As clinical evidence evaluating targeted therapies and immunotherapies in gastroesophageal adenocarcinoma (GEA) continues to grow, approaches to first-line treatment for patients with HER2-positive disease continue to evolve. In addition to recognizing HER2-positive GEA, in order to give the appropriate treatment to individual patients, there are many factors that have to be considered by the oncology team when deciding on the most suitable first line treatment for individual patients.
Newer evidence continues to add to the expanding evidence of HER2-directed therapy in the treatment of first-line HER2-positive GEA. To support treatment of the patients with GEA and to minimize the risk of toxicity, incorporation of all the biomarkers into assessment prior to treatment initiation is crucial.
Understanding HER2-Positive GEA
HER2 (human epidermal growth factor receptor 2) is a protein that in many normal cells constitutes part of the cell surface membrane. It is involved in cell growth, proliferation and inhibition of apoptosis. In GEA about 10% to 20% of tumors show an increased expression of HER2 in cancer cells or have amplified the corresponding gene. In such cases the cancer cells can be targeted with specific therapies aimed at blocking the growth promoting actions of the HER2 protein.
The HER2 status can be determined by IHC (immunohistochemistry) with classification into three categories (0, 1, 3). Cases that are classified as IHC 2+ are typically confirmed by ISH (in situ hybridization) tests to determine HER2 status in GEA.
For the oncology team, therefore, the pathologies have to be reviewed and the appropriate biomarkers tested early in the diagnostic and treatment process for the patient with cancer.
First-Line HER2+ GEA Treatment: Current Clinical Approach
Initial combination chemotherapy with trastuzumab is the mainstay for treatment of patients with HER2-positive advanced or metastatic GEA. The backbone of chemotherapy and addition of HER2-directed therapy (trastuzumab) established it as a first-line strategy for eligible patients.
Subsequent clinical trials, incorporating immune checkpoint inhibitors such as pembrolizumab in combination with trastuzumab and chemotherapy have been evaluated in patients selected appropriately for first line treatment of HER2 positive GEA. In First-Line HER2+ GEA Treatment, multiple factors will need to be considered when determining the appropriate course of treatment beyond a single biomarker.
The Role of PD-L1 Testing
PD-L1 expression, such as assessed by tumor proportion score (TPS) score, or as a combined positive score (CPS) score in gastric cancer and gastroesophageal junction cancer, has been established as a predictive biomarker for immune checkpoint inhibitors, particularly PD-1/PD-L1 inhibitors.
Finally, when considering PD-L1 testing for determining treatment with an immune checkpoint inhibitor, the results must be taken in the context of the available evidence (or study or trial), the patient’s specific clinical situation and their treatment goals. The potential toxicities of treatment must also be considered.
Newer HER2-Directed Strategies
Interest in therapies that have more potent or even broader HER2-targeting activity than trastuzumab is an important ongoing area of research in HER2-positive GEA. Many of these new agents are Antibody-drug conjugates (ADCs), that comprise a HER2-targeting antibody linked to a potent cytotoxic. Their selection for gastric cancer evaluation has been driven by their mechanism to target cancer cells with varying levels of HER2 expression.
Newer HER2-directed therapies are increasingly being studied for use in the various stages of the treatment of HER2-positive gastrointestinal cancers. Importantly, the findings from prior studies have helped to define strategies for the use of therapies that target HER2 in all stages of cancer.
However, the fact that a treatment has shown activity in patients with cancer that is previously treated does not necessarily mean that the same treatment should be used as a first-line treatment for patients with newly diagnosed cancer. In developing an indication, the therapeutic must be considered in the context of the specific clinical situation and considered in the context of the treatment’s regulatory status and evidence supporting use for that specific indication.
Key Factors for Treatment Selection
Consideration of key factors that are patient- and disease-specific are required for selection of an initial regimen for HER2 positive GEA patients.
Disease Burden and Clinical Status
Another important factor when deciding between treatment options is the patient’s disease burden and general clinical condition. Patients with a worse performance status and higher cancer-related symptoms generally have different treatment priorities than patients with less aggressive disease and fewer symptoms.
Biomarker Profile
While the HER2 status of a patient’s cancer is a critical factor in determining a treatment, other biomarkers can also provide clinicians with valuable information on the appropriate treatment. For example, the level of expression of the PD-L1 protein by a tumor can affect the potential benefit of immunotherapy. Additional molecular features may define certain tumors for which patients are eligible for experimental therapies or may affect the choice of subsequent therapies for patients whose initial treatment does not provide adequate benefit.
Tumor samples should be tested for adequate and representative tumor tissue with involvement of all disciplines (pathology, oncology, etc.).
Treatment Tolerability
Combination regimens can increase treatment complexity and therefore a number of factors should be considered when choosing initial treatment including cardiac function as some HER2-directed treatments, particularly trastuzumab and related agents, can cause cardiac toxicity and have effects on cardiac function. Regular monitoring of cardiac function prior to and during treatment can also help to identify patients who require close monitoring of potential cardiac toxicity.
Monitoring Response and Managing Toxicity
Monitoring of response to treatment and any toxicity and/or side effects and managing them where necessary is an ongoing process in the first line treatment of the gastrointestinal cancer patient.
Early recognition of immune-related adverse events (irAEs) is important, as these events may affect a wide range of organs, including the thyroid, liver, lungs, GI tract, and skin. Management typically involves assessment of the affected organ system and severity of symptoms, with treatment modifications, corticosteroid therapy, and specialist.
As with many forms of cancer therapy, careful assessment and management of specific toxicities, including those seen with the use of HER2-targeted therapies (for example, infusion reactions) as well as potential effects on the heart, are also essential.
Looking Ahead
Management of HER2 positive GEA in first line is increasingly moving towards individualization of treatments. HER2 targeted therapy, combined with chemotherapy and immune-checkpoint inhibitors, has led to a complex spectrum of treatment options, which will continue to be increasingly defined by new HER2 targeting agents.
Important considerations for oncology teams managing patients with GEA include accurate assessment of the tumor for HER2 status and other biomarkers, individualized treatment selection based on patient and disease characteristics, and ongoing monitoring and management of treatment-related toxicities, with regular follow-up to assess response to therapy.
Until further evidence emerges it is important to note that to select appropriate first-line treatment and preserve subsequent treatment options for patients with HER2 positive GEA tumors an increasing understanding of HER2 expression in combination with other tumor and patient related factors and of additional immune related biomarkers is needed.
Medical Disclaimer: The information provided in this article is intended for educational purposes only and should not be interpreted as medical advice, clinical guidelines, or a recommendation for any specific treatment.
