.
      ,
      • Giordano S.H.
      • Temin S.
      • Chandarlapaty S.
      • et al.
      Systemic therapy for patients with advanced human epidermal growth factor receptor 2-positive breast cancer: ASCO clinical practice guideline update.
      ,
      • Cardoso F.
      • Senkus E.
      • Costa A.
      • et al.
      4th ESO-ESMO international consensus guidelines for advanced breast cancer (ABC 4).
      ].

      Open research questions in 2020

      • What should be the third-line and beyond approach for advanced HER2-positive breast cancer?
      There is no current recognized single standard third-line therapy option for HER2-positive advanced breast cancer [
      • Giordano S.H.
      • Temin S.
      • Chandarlapaty S.
      • et al.
      Systemic therapy for patients with advanced human epidermal growth factor receptor 2-positive breast cancer: ASCO clinical practice guideline update.
      ,
      • Cardoso F.
      • Senkus E.
      • Costa A.
      • et al.
      4th ESO-ESMO international consensus guidelines for advanced breast cancer (ABC 4).
      ]. Common options include trastuzumab + chemotherapy, trastuzumab + lapatinib and lapatinib + capecitabine. The combination of lapatinib + trastuzumab was compared with lapatinib alone in patients who had received a median of 3 previous trastuzumab-based lines. Results suggest a significant benefit with the combination in terms of progression-free survival (PFS) – 12 weeks vs 8.1 weeks, HR 0.73, 95% CI 0.57 to 0.93, p = 0.08. Overall survival (OS) was likewise improved – 14 vs 9.5 months, HR, 0.74; 95% CI, 0.57–0.97; p = 0.026 [
      • Blackwell K.L.
      • Burstein H.J.
      • Storniolo A.M.
      • et al.
      Randomized study of lapatinib alone or in combination with trastuzumab in women with ErbB2-positive, trastuzumab-refractory metastatic breast cancer.
      ,
      • Blackwell K.L.
      • Burstein H.J.
      • Storniolo A.M.
      • et al.
      Overall survival benefit with lapatinib in combination with trastuzumab for patients with human epidermal growth factor receptor 2–positive metastatic breast cancer: final results from the EGF104900 study.
      ]. The lapatinib + capecitabine combination proved superior to capecitabine alone (PFS 8.4 months vs 4.4 months, HR 0.49, 95% CI 0.34–0.71, p < 0.001), with OS not being adequately evaluable due to crossover [
      • Cameron D.
      • Casey M.
      • Oliva C.
      • Newstat B.
      • Imwalle B.
      • Geyer C.E.
      Lapatinib plus capecitabine in women with HER-2-positive advanced breast cancer: final survival analysis of a phase III randomized trial.
      ,
      • Geyer C.E.
      • Forster J.
      • Lindquist D.
      • et al.
      Lapatinib plus capecitabine for HER2-positive advanced breast cancer.
      ].

      Trastuzumab-deruxtecan

      Trastuzumab-deruxtecan (also known as DS-8201) is an antibody-drug conjugate that is composed of a humanized antibody targeting HER2 and a topoisomerase I inhibitor payload connected via a tetrapeptide-based cleavable linker. DESTINY-Breast01 was a single arm phase II trial, which tested the ideal dosage of this drug as well as its efficacy and safety. DS-8201 showed a response rate of 60.9% in heavily pre-treated HER2-positive population (with a median of 6 previous lines for metastatic disease) and a median PFS of 16.4 months. 86.2% of treated patients were alive at 12 months. It is important to highlight the occurrence of interstitial lung disease (ILD) in 13.6% of patients. Additionally, 2.2% of patients died due to treatment, 35.3% of patients required a delay in dosing, 23.4% a dose reduction and 15.2% discontinued treatment due to adverse events [
      • Modi Shanu
      • Saura Cristina
      • Yamashita Toshinari
      • et al.
      DESTINY-Breast01 Investigators. Trastuzumab Deruxtecan in Previously Treated HER2-Positive Breast Cancer.
      ]. These results led to federal drug administration (FDA) approval of trastuzumab-deruxtecan in patients who received 2 or more lines of anti-HER2 therapy for advanced HER2-positive breast cancer. The phase III DESTINY-Breast02 confirmatory trial comparing trastuzumab-deruxtecan with capecitabine plus trastuzumab or lapatinib is ongoing (NCT03523585) .
      ILD is the most clinically relevant emerging toxicity of trastuzumab-deruxtecan, as shown in an analysis of 7 trials with a total of 665 patients exposed to trastuzumab-deruxtecan. Sixty-six cases were reported (9.9%), with 13 being grade 3 or higher and 5 leading to death [

      Atkinson C. Characterization, monitoring and management of interstitial lung disease in patients with metastatic breast cancer: Analysis of data available from multiple studies of DS-8201a, a HER2-targeted antibody drug conjugate with a topoisomerase I inhibitor payload.

      ]. Other adverse events are also relevant when using trastuzumab-deruxtecan, including neutropenia, nausea and anaemia. It is important to note that, as with other agents which proved to have unexpected toxicities (such as trastuzumab with cardiac toxicity), rates and severity could diminish over time as patient selection and management improves.
      Additional trials with DS-8201 include: (1) DESTINY-Breast03 which is comparing DS-8201 with TDM-1 in second-line (NCT03529110); (2) DESTINY-Breast04 which is testing DS-8201 in HER-low patients. Some lovel activity of trastuzumab-deruxtecan in HER2-low expressing tumors (2+ or 1+ and/or in situ hybridization negative), with a 44.2% response rate, was suggested in a phase I trial [
      • Tamura K.
      • Tsurutani J.
      • Takahashi S.
      • et al.
      Trastuzumab deruxtecan (DS-8201a) in patients with advanced HER2-positive breast cancer previously treated with trastuzumab emtansine: a dose-expansion, phase 1 study.
      ]. DESTINY-Breast04 is a phase III study comparing DS-8201 with physician’s choice chemotherapy (capecitabine, eribulin, paclitaxel, nab-paclitaxel, gemcitabine) for HER2-low patients (NCT03734029). Should this study show an improvement in outcomes, treatment guidelines for tumours heretofore ideintified as luminal or triple negative will need to be adapted. Much remains to be done, however, to better understand HER2-low disease [
      • Tarantino P.
      • Hamilton E.
      • Tolaney S.M.
      • et al.
      HER2-low breast cancer: pathological and clinical landscape.
      ]. It is also important to note that 2 phase 1 studies are exploring combinations of trastuzumab-deruxtecan with immunotherapy – durvalumab in NCT03523572 and pembrolizumab in NCT04042701.

      Tucatinib

      Tucatinib is an irreversible panHER tyrosine kinase inhibitor (TKI). Tucatinib in combination with trastuzumab and capecitabine improved median PFS (7.8 m vs 5.6 m; 33.1% vs 12.3% had not progressed at 1 year, HR 0.54, 95% CI, 0.42–0.71, p < 0.001) and median OS (21.9 m vs 17.4 m, 44.9% vs 26.6% alive at 2 years, HR 0.66; 95% CI, 0.50 to 0.88; P = 0.005) in comparison with trastuzumab, capecitabine and placebo in the phase III HER2CLIMB trial [
      • Murthy R.K.
      • Loi S.
      • Okines A.
      • et al.
      Tucatinib, trastuzumab, and capecitabine for HER2-positive metastatic breast cancer.
      ]. The triplet regimen reached a response rate of 40.6% in a population exposed to a median of three previous lines of treatment. The main toxicities observed were gastrointestinal (diarrhea), oral mucositis and hand-foot syndrome. Grade 3 or more events (55.2% vs 48.7%) and transaminases elevation were more frequent in the tucatinib arm. Tucatinib was discontinued more often than placebo (5.7% vs 3%) and capecitabine was discontinued more often in the tucatinib arm (9.8% vs 9.1%). Based on these results, FDA approval was granted in April 2020 for patients who received one or more previous lines of anti-HER2 therapy, including patients with brain metastasis. It is striking to note that the drug was approved for second-line though HER2CLIMB was conducted in thirdline.

      Neratinib

      Neratinib + capecitabine improved PFS (5.6 m vs 5.5 m; HR 0.76, 95%CI 0.63–0.93) in comparison with lapatinib plus capecitabine in NALA trial. In a landmark analysis showed, PFS curves began to separate with 6-month PFS rates of 47% versus 38% and 1-year rates of 29% versus 15%. The coprimary endpoint of OS was not met (21 m vs 18.7 m; HR 0.88, 95%CI 0.72–1.07). There was 24% grade 3–4 diarrhea despite of mandatory loperamide use in the neratinib arm (vs 13% in the lapatinib arm). Overall, treatment discontinuation was more common in the lapatinib arm (14.5% vs 10.9%) [

      Saura C, Oliveira M, Feng Y-H, et al. Neratinib + capecitabine versus lapatinib + capecitabine in patients with HER2+ metastatic breast cancer previously treated with ≥2 HER2-directed regimens: Findings from the multinational, randomized, phase III NALA trial. J Clin Oncol 2019;37(15_suppl):1002–1002.

      ]. It is noticeable however, that this worse tolerability of lapatinib could be due either to the lack of prophylactic loperamide or the higher dose of capecitabine use in the lapatinib arm. The FDA granted approval for the neratinib and capecitabine combination in March 2020 for patients previously exposed to at least 2 previous lines of anti-HER2 therapy.

      Margetuximab

      Margetuximab is an anti-HER2 antibody, with a Fc engineered domain designed for greater affinity to CD16A and reduced affinity to CD32B. The intended result is enhanced antibody dependent cellular cytotoxicity (ADCC) and thus superior anti-tumour effect as compared to trastuzumab. It is important to note that different alleles of CD16A impact on binding affinity, with the 158F allele determining reduced affinity and thus a weaker immune response under trastuzumab. In the SOPHIA trial, margetuximab associated with chemotherapy versus trastuzumab and chemotherapy in a population previously treated with standard first and second-lines, demonstrated a PFS improvement (5.8 m vs 4.9 m; HR 0.76, 95%CI 0.59–0.98), but no OS gain (21.6 m vs 19.2 m; HR 0.89, 95%CI 0.69–1.13). In a pre-specified subgroup analysis targeting patients with the CD16A 158F allele (86% of the sample), OS was 23.7 months in the margetuximab arm versus 19.4 months in the control arm (HR, 0.79; 95% CI, 0.61–1.04; p = 0.087). Margetuximab had more infusion-related reactions than trastuzumab (13.3% vs 3.4%), but only 1.5% were grade 3 or more [

      Rugo HS, Im S-A, Wright GLS, et al. SOPHIA primary analysis: A phase 3 (P3) study of margetuximab (M) + chemotherapy (C) versus trastuzumab (T) + C in patients (pts) with HER2+ metastatic (met) breast cancer (MBC) after prior anti-HER2 therapies (Tx). J Clin Oncol 2019;37(15_suppl):1000–1000.

      ,

      Hope H. SOPHIA: Second interim OS analysis of margetuximab + CT vs trastuzumab + CT for HER2+ MBC after previous HER2 therapy.

      ]. FDA approval is pending.
      In summary, there are 3 approved novel options for third-line therapy, all showing improvements in efficacy outcomes with different adverse event profiles and, critically, different control arms and populations, though it is important to keep in mind that the combination of trastuzumab, capecitabine and tucatinib is, at the moment, the only one to demonstrate an OS improvement in a population fully exposed to prior pertuzumab and TDM-1. In this respect, NALA results are the weakest with a high proportion of patients who did not receive pertuzumab and TDM-1 (Table 1).
      Currently, therefore, available data does not allow definitive recommendations of one drug/regimen over another. When choosing third-line therapy, several questions should be considered: (1) treatment burden – with tucatinib and neratinib necessitating a large number of daily pills, (2) toxicity – risk of ILD vs impact of diarrhea and hand-foot syndrome on health and Quality of life (QoL), (3) brain disease, and the possibility of local therapy with surgery or radiotherapy.
      It is the opinion of the authors of this manuscript that for most patients, trastuzumab-deruxtecan will be the treatment of choice in third-line, with tucatinib being used for patients with pre-existing lung illness or brain disease not amenable to local therapy in third-line or in fourth-line after trastuzumab-deruxtecan. The results of DESTINY-breast02 will shed further light on the issue. The issue of second-line tucatinib is more difficult – but it is reasonable to consider it an option over TDM-1 in patients in which brain disease is the most important clinical issue. It is important to stress however that no data on a head to head comparison between tucatinib and TDM-1 is available as well as no data on TDM-1 efficacy post-tucatinib exposure.
      • How should be managed patients progressing after receiving the KATHERINE regimen?
      No data is available today on how to proceed. It is reasonable to suggest that patients progressing during or early (within 12 months being an adequate yet empirical cut-off) after TDM-1 should probably be treated as third-line or treated with trastuzumab + pertuzumab (if they have not been exposed to pertuzumab in the early setting). Patients who progress later than 12 months remain an entirely open research question, with re-challenge, dual blockade or moving to further lines being entirely acceptable choices. In fact, there is no data supporting the lack of efficiency of trastuzumab-pertuzumab combinations after TDM-1.
      • How to choose systemic therapy in HER2-positive advanced breast cancer with brain metastasis?
      The incidence of brain metastasis is clinically significant in advanced HER2-positive breast cancer with approximately 50% of patients developing brain metastasis [
      • Maurer C.
      • Tulpin L.
      • Moreau M.
      • et al.
      Risk factors for the development of brain metastases in patients with HER2-positive breast cancer.
      ,

      Sachar Strulov. Publication Number: P1-12-08 Title: The incidence and outcomes of brain metastases in HER2-positive metastatic breast cancer with the advent of modern anti-HER2 therapies Strulov Shachar S, Deal AM M, Vaz-Luis I, Dees EC Claire, Carey LA A, Hassett MJ J, Garrett AL L, Benbow JM M, Hughes ME E, Mounsey L, Lin N and Anders CK K. Lineberger Comprehensive Cancer Center, Chapel Hill, NC; Rambam Health Care Campus, Haifa, Israel and Dana-Farber Cancer Institute, Boston, MA.

      ]. Median survival after brain metastasis is 25–27 months [

      Sperduto PW, Mesko S, Cagney D, et al. Tumor subtype and other prognostic factors in breast cancer patients with brain metastases: The updated graded prognostic assessment (Breast-GPA). J Clin Oncol 2019;37(15_suppl):1079–1079.

      ]. Local treatment with surgery and radiotherapy is the standard of care. Progressive CNS disease with controlled systemic disease is also a frequent scenario [
      • Kabraji S.
      • Ni J.
      • Lin N.U.
      • Xie S.
      • Winer E.P.
      • Zhao J.J.
      Drug resistance in HER2-positive breast cancer brain metastases: blame the barrier or the brain?.
      ], and though little data is available, these patients receive local treatment and continue the same systemic regimen, whenever possible. It is important to note that pivotal studies such as DESTINY-breast02 do not discriminate between CNS and non-CNS progression and that therefore data coming from such studies will not help elucidate this clinically relevant question.
      Though monoclonal antibodies, such as trastuzumab or TDM-1 have shown to have some activity in the CNS, TKIs are likely to have a superioir effect as they have a larger potential to penetrate the blood–brain barrier than antibodies and have demonstrated activity against CNS metastasis in a number of studies [
      • Duchnowska R.
      • Loibl S.
      • Jassem J.
      Tyrosine kinase inhibitors for brain metastases in HER2-positive breast cancer.
      ,

      Terrell-Hall TB, Nounou MI, El-Amrawy F, Griffith JIG, Lockman PR. Trastuzumab distribution in an in-vivo and in-vitro model of brain metastases of breast cancer. Oncotarget [Internet] 2017 [cited 2020 Mar 3];8(48). Available from: http://www.oncotarget.com/fulltext/19634.

      ,
      • Bartsch R.
      • Berghoff A.S.
      • Vogl U.
      • et al.
      Activity of T-DM1 in Her2-positive breast cancer brain metastases.
      ,
      • Fabi A.
      • Alesini D.
      • Valle E.
      • et al.
      T-DM1 and brain metastases: clinical outcome in HER2-positive metastatic breast cancer.
      ,
      • Jacot W.
      • Pons E.
      • Frenel J.-S.
      • et al.
      Efficacy and safety of trastuzumab emtansine (T-DM1) in patients with HER2-positive breast cancer with brain metastases.
      ,
      • Bachelot T.
      • Romieu G.
      • Campone M.
      • et al.
      Lapatinib plus capecitabine in patients with previously untreated brain metastases from HER2-positive metastatic breast cancer (LANDSCAPE): a single-group phase 2 study.
      ]. It is important to note, however, that lapatinib failed to prevent CNS relapses in CEREBEL [
      • Pivot X.
      • Manikhas A.
      • Żurawski B.
      • et al.
      CEREBEL (EGF111438): a phase III, randomized, open-label study of lapatinib plus capecitabine versus trastuzumab plus capecitabine in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer.
      ].
      HER2CLIMB included 45%-46% of patients with untreated brain metastasis. PFS in trastuzumab, capecitabine and tucatinib arm was superior to placebo for the subgroup with CNS disease (7.6 m vs 5.4 m; HR 0.48, 95%CI 0.34–0.69 and 1-year PFS 24.9% vs 0%). Furthermore, in the tucatinib arm, 40.6% of patients experienced an objective response in the brain, vs 22.8% in the placebo arm (p < 0.001). These data match the previous 6.7 m PFS and 42% objective response for brain metastases with this triplet seen in a phase Ib trial [
      • Murthy R.K.
      • Loi S.
      • Okines A.
      • et al.
      Tucatinib, trastuzumab, and capecitabine for HER2-positive metastatic breast cancer.
      ,
      • Murthy R.
      • Borges V.F.
      • Conlin A.
      • et al.
      Tucatinib with capecitabine and trastuzumab in advanced HER2-positive metastatic breast cancer with and without brain metastases: a non-randomised, open-label, phase 1b study.
      ]. An analysis focused on the subpopulation of patients with brain metastasis has further clarified the potential of tucatinib. In patients with previously untreated brain metastasis, median OS was 20.7 vs 11.6 months, HR 0.49, 95% CI 0.30-0.80, p= 0.004. Additionally patients with brain-only progression could receive local therapy and continue on study treatment. Time between first and second brain progression suggests that tucatinib could delay brain progression (median time to progression 7.6 vs 3.1 months, HR 0.33, 95% CI 0.13-0.85, p= 0.02)[
      • Lin Nancy
      • Borges Virginia
      • Anders Carey
      • et al.
      Intracranial Efficacy and Survival With Tucatinib Plus Trastuzumab and Capecitabine for Previously Treated HER2-Positive Breast Cancer With Brain Metastases in the HER2CLIMB Trial.
      ]
      Neratinib likewise appears to reduce brain lesions, delay symptomatic progression of CNS metastasis and the need for intervention [

      Saura C, Oliveira M, Feng Y-H, et al. Neratinib + capecitabine versus lapatinib + capecitabine in patients with HER2+ metastatic breast cancer previously treated with ≥2 HER2-directed regimens: Findings from the multinational, randomized, phase III NALA trial. J Clin Oncol 2019;37(15_suppl):1002–1002.

      ,
      • Awada A.
      • Colomer R.
      • Inoue K.
      • et al.
      Neratinib plus paclitaxel vs trastuzumab plus paclitaxel in previously untreated metastatic ERBB2-positive breast cancer: the NEfERT-T randomized clinical trial.
      ,
      • Freedman R.A.
      • Gelman R.S.
      • Anders C.K.
      • et al.
      TBCRC 022: a phase II trial of neratinib and capecitabine for patients with human epidermal growth factor receptor 2–positive breast cancer and brain metastases.
      ]. In the NEfERT-T study the risk of CNS progression was inferior in the neratinib arm (10.1% vs 20.2%; p = 0.002) [
      • Awada A.
      • Colomer R.
      • Inoue K.
      • et al.
      Neratinib plus paclitaxel vs trastuzumab plus paclitaxel in previously untreated metastatic ERBB2-positive breast cancer: the NEfERT-T randomized clinical trial.
      ]. In the NALA trial, neratinib was associated with fewer required interventions for brain metastasis (18% vs 24%) and with lower cumulative risk in time for these interventions (22.8% vs 29.2%; p = 0.43) [

      Saura C, Oliveira M, Feng Y-H, et al. Neratinib + capecitabine versus lapatinib + capecitabine in patients with HER2+ metastatic breast cancer previously treated with ≥2 HER2-directed regimens: Findings from the multinational, randomized, phase III NALA trial. J Clin Oncol 2019;37(15_suppl):1002–1002.

      ]. The TBCRC022 trial was specifically designed to evaluate the effect of neratinib in CNS lesions. In a lapatinib-naïve population (cohort 3A) the response rate was 49% (all partial responses) and in a lapatinib-exposed (cohort 3B), 33%. Median PFS and OS for cohort 3A were 5.5 m and 13.3 m, respectively, and for cohort 3B were 3.1 m and 15.1 m [
      • Freedman R.A.
      • Gelman R.S.
      • Anders C.K.
      • et al.
      TBCRC 022: a phase II trial of neratinib and capecitabine for patients with human epidermal growth factor receptor 2–positive breast cancer and brain metastases.
      ]. When data for these three studies were combined, the occurrence of CNS response was associated with prolonged PFS (HR 0.58; 95%CI 0.31–1.10) and OS (HR 0.43, 95%CI 0.24–0.76) [

      Awada A. Impact of neratinib on development and progression of central nervous system metastases in patients with HER2-positive metastatic breast cancer: Findings from the NALA, NEfERT-T, and TBCRC 022 trials.

      ].
      To conclude, treating patients with CNS disease remains a challenge. Though the data on tucatinib is provocative, foregoing local treatment for a systemic strategy upfront cannot be considered standard of care until a formal comparison of both strategies is made in a prospective trial. On the other hand, for patients who are not candidates for further local therapy, a TKI-based regimen is a reasonable approach rather than a monoclonal antibody-based approach. Tucatinib, the only drug tested in a triplet regimen and with evidence of OS benefit could be the best choice, though the lack of formal head to head comparisons of all three TKIs in equal circumstances is an important issue.
      • Should Triple Positive Disease be managed differently than ER-negative/HER2-positive disease?
      The management of HER2-positive/ER+ and HER2-positive/ER- is generally similar, with the inclusion of the triple positive subgroup in most trials evaluating HER2-target treatments. Older trials associating aromatase inhibitor (AI) and anti-HER2 agents demonstrated the superiority of the combination [
      • Johnston S.
      • Pippen J.
      • Pivot X.
      • et al.
      Lapatinib combined with letrozole versus letrozole and placebo as first-line therapy for postmenopausal hormone receptor-positive metastatic breast cancer.
      ,
      • Kaufman B.
      • Mackey J.R.
      • Clemens M.R.
      • et al.
      Trastuzumab plus anastrozole versus anastrozole alone for the treatment of postmenopausal women with human epidermal growth factor receptor 2-positive, hormone receptor-positive metastatic breast cancer: results from the randomized phase III TAnDEM study.
      ,
      • Huober J.
      • Fasching P.A.
      • Barsoum M.
      • et al.
      Higher efficacy of letrozole in combination with trastuzumab compared to letrozole monotherapy as first-line treatment in patients with HER2-positive, hormone-receptor-positive metastatic breast cancer – Results of the eLEcTRA trial.
      ]. Current guidelines, however, do not suggest the use of first-line endocrine therapy with anti-HER2 therapy for all patients ER-positive patients. Three distinct roles are suggested in guidelines for endocrine therapy [
      • Giordano S.H.
      • Temin S.
      • Chandarlapaty S.
      • et al.
      Systemic therapy for patients with advanced human epidermal growth factor receptor 2-positive breast cancer: ASCO clinical practice guideline update.
      ]:
      • (1)
        As first-line alone or in combination with anti-HER2 agents for selected patients considered not to be candidates for standard therapy for any reason – such patients with severe heart disease, extreme age and frailty;
      • (2)
        As “maintenance therapy” in addition to dual HER2 blockade with trastuzumab and pertuzumab in first-line, after the chemotherapy induction phase;
      • (3)
        In combination with trastuzumab or lapatinib in heavily pretreated patients or in patients deemed unfit for chemotherapy [
        • Giordano S.H.
        • Temin S.
        • Chandarlapaty S.
        • et al.
        Systemic therapy for patients with advanced human epidermal growth factor receptor 2–positive breast cancer: ASCO clinical practice guideline update.
        ,
        • Cardoso F.
        • Senkus E.
        • Costa A.
        • et al.
        4th ESO-ESMO international consensus guidelines for advanced breast cancer (ABC 4).
        ].
      Recent years have seen a number of studies which contribute data to support this standard as well as suggesting a future path for more specific guidelines. These include the PERTAIN, ALTERNATIVE, PATRICIA and MonarcHER trials.
      The PERTAIN trial, which included only triple positive tumours, randomized patients between an AI + trastuzumab or AI trastuzumab + pertuzumab. Patients could also receive induction docetaxel before initiating an AI (56% of patients did). Median PFS favoured the pertuzumab arm – 18.8 vs 15.8 months, HR 0.65; 95% CI, 0.48 to 0.89; p = 0.0070. Patients in the pertuzumab arm who did not receive induction had a median PFS of 21.7 months. Though this trial did not test “maintenance therapy” formally, patients in the pertuzumab arm had a similar PFS to those in CLEOPATRA (18.9 m and 18.8 m) [
      • Baselga J.
      • Cortés J.
      • Kim S.-B.
      • et al.
      Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer.
      ,

      Rimawi M, Ferrero J-M, de la Haba-Rodriguez J, et al. First-line trastuzumab plus an aromatase inhibitor, with or without pertuzumab, in human epidermal growth factor receptor 2-positive and hormone receptor-positive metastatic or locally advanced breast cancer (PERTAIN): a randomized, open-label phase II trial. J Clin Oncol Off J Am Soc Clin Oncol 2018;JCO2017767863.

      ]. The ongoing PATINA trial (NCT02947685) is evaluating the maintenance strategy by randomizing patients between AI and placebo, and will provide an answer to whether this strategy is valuable or not [
      • Giordano S.H.
      • Temin S.
      • Kirshner J.J.
      • et al.
      Systemic therapy for patients with advanced human epidermal growth factor receptor 2–positive breast cancer: American society of clinical oncology clinical practice guideline.
      ].
      The ALTERNATIVE trial compared trastuzumab + AI with trastuzumab + lapatinib + AI and with lapatinib + AI in second-line setting. Prolonged PFS, response rate and a trend to improved OS were observed with the triplet regimen. Once more, no direct comparisons were done to confirm the benefit of endocrine therapy [

      Johnston SRD, Hegg R, Im S-A, et al. Phase III, randomized study of dual human epidermal growth factor receptor 2 (HER2) blockade with lapatinib plus trastuzumab in combination with an aromatase inhibitor in postmenopausal women with HER2-positive, hormone receptor-positive metastatic breast cancer: Alternative. J Clin Oncol Off J Am Soc Clin Oncol 2017;JCO2017747824.

      ].
      Cyclin D1 (CDK) 4/6 inhibitors, which have changed the treatment of advanced luminal tumours, have shown enhanced activity and have re-sensitized tumors to HER-target therapy in preclinical models, suggesting that it may be a pathway to resistance to anti-HER2 agents [

      Tolaney SM. Monarcher: a randomized phase 2 study of abemaciclib plus trastuzumab with or without fulvestrant versus trastuzumab plus standard-of-care chemotherapy in women with HR+, HER2+ advanced breast cancer (ABC). Ann Oncol 2019;30(suppl_5):v851–v934. 10.1093/annonc/mdz394.

      ]. This rationale led to the development of phase II trials combining CDK 4/6 inhibitors and HER2 directed therapies in triple positive tumors.
      The PATRICIA trial had the particularity of including patients with HER2-positive who were either ER-positive or negative. The ER + group was randomized to palbociclib + trastuzumab (Palb + T) with or without letrozole and the ER-, was treated with palbociclib + trastuzumab. In preliminary results at 6 months, 33.3% for patients in the ER- cohort, 40.0% in the ER + treated with Palb + T and 53.3% in the ER + treated with Palb + T + letrozole were free of disease progression. PAM50 was performed in order to ascertain outcomes by molecular subtype. Luminal subtypes were associated with superior PFS than other subtypes when exposed to trastuzumab + palboclib (12.4 m vs 4.1 m; HR 0.37, 95%CI 0.14–1.0) [

      Ciruelos E, Villagrasa P, Paré L, et al. Abstract PD3-03: SOLTI-1303 PATRICIA phase II trial (STAGE 1) – Palbociclib and trastuzumab in postmenopausal patients with HER2-positive metastatic breast cancer [Internet]. In: Poster discussion abstracts. American Association for Cancer Research; 2019 [cited 2020 Mar 3]. p. PD3-03–PD3-03. Available from: http://cancerres.aacrjournals.org/lookup/doi/10.1158/1538-7445.SABCS18-PD3-03.

      ].
      Finally, MonarcHER, included patients previously exposed to TDM-1 and comprised 3 arms: abemaciclib + trastuzumab + fulvestrant (A); abemaciclib + trastuzumab (B); trastuzumab + physician’s choice. Median PFS was longer in arm A than in arm C (8.3 m vs 5.7 m; HR 0.67, 95%CI 0.45–1.0; p = 0.02) and similar between arms B and C (5.7 m vs 5.7 m; HR 0.94, 95%CI 0.64–1.38; p = 0.38). The response rates were 35.4% (A), 16.5% (B) and 22.8% (C) and the safety profile was as expected for abemaciclib [
      • Tolaney S.M.
      • Wardley A.M.
      • Zambelli S.
      • et al.
      Abemaciclib plus trastuzumab with or without fulvestrant versus trastuzumab plus standard-of-care chemotherapy in women with hormone receptor-positive, HER2-positive advanced breast cancer (monarcHER): a randomised, open-label, phase 2 trial.
      ]. The apparent lack of benefit for abemaciclib in arm B is worthy of note, suggesting that either the improvement in outcomes seen in arm A is due to fulvestrant alone or that abemaciclib does not provide any benefit in the absence of a drug targeting the ER pathway.
      To summarize, despite some new data, today current guidelines on the use of endocrine therapy and management of triple positive disease have not changed. Larger, better designed trials with CDK 4/6 inhibitors are needed before their benefit in HER2-positive disease can be strongly affirmed.
      • Are there any available biomarkers to guide choice of therapy today?
      In clinical practice, the use of anti-HER2 agents is based only in HER2 status which is the only predictive marker of response at this moment, without any substantial changes in the last 2 decades [
      • Wolff A.C.
      • Hammond M.E.H.
      • Hicks D.G.
      • et al.
      Recommendations for human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists clinical practice guideline update.
      ]. Data coming from clinical trials such as NeoSphere and PERNETTA, however, suggest that HER2-positive disease is a clinically heterogeneous disease, and that a portion of patients could be treated with de-escalated regimens containing anti-HER2 therapy alone. In PERNETTA, patients with advanced HER2-positive breast cancer were randomized between standard of care and dual blockade alone in first-line, with all patients receiving TDM-1 in first-line. Results show a significantly shorter PFS without chemotherapy, without any difference in OS. In the neoadjuvant NeoSphere trial, 17% of patients in the dual blockade without chemotherapy arm achieved a complete pathological response. Identifying these patients who respond extremely well to anti-HER2 therapy alone and can be spared the toxicity of chemotherapy has been the focus of substantial translational research efforts, but today despite the identification of several biomarkers, no clinically validated strategy is available, and no treatment for HER2-positive disease is indicated on the basis of specific biomarkers [

      Rugo HS, Im S-A, Wright GLS, et al. SOPHIA primary analysis: A phase 3 (P3) study of margetuximab (M) + chemotherapy (C) versus trastuzumab (T) + C in patients (pts) with HER2+ metastatic (met) breast cancer (MBC) after prior anti-HER2 therapies (Tx). J Clin Oncol 2019;37(15_suppl):1000–1000.

      ,
      • Gingras I.
      • Gebhart G.
      • de Azambuja E.
      • Piccart-Gebhart M.
      HER2-positive breast cancer is lost in translation: time for patient-centered research.
      ,
      • Muntasell A.
      • Servitja S.
      • Cabo M.
      • et al.
      High numbers of circulating CD57+ NK cells associate with resistance to HER2-specific therapeutic antibodies in HER2+ primary breast cancer.
      ].
      In the future, this lack of biomarker-guided therapies may change, though not necessarily towards de-escalation. Clinically validating biomarkers is a long, difficult and expensive endeavor, and therefore it is more common for biomarkers to come into the clinic tied to the indication for new drugs rather than the suppression of older ones. Several examples of potential paths towards biomarker-based escalation are available, such as PIK3CA mutations and PI3K inhibitors, TiLs/PD-L1 and checkpoint inhibitors as well as CD16A-158 alleles and Mergetuximab (which has been previously described). In addition to these examples, liquid biopsy strategies and HER2-mutations are also being explored.

      PIK3CA mutations Pi3K pathway inhibitors

      Pi3K/Akt/mTOR pathway activation is one of the mechanisms of acquired resistance in HER2-positive tumors. Pi3K inhibitors are expected to overcome this resistance and to improve outcomes in previously refractory disease [

      LoRusso PM. Inhibition of the PI3K/AKT/mTOR pathway in solid tumors. J Clin Oncol [Internet] 2016 [cited 2017 Jan 6]. Available from: http://jco.ascopubs.org/cgi/doi/10.1200/JCO.2014.59.0018.

      ]. In the early setting complete pathological response (pCR) becomes less common after neoadjuvant chemotherapy when a PIK3CA mutation is present [
      • Loibl S.
      • von Minckwitz G.
      • Schneeweiss A.
      • et al.
      PIK3CA mutations are associated with lower rates of pathologic complete response to anti-human epidermal growth factor receptor 2 (her2) therapy in primary HER2-overexpressing breast cancer.
      ]. The troubled development of this class, with a high rate of adverse events seen in some trials, have delayed development in HER2-positive disease, but have however shown that outcomes are only improved in the presence of detectable PIK3CA mutations [
      • Baselga J.
      • Im S.-A.
      • Iwata H.
      • et al.
      Buparlisib plus fulvestrant versus placebo plus fulvestrant in postmenopausal, hormone receptor-positive, HER2-negative, advanced breast cancer (BELLE-2): a randomised, double-blind, placebo-controlled, phase 3 trial.
      ,
      • Di Leo A.
      • Johnston S.
      • Lee K.S.
      • et al.
      Buparlisib plus fulvestrant in postmenopausal women with hormone-receptor-positive, HER2-negative, advanced breast cancer progressing on or after mTOR inhibition (BELLE-3): a randomised, double-blind, placebo-controlled, phase 3 trial.
      ]
      The largest presented study in HER2-positive disease, the neoadjuvant NeoPHOEBE trial was closed prematurely because due to limiting hepatic toxicity by buparlisib. Only 16% of the 50 patients recruited had a PIK3CA mutation, and no differences in response rates between buparlisib-trastuzumab and chemotherapy-trastuzumab were found [
      • Loibl S.
      • de la Pena L.
      • Nekljudova V.
      • et al.
      Neoadjuvant buparlisib plus trastuzumab and paclitaxel for women with HER2+ primary breast cancer: A randomised, double-blind, placebo-controlled phase II trial (NeoPHOEBE).
      ].
      There are ongoing phase I trials evaluating α-specific Pi3K inhibitors in HER2-positive cancers: taselisib associated with different anti-HER2 combination agents (NCT02390427); alpelisib + BYL719 (anti-HER3) + trastuzumab (NCT02167854); and alpelisip + TDM-1 (NCT02038010); MEN1611 + trastuzumab with or without fulvestrant (NCT03767335).

      TiLs/PD-L1 immunotherapy agents

      Several datasets point to TiLs impacting on outcomes in HER2-positive disease, and these have been recently reviewed by Soberino et al [
      • Soberino J.
      • Racca F.
      • Pérez-García J.
      • García-Fernández L.F.
      • Cortés J.
      Immunotherapy for HER2-positive breast cancer: changing the paradigm.
      ]. PD-L1 is the most commonly used biomarker to define the use of immunotherapy, though it is well understood to be suboptimal [
      • Weber J.S.
      Biomarkers for checkpoint inhibition.
      ].
      Check-point inhibitors have changed management in several solid tumours. In breast cancer, however, advance has been slower and is thus far limited in terms of approved regimens to triple negative breast cancer [
      • Schmid P.
      • Adams S.
      • Rugo H.S.
      • et al.
      Atezolizumab and nab-paclitaxel in advanced triple-negative breast cancer.
      ]. The significant prognostic and predictive value of TILs in HER2-positive breast cancer highlight its immunogenic nature. In HER2-positive advanced breast cancer, immunotherapy could be effective, based on pre-clinical models and some clinical data coming from early clinical studies [
      • Soberino J.
      • Racca F.
      • Pérez-García J.
      • García-Fernández L.F.
      • Cortés J.
      Immunotherapy for HER2-positive breast cancer: changing the paradigm.
      ].
      PANACEA was the first trial combining anti-PD1 and anti-HER2 agents. This was a phase Ib/II single arm study of pembrolizumab and trastuzumab in a trastuzumab-resistant multi-treated population with 79.3% PDL-1 positivity. In PDL-positive patients, response rate was 15% and disease control rate was 25%. TiLs 5% or higher were significantly more common among patients who benefitted from treatment. There were no responses for PDL-1 negative cohort [

      Loi S, Giobbie-Hurder A, Gombos A, et al. Pembrolizumab plus trastuzumab in trastuzumab-resistant, advanced, HER2-positive breast cancer (PANACEA): a single-arm, multicentre, phase 1b–2 trial. Lancet Oncol [Internet] 2019 [cited 2019 Feb 26]. Available from: https://linkinghub.elsevier.com/retrieve/pii/S147020451830812X.

      ].
      The phase II KATE2 study randomized patients previously treated with trastuzumab and a taxane to TDM-1 plus atezolizumab or placebo. Within a median follow-up of 18.2 m, the median OS was not reached yet. In the PDL-1 positive subgroup, the 1-year OS was superior for the atezolizumab arm (94.3% vs 57.9%), suggesting a possible OS benefit were these data became mature [
      • Emens L.A.
      • Esteva F.J.
      • Beresford M.
      • et al.
      Overall survival (OS) in KATE2, a phase II study of programmed death ligand 1 (PD-L1) inhibitor atezolizumab (atezo)+trastuzumab emtansine (T-DM1) vs placebo (pbo)+T-DM1 in previously treated HER2+ advanced breast cancer (BC).
      ].
      Other immunotherapy combinations are being evaluated in ongoing trials, such as trastuzumab, vinorelbine, avelumab with or without utomilumab in TDM-1 pre-treated patients (AVIATOR study: NCT03414658) and trastuzumab, pertuzumab and paclitaxel with or without atezolizumab in first-line therapy (NCT03199885).

      Liquid biopsy

      Circulating tumor DNA (ctDNA), commonly referred to as “liquid biopsy”, promises to evaluate the amplification of HER2 in a reproducible and non-invasive way which would allow the dynamic monitoring of efficacy and treatment decision making [
      • Shoda K.
      • Ichikawa D.
      • Fujita Y.
      • et al.
      Monitoring the HER2 copy number status in circulating tumor DNA by droplet digital PCR in patients with gastric cancer.
      ,
      • Schlange T.
      • Pantel K.
      Potential of circulating tumor cells as blood-based biomarkers in cancer liquid biopsy.
      ]. A recent study verified the agreement of HER2 amplification in plasma ctDNA with primary tumor tissue, as well as the clinical significance of the change in HER2 copy number during anti-HER2 therapy. One of the cohorts had 26 metastatic patients whose HER2 status was positive in primary tissue. Their plasma copy numbers of HER2 were tracked in real time when receiving combined therapy with pyrotinib and capecitabine. In total, 19 out of 26 were identified as having HER2 amplification in ctDNA before the drug and the level of HER2 copy number in each patient decreased dramatically after 6 weeks of treatment targeting HER2. HER2 copy number did not fall below the amplification level in only two candidates, who experienced remarkably worse PFS (mean 3.2 months vs 21.9 months, p < 0.001). HER2 copy number also correlated with radiologic response to treatment. In some participants, the number of copies of HER2 increased for several weeks before the identification of progressive disease [
      • Guan X.
      • Liu B.
      • Niu Y.
      • et al.
      Longitudinal HER2 amplification tracked in circulating tumor DNA for therapeutic effect monitoring and prognostic evaluation in patients with breast cancer.
      ].
      “Liquid biopsy” is not limited to ctDNA, and can mean evaluation of other potential markers, such as circulating tumour cells and circulating microRNA (ct-miRNA) had also been studied. Recently a study analyzed miRNA from 52 patients from NeoALTTO study [
      • Di Cosimo S.
      • Appierto V.
      • Pizzamiglio S.
      • et al.
      Early modulation of circulating MicroRNAs levels in HER2-positive breast cancer patients treated with trastuzumab-based neoadjuvant therapy.
      ]. Plasma samples were collected at baseline and 2 weeks after trastuzumab. RNA analysis identified two ct-miRNA (ct-miR-148a-3p and ct-miR-374a-5p) whose variation (increase) from baseline value were significantly associated with pathological complete response (p = 0.008 and 0.048, respectively), though, if the basal levels of either did not correlate with response.
      To conclude, liquid biopsy techniques have potential, but are today to be considered strictly experimental in advanced breast cancer management.

      HER2 mutations

      Somatic HER2-mutations are a known mechanism of resistance to anti-HER2 treatment, which can impact the extracellular conformation of the receptor and hyper-activate the intracellular tyrosine kinase domain. In one metanalysis of 31 studies on the topic, with a total of 12,905 patients, the pooled incidence of mutations was 3.9%. 2 of these studies also reported on survival outcomes, suggesting that patients with mutations have worse prognosis [
      • Petrelli F.
      • Tomasello G.
      • Barni S.
      • Lonati V.
      • Passalacqua R.
      • Ghidini M.
      Clinical and pathological characterization of HER2 mutations in human breast cancer: a systematic review of the literature.
      ]. Some pre-clinical as well as limited data coming from small studies suggest that TKIs such as poziotinib and neratinib can be effective in HER2 mutated tumours [
      • Robichaux J.P.
      • Elamin Y.Y.
      • Vijayan R.S.K.
      • et al.
      Pan-cancer landscape and analysis of ERBB2 mutations identifies poziotinib as a clinically active inhibitor and enhancer of T-DM1 activity.
      ,
      • Hyman D.M.
      • Piha-Paul S.A.
      • Won H.
      • et al.
      HER kinase inhibition in patients with HER2- and HER3-mutant cancers.
      ,
      • Kim T.M.
      • Lee K.-W.
      • Oh D.-Y.
      • et al.
      Phase 1 studies of poziotinib, an irreversible pan-HER tyrosine kinase inhibitor in patients with advanced solid tumors.
      ]. In one phase II study, 16 patients with HER2-mutated tumours received neratinib treatment. Outcomes suggest some effect, with a CBR of 31% and a median PFS of 16 [
      • Ma C.X.
      • Bose R.
      • Gao F.
      • et al.
      Neratinib efficacy and circulating tumor DNA detection of HER2 mutations in HER2 nonamplified metastatic breast cancer.
      ].
      • What new drugs, classes or combinations are still in development?
      Many new agents, combinations and classes are in development currently, beyond those previously mentioned. Table 2 summarizes all ongoing studies.
      Table 2Ongoing trials in HER2+ advanced breast cancer.
      DrugTrial/Drug sponsorPhasePopulationRegimenSample size
      IpatasertibNCT04253561 (Roche Pharma AG)IAdvanced HER2+ PI3KCA-mutant breast cancerIpatasertib + trastuzumab + pertuzumab25
      TAEK-VAC-HerByNCT04246671 (Bavarian Nordic)I/IIAdvanced HER2+ cancer.TAEK-VAC-HerBy45
      PyrotinibNCT04246502 (Chinese Academy of Medical Sciences)IIHER2+ metastatic and have not received systemic anticancer therapy for advanced diseaseCapecitabine + pyrotinib vs Capecitabine + trastuzumab + pertuzumab200
      NCT04033172 (Chinese Academy of Medical Sciences)IIHR+/HER2+ metastatic breast cancerPyrotinib + fulvestrant40
      NCT04001621 (Jiangsu HengRui Medicine Co., Ltd.)IITrastuzumab-resistant HER2+ advanced breast cancerPyrotinib + capecitabine100
      NCT03772353 (Jiangsu HengRui Medicine Co., Ltd.)Ib/IIHR+/HER2+ relapsed/metastatic breast cancerLetrozole + pyrotinib + DSHR639032
      NCT03997539 (Jiangsu HengRui Medicine Co., Ltd.)IIHER2+ locally advanced or metastatic breast cancer who have received prior trastuzumab-based therapyPyrotinib + vinorelbine vs Treatment of physician's choice265
      NCT03933982 (Chinese Academy of Medical Sciences)IIHER2+ metastatic breast cancer with brain matastasesPyrotinib + vinorelbine30
      AlpelisibNCT04208178 (Novartis Pharmaceuticals)IIIHER2+ advanced breast cancer with PIK3CA mutationAlpelisib + trastuzumab + pertuzumab vs Placebo + trastuzumab + pertuzumab548
      PoziotinibNCT04172597 (Spectrum Pharmaceuticals, Inc.)IIAdvanced malignancies with EGFR or HER2 activating mutationsPoziotinib150
      NCT02544997 (Samsung Medical Center)IISalvage treatment for metastatic BC with HER2 or EGFR mutation or activated AR or EGFR pathwayPoziotinib30
      GB221NCT04164615/(Genor Biopharma Co., Ltd.)IIIRelapsed or metastatic patients who failed to respond to previous taxanes and/or anthracyclinesGB221 + capecitabine vs Placebo + capecitabine336
      NCT04170595/(Genor Biopharma Co., Ltd.)I/IIMetastatic BC who failed to respond to previous chemotherapy and no more than three lines and never received anti-HER2 treatmentGB221 1,2mg/Kg or 1,6mg/Kg or 1,8mg/Kg vs Trastuzumab vs GB221 + capecitabine vs Trastuzumab + capecitabine132
      PalbociclibNCT03709082 (Pfizer)IIHR+/HER2+ metastatic breast cancer

      Prior treatment with a taxane and

      trastuzumab
      Palbociclib + letrozole + TDM-14
      NCT02947685 (Pfizer)IIIAfter induction treatment for HR+/HER2+ metastatic breast cancerPalbociclib + anti-HER2 therapy (trastuzumab/pertuzumab) + endocrine therapy vs Anti-HER2 therapy (trastuzumab/pertuzumab) + endocrine therapy496
      NCT03530696 (Pfizer)IINo >2 lines of therapy for HER + metastatic breast cancerTDM-1 + palbociclib vs TDM-1132
      NCT04224272 (Zymeworks, Inc.)IIProgressed or been refractory to prior treatment with trastuzumab, pertuzumab and TDM-1ZW25 + palbociclib + fulvestrant76
      NCT03304080 (Icahn School of Medicine at Mount Sinai)I/IINo prior systemic treatment for metastatic breast cancerAnastrozole + palbociclib + trastuzumab + pertuzumab36
      NCT03913234 (Yonsei University)I/IIPostmenopausal patients, without previous systemic therapy for advanced/metastatic breast cancerRibociclib + trastuzumab + letrozole95
      NCT02448420 (SOLTI Breast Cancer Research Group)IIHER2+ locally advanced or metastatic breast cancer who have received chemotherapy and trastuzumab in metastatic settingTrastuzumab + palbociclib + endocrine therapy vs Physician's choice (TDM-1 or chemotherapy)232
      NCT01976169 (Pfizer)IRecurrent or metastatic HER2+ breast cancer and RB-proficientPD-0332991 + TDM-133
      KN026NCT03619681/(Jiangsu Alphamab Biopharmaceuticals Co., Ltd.)IMonotherapy in HER2+ advanced malignant breast or gastric cancerKN02620
      NCT04165993/(Jiangsu Alphamab Biopharmaceuticals Co., Ltd.)IIHER2 expressing or positive metastatic breast cancerKN026 combined with docetaxel vs KN026 monotherapy70
      A16NCT03602079/(Klus Pharma Inc.)IILocally advanced/metastatic solid HER2+ tumors that did not respond or stopped responding to approved therapiesA16682
      UtomilumabNCT03414658 (Pfizer)IIPrevious TDM-1 in any setting

      Previous trastuzumab and pertuzumab in the metastatic setting or within 12 months of neoadjuvant/adjuvant treatment
      Trastuzumab + vinorelbine vs Trastuzumab + vinorelbine + avelumab vs Trastuzumab + vinorelbine + avelumab + utomilumab100
      NCT03364348 (National Cancer Institute)IHER2-overexpressing breast cancer and radiographic evidence of metastatic or locally-recurrent unresectable diseaseTDM-1 + utomilumab vs Trastuzumab + utomilumab79
      NeratinibNCT03377387/(Puma Biotechnology, Inc.)I/II>4 prior chemotherapy-based treatments in the metastatic setting are allowed.

      Previous TDM-1

      Previous neratinib is not permitted. Previous capecitabine is allowed, if not combined with neratinib.
      Capecitabine + neratinib48
      NCT01494662/(Puma Biotechnology, Inc.)IIHER2+ breast cancer with brain matastasesNeratinib vs Neratinib + craniotomy vs Neratinib + capecitabine (no prior lapatinib) vs Neratinib + capecitabine (with prior lapatinib) vs Neratinib + TDM-1 (previously untreated brain matastases) vs Neratinib + TDM-1 (progressive brain matastases) vs Neratinib + TDM-1 (progressive brain matastases and prior TDM-1)168
      NCT03101748/(Puma Biotechnology, Inc.)I/IIPrimary metastatic or locally advanced breast cancerNeratinib + paclitaxel + ertuzumab + trastuzumab vs Neratinib + paclitaxel + ertuzumab + trastuzumab + doxorubicin + cyclophosphamide vs Neratinib + paclitaxel + doxorubicin + cyclophosphamide99
      NCT03289039/(Puma Biotechnology, Inc.)IIPrior therapy with trastuzumab, pertuzumab or TDM-1 in any settingNeratinib vs Neratinib + fulvestrant
      Hemay022NCT03308201/(Tianjin Hemay Pharmaceutical Co., Ltd.)IER+/HER + breast cancer

      Post-menopausal females suitable for exemestane
      Hemay022 + Exemestane48
      NCT02476539/(Tianjin Hemay Pharmaceutical Co., Ltd.)IHER2+ advanced breast cancerHemay02257
      EribulinNCT03264547/(Eisai Co., Ltd.)IIIHER2+ advanced/recurrent cancer without prior chemotherapy agentsTrastuzumab + ertuzumab + taxane vs Trastuzumab + pertuzumab + eribulin480
      SYD985NCT03262935/(Byondis B.V.)IIIProgression during or after at least two HER2-targeting regimens for locally advanced or metastatic disease or progression during or after TDM-1SYD985 vs Physician’s choice345
      TVB-2640NCT03179904 (National Cancer Institute)II≤4 prior chemotherapy regimens in the metastatic settingFASN inhibitor TVB-2640 + paclitaxel + trastuzumab80
      AtezolizumabNCT03125928 (Genentech, Inc.)IIHER2+ unresectable locally recurrent or metastatic breast cancerAtezolizumab + paclitaxel + trastuzumab + pertuzumab50
      NCT03417544 (Genentech, Inc.)IIHER2+ with unequivocal evidence of new and/or progressive brain matastasesAtezolizumab + trastuzumab + pertuzumab33
      NCT03199885 (National Cancer Institute)IIIHER2+ metastatic breast cancerPertuzumab + trastuzumab + paclitaxel + atezolizumab vs Pertuzumab + trastuzumab + paclitaxel + placebo600
      NCT03650348 (Pieris Pharmaceuticals, Inc.)IHER2+ advanced or metastatic solid tumorsPRS-343 + atezolizumab70
      IFN-γNCT03112590 (Horizon Pharma Ireland, Ltd.)IHER2+ unresectable locally advanced or metastatic breast cancerInterferon-γ + paclitaxel + trastuzumab + pertuzumab43
      RC48-ADCNCT03052634 (RemeGen)I/IIHER2+ locally advanced or metastatic breast cancerRC48-ADC vs Lapatinib + capecitabine165
      NCT03500380 (RemeGen)IIHER2+ locally advanced or metastatic breast cancerRC48-ADC vs Lapatinib + capecitabine228
      OlaparibNCT03931551 (MedSIR)IIHER2+ and gene alterations in HRR DNA pathwayOlaparib + trastuzumab33

      Antibody-drug conjugates

      Antibody-drug conjugates (ADC) combine the specificity of an antibody with the cytotoxic potential of chemotherapy agents [
      • Pondé N.
      • Aftimos P.
      • Piccart M.
      Antibody-drug conjugates in breast cancer: a comprehensive review.
      ]. Three ADCs are approved today for use in breast cancer, with 2 being specifically targeted against HER2 – TDM-1 and Trastuzumab-deruxtecan [
      • Beck A.
      • Goetsch L.
      • Dumontet C.
      • Corvaïa N.
      Strategies and challenges for the next generation of antibody–drug conjugates.
      ].
      Other antibody-drug conjugates tested for HER2-positive metastatic breast cancer demonstrated clinical efficacy in phase I trials, including MEDI4276 (antibody conjugated to a microtubule inhibitor), RC48 (conjugated to a tubulin polymerization inhibitor, monomethyl auristatin E (MMAE)) and ARX88 [

      Pegram M. 47O – Phase 1 study of bispecific HER2 antibody-drug conjugate MEDI4276 in patients with advanced HER2-positive breast or gastric cancer.

      ,

      Xu B, Wang J, Zhang Q, et al. An open-label, multicenter, phase Ib study to evaluate RC48-ADC in patients with HER2-positive metastatic breast cancer. J Clin Oncol 2018;36(15_suppl):1028–1028.

      ,

      Hu X. P1-18-16: A phase 1 study of ARX788, a HER2-targeting antibody-drug conjugate, in patients with metastatic HER2-positive breast cancer.

      ]. Trastuzumab-duocarmazine (SYD985) was tested for both HER2-positive and HER2-low, heavily pretreated, tumors. Response rates were 36% and 60%,respectively, in the phase I trial [

      Aftimos P, van Herpen C, Mommers E, et al. Abstract P6-12-02: SYD985, a novel anti-HER2 ADC, shows promising activity in patients with HER2-positive and HER2-negative metastatic breast cancer [Internet]. In: Poster Session Abstracts. American Association for Cancer Research; 2017 [cited 2020 Mar 3]. p. P6-12-02–P6-12-02. Available from: http://cancerres.aacrjournals.org/lookup/doi/10.1158/1538-7445.SABCS16-P6-12-02.

      ]. In the expansion cohort, including 99 patients, the overall response rate for HER2-positive tumors was 33%, with a median PFS of 9.4 m. In the HER2-low population, it was 27% for hormone receptor positive and 40% for triple negative tumours [

      Saura C. A phase I expansion cohorts study of SYD985 in heavily pretreated patients with HER2-positive or HER2-low metastatic breast cancer. Chicago, IL, USA.

      ]. An ongoing phase III (TULIP) trial comparing SYD985 with physician’s choice in patients with HER2-positive metastatic tumors progressing after at least two previous anti-HER2 therapies, is currently recruiting (NCT 03262935).
      Another approach, which is still in development, is to combine a monoclonal antibody to a payload agonist of myeloid cells, in order to drive a broad spectrum of anti-tumor immune response based on a potent activation of these cells. SBT6050 is an ADC composed by trastuzumab and TLR8 agonist. In preclinical models, it was associated with some efficacy in several tumor models as a single agent or in association with trastuzumab (the drugs bind to different epitopes, making this association feasible) [

      Odegard V. PD4-09: Preclinical studies support the development of SBT6050, an anti-HER2 antibody conjugated to a potent TLR8 agonist, for treatment of moderate and high HER2-expressing tumors that lack pre-existing T cell infiltrate.

      ].

      Bispecific antibodies

      Bispecific antibodies are antibodies capable of recognizing two different epitopes or antigens, blockading different pathways at the same time [
      • Labrijn A.F.
      • Janmaat M.L.
      • Reichert J.M.
      • Parren P.W.H.I.
      Bispecific antibodies: a mechanistic review of the pipeline.
      ].
      MCLA-128 is a bispecific humanized antibody targeting HER2 and HER3. Its efficacy in tumors NGR1 fusion-positive was demonstrated for lung, pancreas and other sites (basket design) in a clinical proof-of-concept clinical trial, and now a phase II study is ongoing [
      • Schram A.M.
      • Drilon A.
      • Mercade T.M.
      • et al.
      A phase II basket study of MCLA-128, a bispecific antibody targeting the HER3 pathway, in NRG1 fusion-positive advanced solid tumours.
      ]. In October 2019, an interim unplanned analysis of the phase II trial evaluating MCLA-128 in HER2-positive and HR+/HER2-low breast tumors was performed. The disease control and response rates were superior in the HER2-positive population, in which MCLA-128 was combined with trastuzumab and vinorelbine (75% disease control; 4% of confirmed responses and 17% unconfirmed in third line and beyond).
      GBR 1302 targets HER2 and CD3 domains and was associated with stable disease (but no responses) in one early study. Infusion related reactions were the most common adverse effects and left ventricular ejection fraction decrease occurred in approximately 10% of the patients [

      Wermke M. Preliminary results from a phase 1 study of GBR 1302, a bispecific antibody T-cell engager, in HER2 positive cancers.

      ]. These data will probably encourage a phase II trial development.
      ZW25 is a biparatopic anti-HER2 antibody, which binds two different epitopes in HER2 with preclinical evidence of potent inhibition of the pathway [

      ZW25 effective in HER2-positive cancers. Cancer Discov 2019;9(1):8.1–8.

      ] which has shown some activity in various HER-positive tumours in phase 1. Two phase 1 trials are ongoing with this agent, one in pretreated HER2-positive tumours (NCT02892123) and one in triple positive-breast cancer in combination with fulvestrant and palbociclib (NCT04224272)

      Tyrosine kinase inhibitors

      Tyrosine kinase inhibitors target the intracellular domains of receptors, thus bypassing extracellular domain conformational changes, which are a mechanism of resistance to monoclonal antibodies such as trastuzumab [
      • Pohlmann P.R.
      • Mayer I.A.
      • Mernaugh R.
      Resistance to trastuzumab in breast cancer.
      ]. Anti-HER2 agents in this class include lapatinib, tucatinib and neratinib. 2 more agents, pyrotinib and poziotinib are in advanced stages of development.
      Pyrotinib is an irreversible pan-HER inhibitor (targets HER1, HER2 and HER4) that showed 50% overall response rate and a median PFS of 35.4 weeks in a phase I trial [
      • Ma F.
      • Li Q.
      • Chen S.
      • et al.
      Phase I study and biomarker analysis of pyrotinib, a novel irreversible pan-ErbB receptor tyrosine kinase inhibitor, in patients with human epidermal growth factor receptor 2–positive metastatic breast cancer.
      ]. A phase II Chinese trial published in 2019 compared the combination of pyrotinib or lapatinib and capecitabine for HER2-positive breast cancer with 2 prior lines for metastatic disease. Only 29.7% of the population had received prior anti-HER2 therapy for advanced tumors. Pyrotinib was associated with increased PFS (18.1 m vs 7.0 m; HR 0.36, 95%CI 0.23–0.58) and overall response rate (78.5% vs 57.1%; p = 0.01), with more grade 3–4 adverse events (diarrhea, hand-foot syndrome, vomiting and neutropenia without fever were predominant) [
      • Ma F.
      • Ouyang Q.
      • Li W.
      • et al.
      Pyrotinib or lapatinib combined with capecitabine in HER2–positive metastatic breast cancer with prior taxanes, anthracyclines, and/or trastuzumab: a randomized, phase II study.
      ]. These results have been confirmed in Considering the absence of HER2-target therapies in first and second-lines in most cases, this could not be considered a worldwide representative population, and so, more studies are needed to evaluate the most appropriate scenario to use this drug outside of China.
      Another irreversible pan-HER inhibitor, poziotinib, was initially evaluated in a phase I trial that included multiple types of metastatic tumors, with the majority being exposed to 4 or more lines of previous regimens. The overall response rate was 16% and 47% had stable disease. [
      • Kim T.M.
      • Lee K.-W.
      • Oh D.-Y.
      • et al.
      Phase 1 studies of poziotinib, an irreversible pan-HER tyrosine kinase inhibitor in patients with advanced solid tumors.
      ] The NOV120101-203 trial enrolled 106 patients with metastatic HER2-positive breast cancer and previous 2 anti-HER2 therapies to poziotinib monotherapy. This drug exhibited a 4.04 m a median of PFS and 25.5% response rate [
      • Park Y.H.
      • Lee K.-H.
      • Sohn J.H.
      • et al.
      A phase II trial of the pan-HER inhibitor poziotinib, in patients with HER2-positive metastatic breast cancer who had received at least two prior HER2-directed regimens: results of the NOV120101-203 trial: pan-HER inhibitor poziotinib for refractory HER2+ MBC patients.
      ].

      Conclusion

      In 2019, important data on several options of third-line (and beyond) were presented leading to their rapid approval by the FDA, raising questions about the best choice of treatment to be adopted for advanced HER2-positive breast cancer in third-line (Fig. 1). The trials which led to approval are, however, vulnerable to criticism and their designs mean that currently there is little data to base decisions on. It is the opinion of the authors of this manuscript, however, that trastuzumab-deruxtecan will likely be the choice of third-line for most patients, with tucatinib being used for patients with severe lung comorbidities or CNS disease that is not amenable to local treatment. Sadly, despite substantial research efforts, no biomarkers are today available to base decision-making. Trials that integrate biomarkers into design are urgently needed.
      Figure thumbnail gr1
      Fig. 1Possible new treatment sequencing for HER2+ metastatic breast cancer.

      Role of funding source

      There was no funding for this manuscript

      Declaration of Competing Interest

      Marcelle G. Cesca reports travelling grants from United Medical.
      Lucas Vian reports no conflict of interest.
      Sofia Cristóvão-Ferreira reports no conflict of interest.
      Noam Pondé reports he has received fees from Novartis, Lilly, AstraZeneca and Roche. He has received travel grants from Novartis, AstraZeneca and Lilly.
      Evandro de Azambuja reports honoraria and advisory board from Roche/GNE, Novartis and SeaGen, travel grants from Roche/GNE and GSK/Novartis and research grant to my institution from Roche/GNE, Astra-Zeneca, GSK/Novartis and Servier.

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