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FAQs: HER2-Positive GI Cancers
Targeted Therapies for HER2-Positive Gastrointestinal Cancers: Experts Answer Your Questions

Released: July 12, 2023

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Key Takeaways
  • HER2 testing is essential to guide treatment decisions across gastrointestinal cancers, but there is no consensus on a recommended testing protocol for clinical practice, and many options (immunohistochemistry, in situ hybridization, or next-generation sequencing) can be considered.
  • Single-agent HER2-targeted antibody‒drug conjugate therapy has shown limited activity in HER2-low gastrointestinal cancers.
  • Zanidatamab, a bispecific antibody, demonstrated a response rate of approximately 40% in patients with HER2-positive biliary tract cancer.

In this commentary, Geoffrey Ku, MD; Kanwal Raghav, MD; and Zev A. Wainberg, MD, answer frequently asked questions about their strategies for testing patients’ HER2 biomarker status in gastric, colorectal, and other gastrointestinal (GI) cancers; how this status affects treatment options and potential outcomes; and the available safety and efficacy data for HER2-targeting therapies. The questions below were submitted by an audience of healthcare professionals during an educational webinar on these topics.

In your opinion, what is the best strategy to take when testing patients’ HER2 biomarker status in clinical practice?

Kanwal Raghav, MD:
The best answer is whatever you think you can do in your practice. If next-generation sequencing (NGS) is what you are doing for all of your patients and the platform can test for amplification, then that is a good method, but immunohistochemistry (IHC) testing is a very cheap alternative that is available everywhere. From the data that I have seen with both antibody‒drug conjugates (ADCs) and dual anti‒HER2-targeting therapy, if you can only identify a score of 3+, even if you could not assess amplification status for borderline 2+ scores, then I think you have covered numerous patients who would benefit from this strategy. On the other hand, we do circulating tumor DNA (ctDNA) tests in my practice, so it is screening for all actionable markers—but the point is that we, as oncology professionals, should make all efforts to determine if a patient is HER2 positive.

Zev A. Wainberg, MD:
In an oral abstract session at ASCO 2023, researchers found a discrepancy between tissue-based and ctDNA test results for previously treated patients with HER2-positive metastatic biliary tract cancer (BTC). Imagine you do not have a patient’s tissue or it has been lost for some reason, but ctDNA test results come back as HER2 positive. Is the ctDNA result sufficient for you to treat your patient with HER2-targeting therapy?

Kanwal Raghav, MD:
If the ctDNA test comes back positive, I would give the patient the benefit of the doubt and treat them with HER2-targeted therapy. It is a negative result that I would be more worried about.

Geoffrey Ku, MD:
I do not think you are going to get a false HER2-positive result using ctDNA testing. The challenge I have is that ctDNA testing is not universally recommended. I do not routinely use ctDNA testing; we do tumor biomarkers and NGS at my practice. I rely on those results, but I have had rare discrepancies where the primary tumor came back as HER2 negative and a separate liver biopsy is HER2 positive. Unless you biopsy all metastatic sites, you would never detect that discrepancy. In addition, there could be a role for using ctDNA testing at baseline to make sure you are not missing something that is actionable.

Can patients with HER2-low expression who would benefit from targeted therapy be identified for such treatment in gastric cancer like they are in breast cancer?

Kanwal Raghav, MD:
I think the definitions of HER2 low and HER2 high do have a biological connotation. We know that tumor cells with HER2 scores of 1+ and 2+ are not amplified and not biologically addicted to the HER2 pathway, but when it comes to ADCs, all that is needed is some degree of expression from cells, so targeted therapy will not work in patients with a score of 0. In HER2-low breast cancer (IHC 1+ or IHC 2+/in situ hybridization [ISH] negative), however, we have seen that HER2-targeted ADCs will work. The bystander effect is critical to this, which is one of the many qualities of ADCs that we have only now started to unearth.

When a tissue score is 2+ or 1+, that reflects target expression, but not the circulation and internalization dynamics of the tumor. In lung cancer, for example, the HER2-targeting ADC trastuzumab deruxtecan (T-DXd) works in HER2-mutant lung cancers, irrespective of expression level. Therefore, I think the HER2-low category can be successfully targeted in patients with gastric and/or colorectal cancer, but prior exposure and relative resistance to topoisomerase inhibitors such as irinotecan could be a limiting factor. Furthermore, combination strategies could be effective in this setting.

In colorectal cancer, for example, researchers are looking to increase the sensitivity of the payload by combining the ADC with a DNA damage response (DDR) inhibitor. If you can prevent the repair of that DNA by using an ATR or ATM inhibitor, then you could increase the damage to cancer cells done by these ADCs. Similarly, if you combine ADCs with certain small-molecule tyrosine kinase inhibitors, you can increase the internalization dynamics, increasing the amount of drug that is delivered inside the cancer cell.

Geoffrey Ku, MD:
I agree in principle with the need for combination therapies. In DESTINY-Gastric01, the East Asian study that led to approval of T-DXd in Japan and the United States, there were 2 exploratory subgroups: one IHC 2+/ISH negative and the other IHC 1+. The confirmed overall response rate was 43% in patients with classically HER2-positive disease, 26% in the IHC 2+/ISH-negative group, and 10% in the IHC 1+ group. For comparison, the response rate for HER2-low breast cancer reported at the plenary session last year was approximately 50% This shows that HER2-low GI cancers are a totally different entity than HER2-low breast cancer and that single-agent activity is probably insufficient in this area. One could try combining T-DXd with chemotherapy, but the challenge is that T-DXd is a strong chemotherapy on its own. Combining it with a nonchemotherapy that does not have overlapping toxicities, such as a DDR inhibitor, is a very attractive approach.

Zev A. Wainberg, MD:
One of the challenges in studying HER2-low GI cancers will be finding the patients. There might be a sufficient number of patients with gastric cancer in East Asia, but colorectal cancer may be impossible because of the low frequency of HER2 expression.

Kanwal Raghav, MD:
In my experience in colorectal cancer, including patients with IHC 1+, 2+, or 3+ would increase the proportion of HER2 positivity to approximately 15%, so expanding to include HER2-low status can increase accrual significantly. 

Geoffrey Ku, MD:
The same can be said in my experience with gastric cancer. HER2-low status most likely comprises a higher percentage of this patient population than HER2-positive status.

Zev A. Wainberg, MD:
The take-home message is that oncology professionals should be testing for the HER2 biomarker more because what we do not test for, we will not find. In colon cancer, especially, HER2 status is not widely assessed, so we need to do a better job of identifying patients with this biomarker.

In gastric cancer, loss of HER2 expression is a mechanism of acquired resistance to HER2-targeted therapy. Does this also happen in colon cancer?

Kanwal Raghav, MD:
In the limited sample size of the patients who have received treatment in clinical trials, researchers have not found HER2 loss as a major mechanism of resistance to therapy, at least in colorectal cancer. This may be because of low intratumor heterogeneity in colorectal cancer, which is more similar to that seen in breast cancer than in gastric cancer. HER2 staining in gastric cancer tends to be basolateral, but in colorectal it is often circumferential.

Are the HERIZON-BTC-01 data presented at ASCO 2023 for zanidatamab in HER2-positive BTC sufficient for the FDA to grant accelerated approval for this treatment?

Kanwal Raghav, MD:
I would say that the data are sufficient for accelerated approval of zanidatamab, as this is an orphan drug for an orphan disease. One could argue that all these patients, even in the first-line setting, have very limited options. In the treatment-refractory setting, outcomes associated with BTC are very poor. The response rate seen with zanidatamab is approximately 40% in patients with BTC previously treated with gemcitabine, which is very similar to what we see with dual anti-HER2 therapy in other GI tumors, so I think that it is worth an accelerated approval. Of course, more confirmatory studies and biomarker selection are still needed.

Zev A. Wainberg, MD:
Tumor-agnostic indications usually are given when large datasets are not available in individual diseases. For a HER2-targeting therapy, this is unlikely because we do have large datasets in gastric and colon cancer. Case in point, accelerated approval was just given to tucatinib plus trastuzumab in HER2-positive colon cancer. By these standards, I expect an accelerated approval for zanidatamab in BTC based on these data.  

Your Thoughts?
How does your practice test for the HER2 biomarker in patients with GI cancers? Please answer the polling question and join the conversation by posting a comment in the discussion section.

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How does your practice initially test patients with GI cancers for HER2 expression level?

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