Table 1

A brief summary of newly approved targeted therapies for TN and Her2-neu-postive BC

ClassesMechanism of actionsAgentsMain clinical trialsFDA approval date
PARPIPARPI act by inhibiting DNA repair and replication in cancer cells deficient in BRCA1/BRCA2-dependent homologous recombination pathways through a process known as synthetic lethality.106 Olaparib (Lynparza)The ICEBERG trial: phase II, the RR was significantly high in olaparib group (33%).25 26
The OlympiAD trial: phase III, the 7 months PFS and ORR was doubled in olaparib group (59.9% vs 28.8%).23
January 2018
Talazoparib (Talzenna)The EMBRACA trial: phase III, talazoparib demonstrated a significantly better PFS to CT (8.6 vs 5.6 months), and the OS rate was 62.6% vs 27.2%.
The ABRAZO trial: phase II, the RR was 37% vs 21% in talazoparib group.30
July 2018
Checkpoint inhibitors (anti-PD-1/PD-L1, and CTLA-4)CTLA-4 enhancing the activation of T lymphocytes. Targeting PD-1/PD-L1 normalize the antitumor immune response. Immune checkpoint inhibitors block these checkpoint proteins from binding with their partner proteins that allows the T cells to kill cancer cells.107 Pembrolizumab (anti-PD-1 antibody- Keytruda)The KEYNOTE-522 trial: phase III, the trial demonstrated superior RR in Keytruda group after 15.5 months of follow-up (64.8% vs 51.2%).52
The KEYNOTE-355 trial: phase III, the trial demonstrated significantly higher PFS at 9.7 months compared with CT alone 5.6 months.55 56
November 2020
Nivolumab (anti-PD-1 antibody) and ipilimumab (anti-CTLA-4 antibody)The TONIC trial: phase II, This study demonstrated modest ORR with nivolumab as only one (2%) patient had the stable disease lasting >24 weeks.54
The Dart, SWOG S1609 trial: phase II, the preliminary result demonstrated an ORR of 12%, but 24% of patients had stable disease over 12 months.58
This combination has not been approved by FDA yet
NTRKINTRK1, NTRK2, NTRK3, and their genes encode TRK proteins. TKIs inhibit corresponding kinases from phosphorylating tyrosine residues of their substrates and then block the activation of downstream signaling pathways.108 LarotrectinibThe LOXO-TRK-14001, SCOUT and the NAVIGATE trials: phase I/II/III, the ORR was 75% with CRR approximately 16%. The median time to response was 1.8 months. The PFS duration in this study was not yet reached at the time of the last data cut-off. In total, 55% of the patients remained stable over 12 months.60 November 2018
EntrectinibThe ALKA, STARTRK-1, and STARTRK-2 trials: phase I/II, the trials demonstrated highest RR approaching 100% among treatment-naïve children whose cancers harboring an NTRK. It was slightly less among young adults 86%, and 57% among adults.66 August 2019
ADCsADCs functions through target-dependent and target-independent mechanism. The target-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 also known as antibody-dependent cell-mediated cytotoxicity.68 72 73 Ado-trastuzumab emtansive or T-DM1 (Kadcyla)The 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 ORR 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
February 2013
Ado-trastuzumab-deruxtecan (DS-8201)The DESTINY-Breast01 trial: reported RR in the trial was approximately 61% with a median PFS of 16.4 months.19
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.110
December 2019
MargetuximabThe 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
TROPITrop-family proteins, including Trop-1, Trop-2, Trop-3, and Trop-4. Only Trop-2 plays a key role in promoting tumor growth. The TROP2 inhibitor recognizes Trop-2. The small molecule, SN-38, is a topoisomerase I inhibitor, which is covalently attached to the antibody by a linker binds to Trop-2-expressing cancer cells and is internalized with the subsequent release of SN-38 via hydrolysis of the linker. SN-38 interacts with topoisomerase I and prevents re-ligation of topoisomerase I-induced single strand breaks. The resulting DNA damage leads to apoptosis and cell death.80 Sacituzumab govitecan-hziy (Trodelvy)The IMMU-132-01 trial: phase I/II, this study demonstrated an impressive RR approximately 33% and the median duration of the response 7.7 months. The median PFS was 5.5 months and the median OS was 13.0 months.81 April 2020
Her2-TKITKIs are small molecular drugs that activates 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 signals94 Lapatinib (Tykerb)The 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 TTP (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 March 2007
The 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.96 97
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 months vs 5.5 months).102 103
February 2020
Tucatinib (TUKYSA)The HER2CLIMB trial: phase, 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; CT, chemotherapy; CTLA-4, cytotoxic T-lymphocyte-associated protein 4; DOR, duration of response; FDA, Food and Drug Administration; NTRKI, neurotrophic receptor tyrosine kinase inhibitors; ORR, objective response rate; OS, overall survival; PARPI, poly-ADP-ribose polymerase inhibitor; PD-1, programmed cell death protein 1; PD-L1, programmed death-ligand 1; PFS, progression-free survival; TKI, tyrosine kinase inhibitors; TRK, tropomyosin receptor kinase; TROPI, trophoblast cell surface antigen inhibitors; TTP, time to progression.