Clinical benefit of various HER2-directed regimens in gastrointestinal malignancies: a retrospective cohort study
Vishesh Khanna1, Swetha Vadde1, A Solomon Henry2
1Division of Oncology, Department of Medicine, Stanford University School of Medicine, Stanford, CA, United States.
Background:
Multiple drugs targeting the human epidermal growth factor receptor-2 (HER2) have shown clinical activity in gastrointestinal (GI) cancers. How to best integrate these various options in clinical practice alongside conventional therapy, however, is unclear.
Methods:
We assessed the clinical outcomes of 103 patients with advanced HER2-altered GI malignancies who received ≥ 1 line of anti-HER2 therapy at our institution between 2010 and 2023.
Results:
Next-generation sequencing (NGS) detected an ERBB2 amplification in 66% (27/41) of tumors that were HER2 + by IHC/ISH. Conversely, all patients with ERBB2 amplification were HER2 + by IHC. In the second-line and beyond, trastuzumab plus pertuzumab had the longest median time to treatment discontinuation (7.9 months), followed by trastuzumab deruxtecan (5.0 months). Among 25 patients who received ≥ 2 anti-HER2 agents, 24% had more durable clinical benefit to their second-line HER2 therapy compared to their first, as measured by the growth modulation index.
Conclusions:
Multimodal HER2 testing is needed to accurately identify candidates for HER2-targeted treatment, as NGS alone misses a significant proportion of cases. Patients who develop resistance to one anti-HER2 agent may still achieve benefit from subsequent HER2-directed regimens. Early and serial treatment with HER2-directed agents should be considered for patients with HER2 + GI cancers.
Insights
Accurate human epidermal growth factor receptor-2 (HER2) testing is crucial for identifying gastrointestinal cancer patients who can benefit from HER2-targeted therapies. Subsequent HER2-directed treatments can still be effective even after resistance develops.
Area of Science:
- Oncology
- Gastrointestinal Cancers
- Targeted Therapy
Background:
- Multiple drugs targeting human epidermal growth factor receptor-2 (HER2) show clinical activity in gastrointestinal (GI) cancers.
- Optimal integration of HER2-targeted therapies with conventional treatments remains unclear.
Purpose of the Study:
- To assess clinical outcomes of patients with advanced HER2-altered GI malignancies treated with anti-HER2 therapy.
- To evaluate the effectiveness of different anti-HER2 agents and treatment sequencing.
Main Methods:
- Retrospective analysis of 103 patients with advanced HER2-altered GI malignancies receiving at least one line of anti-HER2 therapy (2010-2023).
- Utilized next-generation sequencing (NGS), immunohistochemistry (IHC), and in situ hybridization (ISH) for HER2 testing.
- Assessed clinical benefit using time to treatment discontinuation and growth modulation index.
Main Results:
- Next-generation sequencing (NGS) detected ERBB2 amplification in 66% of HER2-positive (by IHC/ISH) tumors.
- Trastuzumab plus pertuzumab demonstrated the longest median time to treatment discontinuation (7.9 months) in second-line and beyond.
- 24% of patients receiving ≥2 anti-HER2 agents experienced more durable benefit from second-line therapy compared to first-line.
Conclusions:
- Multimodal HER2 testing is essential for accurate patient identification, as NGS alone misses cases.
- Patients resistant to one anti-HER2 agent may benefit from subsequent HER2-directed regimens.
- Consider early and serial HER2-directed treatment for HER2-positive GI cancers.
