T-DXd Demonstrates Real-World Efficacy in Advanced Breast Cancer With Dynamic HER2 Expression

Paolo Tarantino, MD

Administration of fam-trastuzumab deruxtecan (T-DXd; Enhertu) significantly prolonged time-to-next treatment in patients with HER2-positive or HER2-low metastatic breast cancer, including patients who experienced changes in HER2 status during the treatment course, according to real-world findings from the RELIEVE study as presented at the 2023 San Antonio Breast Cancer Symposium.¹

In 191 real-world patients with HER2-positive (HER2+), HER2-low, and HER2-0 status, the median time to next treatment (TTNT) after T-DXd was 10.4 months, 7.6 months, and 3.7 months, respectively, at 10.4 months median follow-up (P < .001). Patients whose HER2 expression changed from HER2-low to HER2-0 during the study period had a median TTNT of only 3.0 months, whereas it was 5.6 months when switching from HER2-0 to HER2-low, and 9.4 months for stable HER2-low expression (P = .006).

“We know that T-DXd is an approved treatment for HER2+ and HER2-low 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 Paolo Tarantino, MD, an 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 T-DXd in patients whose HER2 expression changes after a pretreatment biopsy. Additionally, data are limited on subsequent therapies after T-DXd.

Investigators in the RELIEVE study collected data on patients with aBC who received T-DXd 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, they looked at progression-free survival (PFS), overall survival (OS), toxicities, and TTNT with post-T-DXd regimens.

Of the 191 patients, 126 had HER2+, 44 had HER2-low, and 21 had HER2-0 expression. The median age at metastatic diagnosis was 50.9 (range, 21.4-78.0). They had received a median of 2 prior lines of chemotherapy (range, 0-9) and a median of 4 prior lines of therapy in the advanced setting (range, 0-16). Twenty-six percent had de novo metastatic breast cancer and 38% had prior brain metastases.

The median OS in the patients with HER2+ expression was 23.1 months, for HER2-low it was 14.2 months, and for HER2-0 it was 9.5 months with a P value of .003. The TTNT of the subsequent therapy after T-DXd was 4.0 months with HER2+, 3.1 months with HER2-low, and 4.3 months with HER2-0 , without significant difference (P = .62).

Ten patients switched from HER2-low to HER-0 in the primary tumor after the pre–T-DXd 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,2 and so we decided to look at this discordance and its impact on the activity of T-DXd.”

In 5 patients who switched from HER2-low to HER2-0 between first metastatic diagnosis and the pre–T-DXd biopsy and then received T-DXd, the TTNT was 8.5 months; in 19 whose expression switched from HER2-0 to HER2-low at this point, the TTNT was 5.4 months, and for the 25 with stable HER2-low status between these biopsies, TTNT was 8.6 months (P = .4119).¹

TTNT was 7.4 months for patients with hormone receptor–negative disease compared with 10.2 months for those with hormone receptor–positive disease, which was not significantly different (P = .25). It was also not a significant difference (P = .5) between those who received 2 or fewer prior chemotherapies (10.1 months TTNT) vs greater than 2 (8.8 months TTNT).

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

Interstitial lung disease 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 AE was resolved in 63.6% of cases. Cardiotoxicity constituting a decrease in left ventricular ejection fraction of at least 10% from baseline to a value of over 50% was reported in 5 patients (2.6%).

Correlative analysis on 58 patients with HER2-negative tumors found that 6 (10.3%) also had hemizygous ERBB2 deletions and these patients had a numerically lower TTNT of 4.1 months vs 7.6 months in those with no ERBB2 deletions (P = .41).

DNADX, a novel machine learning approach to sequencing, was performed with circulating free DNA from pretreatment plasmas in 81 patients, 39 with HER2+, 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 (log-rank P = .027). They also had a median TTNT of 10 months for high HER2 signature vs 7 months for medium HER2 signature and 5 months for low HER2 signature, which was also statistically significant (log-rank P = .045). These findings were independent of their HER2 status by immunohistochemistry.

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

References:

1. Impact of HER2 expression dynamics on the real-world activity of trastuzumab deruxtecan for metastatic breast cancer (RELIEVE). Presented at: San Antonio Breast Cancer Conference; December 5-9, 2023; San Antonio, TX. Abstract PS08-09.
2. Tarantino P, Gandini S, Nicolò E, et al. Evolution of low HER2 expression between early and advanced-stage breast cancer. Eur J Cancer. 2022;163:35-43. doi:10.1016/j.ejca.2021.12.022