Table 1.
Clinical trials targeting ERBB2-positive mCRC.
| Types of Drugs | Trial/Phase | Interventions | Description | Outcomes/Status |
|---|---|---|---|---|
| Anti-HER2 mAbs | My Pathway (phase II) | Trastuzumab plus pertuzumab | KRAS-unselected, chemorefractory, HER2 amplified mCRC (n = 56); HER2 positivity assigned based on IHC (3+ staining), FISH (ERBB2:CEP17 > 2.0) and/or NGS (ERBB2 copy number gain) | mOS 11.5 months, mPFS 2.9 months, ORR 32% |
| TRIUMPH (phase II) | Pertuzumab plus trastuzumab | HER2 amplification mCRC (n = 30); ERBB2 amplifications determined using tissue and/or ctDNA analysis | mOS 10.1 months (tissue+) and 8.8 months (ctDNA+), mPFS 4.0 months (tissue+) and 3.1 months (ctDNA+), ORR 30% (tissue+) and 28% (ctDNA+) | |
| Anti-HER2 mAbs+TKIs | HERACLES-A (phase II) | Trastuzumab plus lapatinib | KRAS-WT, chemorefractory, HER2-positive mCRC (n = 27); HER2 positivity (HERACLES pathological criteria) | mOS 10 months, mPFS 4.7 months, ORR 28% |
| Anti-HER2 mAbs+TKIs | MOUNTAINEER (phase II) | Tucatinib plus trastuzumab | RAS-WT, chemorefractory, HER2 amplification/overexpression mCRC (n = 26); HER2 positivity determined using IHC (3+ or 2+ staining and FISH-positive), FISH and/or NGS | mOS 17.3 months, mPFS 6.2 months, ORR 55%, DCR NR |
| NCT04579380 (phase II) | Tucatinib plus trastuzumab | HER2 overexpression/alterations, unresectable, or metastatic solid timors (n = 270, including CRC); HER2 status detected in fresh or archival tumor tissue or blood | Recruiting | |
| NCT04380012 (phase II) | Pyrotinib plus trastuzumab | HER2-positive advanced CRC(n = 40); HER2 positivity confirmed by IHC (3+ or 2+ in more than 50% of cells) and SISH/FISH (HER2:CEP17 > 2.0) | Recruiting | |
| Anti-HER2 ADCs | HERACLES-B (phase II) | T-DM1 plus pertuzumab | RAS-/BRAF-WT, chemorefractory and HER2+mCRC (n = 31); HER2 positivity (HERACLES pathological criteria) | ORR 80%, mOS 4.1 months, DCR 9.7% |
| DESTINY-CRC01 (phase II) | T-DXd (DS-8201a) | RAS-/BRAF V600E-WT, disease progression on two or more prior regimens, HER2 expressing mCRC (n = 78); HER2 positivityCohort A: HER2 IHC 3+ or IHC 2+ staining and ISH-positive (n = 53) Cohort B: IHC 2+ staining and ISH-negative (n = 7) Cohort C: IHC 1+ staining (n = 18) | ORR 83%, mPFS NR, mOS NR, DCR 45.3% | |
| TKIs+anti-EGFR therapy | NSABP FC-7 (phase Ib) | Neratinib plus cetuximab | Resistant to Cetuximab or Panitumumab and quadruple-WT (KRAS, NRAS, BRAF, PI3KCA) disease (n = 21); HER2 amplification assessed by CISH (ERBB2:CEP17 > 2.0) or NGS (ERBB2 copy number > 2.0) | RP2D of neratinib: 240 mg/day; no OS; SD was seen at all neratinib doses |
| Dual-targeted antibodies | NCT03929666 (phase II) | ZW25 plus standard QT | Unresectable, locally advanced, recurrent, or metastatic HER2-expressing cancers (n = 362, including CRC); HER2 expressing (IHC 3+ with or without gene amplification; or IHC 0, 1+ or 2+ with gene amplification) | Recruiting |
| NCT03821233 (phase I) | ZW49 | Locally advanced (unresectable) or metastatic HER2-expressing cancers (n = 174) | Recruiting | |
| NCT03602079 (phase I/II) | A166 | Relapsed/refractory, HER2 expressing/amplified cancers (n = 49, including CRC); Low HER2 expression (IHC 1+ and IHC 2+ without FISH confirmation) and HER2 positive (IHC2+ with FISH confirmation and IHC 3+) | Active, not recruiting | |
| Anti-HER2 CAR- macrophages | NCT04660929 (phase I) | CT-0508 | HER2 overexpressing solid tumors (n = 18, including CRC) | Recruiting |
| CAR-T+Oncolytic adenovirus | NCT03740256 (phase I) | CAdVEC | Advanced HER2 positive solid tumors (n = 45, including CRC); HER2 positivity defined as IHC 3+ or IHC 2+ staining | Recruiting |
Abbreviations: mAbs: monoclonal antibodies, ADCs: antibody-drug conjugates, TKIs: tyrosine kinase inhibitors, ctDNA: circulating tumor DNA, m: month, mPFS: median progression-free survival, ORR: overall response rates, PR2D: recommended phase 2 dose, SD: stable disease, HR: hazard ratio, NR: not reported, QT: chemotherapy, T-DM1: trastuzumab emtansine, TD: trastuzumab deruxtecan, CAR: chimeric antigen receptor, WT: wild type.