Exploring the Role of ADCs in Brain Metastases and Primary Brain Tumors: Insight and Future Directions
Simple Summary
Abstract
1. Introduction
2. Primary Brain Tumors
Reference | Type of Trial | Population | Intervention | Target | Endpoints |
---|---|---|---|---|---|
[35] | Phase III | rGBM (first recurrence) | CB vs. gliadel wafers | IL-13 | No survival difference |
[36] | Phase IIb | rGBM | MDNA55 (Bizaxofusp) | IL-4 | mOS: 11.64 months [80% one-sided CI 8.62, 15.02] |
3. Brain Metastases
3.1. Non-Small Cell Lung Cancer
3.1.1. Trastuzumab Deruxtecan
3.1.2. Datopotamab Deruxtecan
3.1.3. Patritumab Deruxtecan
3.1.4. Telisotuzumab–Vedotin
3.2. Breast Cancer
3.2.1. Ado-Trastuzumab Emtansine
3.2.2. Trastuzumab Deruxtecan
3.2.3. Sacituzumab Govitecan
4. Combination with Radiation Therapy
5. Discussion
6. Conclusions
Author Contributions
Funding
Conflicts of Interest
Appendix A
Clinical Trial | Response Endpoint | ADC | Target | Linker Type | Payload Action | Population | CNS Metastasis Eligibility | Trial Type | Status |
---|---|---|---|---|---|---|---|---|---|
HER3-DXd in Breast Cancer and NSCLC Brain Metastases and Solid Tumor Leptomeningeal Disease (TUXEDO-3) (NCT05865990) | iORR as defined by RANO -BM criteria | Patritumab deruxtecan (HER3-DXd) | HER3 | Cleavable | Topoisomerase I inhibitor (Deruxtecan) | Patients with previously treated a/m NSCLC with newly diagnosed or progressive BM | Patients are eligible if steroid use is <8 mg of Dexamethasona/day | Phase II | Active, not recruiting |
Datopotamab Deruxtecan (Dato-DXd) for Non-Small Cell Lung Cancer (NSCLC) patients with Active Brain Metastases (TUXEDO-5) (NCT06676917) | iORR as defined by RANO-BM criteria | Datopotamab Deruxtecan (Dato-DXd) | TROP2 | Cleavable | Topoisomerase I inhibitor (Deruxtecan) | Patients with previously treated a/m non squamous NSCLC with active BM | Patients with BM and leptomeningeal disease are allowed if there is no indication for immediate local therapy | Phase II | Recruitment not yet open; the estimated study start date is April 2025 |
Sacituzumab Tirumotecan (MK-2870) Versus Chemotherapy in Previously Treated a/m Nonsquamous NSCLC with EGFR Mutations or Other Genomic Alterations (NCT06074588) | PFS as defined by RECIST v 1.1 and OS | Sacituzumab tirumotecan (MK-2870) | TROP2 | Cleavable | Topoisomerase I Inhibitor (Tirumotecan) | Patients with a/m non-squamous NSCLC with treatment-refractory progressive disease | Previously treated BM included; active BM and leptomeningeal disease excluded | Phase III | Recruiting |
Phase III, Open-label, First-line Study of Dato-DXd in Combination with Durvalumab and Carboplatin for Advanced NSCLC Without Actionable Genomic Alterations (AVANZAR) (NCT05687266) | PFS as defined by RECIST v1.1 and OS | Datopotamab Deruxtecan (Dato-DXd) | TROP2 | Clevable | Topoisomerase I inhibitor (Deruxtecan) | Patients with a/m NSCLC without actionable genomic alterations with approved and a viable target therapy | Active BM and leptomeningeal disease excluded | Phase III | Active, not recruiting |
Study of Pembrolizumab (MK-3475) Monotherapy Versus Sacituzumab Govitecan in Combination with Pembrolizumab for Participants With Metastatic Non-small Cell Lung Cancer (NSCLC) With Programmed Cell Death Ligand 1 (PD-L1) Tumor Proportion Score (TPS) ≥ 50% (MK-3475-D46) (NCT05609968) | PFS as defined by RECIST v1.1 and OS | Sacituzumab govitecan (SG) | TROP2 | Cleavable | Topoisomerase I Inhibitor (govitecan) | Patients with a/m NSCLC without an indication of EGFR-ALK-1, or ROS-1-targeted therapies with PD-L1 expression > 50% | Active BM and leptomeningeal disease excluded | Phase III | Recruiting |
Study of Dato-DXd Plus Pembrolizumab vs. Pembrolizumab Alone in the First-line Treatment of Subjects with Advanced or Metastatic NSCLC Without Actionable Genomic Alterations (TROPION-Lung08) (NCT05215340) | PFS as defined by RECIST v1.1 and OS | Datopotamab Deruxtecan (Dato-DXd) | TROP2 | Cleavable | Topoisomerase I Inhibitor (Deruxtecan) | Patients with a/m non-squamous NSCLC without actionable genomic alterations (mKRAS eligible) with PD-L1 expression > 50% | Active and untreated BM excluded; leptomeningeal disease excluded | Phase III | Recruiting |
A Study of YL202 in Selected Patients with Advanced Solid Tumors (NCT06107686) | ORR as defined by RECIST v1.1 | YL202 | HER3 | Cleavable | Topoisomerase I Inhibitor (YL0010014) | Patients with a/m NSCLC | Patients with BM excluded | Phase II | Recruiting |
A Study of Disitamab Vedotin in Previously Treated Solid Tumors That Express HER2 (NCT06003231) | ORR as defined by RECIST v1.1 | Disitamab Vedotin | HER2 | Cleavable | Auristatin microtubule inhibitor (monomethyl auristatin E) | Patients with a/m solid tumors, including NSCLC, with HER2 overexpression | Active and untreated BM and leptomeningeal disease excluded | Phase II | Recruiting |
A Phase 2 Study of BA3011 Alone and in Combination with PD-1 Inhibitor in Adult Patients with Metastatic Non-small Cell Lung Cancer (NSCLC) Who Had Prior Disease Progression on a PD-1/L-1 Inhibitor, EGFR, or ALK Inhibitor. (NCT04681131) | ORR as defined by RECIST v1.1 | CAB-AXL-ADC | AXL | Cleavable | Auristatin microtubule inhibitor (monomethyl auristatin E) | Patients with a/m NSCLC | Patients with active BM excluded | Phase II | Active, non recruiting |
Datopotamab Deruxtecan (Dato-DXd, DS-1062a) in Advanced and/or Unresectable Non-Small Cell Lung Cancer (ICARUS-LUNG01) (NCT04940325) | ORR as defined by RECIST v1.1 | Datopotomab Deruxtecan (Dato-DXd) | TROP2 | Cleavable | Topoisomerase I Inhibitor (Deruxtecan) | Patients with a/m NSCLC | BM eligible only if treated and clinically stable without medical treatment | Phase II | Active, non recruiting |
CAB-ROR2-ADC Safety and Efficacy Study in Patients with TNBC or Head & Neck Cancer (Ph1) and NSCLC or Melanoma (Ph2) (NCT03504488) | ORR | Ozuriftamab vedotin | ROR2 | Cleavable | Auristatin microtubule inhibitor (monomethyl auristatin E) | Patients with a/m solid tumors, including NSCLC, that is refractory or not amenable to the standard-of-care therapy | Uncontrolled BM excluded | Phase I/II | Active, non recruiting |
A Clinical Trial of TQB2102 for Injection in Non-small Cell Lung Cancer with HER2 Gene Abnormality (NCT06496490) | ORR | TQB2102 | HER2 | Cleavable | Topoisomerase I Inhibitor (topotecan) | Patients with a/m NSCLC refractory to standard-of-care therapy | Stable BM included Uncontrolled BM or Leptomeningeal disease excluded | Phase II | Recruiting |
Study to Investigate Luveltamab Tazevibulin in Adults with Advanced or Metastatic Non-small Cell Lung Cancer (NCT06555263) | ORR as defined by RECIST v1.1 | Luveltamab Tazevibulin | FOLR1 | Cleavable | Auristatin microtubule inhibitor (hemiasterina) | Patients who are a/m NSCLC-positive per FOLR1 expression per central testing | Untreated BM are excluded | Phase II | Recruiting |
A First-in-human Study Using BDC-1001 as a Single Agent and in Combination with Nivolumab in Advanced HER2-Expressing Solid Tumors (NCT04278144) | ORR | BDC-1001 | HER2 | Non cleavable | ISAC (Trastuzumab conjugated with TLR7/8 agonist) | Patients with an a/m solid tumor with documented HER2-protein expression or gene amplification for which approved therapies have been exhausted or not clinically indicated | Untreated BM or active BM are excluded | Phase I/II | Active, non recruiting |
Phase I–II, FIH, TROP2 ADC, Advanced Unresectable/Metastatic Solid Tumors, Refractory to Standard Therapies (A264) (NCT04152499) | ORR (phase II) | SKB264 | TROP2 | Cleavable | Microtubule inhibitor (Belotecan-based payload) | Patients with a/m solid tumors, including NSCLC, that is refractory or not amenable to the standard-of care-therapy | Symptomatic BM or any radiation or surgery for BMs within 1 month of first infusion of study drug are the exclusion criteria (Phase I). Patients with active BM or leptomeningeal disease are excluded (Phase II) | Phase I/II | Recruiting |
PRO1184 for Advanced Solid Tumors (PRO1184-001) (NCT05579366) | ORR as defined by Recist v1.1 (phase II) | PRO1184 | FOLR1 | Cleavable | Topoisomerase I Inhibitor (exatecan) | Patients with a/m solid tumors, including NSCLC, that is refractory or not amenable to the standard-of-care therapy | Active BMs are excluded | Phase I/II | Recruiting |
Study of DF1001 in Patients with Advanced Solid Tumors (NCT04143711) | ORR as defined by RECIST v1.1 | DF1001 | HER2 | Cleavable | Induce cell death by targeting NK cells and T-cell activation signals | A/m NSCLC patients with HER2 overexpression/amplification/mutation who progressed after a platinum-based CT and have received and progressed on or after anti PD-(L)1 therapy. Those for whom a/m NSCLC progressed during or after platinum doublet-based chemotherapy (expansion NSCLC cohort) | Active BMs or a history of BM are the exclusion criteria | Phase I/II | Recruiting |
Study of REGN5093-M114 (METxMET Antibody–Drug Conjugate) in Adult Patients with Mesenchymal–Epithelial Transition Factor (MET) Overexpressing Advanced Cancer (NCT04982224) | ORR (Phase II) | REGN5093-M114 | METxMET | Cleavable | Auristatin microtubule inhibitor (M24) | Patients with a/m NSCLC with MET Overexpression | Untreated/active BM and leptomeningeal disease excluded | Phase I/II | Recruiting |
Clinical Study of Antibody–Drug Conjugate MYTX-011 in Subjects with Non-Small Cell Lung Cancer (NCT05652868) | ORR, OS and PFS are secondary endpoints | MYTX-011 | MET | Clevable | Auristatin microtubule inhibitor (Monomethyl auristatin E) | Patients with a/m NSCLC with MET alterations that is refractory to the standard-of-care therapy | Untreated/active BM and leptomeningeal disease excluded | Phase I | Recruiting |
An Efficacy and Safety Study of Cofetuzumab Pelidotin in Participants with PTK7-Expressing, Recurrent Non-Small Cell Lung Cancer (NCT04189614) | OS, PFS and DOR are secondary endpoints | Cofetuzumab pelidotin | PTK7 | Cleavable | Auristatin microtubule inhibitor (Auristatin-0101) | Patients with recurrent and treatment-refractory NSCLC with PTK7 expression | Asymptomatic and treated BM included, active BM excluded | Phase I | Active, non recruiting |
A Study to Evaluate TROP2 ADC LCB84 Single Agent and in Combination with an Anti-PD-1 Ab in Advanced Solid Tumors (NCT05941507) | PFS, ORR, DOR, TTP as defined by RECIST v1.1, iRECIST, and RANO-BM OS | LCB84 | TROP2 | Cleavable | Microtubule inhibitor (Monomethyl auristatin E) | Patients with advanced solid tumors, including NSCLC that is refractory or not amenable to the standard-of-care therapy | Stable and treated BM included | Phase I/II | Recruiting |
DS8201a and Pembrolizumab in Participants with Locally Advanced/Metastatic Breast or Non-Small Cell Lung Cancer (NCT04042701) | ORR | Trastuzumab deruxtecan | HER2 | Cleavable | Topoisomerase I Inhibitor (Deruxtecan) | Patients with a/m breast cancer or NSCLC with HER2 overexpression or HER2-mutant disease | Active BM excluded | Phase I | Recruiting |
Phase Ib Study of the Safety of T-DXd and Immunotherapy Agents with and Without Chemotherapy in Advanced or Metastatic HER2-positive, non-squamous NSCLC (DL03) (NCT04686305) | PFS, ORR, DOR, as defined by RECIST v1.1, OS | Trastuzumab Deruxtecan (T-DXd) | HER2 | Cleavable | Topoisomerase I Inhibitor (Deruxtecan) | Patients with a/m non-squamous NSCLC that are refractory to systemic therapy or treatment-naive with HER2 overexpression | Untreated and symptomatic BM excluded | Phase I | Recruiting |
A Study of LY4052031 in Participants with Advanced or Metastatic Urothelial Cancer or Other Solid Tumors (NEXUS-01) (NCT06465069) | ORR defined by RECIST v1.1 | LY4052031 | NECTIN4 | Cleavable | Topoisomerase I Inhibitor (Camptothecin-98) | Patients with a/m solid tumors, including NSCLC that is refractory or not amenable to the standard-of-care therapy | Known or suspected uncontrolled BM excluded | Phase I | Recruiting |
A Study of LY4170156 in Participants with Selected Advanced Solid Tumors (NCT06400472) | ORR defined by RECIST v1.1 | LY4170156 | FOLR1 | Cleavable | Topoisomerase I Inhibitor (Camptothecin-98) | Patients with advanced solid tumors, including NSCLC that is refractory or not amenable to the standard-of-care therapy | Active and untreated BM, and history of leptomeningeal disease excluded | Phase I | Recruiting |
A Study of LY4101174 in Participants with Recurrent, Advanced or Metastatic Solid Tumors (NCT06238479) | ORR defined by RECIST v1.1 (primary endpoint) DOR, PFS, TTR, DCF as defined by RECIST v1.1 OS | LY4101174 | NECTIN4 | Cleavable | Topoisomerase I Inhibitor (Camptothecin-98) | Patients with a/m solid tumors, including NSCLC that is refractory or not amenable to the standard-of-care therapy | Known or suspected uncontrolled BM excluded | Phase I | Recruiting |
Safety of GQ1001 in Adult Patients with HER2-Positive Advanced Solid Tumors (NCT04450732) | ORR, DCR, PFS and DoR as defined by RECIST v1.1 | GQ1001 | HER2 | Cleavable | Microtubule inhibitor (Maytansinoide DM1) | Patients with a/m HER2-expressing solid tumors, including NSCLC that is refractory or not amenable to the standard-of-care therapy | Treated and asymptomatic BM included untreated and symptomatic BM excluded | Phase I | Recruiting |
Phase I–II, FIH, TROP2 ADC, Advanced Unresectable/Metastatic Solid Tumors, Refractory to Standard Therapies (A264) (NCT04152499) | ORR, DoR, PFS as defined by RECIST v1.1 OS | Sacituzumab tirumotecan | TROP2 | Cleavable | Topoisomerase I inhibitor (belotecan derivative) | Patients with a/m solid tumors, including metastatic NSCLC, that is refractory or not amenable to the standard of-care-therapy | Symptomatic and active BM, history of LMD, brainstem metastasis, and spinal cord metastasis excluded | Phase I/II | Recruiting |
Phase 1 Study of CPO301 in Adult Patients with Advanced or Metastatic Solid Tumors (NCT05948865) | Efficacy assesment not specified | CPO301 | EGFR | Cleavable | Non-specified | Patients with a/m solid tumors, including metastatic NSCLC, that is refractory or not amenable to the standard-of-care therapy | Known, active, or uncontrolled BM or leptomeningeal disease excluded | Phase I | Recruiting |
A Study of PF-08046050 (SGN-CEACAM5C) in Adults with Advanced Solid Tumors (NCT06131840) | ORR, DoR, PFS as defined by RECIST v1.1 Best response OS | PF-08046050 | CEACAM5 | Cleavable | Topoisomerase I inhibitor | Patients with a/m solid tumors, including metastatic NSCLC, that is refractory or not amenable to the standard-of-care therapy | Stable and treated BM included | Phase I | Recruiting |
PRO1184 for Advanced Solid Tumors (PRO1184-001) (NCT05579366) | ORR, DoR, PFS as defined by RECIST v1.1 OS | PRO1184 | FOLR1 | Cleavable | Topoisomerase I inhibitor | Patients with a/m solid tumors, including NSCLC that is refractory or not amenable to the standard-of-care therapy | Previously treated and stable BM included active BM or leptomeningeal diseaseexcluded | Phase I/II | Recruiting |
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ADC | Target | Linker Type | Payload | Indications | Registration Trial |
---|---|---|---|---|---|
Mirvetuximab soravtansine | Folate receptor alpha | Cleavable | Maytansinoid DM4 | Folate receptor-alpha (FRα)-positive, platinum-resistant high-grade serous epithelial ovarian, fallopian tube, or primary peritoneal cancer patients who have received 1 to 3 prior systemic treatment regimens | SORAYA (NCT04296890) |
Tisotumab vedotin | Tissue Factor | Cleavable | Monomethyl Auristatin E (MMAE) | Recurrent or metastatic cervical cancer with disease progression to chemotherapy | InnovaTV 301 (NCT04697628) |
Ado-trastuzumab emtansine | HER2 | Non cleavable | Maytansine DM1 | EBC: Adjuvant treatment of patients with HER2-positive EBC who have residual invasive disease after neoadjuvant taxane- and trastuzumab-based treatment. MBC: Patients with HER2-positive MBC who previously received trastuzumab and a taxane, separately or in combination | KATHERINE (NCT01772472) EMILIA (NCT00829166) |
Enfortumab vedotin | Nectin-4 | Clevable | Monomethyl Auristatin E (MMAE) | Adult patients with locally advanced or metastatic urothelial cancer who have received an anti PD-(L)1 agent, and platinum-based chemotherapy | EV-301 (NCT03474107) |
Trastuzumab deruxtecan | HER2 | Cleavable | Deruxtecan | Breast cancer: Unresectable or metastatic HER2-positive (IHC 3+ or ISH positive) BC patients who have received a prior anti-HER2-based regimen Patients with unresectable or metastatic HER2-low (IHC 1+ or IHC 2+/ISH−) BC, as determined by an FDA-approved test, who have received a prior chemotherapy in the metastatic setting Non-small cell lung cancer: Unresectable or metastatic NSCLC patients whose tumors have activating HER2 mutations, as detected by an FDA-approved test, and who have received a prior systemic therapy (accelerated approval) Gastric cancer: Locally advanced or metastatic HER2-positive (IHC 3+ or IHC 2+/ISH positive) gastric or gastroesophageal junction (GEJ) adenocarcinoma patients who have received a prior trastuzumab-based regimen Solid tumors: Patients with unresectable or metastatic HER2-positive (IHC3+) solid tumors who have received prior systemic treatment (accelerated approval) | DESTINY-Breast03 (NCT03529110) DESTINY-Breast04 (NCT03734029) DESTINY-Lung02 (NCT04644237) DESTINY-Gastric01 (NCT03329690) DESTINY-PanTumor02 (NCT04482309) |
Sacituzumab Govitecan | TROP2 | Cleavable | Camptothecin analog (SN38) | BC: Unresectable locally advanced or metastatic triple-negative BC patients who have received 2 or more prior systemic therapies Urothelial cancer: Locally advanced or metastatic urothelial cancer (mUC) patients who have previously received platinum-based chemotherapy and an anti PD-(L)1 inhibitor. (accelerated approval) | ASCENT (NCT02574455) IMMU-132-01 (NCT01631552) TROPHY (NCT03547973) |
Datopotomab Deruxtecan | TROP2 | Cleavable | Topoisomerase I inhibitor (Deruxtecan) | Patients with unresectable or metastatic hormone receptor-positive, HER2-breast cancer that has progressed after endocrine-based therapy and chemotherapy for unresectable or metastatic disease | TROPION-Breast01 (NCT05104866) |
Clinical Trial | Response Endpoint | Treatment | Target | Linker Type | Payload Action | Population | Trial Type | Status |
---|---|---|---|---|---|---|---|---|
AMG 595 First-in-Human in Recurrent Gliomas (NCT01475006) | ORR by Macdonald criteria | AMG 595 | EGFRvIII | Non-Cleavable | Microtubule inhibitor (Maytansinoid DM1) | Patients with rGBM (Part 1 and 2) or WHO Grade III anaplastic astrocytoma (Part 1 only) expressing EGFRvIII | Phase I | Completed. No results published (last update 2016) |
Safety and Efficacy of L19TNF in Patients with Isocitrate Dehydrogenase (IDH) Wildtype WHO Grade III/IV Glioma at First Relapse (GLIOMOON) (NCT03779230) | PFS, OS, ORR by iRANO criteria | Onfekafusp alfa (L19TNF) | Fibronectin | NA | TNFalpha | Patients with WHO Grade III/IV Glioma at First Relapse | Phase I/II | Completed |
Safety and Efficacy of L19TNF Plus Temozolomide Chemoradiotherapy in Patients with Newly Diagnosed Glioblastoma (GLIOSUN) (NCT04443010) | OS, PFS, ORR, DCR, BORR by iRANO | Onfekafusp alfa (L19TNF) + TMZ | Fibronectin | NA | TNFalpha | Patients with newly diagnosed GBM | Phase II | Recruiting |
A Study to Evaluate Safety and Efficacy of L19TNF Plus Lomustine in Patients with Glioblastoma at First Progression (GLIOSTAR) (NCT04573192) | OS, PFS by iRANO | Onfekafusp alfa (L19TNF) + lomustine | Fibronectin | NA | TNFalpha | Patients with GBM at first progression | Phase I/II | Recruiting |
Neuro/Sacituzumab Govitecan/Breast Brain Metastasis/Glioblastoma/Ph 0 (NCT03995706) | Ratio of SN-38 and its metabolites relative to serum concentration | Sacituzumab Govitecan | TROP2 | Cleavable | Topoisomerase I Inhibitor (govitecan) | Patients with rGBM/BM from breast | Phase 0 | Completed |
Clinical Trial | Type of Trial | ADC | Target | Linker Type | Payload Action | Population | CNS Metastasis Eligibility | Intracranial Activity | Intracranic Response Criteria |
---|---|---|---|---|---|---|---|---|---|
TROPION-Lung05 (NCT04484142) | Phase II | Datopotamab Deruxtecan (Dato-DXd) | TROP-2 | Cleavable | Topoisomerase I inhibitor (Deruxtecan) | a/m NSCLC with AGAs who progressed following targeted therapy and platinum-based CT | Clinically inactive BM (not requiring medical therapy) eligible. Leptomeningeal disease excluded | iORR 22% iDCR 72% | RECIST v1.1 |
DESTINY-Lung01 (NCT03505710) DESTINY-Lung02 (NCT04644237) | Phase II | Trastuzumab-Deruxtecan (T-DXd) | HER2 | Cleavable | Topoisomerase I inhibitor (Deruxtecan) | HER2-overexpressing or HER2-mutant unresectable or metastatic NSCLC | No exclusion criteria for patients with brain metastases, including leptomeningeal carcinomatosis | 5.4 mg/kg Cohort (DL-02): iORR 25% iDCR 81.3% 6.4 mg/kg Cohort (DL-01/02): iORR 18.5% iDCR 76% | RECIST v1.1 |
HERTHENA-Lung01 (NCT04619004) | Phase II | Patritumab Deruxtecan (HER3-DXd) | HER3 | Cleavable | Topoisomerase I inhibitor (Deruxtecan) | a/m NSCLC with canonical EGFR mutation who progressed on at least one EGFR TKI and one platinum-based CT | Clinically inactive BM (not requiring medical therapy) eligible. Leptomeningeal disease excluded | iORR 33.3% iDCR 76.6% | RECIST v1.1 |
Clinical Trial | Type of Trial | ADC | Target | Linker Type | Payload Action | Population | CNS Metastasis Eligibility | CNS Endpoints | Intracranic Response Criteria |
---|---|---|---|---|---|---|---|---|---|
EMILIA (NCT008291) | Retrospective exploratory analysis | Trastuzumab emtansine (T-DM1) | HER2 | Non-cleavable | Microtubule Inhibitor (Maytansinoid DM1) | HER2-positive a/m BC, previously treated with trastuzumab and a taxane | Treated, asymptomatic | Patients with baseline BM mOS: 26.8 vs. 12.9 mo | RECIST v1.1 |
TH3RESA (NCT014191) | Phase III | Trastuzumab emtansine (T-DM1) | HER2 | Non-cleavable | Microtubule Inhibitor (Maytansinoid DM1) | HER2-positive mBC pretreated with ≥2 HER2 directed regimens | Treated, asymptomatic | Patients with baseline BM mPFS: 5.8 vs. 2.9 mo | RECIST v1.1 |
KAMILLA (NCT017025) | Exploratory analysis | Trastuzumab emtansine (T-DM1) | HER2 | Non-cleavable | Microtubule Inhibitor (Maytansinoid DM1) | HER2-positive a/m BC progressing after CT and anti-HER2 therapy or ≤6 mo after adjuvant therapy | Controlled or untreated and asymptomatic | iORR: 21.4%, iCR: 2.4% | RECIST v1.1 |
DESTINY-Breast01 (NCT032484) | Phase II | Trastuzumab Deruxtecan (T-DXd) | HER2 | Cleavable | Topoisomerase I Inhibitor (Deruxtecan) | HER2-positive mBC previously treated with T-DM1 | Treated, asymptomatic | iORR: 41.2% | RECIST v1.1 |
DESTINY-Breast03 (NCT035291) | Phase III | Trastuzumab Deruxtecan (T-DXd) | HER2 | Cleavable | Topoisomerase I Inhibitor (Deruxtecan) | HER2-positive mBC previously treated with trastuzumab and a taxane | Treated or asymptomatic | iORR: 79 vs. 35% | RECIST v1.1 |
TUXEDO-1 (NCT047520) | Phase II | Trastuzumab Deruxtecan (T-DXd) | HER2 | Cleavable | Topoisomerase I Inhibitor (Deruxtecan) | HER2-positive mBC and newly diagnosed untreated BM/BM progressing after previous local therapy, previous exposure to trastuzumab and pertuzumab and no indication for immediate local therapy | Newly diagnosed untreated/progressing after previous local therapy | iORR: 73.3% iCR: 13.3% iPR: 60% iSD: 20% | RANO-BM |
DESTINY-Breast12 (NCT047397) | Phase IIIb/IV | Trastuzumab- Deruxtecan (T-DXd) | HER2 | Cleavable | Topoisomerase I Inhibitor (Deruxtecan) | HER2-positive mBC treated with one or more prior anti-HER2–based regimens | Stable or active (untreated/previously treated and progressing) | iORR: 71.7% (79.2% with stable BM and 62.3% with active BM) | RECIST v1.1 |
DEBBRAH (NCT044205) | Phase II | Trastuzumab- Deruxtecan (T-DXd) | HER2 | Cleavable | Topoisomerase I Inhibitor (Deruxtecan) | HER2-positive or HER-2 low a/m BC pretreated | Cohort 2: asymptomatic, untreated Cohort 3: progressing after local therapy | CNS ORR: 50% (cohort 2) 44.4% (cohort 3) | RANO-BM |
ASCENT (NCT025744) | Subgroup analysis | Sacituzumab Govitecan (SG) | TROP2 | Cleavable | Topoisomerase I Inhibitor (govitecan) | relapsed or refractory mTNBC | Stable | mOS in BM population: 6.8 vs. 7.5 mo | RECIST v1.1 |
Clinical Trial | Response Endpoint | ADC | Target | Linker Type | Payload Action | Population | CNS Metastasis Eligibility | Trial Type | Status |
---|---|---|---|---|---|---|---|---|---|
DATO-BASE: DATOpotamab-deruxtecan for Breast Cancer Brain MetAstaSEs (NCT06176261) | iORR as defined by RANO-BM criteria | Datopotamab Deruxtecan (Dato-DXd) | TROP2 | Cleavable | Topoisomerase I Inhibitor (Deruxtecan) | HER2-negative mBC | Cohorts A and B: newly diagnosed or progressing after local and/or systemic therapy Cohort C: leptomeningeal disease | Phase II | Recruiting |
T-DXd Therapy for HER2-low Breast Cancer Patients with Brain Metastases (TUXEDO-4) (NCT06048718) | iORR as defined by RANO-BM criteria | Trastuzumab Deruxtecan (T-DXd) | HER2 | Cleavable | Topoisomerase I Inhibitor (Deruxtecan) | HER2-low mBC with newly diagnosed or progressing Bm with or without untreated type II LMD, who received ≥1 line of systemic treatment in the advanced setting | Newly diagnosed or progressive, without indication for immediate local therapy | Phase II | Recruiting |
Testing Sacituzumab Govitecan Therapy in Patients With HER2-Negative Breast Cancer and Brain Metastases (NCT04647916) | iORR as defined by RANO-BM criteria | Sacituzumab govitecan (SG) | TROP2 | Cleavable | Topoisomerase I Inhibitor (govitecan) | HER2-negative mBC with BM | ≥1 BM not previously treated or progressed to RT | Phase II | Recruiting |
HER3-DXd in Breast Cancer and NSCLC Brain Metastases and Solid Tumor Leptomeningeal Disease (TUXEDO-3) (NCT05865990) | iORR as defined by RANO-BM criteria | Patritumab deruxtecan (HER3-DXd) | HER3 | Cleavable | Topoisomerase I Inhibitor (Deruxtecan) | mBC or aNSCLC with active BM), who received ≥1 line of systemic treatment in the advanced setting or with active LMD after RT from an advanced solid tumor who do not need immediate local treatment, and have not received prior treatment with an anti-HER3 | Active BM from MBC (Cohort 1) and aNSCLC (Cohort 2), untreated LMD (Cohort 3) | Phase II | Active, not recruiting |
Patritumab Deruxtecan (U3-1402) in Unresectable Locally Advanced or Metastatic Breast Cancer (ICARUS BREAST) (NCT04965766) | ORRas defined by RECIST | Patritumab deruxtecan (HER3-DXd) | HER3 | Clevable | Topoisomerase I Inhibitor (Deruxtecan) | HR+, ABC, resistant to ET and CDK4/6i, that must have received only one line of chemotherapy for ABC | Clinically inactive, treated, asymptomatic | Phase II | Active, not recruiting |
A Phase 1b/2 Study of T-DXd Combinations in HER2-positive Metastatic Breast Cancer (DESTINY-Breast07) (NCT04538742) | ORR, PFS, PFS2, DoR as defined by RECIST, OS | Trastuzumab Deruxtecan (T-DXd) | HER2 | Cleavable | Topoisomerase I Inhibitor (Deruxtecan) | HER2-positive a/mBC, ≥1 line of systemic treatment in the advanced setting (Part 1), no prior lines for a/mBC (Part 2 Modules 0–5), zero or one prior lines for a/mBC allowed (Part 2 Modules 6 and 7 | Stable (Modules 0–5); untreated, not needing local therapy or previously treated that have progressed since prior local therapy (Module 6 and 7) (<2 mg dexamethasone/day) | Phase Ib/II | Active, not recruiting |
PRE-I-SPY Phase I/Ib Oncology Platform Program (PRE-I-SPY-PI) (NCT05868226) | ORR, DoR, PFS, CBR as defined by RECIST | Trastuzumab Deruxtecan (T-DXd) | HER2 | Cleavable | Topoisomerase I Inhibitor (Deruxtecan) | HER2 expressing (>HER2 1+) mBC | Treated and clinically stable | Phase I/Ib | Recruiting |
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Bruzzone, F.; Barigazzi, C.; Di Muzio, A.; Tallarico, I.; Dipasquale, A.; Losurdo, A.; Persico, P.; Navarria, P.; Pessina, F.; Santoro, A.; et al. Exploring the Role of ADCs in Brain Metastases and Primary Brain Tumors: Insight and Future Directions. Cancers 2025, 17, 1591. https://doi.org/10.3390/cancers17091591
Bruzzone F, Barigazzi C, Di Muzio A, Tallarico I, Dipasquale A, Losurdo A, Persico P, Navarria P, Pessina F, Santoro A, et al. Exploring the Role of ADCs in Brain Metastases and Primary Brain Tumors: Insight and Future Directions. Cancers. 2025; 17(9):1591. https://doi.org/10.3390/cancers17091591
Chicago/Turabian StyleBruzzone, Francesco, Chiara Barigazzi, Antonio Di Muzio, Isabel Tallarico, Angelo Dipasquale, Agnese Losurdo, Pasquale Persico, Pierina Navarria, Federico Pessina, Armando Santoro, and et al. 2025. "Exploring the Role of ADCs in Brain Metastases and Primary Brain Tumors: Insight and Future Directions" Cancers 17, no. 9: 1591. https://doi.org/10.3390/cancers17091591
APA StyleBruzzone, F., Barigazzi, C., Di Muzio, A., Tallarico, I., Dipasquale, A., Losurdo, A., Persico, P., Navarria, P., Pessina, F., Santoro, A., & Simonelli, M. (2025). Exploring the Role of ADCs in Brain Metastases and Primary Brain Tumors: Insight and Future Directions. Cancers, 17(9), 1591. https://doi.org/10.3390/cancers17091591