Close-up on HER2 alterations in advanced NSCLC

Sherrie Rice

August 2022—HER2 is a known oncogenic driver and emerging biomarker in non-small cell lung cancer, and while the therapeutic implication is not yet fully known in NSCLC, “we need to pay attention to it,” said Fred R. Hirsch, MD, PhD, executive director of the Mount Sinai Center for Thoracic Oncology and associate director, Tisch Cancer Institute, in a CAP TODAY webinar sponsored by Daiichi-Sankyo and AstraZeneca.

The estimated prevalence of a HER2 gene mutation in advanced NSCLC is two to four percent, he said. The prevalence of HER2 gene amplification varies by test method: two to four percent by next-generation sequencing and 10 to 20 percent by FISH. And the prevalence of HER2 protein overexpression by immunohistochemistry varies by study and antibody, he said, and ranges from six percent to 35 percent. NSCLC patients with mutation, amplification, or overexpression are currently in clinical practice treated comparably to patients who have no molecular alteration.

Most of the mutations (about 50 percent) occur in exon 20, but the abnormalities also occur in exons 18, 19, and 21. “HER2 mutations are not frequently seen alongside other actionable mutations in non-small cell lung cancer. In fact, they are mutually exclusive of other driver mutations,” said Dr. Hirsch, citing a study of 1,007 patients in which 2.4 percent (24) had a HER2 mutation and all but one was mutually exclusive of other driver mutations—EGFR, KRAS, BRAF, and ALK. They can co-occur, however, with several nonactionable mutations. Co-occurring TP53 mutations have been reported at a rate of more than 50 percent, and co-occurring mutations in RB1 have been reported in 8.9 percent.

“We don’t know exactly what the therapeutic implication of that is or the prognostic implication,” said Dr. Hirsch, who is also professor of medicine and pathology and the Joe Lowe and Louis Price professor of medicine at Icahn School of Medicine at Mount Sinai. Clinical trials are underway.

The data on immunotherapy in HER2-mutated NSCLC are derived from retrospective studies and “not very encouraging,” he said. “In non-oncogenic driver populations, we would expect 30 to 40 percent response rates for immunotherapy,” but the response rates in patients with tumors having a molecular driver in multiple studies with and without chemotherapy were found to be lower—from seven percent to 29 percent. “We also see lower progression-free survival and overall survival.” Thus, immunotherapy “is not a good choice in the future for the oncogenic driver population,” Dr. Hirsch said. Many possible approaches are being studied in patients with HER2-mutant metastatic NSCLC, including antibody-drug conjugates, immunotherapy combinations, and small-molecule inhibitors.

HER2 mutations are different from HER2 amplification and HER2 overexpression, and each of the HER2 alterations is discovered using different testing methods. For HER2 mutations, NGS is the preferred method. For HER2 amplification, in situ hybridization and NGS are used, and immunohistochemistry is used for protein overexpression. In each of the three, the relevance in metastatic NSCLC is under investigation.

Broad molecular profiling, typically with NGS, is recommended in patients with metastatic non-squamous NSCLC and some squamous cell carcinoma NSCLC, “and we recommend that the profiling include the HER2 mutation,” Dr. Hirsch said. Tissue is still for many the preferable source for NGS, he said. Specificity is 95 to 100 percent, and sensitivity is 90 percent or greater. Though the turnaround time today—from seven to 20 working days—is acceptable, he said he’d like to see it at seven to 10 working days.

“Liquid biopsy is coming quicker and quicker into the diagnostic scenario,” he noted, adding that specificity is close to 100 percent. If the liquid biopsy is positive, “you can make a treatment decision based on it.” With sensitivity at about 80 percent, he recommends trying to get a tissue biopsy when the blood-based result is negative. “The technology is getting better—more and more sensitive,” he said, and among its benefits is its typically faster turnaround time and that it can capture tumor heterogeneity.

“So I’m a believer that we will see further advantages and use of NGS based on liquid biopsy.”