HER2 Status May Influence Time to Next Treatment Post-Enhertu

A recent study of patients who received Enhertu (trastuzumab deruxtecan) for advanced breast cancer has revealed valuable data regarding efficacy in patients whose HER2 expression status switched during treatment.

In 191 patients with HER2-positive, HER2-low and HER2-0 status, the time to next treatment (TTNT) after receiving Enhertu was 10.4 months, 7.6 months and 3.7 months, respectively, at 10.4 months median follow-up.

However, patients whose HER2 expression changed from HER2-low to HER2-0 during the study period had a median TTNT of only three months. TTNT was 5.6 months when switching from HER2-0 to HER2-low and 9.4 months for stable HER2-low expression.

“We know that (Enhertu) is an approved treatment for HER2-positive and HER2-negative metastatic breast cancer, but we have limited real-world data with this agent, and most importantly, we don’t know the activity of this agent among patients with changes in HER2 status during the course of disease,” explained Dr. Paolo Tarantino, advanced research fellow in the breast oncology program at Dana-Farber Cancer Institute, in his presentation at the 2023 San Antonio Breast Cancer Symposium.

The investigators noted in their poster presentation that HER2-low expression is a highly unstable biomarker and no data are available on the activity of Enhertu in patients whose HER2 expression changes after a pretreatment biopsy. Additionally, data are limited on subsequent therapies after Enhertu.

Investigators in the RELIEVE study collected data on patients with advanced metastatic breast cancer who received Enhertu between July 2017 and February 2022 at Dana-Farber Cancer Institute and between March 2020 and April 2022 at Duke Cancer Center.

In addition to TTNT, the researchers analyzed progression-free survival (PFS; length of time during and after treatment when a patient lives with cancer but it does not worsen), overall survival (OS; length of time from diagnosis or start of treatment when a patient is still alive), toxicities and TTNT with post-Enhertu regimens.

Of the 191 patients, 126 had HER2-positive, 44 had HER2-low and 21 had HER2-0 expressions. The median age at metastatic diagnosis was 50.9. They had received a median of two prior lines of chemotherapy and a median of four prior lines of therapy in the advanced setting. There were 26% of patients who had de novo metastatic breast cancer and 38% had prior brain metastases, according to the study.

The median OS in the patients with HER2-positive expression was 23.1 months. For HER2-low, the OS was 14.2 months and for HER2-0, it was 9.5 months. The TTNT of the subsequent therapy after Enhertu was 4 months with HER2-positive, 3.1 months with HER2-low and 4.3 months with HER2-0 expressions, without significant difference.

Ten patients switched from HER2-low to HER-0 in the primary tumor after the pre-Enhertu biopsy, whereas 21 patients switched from HER2-0 to HER2-low and 21 had stable HER2-low expression.

“We know HER2-low is a dynamic definition,” said Tarantino. “There are primary tumors that are HER2-low that become (HER2-0) in the metastatic setting and the opposite way around, and so we decided to look at this discordance and its impact on the activity of (Enhertu).”

In five patients who switched from HER2-low to HER2-0 between the first metastatic diagnosis and the pre-Enhertu biopsy and then received Enhertu, the TTNT was 8.5 months.

The TTNT was 5.4 months in 19 patients whose expression switched from HER2-0 to HER2-low at this point, and the TTNT was 8.6 months for 25 patients with stable HER2-low status between these biopsies.

TTNT was 7.4 months for patients with hormone receptor (HR)–negative disease, compared with 10.2 months for those with HR-positive disease, which was not significantly different. There was also not a significant difference between those who received two or fewer prior chemotherapies (10.1 months TTNT) versus those greater than two (8.8 months TTNT).

At the time of follow-up, 55 patients (28.8%) continued receiving Enhertu, 108 (56.5%) had disease progression and 28 (14.7%) stopped treatment due to toxicity. Dose reduction was needed in 61 (31.9%) for side effects, including fatigue (14.7%), nausea/vomiting (9.9%) and blood toxicity (6.3%).

Interstitial lung disease (diseases causing scarring of the lungs) was reported in 22 patients (11.5%), 6.2% of which was grade 1, 3.1% was grade 2, 1.6% was grade 3 and 0.5% was grade 4. This side effect was resolved in 63.6% of cases.

DNADX, a novel machine-learning approach to sequencing, was performed with circulating free DNA from pretreatment plasmas in 81 patients, 39 with HER2-positive, 28 with HER2-low and 14 with HER2-0 status.

Fifty-one patients were found to have a tumor fraction of greater than 1%. In these 51 patients, the uppermost tertile with a high DNADX HER2 signature had a significantly longer PFS.

The respective patients also had a median TTNT of 10 months for high HER2 signature versus seven months for medium HER2 signature and five months for low HER2 signature, which was also statistically significant, according to the data. These findings were independent of their HER2 status by immunohistochemistry.

“In conclusion, (Enhertu) showed the longest TTNT in patients with HER2-positive disease or with stable HER2-low disease among the primary and metastatic setting,” Tarantino said. “Real-world TTNT remains short (post-Enhertu), and so we definitely need to study this setting more and develop novel regimens.”

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