Optimizing the potential of antibody–drug conjugates in oncology

Antibody–drug conjugates (ADCs) consist of antibodies linked with payloads. Payloads are usually cytotoxic chemotherapy, but new cytotoxic agents are being explored (targeted therapies, immunotherapeutics, etc.). Theoretically, ADCs work as drug delivery systems by delivering high doses of cytotoxic agents inside the cancer cells thereby increasing cancer cell death while sparing normal tissues. 1 Tolcher A.W. Antibody drug conjugates: lessons from 20 years of clinical experience. Ann Oncol Off J Eur Soc Med Oncol. 2016; 27: 2168-2172 Abstract Full Text Full Text PDF PubMed Scopus (109) Google Scholar The field has gained major interest after an anti-human epidermal growth factor receptor 2 (HER2) ADC, named trastuzumab deruxtecan (T-DXd), showed transformative results in patients with HER2-overexpressing metastatic breast cancer (mBC). For example, in the DESTINY-Breast02 randomized trial, the median overall survival for patients treated with T-DXd and standard chemotherapy was 39.2 versus 26.5 months, respectively (hazard ratio 0.66, 95% confidence interval 0.50-0.86, P = 0.0021). 2 André F. Hee Park Y. Kim S.B. et al. Trastuzumab deruxtecan versus treatment of physician’s choice in patients with HER2-positive metastatic breast cancer (DESTINY-Breast02): a randomised, open-label, multicentre, phase 3 trial. Lancet Lond Engl. 2023; 401: 1773-1785 Abstract Full Text Full Text PDF PubMed Scopus (32) Google Scholar Similar results were obtained in trials addressing more heavily pretreated patients, such as DESTINY-Breast01, or comparing T-DXd with a less potent ADC, trastuzumab emtansine (T-DM1), in DESTINY Breast 03. 3 Modi S. Saura C. Yamashita T. et al. Abstract PD3-06: updated results from DESTINY-breast01, a phase 2 trial of trastuzumab deruxtecan (T-DXd) in HER2 positive metastatic breast cancer. Cancer Res. 2021; 81: PD3-PD06 Crossref Google Scholar ,4 Hurvitz S.A. Hegg R. Chung W.P. et al. Trastuzumab deruxtecan versus trastuzumab emtansine in patients with HER2-positive metastatic breast cancer: updated results from DESTINY-Breast03, a randomised, open-label, phase 3 trial. Lancet. 2023; 401: 105-117 Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar The same drug was developed for ERBB2-mutant non-small-cell lung cancer (NSCLC), HER2-overexpressing gastric and colon cancer, HER2-low mBC and, more recently, in HER2-expressing cancers irrespective of the organ of origin. 5 Li B.T. Smit E.F. Goto Y. et al. Trastuzumab deruxtecan in HER2-mutant non-small-cell lung cancer. N Engl J Med. 2022; 386: 241-251 Crossref PubMed Scopus (304) Google Scholar , 6 Shitara K. Bang Y.J. Iwasa S. et al. Trastuzumab deruxtecan in previously treated HER2-positive gastric cancer. N Engl J Med. 2020; 382: 2419-2430 Crossref PubMed Scopus (582) Google Scholar , 7 Yoshino T. Di Bartolomeo M. Raghav K.P.S. et al. Trastuzumab deruxtecan (T-DXd; DS-8201) in patients (pts) with HER2-expressing metastatic colorectal cancer (mCRC): final results from a phase 2, multicenter, open-label study (DESTINY-CRC01). J Clin Oncol. 2022; 40: 119 Crossref Google Scholar , 8 Modi S. Jacot W. Yamashita T. et al. Trastuzumab deruxtecan in previously treated HER2-low advanced breast cancer. N Engl J Med. 2022; 387: 9-20 Crossref PubMed Google Scholar , 9 Meric-Bernstam F. Makker V. Oaknin A. et al. Efficacy and safety of trastuzumab deruxtecan (T-DXd) in patients (pts) with HER2-expressing solid tumors: DESTINY-PanTumor02 (DP-02) interim results. J Clin Oncol. 2023; 41: LBA3000 Crossref Google Scholar While not as outstanding as HER2-overexpressing mBC, these trials reported consistent clinically meaningful benefit across HER2-expressing tumors and HER2-low mBC. Beyond HER2, several other ADCs have been developed. Anti-TROP2 ADCs, sacituzumab govitecan (SG) and datopotamab deruxtecan, have shown benefit across a wide range of tumor types, including metastatic triple-negative breast cancer (TNBC), urothelial cancer (UC) and NSCLC. 10 Bardia A. Tolaney S.M. Loirat D. et al. Sacituzumab govitecan (SG) versus treatment of physician’s choice (TPC) in patients (pts) with previously treated, metastatic triple-negative breast cancer (mTNBC): final results from the phase 3 ASCENT study. J Clin Oncol. 2022; 40: 1071 Crossref Google Scholar , 11 Bardia A. Krop I. Meric-Bernstam F. et al. Abstract P6-10-03: datopotamab deruxtecan (Dato-DXd) in advanced triple-negative breast cancer (TNBC): updated results from the phase 1 TROPION-PanTumor01 study. Cancer Res. 2023; 83 (03): P6-P10 Crossref Google Scholar , 12 Spira A. Lisberg A. Sands J. et al. OA03.03 datopotamab deruxtecan (Dato-DXd; DS-1062), a TROP2 ADC, in patients with advanced NSCLC: updated results of TROPION-PanTumor01 phase 1 study. J Thorac Oncol. 2021; 16: S106-S107 Abstract Full Text Full Text PDF Google Scholar , 13 Tagawa S.T. Balar A.V. Petrylak D.P. et al. TROPHY-U-01: a Phase II open-label study of sacituzumab govitecan in patients with metastatic urothelial carcinoma progressing after platinum-based chemotherapy and checkpoint inhibitors. J Clin Oncol Off J Am Soc Clin Oncol. 2021; 39: 2474-2485 Crossref PubMed Scopus (200) Google Scholar Enfortumab vedotin, a nectin-4-directed ADC, has also shown improved survival outcomes in patients with metastatic UC. 14 Powles T. Rosenberg J.E. Sonpavde G.P. et al. Enfortumab vedotin in previously treated advanced urothelial carcinoma. N Engl J Med. 2021; 384: 1125-1135 Crossref PubMed Scopus (388) Google Scholar Although these data are consistent and indicate that ADCs are a new field of innovation, it remains unclear whether this class of drugs will transform cancer treatment or only modestly improve outcomes in selected patients. In this context, which data are missing to establish ADCs as a transformative therapy across tumor histologies and targets?