With 20% of breast cancers driven by alterations to the HER2 gene, inhibiting the expression of this gene has been an objective of researchers and clinicians for decades, and a number of inhibitory therapies have been developed. Today, these therapies are benefitting not just breast cancer patients, but patients with other types of cancer as well. HER2 mutations are implicated in a number of cancers, including gastrointestinal (GI) and thoracic cancer, and Fox Chase is investigating and applying drugs developed in the breast cancer arena and using expanded molecular testing to bring more effective treatment to patients.

HER2-Targeted Therapies for GI Cancers

HER2 overexpression was first recognized as a driver of GI cancers in the early 2000s. The mutation is implicated in 20% of patients with gastric cancer, 5–10% of patients with bile duct or gall bladder cancer, and 2–5% of patients with colon cancer. Consequently, there has been considerable research into whether drugs that have proven effective for treating HER2-positive breast cancer may be effective for patients with these HER2-positive GI cancers. 

“For gastric cancer, we’ve used trastuzumab—the first FDA-approved HER2 inhibitor, which was originally approved to treat metastatic breast cancer—for a very long time,” said Efrat Dotan, MD, Chief of the Division of Gastrointestinal Medical Oncology and an Associate Professor in the Department of Hematology/Oncology at Fox Chase. “We now have more data that using a drug called trastuzumab deruxtecan, or TDxd, is a another really good option in the second-line setting for these patients.”

Of course, not all HER2-positive patients respond to these treatments, and not all of the treatments are curative. For instance, TDxd—which works by attaching to HER2-expressing cancer cells and injecting chemotherapy into those cells—has not proven curative in patients with gastric cancer. “Pretty much all patients on this treatment ultimately see their cancer progress, so there’s still room for improvement,” said Namrata Vijayvergia, MD, Assistant Chief of Gastrointestinal Medical Oncology and an Associate Professor in the Department of Hematology/Oncology at Fox Chase.

Vijayvergia is researching whether combining TDxd with the oral cancer drug called neratinib will improve patient outcomes. Based on preclinical data indicating that neratinib increases cellular uptake of TDxd, she is leading a phase I clinical trial sponsored by Fox Chase to test what dose of this drug combination is safe to administer to patients.

“We are starting at the standard dose for the TDxd and we’re slowly increasing the dose of the neratinib in cohorts of patients,” said Vijayvergia. “Once we identify the right dose, the next step is to give it to a larger population of patients to see its benefit.”

The study is also testing whether changes in HER2 expression can be detected in blood samples as treatment progresses. If proven feasible, this “liquid biopsy” would eliminate the need for more invasive tissue biopsies throughout treatment.

Currently, the phase I trial is open to a second cohort of patients and will expand to two sites by late spring.

If you are treating a patient with HER2-positive metastatic or unresectable gastric adenocarcinoma who has been unable to tolerate treatment or has seen their cancer progress on chemotherapy, please consider referring them for this trial. Learn more about this trial.

Testing Leads to More Effective Therapy for HER2-Positive Thoracic Cancer

Beyond its genesis treating HER2-positive breast cancer and its expansion to treat HER2-positive gastric cancer, TDxd has been an effective treatment for thoracic cancer as well. Specifically in patients with HER2-positive adenocarcinoma, the drug has produced a 50% response rate.

“This is a higher response rate than we would get with any chemotherapy, and the responses are fairly durable. So patients can go, eight, eleven, twelve months and maintain responses,” said Hossein Borghaei, DO, MS, Chief of the Division of Thoracic Medical Oncology and a Professor in the Department of Hematology/Oncology at Fox Chase.

To identify the lung cancer patients who will benefit from this drug, Fox Chase has established reflex testing, whereby every patient who is diagnosed with lung cancer automatically receives molecular testing.

“By not having to wait for a medical oncologist to request the testing, we shave off time that’s required to get the data back so that the patient’s treatment is not delayed,” said Borghaei. “Identifying these things early means that the patient can get an effective drug early on.”