Exploring Resistance to HER2-Targeted Therapy for Breast Cancer

Ron Bose, MD, PhD, associate professor in the department of medicine and the department of cell biology and physiology at the Washington University School of Medicine in St. Louis, discusses the rationale for a trial of neratinib (Nerlynx) plus alpelisib (Piqray) for patients with HER2-positive breast cancer.

Resistance to HER2-targeted inhibitors has led to research into mutations associated with drug resistance. There have been several trials of HER2-mutation cancers, including the SUMMIT basket trial (NCT01953926) of patients with solid tumors harboring HER2 or EGFR exon 18 mutations, the MutHER trial (NCT0167087) of neratinib plus fulvestrant (Faslodex) for HER2-positive breast cancer, and the plasmaMatch trial (NCT03182634) of circulating tumor DNA (ctDNA) screening for therapeutic targets in advanced breast cancer.

Median progression-free survival (PFS) for patients receiving neratinib and fulvestrant was around 5 months. This makes overcoming resistance to neratinib to improve PFS a major priority in this setting, according to Bose.

These studies identified HER3 kinase domain mutations as a source of drug resistance, leading to the design of a new clinical trial of the combination of neratinib plus alpelisib. A HER3 mutation led to increased PI3K signaling, which could be inhibited by alpelisib.

TRANSCRIPTION:

0:08 | What motivated the study is there's been 3 clinical trials focusing on HER2 mutations. One is the SUMMIT trial, which is a basket trial of neratinib for HER2-mutant cancers. The next is the MutHER trial, which is a breast cancer-specific trial for HER2 mutations, and third is the British plasmaMATCH trial, which is a ctDNA-based trial which included an arm for HER2-mutated breast cancer. In all of these cases, we're seeing evidence that median PFS, when you're combining neratinib plus fulvestrant, because most of these cancers are [estrogen receptor]–positive also, is about 5 months. So looking at mechanisms of resistance and looking at strategies to try to extend median PFS is going to be very important. And they identified HER3 kinase domain mutations as a mechanism of drug resistance. They proposed that alpelisib would be a good strategy to overcome this drug resistance. And this would be a regimen that can move forward into a clinical trial.