Cynthia Ma, MD, PhD, explains key efficacy findings regarding HER-targeted therapy to treat patients with HER2-mutant breast cancer.
During the American Association for Cancer Research Annual Meeting, CancerNetwork® spoke with Cynthia Ma, MD, PhD, from Washington University in St. Louis, about the different patient cohorts treated in a phase 2 study (NCT016770877) of neratinib (Nerlynx)–based therapy for HER2-mutant cancer. Investigators found that neratinib or neratinib plus fulvestrant was met with promising efficacy and tolerability for patients with this disease.
The study had 3 cohorts of patients [and was] based on previous studies demonstrating that most of the HER2-mutated breast cancers actually are estrogen receptor [ER] positive. We have 2 cohorts that enrolled patients who had hormone receptor–positive disease and [a] third cohort to include patients who were HER2-negative as well as ER and [progesterone receptor] negative. These are [patients with triple-negative disease]. The reason to have 2 cohorts for the ER-positive [disease] is because we’re combining neratinib with fulvestrant. Some patients have had fulvestrant, so we had a fulvestrant pre-treated cohort, and another cohort of patients who have not had fulvestrant. In the 2 ER-positive cohorts, patients received neratinib [alone] and in combination with fulvestrant; for the ER-negative, or the triple-negative cohort, they received neratinib single agent.
What we found was there was about a 30% to 40% clinical benefit rate in the ER-positive cohorts and about a 20% clinical benefit rate in the ER-negative cohort. The progression-free survival ranged from 4 to 5 months in the ER-positive cohorts. In the ER-negative cohort, it was a little shorter. The 3 cohorts are designed based on a 2 stage, phase 2 design. Although the efficacy did not really meet our subsequent efficacy criteria, a majority of the patients were heavily pretreated. In the ER-positive cohort, a majority of the patients had received prior targeted therapy, especially the CDK4/6 inhibitors, and some have received mTOR inhibitors and the efficacy actually was seen in patients who have had those prior therapies as well.
Another finding from the trial, which is very important for future studies, is that at the time of progression on the study drugs—for example, neratinib and fulvestrant in the ER-positive cohort, or neratinib in the ER-negative cohort—patients were given the option to continue treatment but add trastuzumab [Herceptin], which is an antibody against the HER2 extracellular domain. What we found was adding trastuzumab was able to induce response in patients who have [experienced] progression on the prior treatments. This led to the hypothesis that dual HER2 targeting is really important. And currently, this concept is being tested in the ongoing SUMMIT trial [NCT01953926], which is sponsored by Puma Biotechnology, looking at the triplets of Herceptin, or trastuzumab, in combination with neratinib and fulvestrant in patients who have had progression on CDK4/6 inhibitors [and are] ER-positive, or the doublet of Herceptin and neratinib in the triple-negative, HER2-mutated population. These are important findings for the next study.
In addition, we’ve done circulating tumor DNA analysis on the baseline and on treatment as well as the samples at the time of progression. We’ve found that there are additional acquired HER2 mutations at the time of progression for several patients, meaning that perhaps additional HER2-targeted agents that may overcome these acquired mutation will be important for this population.
Finally would be the finding of lobular cancer, that HER2 mutations are particularly sensitive to this combination. It’s interesting that lobular cancer has a higher rate of HER2 mutations. Depending on the studies, it could range to over 10% of the incidence. For physicians, it will be important to test patients with sequencing platforms to see whether they have protein mutations in the tumor. Some of the patients actually enrolled based on the blood the circulating tumor DNA tumor analysis, especially for patients with lobular breast cancer that’s HER2-negative in the metastatic setting. It will be important to analyze their tumor or blood for this particular HER2 mutation.
Ma C, Luo J, Freedman R, et al. A phase II trial of neratinib (NER) or NER plus fulvestrant (FUL) (N+F) in HER2 mutant, non-amplified (HERmut) metastatic breast cancer (MBC): Part II of MutHER. Cancer Res. 2021;81(suppl 13):CT026. doi:10.1158/1538-7445.AM2021-CT026