Resistance to Antibody-Drug Conjugates Targeting HER2 in Breast Cancer: Molecular Landscape and Future Challenges
Abstract
:Simple Summary
Abstract
1. Introduction
2. Mechanisms of Resistance to T-DM1
2.1. Receptor Related Mechanisms of Resistance to T-DM1
2.2. Intracellular Mechanisms of Resistance to T-DM1
3. Emerging Mechanisms of Resistance to T-DXd: The DAISY Trial
4. Novel Combination Strategies to Overcome or Prevent Resistance
4.1. Tyrosine Kinase Inhibitors and ADCs
4.2. Statins and ADCs
4.3. Immune-Checkpoint Inhibitors and ADCs
4.4. DNA-Damaging Agents and ADCs
5. Next Generation ADCs to Overcome or Prevent Resistances
6. Current Issues and Future Challenges
7. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Abbreviations
References
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Treatment | NCT Number | Ph. | Patients | Study Design | Endpoints |
---|---|---|---|---|---|
ADCs + TKIs | |||||
T-DM1 + lapatinib | NCT02073916 | Ib | HER2+ mBC | T-DM1 + Lapatinib + nab-paclitaxel | Safety |
T-DM1 + tucatinib | NCT01983501 | I | HER2+ mBC | T-DM1 + Tucatinib | Safety |
T-DM1 + neratinib | NCT02236000 | Ib/II | HER2+ mBC | T-DM1 + Neratinib | Safety, ORR |
T-DM1 + lapatinib | NCT02073487 | II | HER2+ BC | Neoadjuvant T-DM1 + Lapatinib followed by Abraxane vs. Trastuzumab + Pertuzumab Followed by Paclitaxel | pCR, RCB |
T-DM1 + neratinib | NCT05388149 | II | MRD+ HER2+ BC | T-DM1 + Neratinib | ctDNA clearence |
T-DXd + tucatinib | NCT04539938 | II | HER2+ mBC | T-DXd + Tucatinib | ORR |
T-DM1 + tucatinib | NCT03975647 | III | HER2+ mBC | Tucatinib/Placebo + T-DM1 | PFS, OS |
T-DM1 + tucatinib | NCT04457596 | III | High risk HER2+ BC | Tucatinib/ Placebo + T-DM1 | iDFS |
ADCs + ICIs | |||||
T-DM1 + pembrolizumab | NCT03032107 | Ib | HER2+ mBC | Pembrolizumab + T-DM1 | Safety |
T-DM1 + atezolizumab | NCT02605915 | Ib | HER2+ BC | Atezolizumab + T-DM1 vs. (Atezolizumab + Trastuzumab + Pertuzumab ± Docetaxel) | Safety |
T-DM1 + utomilumab | NCT03364348 | Ib | HER2+ mBC | Utomilumab + T-DM1 vs. Utomilumab + Trastuzumab | Safety, ORR |
T-DXd + Durvalumab | NCT04556773 | Ib | HER2low mBC | T-DXd + Durvalumab | Safety, ORR |
T-DXd + Nivolumab | NCT03523572 | Ib | HER2+ mBC | T-DXd + Nivolumab | Safety, ORR |
T-DXd + pembrolizumab | NCT04042701 | Ib | mBC | T-DXd + Pembrolizumab | Safety, ORR |
T-DM1 + atezolizumab | NCT02924883 | II | HER2+ mBC | T-DM1 + Atezolizumab/placebo | PFS, OS, ORR |
T-DM1 + atezolizumab | NCT04740918 | III | HER2+ PDL1+ mBC | T-DM1 + Atezolizumab/placebo | PFS, OS |
ADCs + DNA-damaging agents | |||||
T-DXd + Ceralasertib | NCT04704661 | I/Ib | HER2+ solid tumors | Ceralasertib + T-DXd | Safety |
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Guidi, L.; Pellizzari, G.; Tarantino, P.; Valenza, C.; Curigliano, G. Resistance to Antibody-Drug Conjugates Targeting HER2 in Breast Cancer: Molecular Landscape and Future Challenges. Cancers 2023, 15, 1130. https://doi.org/10.3390/cancers15041130
Guidi L, Pellizzari G, Tarantino P, Valenza C, Curigliano G. Resistance to Antibody-Drug Conjugates Targeting HER2 in Breast Cancer: Molecular Landscape and Future Challenges. Cancers. 2023; 15(4):1130. https://doi.org/10.3390/cancers15041130
Chicago/Turabian StyleGuidi, Lorenzo, Gloria Pellizzari, Paolo Tarantino, Carmine Valenza, and Giuseppe Curigliano. 2023. "Resistance to Antibody-Drug Conjugates Targeting HER2 in Breast Cancer: Molecular Landscape and Future Challenges" Cancers 15, no. 4: 1130. https://doi.org/10.3390/cancers15041130
APA StyleGuidi, L., Pellizzari, G., Tarantino, P., Valenza, C., & Curigliano, G. (2023). Resistance to Antibody-Drug Conjugates Targeting HER2 in Breast Cancer: Molecular Landscape and Future Challenges. Cancers, 15(4), 1130. https://doi.org/10.3390/cancers15041130