HER-2 positive + RAS wild-type

Pyrotinib plus trastuzumab demonstrates clinically meaningful efficacy and a manageable safety profile in heavily pretreated HER2-positive metastatic colorectal cancer. These findings support advancing this regimen as a potential alternative in refractory HER2-positive mCRC, particularly in the RAS/BRAF wild-type subgroup.

To our knowledge, this is the largest analysis of HER2 status in patients with untreated mCRC enrolled in RCT. Waiting for targeted approaches, HER2-pos and mut do not predict benefit from bev/anti-EGFRs and should be regarded as negative prognostic factors in pMMR/MSS RAS/BRAF wild-type mCRC.

P2, N=25, Active, not recruiting, University of Wisconsin, Madison | Recruiting --> Active, not recruiting

Multiple HER2-targeted regimens are now part of National Comprehensive Cancer Network and European Society for Medical Oncology guidelines with two recent Food and Drug Administration approvals for previously treated HER2-positive metastatic colorectal cancer for tucatinib (in combination with trastuzumab) and for trastuzumab-deruxtecan in patients with previously treated HER2-positive metastatic colorectal cancer. This review explores the prognostic and predictive value of HER2 as a biomarker in CRC, describing its molecular structure, the clinical characteristics of patients with HER2 alterations, diagnostic approaches and the most relevant clinical trials assessing its current and future role as a therapeutic target in metastatic colorectal cancer.

P2, N=24, Not yet recruiting, Peking Union Medical College Hospital; Peking Union Medical College Hospital

As the landscape of HER2-directed therapies continues to evolve, these findings suggest that ERBB2 alterations and HER2 expression may represent a potential therapeutic target in LGSC.

It is also associated with resistance against epidermal growth factor receptor (EGFR)-targeted therapies like cetuximab and panitumumab, for treatment of RAS wild-type mCRC. Furthermore, anti-HER2 therapies exhibited non-toxic profile and high efficacy in chemorefractory cases. This review delves into modern management of anti-HER2 therapies in CRC with a particular focus on recent advances and current knowledge about the prognostic and predictive value of HER2.

P2, N=112, Recruiting, Gruppo Oncologico del Nord-Ovest | Trial primary completion date: May 2025 --> May 2026

The MOUNTAINEER-03 phase III trial is designed to investigate the efficacy and safety of first-line tucatinib in combination with trastuzumab and modified FOLFOX6 (mFOLFOX6) versus standard of care (mFOLFOX6 plus bevacizumab or cetuximab) in patients with untreated HER2+, RAS WT locally advanced unresectable or mCRC...Key secondary endpoints are overall survival and confirmed objective response rate (according to RECIST v1.1 per BICR). Safety assessments will include surveillance and recording of adverse events, physical examination findings, vital signs, cardiac assessments, Eastern Cooperative Oncology Group performance status, concomitant medications, and laboratory tests.Clinical trial registration: NCT05253651 (ClinicalTrials.gov).

P1, N=279, Completed, Jazz Pharmaceuticals | Active, not recruiting --> Completed

Among 22 HER2-positive/heterogenous cases with successful ISH testing, 100% (22/22) demonstrated amplification via ISH. Because the classification of tumors as HER2-positive/heterogenous by IHC correlated very closely with ISH positivity, our results suggest that ISH is likely unnecessary for CRCs with 3+ HER2 overexpression in 10-49% of neoplastic cells.

KRAS-mut represents a genotypically distinct group of ECs. Overlap exists with genomic predictors (TMB-high, MSI-high) of immunotherapy response, suggesting a possible biomarker-driven combination option with immunotherapy. Clinical trials to evaluate these strategies should be developed.