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HER2 Positive Gastroesophageal Cancers FAQ
Expert Answers to FAQs on Management of HER2-Positive Gastroesophageal Cancers

Released: July 02, 2024

Expiration: July 01, 2025

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Key Takeaways
  • Next-generation sequencing can help identify patients eligible for HER2-directed therapy who might have been misclassified by immunohistochemistry due to limited tissue sampling and tumor heterogeneity.
  • In patients responding to first-line treatment with chemotherapy plus trastuzumab and pembrolizumab, oncologists may consider stopping the platinum agent at around 6 months to prevent dense neuropathy and if the disease remains stable, with 5-fluorouracil continued for several more months based on tolerance; stopping 5-fluorouracil and switching to capecitabine is also reasonable. If tolerated, trastuzumab and pembrolizumab may be continued for 2 years total.
  • Prompt consultation with pulmonary specialists can help guide management of interstitial lung disease related to trastuzumab deruxtecan.

In this commentary, Jaffer A. Ajani, MD, answers questions posed by an audience of healthcare professionals during a live webinar titled, “Redefining the Possibilities for Patients With HER2-Positive Gastroesophageal Cancers.”

If you have a patient whose tumor shows HER2 immunohistochemistry (IHC) 1+ but next-generation sequencing (NGS) identifies ERBB2 (HER2) amplification, would you add HER2-directed therapy?
This is a challenging scenario because we currently lack robust data. The discrepancy between the IHC and NGS results may be due to tumor heterogeneity and tumor sampling. IHC takes a more limited snapshot of tissue-based samples, whereas NGS samples the entire tumor. In our clinic, we have seen such discrepancies in HER2 results for tissue sampled on the left side vs right side as well as tests performed by our clinic vs by the referring oncologist. The guidelines are entirely clear on this issue.

In this scenario, based on the NGS result, I would strongly consider adding HER2-directed therapy for this patient.

When patients respond to the KEYNOTE-811 regimen (chemotherapy plus trastuzumab plus pembrolizumab), do you consider stopping chemotherapy at around 6 months and continuing only trastuzumab plus pembrolizumab?
In my practice, I will stop chemotherapy after approximately 6 months while still keeping patients on trastuzumab. Many oncologists do stop the platinum agent at around 6 months while continuing the 5-fluorouracil (5-FU) with trastuzumab plus pembrolizumab. If the disease remains stable and the patient grows tired of chemotherapy, you can consider dropping the 5-FU or switching to capecitabine to give the patient a break from the infusion pump.

Is trastuzumab deruxtecan (T-DXd) under investigation in the first-line setting?
Yes, T-DXd is under clinical trial investigation in the first-line setting for HER2-positive gastroesophageal cancers (NCT04379596). One challenge here is the potential for increased toxicity when T-DXd is combined with standard first-line chemotherapy components. A workaround for this is to combine T-DXd with lower doses of 5-FU and to minimize use of oxaliplatin. There is still a lot of work that must be done to find the optimal first-line chemotherapy combination with T-DXd.

When patients develop interstitial lung disease (ILD) related to T-DXd, do you manage the ILD yourself or refer the patient to specialists?
Because my pulmonary colleagues are now very familiar with managing ILD in patients with solid tumors, I try not to manage the ILD myself. If the patient has a chest x-ray or CT scan that is abnormal, I immediately ask my specialist colleagues for guidance.

That being said, oncologists should bear in mind that ILD related to T-DXd is managed far more conservatively than pneumonitis related to PD-1 inhibition. Even with grade 1 ILD, we must immediately hold T-DXd because continuing it risks the ILD becoming more severe and intractable. This is different from when patients receiving PD-1 inhibition develop mild pneumonitis, where we might continue the PD-1 inhibitor.

Do you think zanidatamab could be approved in the not-too-distant future?
Zanidatamab, which binds to 2 different epitopes on the extracellular domain of the HER2 receptor, may be the closest to entering practice among the current investigational HER2-directed agents. This assumes that we would see positive data from the phase III HERIZON-GEA-01 trial comparing first-line zanidatamab plus chemotherapy with or without tislelizumab vs trastuzumab plus chemotherapy in advanced HER2-positive gastric/gastroesophageal junction adenocarcinoma (NCT05152147). I used this agent in the phase I/II trials and was struck by the high response rate. Diarrhea is part of the safety profile for zanidatamab, but I found that to be manageable.

Your Thoughts?
What challenges do you face with HER2 testing and treatment selection when managing HER2-positive gastroesophageal cancers? Join the discussion by answering the polling question and posting a comment. Also, please download the slides from the live webinar to learn more about this topic.

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