Table 3

Newly approved agents for Her2-neu-positive breast cancer

AgentsDrug classesMain clinical trialsMechanism of actionsFDA approval date
Ado-trastuzumab emtansive or T-DM1 (Kadcyla)ADCThe EMILIA trial: phase III, the outcomes of this study showed that trastuzumab emtansine significantly improved both the PFS and OS (median 9.6 vs 6.4 months). At the second interim analysis, the median OS was 30.9 vs 25.1 months. The objective response rate was higher with T-DM1 (43.6% vs 30.8%).18
*The TH3RESA trial: phase III, trastuzumab emtansine treatment resulted in a significant improvement in OS (median 22.7 vs 15.8 months) versus treatment of physician’s choice.109
ADCs functions through target-dependent and target-independent mechanism. The targed-dependent mechanism relies on the target-binding capacity, followed by cellular internalization and degradation with payload release. The target-independent effect is based on extracellular cleavage or leakage of the payload from the target cells acting on neighboring antigen-negative cells and stromal tissue. ADCs can also act via antibody-mediated receptor signalling pathway causing immune response activation via the Fc domain of the mAbs, which is also known as antibody-dependent cell-mediated cytotoxicity.68 72 73 February 2013
Ado-Trastuzumab-deruxtecan (DS-8201)ADCThe DESTINY-Breast01 trial: reported RR in the trial was approximately 61% with a median PFS of 16.4 months.
*The DESTINY-Breast03 trial: phase III, this study showed that treatment with DS-8201 led to a highly significant 72% reduction in the risk of disease progression versus trastuzumab emtansine.
December 2019
MargetuximabADCThe SOPHIA trial: phase III, the confirmed ORR in this study was 22%, with a median DOR of 6.1 months in the margetuximab arm compared with an ORR of 16% and a median DOR of 6.0 months in the control arm.93 December 2020
Lapatinib (Tykerb)Her2-TKIThe NCT00078572 trial (Lapatinib plus Capecitabine for HER2-Positive Advanced Breast Cancer): phase III, the initial results of the trial demonstrated that lapatinib plus capecitabine is superior to capecitabine alone. The addition of lapatinib prolonged the time to progression (8.4 months compared with 4.4 months) and indicated a trend toward improving the OS and producing fewer cases with CNS involvement at first progression.97 98 TKIs are small molecular drugs that activate apoptosis and inhibiting proliferation of malignant cells. It competitively binds intracellular ATP binding domains of EGFR family due to the homological structure of the ATP, resulting in inhibiting tyrosine kinase phosphorylation, subsequently blocking downstream signals.110 March 2007
Her2-TKIThe ExteNET trial: phase III, at the 5-year follow-up analysis, the disease-free survival rate was 90.2% in the neratinib group and 87.7 in the placebo group.99 100
The NEfERT-T clinical trial: phase II, the conclusion of this study showed that neratinib-paclitaxel was not superior to trastuzumab-paclitaxel in terms of the PFS.98
The NALA trial: phase III, this study demonstrated only modest improving in PFS among patients treated with combination of neratinib with capecitabine versus lapatinib with capecitabine. More importantly was the observation that neratinib with capecitabine significantly improved median PFS in patients with CNS metastases (7.8 vs 5.5 months).102 103
February 2020
Tucatinib (TUKYSA)Her2-TKIThe HER2CLIMB trial: phase II, the overall PFS at 1 year in the experimental arm was 33.1% vs 12.3%. The median duration of PFS was 7.8 and 5.6 months, respectively. Even more impressive was the OS rate 44.9% at 2 years in the tucatinib group and 26.6% in placebo group. The median OS was 21.9 months in tucatinib group and 17.4 months in placebo group. Among the patients with brain metastases, the PFS at 1 year was 24.9% in the tucatinib group and 0% in the placebo group.104 105 April 2020
  • ADCs, antibody drug conjugates; CNS, central nervous system; DOR, duration of response; mAb, monoclonal antibody; NTRKI, neurotrophic receptor tyrosine kinase inhibitors; ORR, objective response rate; OS, overall survival; PARPI, poly-ADP-ribose polymerase inhibitor; PFS, progression-free survival; TKI, tyrosine kinase inhibitors; TROPI, trophoblast cell surface antigen inhibitors.