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• W4386866116 abstract "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, others). 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 1Tolcher A.W. Antibody drug conjugates: lessons from 20 years of clinical experience.Ann. Oncol. Off. J. Eur. Soc. Med. Oncol. 2016; 27: 2168-2172Abstract Full Text Full Text PDF PubMed Scopus (0) 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 vs. 26.5 months, respectively (HR 0.66, 95% CI: 0.50-0.86, P=0.0021)2André F. 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: 1773-1785Abstract Full Text Full Text PDF PubMed Scopus (0) 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 033,4. 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 origin5Li B.T. et al.Trastuzumab Deruxtecan in HER2-Mutant Non–Small-Cell Lung Cancer.N. Engl. J. Med. 2022; 386: 241-251Crossref PubMed Scopus (245) Google Scholar, 6Shitara K. et al.Trastuzumab Deruxtecan in Previously Treated HER2-Positive Gastric Cancer.N. Engl. J. Med. 2020; 382: 2419-2430Crossref PubMed Scopus (498) Google Scholar, 7Yoshino, T. 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. 40, 119–119 (2022).Google Scholar, 8Modi S. et al.Trastuzumab Deruxtecan in Previously Treated HER2-Low Advanced Breast Cancer.N. Engl. J. Med. 2022; 387: 9-20Crossref PubMed Google Scholar, 9Meric-Bernstam, F. 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. 41, LBA3000–LBA3000 (2023).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 10Bardia, A. 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. 40, 1071–1071 (2022).Google Scholar, 11Bardia A. 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): P6-10Crossref Google Scholar, 12Spira, A. 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. 16, S106–S107 (2021).Google Scholar, 13Tagawa S.T. 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: 2474-2485Crossref PubMed Scopus (0) Google Scholar. Enfortumab vedotin, a nectin-4 directed ADC, has also shown improved survival outcomes in patients with metastatic UC14Powles T. et al.Enfortumab Vedotin in Previously Treated Advanced Urothelial Carcinoma.N. Engl. J. Med. 2021; 384: 1125-1135Crossref PubMed Scopus (321) 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? First, there is a need to better understand the molecular mechanisms behind drug sensitivity to personalize the choice of ADC for each patient. The first question to address is the explanation of the outlier sensitivity of HER2-overexpressing mBC to T-DXd, which involves understanding the optimal target density, tumor distribution, and cell membrane localization to maximize ADC efficacy. While one could argue that this sensitivity is related to target expression, it is worth mentioning that ADCs targeting other overexpressed targets did not demonstrate the same level of efficacy so far. Understanding this outlier scenario will help to further improve ADC design. There are still controversies about whether the level of target expression matters in explaining ADC efficacy. In patients with ovarian cancer, mirvetuximab soravtansine proved superior outcomes over chemotherapy only in patients with high folate receptor alpha (FRα) expression 15Matulonis U.A. et al.Efficacy and Safety of Mirvetuximab Soravtansine in Patients With Platinum-Resistant Ovarian Cancer With High Folate Receptor Alpha Expression: Results From the SORAYA Study.J. Clin. Oncol. 2023; 41: 2436-2445Crossref PubMed Scopus (20) Google Scholar,16Moore K.N. et al.Phase III, randomized trial of mirvetuximab soravtansine versus chemotherapy in patients with platinum-resistant ovarian cancer: primary analysis of FORWARD I.Ann. Oncol. Off. J. Eur. Soc. Med. Oncol. 2021; 32: 757-765Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar. Conversely, in ASCENT trial, SG performed better than standard chemotherapy across a wide range of TROP2 expression, although very low levels of TROP2 were associated with numerically lower benefit17Bardia A. et al.Biomarker analyses in the phase III ASCENT study of sacituzumab govitecan versus chemotherapy in patients with metastatic triple-negative breast cancer.Ann. Oncol. Off. J. Eur. Soc. Med. Oncol. 2021; 32: 1148-1156Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar. In DAISY trial, PFS was shorter in patients with HER2 non-expressing mBC treated with T-DXd18Mosele F. et al.Trastuzumab deruxtecan in metastatic breast cancer with variable HER2 expression: the phase 2 DAISY trial.Nat. Med. 2023; : 1-11https://doi.org/10.1038/s41591-023-02478-2Crossref Scopus (1) Google Scholar. Nevertheless, these outlier negative populations represent a small proportion of patients. One possible explanation for the lack of correlation between receptor expression and efficacy in most of the patients could be the cell membrane localization of the receptor and its internalization capability. Indeed, ADCs require receptor internalization to deliver payloads. Further research will need to determine whether the high level of target internalization could predict efficacy better that target expression, regardless of the location. Furthermore, payload cleavage and sensitivity to the payload are two other major determinants of drug efficacy. Since payload cleavage occurs in late endosomes and lysosomes in most modern ADCs, revitalizing research in cell biology is necessary to better investigate the optimal conditions of cleavage in patients. Finally, defining the determinants of payload sensitivity is of utmost relevance to personalize ADCs administration. It is very likely that new tools in spatial biology, which can co-localize targets of antibody and payloads, will make major strides forward personalized ADCs. In Table 1, we described the companion and potential biomarkers for ADCs approved in solid tumors. Beyond personalization of ADC administration, combination is the second key axis of development to optimize the potential of ADCs. Developing optimal combinations requires a better understanding of the mechanisms of action and resistance to modern ADCs. Interestingly, it has been reported that T-DXd administration does not alter tumor lymphocytic infiltration, providing a strong rationale to combine ADCs with immune checkpoint inhibitors (ICIs) or Bispecific T cell engagers. Nevertheless, it has been observed that programmed death-ligand 1 (PD-L1) could decrease after T-DXd administration, suggesting that the optimal immunotherapy agents to combine with ADCs are others than PD-L1 inhibitors18Mosele F. et al.Trastuzumab deruxtecan in metastatic breast cancer with variable HER2 expression: the phase 2 DAISY trial.Nat. Med. 2023; : 1-11https://doi.org/10.1038/s41591-023-02478-2Crossref Scopus (1) Google Scholar. Further analyses of the changes in the tumor microenvironment several weeks after ADC administration could reveal which ICI should be targeted in combination with ADCs. Poly (ADP-ribose) polymerase (PARP) and ataxia telangiectasia mutated (ATM) inhibitors have been reported to be synergistic with T-DXd, mainly by increasing sensitivity to the payload 19Li Y. et al.Combined inhibition of PARP and ATR synergistically potentiates the antitumor activity of HER2-targeting antibody-drug conjugate in HER2-positive cancers.Am. J. Cancer Res. 2023; 13: 161-175PubMed Google Scholar. However, one of the major barrier is the toxicity of these combinations. Beyond investigating new schedules, one possible solution would be to develop ADCs that include multiple, synergistic payloads. As example, topoisomerase I inhibitors and PARP inhibitors could be combined as payloads in the same or multiple antibody backbones. Being able to monitor ADC uptake, target expression, and response to payload (e.g. gH2AX for DXd) longitudinally will help in defining the optimal sequence of therapy for each patient. Circulating tumor cells could be a useful tool to monitor such markers and, therefore, adapt therapy accordingly. Finally, understanding the most common mechanisms of resistance to a given ADC in clinical trials and ultimately in each patient will provide a better picture about which component of the ADC (antibody, linker, payload) should be modified. In this regard, the use of organoids could be particularly useful for testing sensitivity to the payload and to the whole ADC separately, as well as for detecting ADC uptake and internalization specific to each patient.Table 1ADCs approved for patients with solid tumors and biomarkersADCCompanion biomarkerExamples of candidate biomarkers at different steps of ADC mechanisms of actionT-DXdHER2Spatial distribution of the target18Mosele F. et al.Trastuzumab deruxtecan in metastatic breast cancer with variable HER2 expression: the phase 2 DAISY trial.Nat. Med. 2023; : 1-11https://doi.org/10.1038/s41591-023-02478-2Crossref Scopus (1) Google ScholarReceptor endocytosis20Ritchie M. Tchistiakova L. Scott N. Implications of receptor-mediated endocytosis and intracellular trafficking dynamics in the development of antibody drug conjugates.mAbs. 2013; 5: 13-21Crossref PubMed Scopus (186) Google ScholarLysosomal PH21Ríos-Luci C. et al.Resistance to the Antibody-Drug Conjugate T-DM1 Is Based in a Reduction in Lysosomal Proteolytic Activity.Cancer Res. 2017; 77: 4639-4651Crossref PubMed Scopus (89) Google ScholarResistance to payload 22Coates J.T. et al.Parallel Genomic Alterations of Antigen and Payload Targets Mediate Polyclonal Acquired Clinical Resistance to Sacituzumab Govitecan in Triple-Negative Breast Cancer.Cancer Discov. 2021; 11: 2436-2445Crossref PubMed Scopus (41) Google ScholarT-DM1HER2Mirvetuximab soravtansineFolate receptor alphaSacituzumab govitecanNoneEnfortumab vedotinNoneTisotumab vedotinNone Open table in a new tab Third, the major unknown in the field of ADCs is whether they can prevent and cure tumor metastases. Data are so far too preliminary to generate any conclusion on this question. On one hand, we are starting to see patients with long-term complete tumor responses, raising the question of whether it is reasonable to stop the treatment, similar to some advanced cancers cured by immunotherapy. On the other hand, future clinical research will need to define the optimal ADC duration and schedule for early-stage cancers as well. Finally, as a result of the prior axes, there is a need to accelerate the tumor-agnostic approval and adoption of ADCs. To achieve this, several steps should be pursued. Firstly, the design of larger clinical trials that evaluate ADC activity in diverse tumor types. These studies, known as ADC-biomarker driven tumor-agnostic trials, will provide valuable insights into the efficacy of ADCs across various cancer types. Secondly, it is essential to establish updated international guidelines that define treatment algorithms involving ADCs for non-tumor specific indications. These guidelines will provide clear and standardized procedures for using ADCs in a tumor-agnostic context, ensuring that patients receive the most appropriate and effective treatment. Lastly, by implementing these measures, regulatory authorities should consider adopting a biomarker-guided approach to ADC approval. Shifting the focus from tumor-specific indications to biomarker-driven criteria can potentially accelerate the approval of ADCs that demonstrate promising results in targeting specific biomarkers, regardless of the tumor origin. While the wave of ADCs coming to clinics is impressive, there is a need for translational research to optimize their potential. This includes three axes, i.e. defining determinants of sensitivity to personalized ADCs, determining optimal combinations, and lastly, defining the optimal duration, dose, and schedule to cure patients with early (and potentially advanced) tumors. Without addressing these points, there is a risk that the clinical use of this new class of agents will not be optimized and may not have the transformative impact on cancer outcome as it should do. Lastly but not least, while the current position paper was focused on ADCs targeting cancer cells, there is a need to explore the use of ADCs to eliminate tumor-promoting cells of the microenvironment, such as MSDC, fibroblasts, regulatory T cells, endothelial cells, M2 macrophages, and others (Table 2).Table 2Research needs to optimize the potential of ADCsAxesResearch questionsRequired tools & DataTo personalize ADC administration in order to maximize the likelihood of response in each patientoHow to explain outlier sensitivity of HER2-overexpressing mBC to T-DXdoRole of antibody target expression and localization (internalization) in the drug efficacyoIs there a primary resistance to payloads?oCan the ADC be uncleaved and why?oCan an ADC with equivalent efficacy reverse resistance to another one?oSpatial biology that will co-localize targets of antibody and payloadsTo develop combinationsoWhich ICI mediates immune suppression after ADC infusion?oWhich targeted therapies increase drug internalization and synergize with the payload? (mTOR inh, PARP inh, others)oHow to combine ADC with targeted agents? (safety)oOn treatment biopsies to assess changes in tumor microenvironmentoAnalyses of mechanisms of resistance using ex-vivo models, including organoidsoConstruction of ADCs that include multiple payloadsTo define whether ADCs can cure patients with early (and advanced) cancersoWhich dose, schedule and duration cure patients with early stage cancers?oClinical trials to compare multiple dose, schedule and duration, with on treatment biopsiesTo speed up tumor-agnostic ADC development and approvaloHow more rapidly to establish the efficacy of ADCs across different tumor types?oHow to speed up a tumor-agnostic, biomarker-driven ADC approval?oBetter-designed clinical trials to assess the effectiveness of ADCs against different types of tumors expressing biomarkers of ADC sensitivityoGuidelines and recommendations including biomarker-guided treatment algorithms for the clinical use of ADCs against different tumor typesTo design ADCs that target tumor promoting cells from the microenvironmentoWhich proteins of the microenvironment should be targeted?oAre cells from the microenvironment as sensitive as cancer cells to 3rd generation ADCs?oDrug design & preclinical development Open table in a new tab F.M. received consultant fees from Novartis and Pegascy. G.M has no disclosures. B.P. received fees as advisor/consultant from Pierre Fabre (self), Daiichi Sankyo (self), Merck Sharp & Dohme (institution), Seattle Genetics (institution), Eli Lilly (institution) and Novartis (institution); funding to institution for research support from Daiichi Sankyo and AstraZeneca; and travel expenses from AstraZeneca, Pfizer and Gilead. F.A. received research funding and served as speaker/advisor (compensated to the hospital) from Roche, AstraZeneca, Daiichi Sankyo, Pfizer, Novartis and Eli Lilly. Funding: No funding is declared. 3Modi S. 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: PD3-06Crossref Google Scholar, 4Hurvitz S.A. 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.The Lancet. 2023; 401: 105-117Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar." @default.
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• W4386866116 title "Optimizing the potential of Antibody Drug Conjugates in oncology" @default.
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