In the increasingly common scenario of a patient with multiple positive biomarkers, a clear hierarchy exists for treatment decisions. Based on the robustness and maturity of clinical trial data, HER2-directed therapy is the top priority, followed by PD-L1 immunotherapy, with Claudin-18.2 targeting considered third.
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While Trastuzumab deruxtecan (TDXD) is effective in HER2-low breast cancer, there is no evidence that it benefits patients with HER2-low or HER2-intermediate (IHC 2+/FISH negative) gastric cancer. Its use should be strictly limited to truly HER2-positive cases in this disease.
In the SPOTLIGHT trial, adding zolbituximab to FOLFOX for Claudin-18.2 positive patients improved progression-free and overall survival. However, it did not significantly increase the objective response rate, demonstrating that survival benefit can be decoupled from tumor shrinkage metrics.
For frail elderly patients with HER2+ gastric cancer, starting with targeted therapy and immunotherapy alone can gauge response and tolerance. Cytotoxic chemotherapy can be added later if the patient's performance status improves, distinguishing disease-related frailty from baseline comorbidities.
Clinicians ordering "NGS for lung" often misunderstand that Next-Generation Sequencing alone does not cover all actionable biomarkers, such as PD-L1 or HER2. This requires pathologists to interpret the clinician's intent and order a more comprehensive and appropriate test panel.
Comparing control arms from the TOGA (11 months OS), KEYNOTE-811 (16 months), and HORIZON (19 months) trials reveals a steady improvement in patient outcomes. This trend, likely due to better second-line therapies and supportive care, makes it harder for new agents to show a relative benefit.
In HER2-positive colorectal cancer, the choice of targeted therapy depends on RAS mutation status. The tucatinib/trastuzumab combination is effective only in RAS wild-type patients. In contrast, the antibody-drug conjugate trastuzumab deruxtecan (TDXD) shows efficacy regardless of whether a RAS mutation is present.
HER2 amplification is a primary resistance mechanism to anti-EGFR therapies in colorectal cancer. Therefore, oncologists should avoid using drugs like panitumumab or cetuximab in HER2-positive patients, even if they are RAS wild-type, as these patients experience rapid progression on such regimens.
Due to selective pressure from first-line treatment, 30-40% of HER2-positive gastroesophageal cancers lose HER2 expression by the time of progression. It is crucial to re-test these patients, either via tissue biopsy or ctDNA, to confirm continued HER2 positivity before initiating second-line HER2-targeted therapy like TDXD.
Clinicians advise against continuing targeted agents like zolbituximab or trastuzumab after disease progression in gastroesophageal cancer. The biological heterogeneity of this cancer type means that if a targeted therapy isn't working, it's unlikely to provide benefit with a different chemotherapy backbone.
In the rare case of a biliary tract cancer with both HER2 positivity and an FGFR2 fusion, clinicians should likely prioritize an FGFR inhibitor. FGFR2 fusions are considered more homogenous and potent early driver events compared to the often heterogeneous expression of HER2.