Introduction
Pharmacodynamic of ADCs
Current FDA-approved ADCs for HER2-positive breast cancer
Trastuzumab emtansine
Trastuzumab deruxtecan
NCT identifier | Trial name | Phase | Experimental arm | Control arm | Setting | Population | Primary endpoint |
---|---|---|---|---|---|---|---|
NCT03523585 | DESTINY-Breast02 | III | T-DXd | Investigator’s choice | Prior T-DM1 | HER2+ MBC | PFS |
NCT03529110 | DESTINY-Breast03 | III | T-DXd | T-DM1 | Prior taxane +trastuzumab | HER2+ MBC | PFS |
NCT03734029 | DESTINY-Breast04 | III | T-DXd | Investigator’s choice | 1 or 2 prior chemotherapies. POD on ET if HR+ | HER2-low MBC | PFS |
NCT04132960 | DAISY | II | T-DXd | - | ≥ 2nd line | MBC C1: HER2 over-expressing C2: HER2 low expressing C3: non expressing d | BOR |
NCT04752059 | TUXEDO-1 | II | T-DXd | - | ≥ 2nd line | Newly diagnosed or progressing BM HER2+MBC | CNS ORR |
NCT04784715 | DESTINY-Breast09 | III | T-DXd+/− P | THP | 1st line | No prior chemo or POD ≤ 6 mo from adj therapy HER2+ MBC | PFS |
NCT04622319 | DESTINY-Breast05 | III | T-DXd | T-DM1 | Post-neoadjuvant | Primary BC with residual invasive disease | IDFS |
NCT04420598 | DEBBRAH | II | T-DXd | - | ≥ 2nd line | BM or LMD in HER2+or HER2-low MBC | CNS ORR, 16w PFS and OS of T-DXd |
NCT04494425 | DESTINY-Breast06 | III | T-DXd | treatment of Investigator’s Choice | ≥ 3rd line | HR+ HER2-low MBC | PFS |
NCT04257162 | HER2-PREDICT | - | T-DXd | - | - | Patients treated with T-DXd+ | ERBB2 mRNA cut-point predictive of T-DXd response |
NCT04042701 | - | Ib/II | T-DXd+ pembrolizumab | - | ≥ 2nd line | HER2+ or low MBC and HER2+ or mut NSCLC | DLT and ORR |
NCT04553770 | - | II | T-DXd+/− ANA | - | Neoadjuvant setting | HR+ HER2-low EBC | pCR rate |
NCT04556773 | DESTINY-Breast 08 | Ib | T-DXd+ Durva or T or Capi or ANA or Fulv or Cape | - | ≥ 2nd line | HER2-low MBC | Safety |
NCT04294628 | - | I | T-DXd | - | ≥ 2nd line | Any advanced solid tumor, HER2+ | Effect of T-DXd on Top1cc |
NCT04539938 | HER2CLIMB-04 | II | T-DXd+ tucatinib | - | ≥ 2nd line | HER2+MBC | ORR |
NCT04704661 | DASH | I/Ib | T-DXd and AZD6738a | - | ≥ 2nd line | HER2+/low/ mutant solid tumors | DLT and RP2D |
NCT03742102 | BEGONIA | Ib/II | Durvalumab + T-DXd or Capi or Oleb or T or DS-1062c | - | 1st line | TNBC | Safety and ORR |
ADCs under investigation
ADC name | Ab | Linker | Payload | DAR | Ongoing clinical trialsa |
---|---|---|---|---|---|
SYD985 | Trastuzumab | Valine-citrulline linker (cleavable) | Seco-DUBA (DNA-alkylating) | 2.8 | NCT03262935 NCT04602117 NCT04235101 NCT01042379 |
ZW49 | ZW25 | Cleavable | N-acyl sulfonamide auristatin (microtubule inhibitor) | N.A. | NCT03821233 |
PF-06804103 | Trastuzumab-derived Ab | Maleimidocaproyl-valine-citrulline linker (cleavable) | Aur-06380101 | 4 | NCT03284723 |
MRG002 | Anti-HER2 IgG1 | N.A. | Monomethyl auristatin E | NA | CTR20181778 NCT04492488, NCT04742153 |
GQ1001 | Anti-HER2 IgG | NA | NA | NA | NCT04450732 |
ARX788 | Modified heavy chain Ala114 of anti-HER2 mAb | Amberstatin (AS269) (non-cleavable) | Dolastatin monomethyl auristatin F (microtubule inhibitor) | 1.9 | NCT03255070 |
A166 | Trastuzumab | Valine citrulline peptide (cleavable linker) | Duostatin-5 (microtubule inhibitor) | N.A. | NCT03602079 |
XMT-1522 | HT-19 (anti-HER2 IgG1) | Cleavable hydrophilic polymer | AF-HPA (microtubule inhibitor) | 12 | NCT02952729 |
RC48-ADC | Hertuzumab (anti-HER2 humanized Ab) | Valine citrulline peptide (cleavable linker) | Monomethyl auristatin E (microtubule inhibitor) | 4 | NCT04329429 NCT04280341 NCT04311034 NCT04714190 NCT04073602 NCT04264936 NCT03556345 NCT03500380 NCT03052634 |
BDC-1001 | Trastuzumab | Non cleavable linker | TLR7/8 inhibitor | NA | NCT04278144 |
FS-1502 | Trastuzumab | NA | Monomethyl Auristatin F | NA | NCT03944499 |
GQ1001 | NA | NA | NA | NA | NCT04450732 |
ALT-P7 | Trastuzumab biobetter HM2 | Cysteine-containing peptide | Monomethyl auristatin E (microtubule inhibitor) | NA | NCT03281824 |
Trastuzumab duocarmazine
A166
XMT-1522
RC48-ADC
ALT-P7 (HM2/MMAE)
ARX788
PF-06804103
ADCs in pre-clinical development
Activity of ADCs in HER2-low breast cancer
ADCs for central nervous system (CNS)
Toxicity profile
Toxic effect | ADCs | Frequency | Possible mechanism |
---|---|---|---|
Thrombocytopenia | T-DM1 [7] T-DXd [15] | 14.3% 4.3% | DM1-induced impairment of megakaryocytes differentiation Bone marrow toxicity of payload |
Neutropenia | T-DM1 [7] T-DXd [15] SYD985 [18] RC48-ADC [23] ALT-P7 [24] | 2.4% 20% 14% 10% 14% | Bone marrow toxicity of payloads |
Anemia | T-DM1 [7] T-DXd [15] | 3.8% 8.6% | Bone marrow toxicity of payloads |
Leukopenia | RC48-ADC [23] | 6.7% | Bone marrow toxicity of payloads |
Decreased lymphocyte count | T-DXd [15] | 8.1% | Bone marrow toxicity of payloads |
Fatigue | T-DM1 [7] T-DXd [15] SYD985 [18] PF-06804103 [28] | 2.4% 6% 3% 5.7% | Unknown |
Arthralgia | PF-06804103 [28] | 5.7% | Unknown |
Increased ALT Increased ALT | T-DM1 [7] RC48-ADC [23] RC48-ADC [23] | 15% 3.3% 3.3% | Cytotoxic activity on the hepatocytes (clearance of T-DM1 depends mainly on the hepatobiliary and gastrointestinal route) |
Nausea | T-DXd [15] | 7.6% | Off-target effect of the payload |
Vomiting | T-DXd [15] | 4.3% | Off-target effect of the payload |
Diarrhea | T-DXd [15] | 2.7% | Off-target effect of the payload |
Peripheral neuropathy | T-DM1 [49] PF-06804103 [28] | 13% 5.7% | Degeneration of the axons, time-dependent, due to the DM1 component Systemic release of payload |
Toxic effect | ADCs | Frequency | Possible mechanism |
---|---|---|---|
Interstitial lung disease Pneumonitis | T-Dxd [46] ARX788 [25] | Any grade: 15.5% Grade 3:1% Grade 4: 0.1% Grade 5: 2.4% Any grade: 19.6% Grade 3: 2% | Alveolar inflammation and fibrosis due to off-target activity of DXd Unknown |
LVEF drop | T-DM1 [44] T-Dxd [15] | Any grade: 2% Grade 3–4: 0.7% Any grade: 1.6% Grade 3–4: 0.5% | Target-related: morphologic and functional potentially reversible damage to cardiomyocytes inducted by anti HER2-Ab |
Prolonged QT | T-Dxd [15] | Any grade: 4.9% Grade 3–4: 1.1% | Unknown |
Ocular toxicities | SYD985 [18] A166 [19] ARX788 [25] | Conjunctivitis All grades: 31% Grade 3/4: 3% Keratitis: All grades: 19% Grade 3/4: 2% Overall and any grade: 80% Overall and any grade: 41.2 % | Systemic releasing of the payload |