Table 3: Selected biomarkers as therapeutic targets in the management of patients with HER2-positive metastatic breast cancer – helpful implications from recent clinical trials.

Therapeutic Target Targeted Medication, Class Trial Name, Phase Identifier Clinical Implications of the Trial Relevant to the Patient Management [Author, Year; Reference Number]
HER2 Trastuzumab HER2 inhibitor HERA (HERceptin Adjuvant), P 3
NCT00045032		 1 year of adjuvant trastuzumab after CHT for pts with HER2-positive BC significantly improved long-term Disease-Free [Cameron et al. 2017; 29]
HER2 Pertuzumab HER2 inhibitor CLEOPATRA, P 3
NCT00567190		 Combination of pertuzumab with docetaxel and trastuzumab, in pts with HER2-positive mBC increased PFS [Baselga et al. 2012; 30]
HER2 Trastuzumab emtansine
(T-DM1), Anti-HER2 ADC:
HER2 inhibitor, microtubule inhibitor		 EMILIA
P 3
NCT00829166		 T-DM1 prolonged PFS and OS, with less toxicity (compared to lapatinib plus capecitabine), in patients with HER2-positive mBC, previously treated with trastuzumab and a taxane [Verma et al. 2012; 31]
HER2 Trastuzumab deruxtecan (DS-8201) Anti-HER2 ADC, Topoisomerase I inhibitor DESTINY-Breast01
P 2
NCT03248492		 Trastuzumab deruxtecan revealed durable antitumor activity in pretreated (with T-DM1) pts with HER2-positive mBC; in the trastuzumab deruxtecan arm: ORR = 60.3%; median PFS = 16.4 ms; interstitial lung disease is a serious AE that requires vigilant monitoring/intense therapy
[Modi et al. 2020; 32]
HER2 Trastuzumab duocarmazine (SYD985); Anti-HER2 ADC Duocarmycin derivative – an alkylating agent P 1 (ongoing)
NCT02277717
(SYD985 dose-escalation/dose-expansion)		 Trastuzumab duocarmazine has shown clinical activity in pretreated pts with HER2-positive mBC (HER2-positive, T-DM1-resistant, HER2-low expression BC), with manageable safety; ORR in HER2-positive BC = 33%; ORR in HER2-low, HR-positive BC = 27%; ORR in HER2-low, HR-negative BC = 40% [Banerji et al. 2019; 33]
HER2 Margetuximab
novel Anti-HER2
mAB; (Fc-engineered)		 SOPHIA
P 3
NCT02492711		 In pts with HER2-positive mBC (after anti-HER2 therapy, e.g. pertuzumab), margetuximab + CHT improved PFS compared to trastuzumab + CHT; PFS benefits were stronger in low-affinity CD16A-158F allele carriers [Rugo et al. 2019; 34]
HER2 Tucatinib
Novel selective HER2 TKI		 HER2CLIMB
P 3
NCT02614794		 In pretreated pts with HER2-positive mBC (with CNS metastases) adding tucatinib to a combination of trastuzumab/capecitabine resulted in longer median PFS (7,6 vs. 5,4 ms) and OS (21,9 vs. 17,4 ms) compared to the placebo arm; tucatinib exerts a stronger activity (than other TKIs) for CNS metastases and has a lower rate of AEs (e.g., skin reactions, diarrhea) [Murthy et al. 2020; 35]
HER2 Neratinib
An irreversible pan HER2 TKI		 SUMMIT basket trial
P 2
NCT01953926		 Neratinib (+ fulvestrant) is clinically active in pretreated pts with HER2-mutant, HR-positive mBC; median PFS = 5.4 months; ORR = 30%; CBR = 47%; Synergistic effects with trastuzumab exist in pts with HER2-positive mBC (including those with brain metastases); Neratinib/capecitabine improved median PFS (with a trend for improved OS) compared to Lapatinib/capecitabine; Neratinib/capecitabine delayed time to intervention for brain metastases [Smyth et al. 2019; 36]
HER2 Neratinib
An irreversible pan HER2 TKI		 NALA
P 3
NCT01808573		 In pretreated pts with HER2-positive mBC, in the Neratinib/capecitabine arm vs. Lapatinib/capecitabine arm: PFS rates = 28.8% vs. 14.8%; OS rates = 72.5% vs. 66.7%; ORR = 32.8% vs 26.7%; CBR = 44.5% vs. 35.6% activity for CNS metastases [Saura et al. 2019; 37]
HER2 Poziotinib
An irreversible pan HER2 TKI		 NOV120101-203
P 2
NCT02418689		 In pretreated pts with HER2-positive mBC, Poziotinib (as monotherapy, in a single-arm trial) revealed median PFS = 4 ms; DCR = 75% [Park et al. 2018; 38]
HER2 Pyrotinib
An irreversible pan HER2 TKI		 P 2
NCT003080805		 Pyrotinib or lapatinib (with capecitabine) in pts with HER2-positive mBC (post treatment with anthracyclines/taxanes/trastuzumab); in the arm: Pyrotinib/capecitabine: ORR = 78.5%; median PFS = 18.1 ms, vs. the arm Lapatinib/capecitabine: ORR = 57.1%; median PFS = 7.0 ms [Ma et al. 2019; 39]
CDK4/6 Palbociclib
CDK4/6 inhibitor		 PATINA
P 3 (ongoing)
NCT02947685		 Palbociclib added to trastuzumab, pertuzumab, and an AI vs. anti-HER2 therapy + ET, after induction treatment for HR-positive/HER2-positive mBC; evaluation of PFS with using the combination of palbociclib with anti-HER2 therapy + ET vs. anti-HER2 therapy + ET alone; (pending OS, tumor control measurements, safety, and QoL) [Loibl et al. 2018; 40]
CDK4/6 Abemaciclib
CDK4/6 inhibitor		 MonarcHER
P 2 (ongoing)
NCT02675231		 Combination of abemaciclib + trastuzumab and fulvestrant in pts with pretreated HR-positive, HER2-positive mBC has shown benefits: median PFS = 8.3 ms, compared to PFS =5.7 ms for trastuzumab + CHT; response rate with the combination of abemaciclib + trastuzumab and fulvestrant = 33% [Tolaney et al. 2019; 41]
mTOR Everolimus
mTOR inhibitor		 BOLERO-1
P 3
NCT00876395		 Everolimus in combination with trastuzumab + paclitaxel, as first-line treatment for pts with HER2-positive mBC, resulted in median PFS that was 7,2 ms longer upon adding everolimus in HR-negative, HER2-positive mBC) [Hurvitz et al. 2015; 42]
mTOR Everolimus
mTOR inhibitor		 BOLERO-3
P 3
NCT01007942		 Everolimus in combination with trastuzumab + vinorelbine in pts with HER2-positive mBC (pretreated with a taxane) has shown benefits: median PFS = 7.0 ms in the combination arm vs. PFS = 5.78 ms the placebo arm (trastuzumab + vinorelbine) [Andre et al. 2014; 43]
PD-L1 Pembrolizumab
PD-L1 inhibitor		 PANACEA
P 1b-2
NCT02129556		 Pembrolizumab + trastuzumab (single-arm trial) in trastuzumab-resistant, HER2-positive mBC; in PD-L1-positive subgroup of pts, the combination therapy revealed durable clinical benefits/acceptable safety; ORR = 15% [Loi et al. 2019; 44]
PD-L1 Atezolizumab
PD-L1 inhibitor		 KATE2
P 2
NCT02924883		 Atezolizumab added to T-DM1 in pts with HER2-positive mBC did not significantly increase median PFS compared to T-DM1 (placebo arm) in the ITT group; however, the median PFS was longer in PD-L1-positive subgroup [Emens et al. 2019; 45]

Abbreviations: ADC, Antibody Drug Conjugate; AEs, Adverse Events; AI, Aromatase Inhibitor; BC, Breast Cancer; CDK, Cyclin Dependent Kinase; CHT, Chemotherapy; CNS, Central Nervous System; DFS, Disease-Free Survival; ER, Estrogen Receptor; ET, Endocrine Therapy; HER2, Human Epidermal Growth Factor Receptor 2; HR, Hormone Receptor; ITT, Intent-To-Treat; m, Metastatic; mAb, Monoclonal Antibody; ms, Months; mTOR, Mechanistic Target of Rapamycin; ORR, Overall Response Rate; OS, Overall Survival; pts, Patients; PD-L1, Programmed Death Ligand 1; PFS, Progression-Free Survival; P, Phase; QoL, Quality of Life; ref., Reference; T-DM1, Trastuzumab Emtansine; TKI, Tyrosine Kinase Inhibitor; vs., versus.