Trastuzumab deruxtecan in metastatic breast cancer with variable HER2 expression: the phase 2 DAISY trial

Abstract

The mechanisms of action of and resistance to trastuzumab deruxtecan (T-DXd), an anti-HER2–drug conjugate for breast cancer treatment, remain unclear. The phase 2 DAISY trial evaluated the efficacy of T-DXd in patients with HER2-overexpressing (n = 72, cohort 1), HER2-low (n = 74, cohort 2) and HER2 non-expressing (n = 40, cohort 3) metastatic breast cancer. In the full analysis set population (n = 177), the confirmed objective response rate (primary endpoint) was 70.6% (95% confidence interval (CI) 58.3–81) in cohort 1, 37.5% (95% CI 26.4–49.7) in cohort 2 and 29.7% (95% CI 15.9–47) in cohort 3. The primary endpoint was met in cohorts 1 and 2. Secondary endpoints included safety. No new safety signals were observed. During treatment, HER2-expressing tumors (n = 4) presented strong T-DXd staining. Conversely, HER2 immunohistochemistry 0 samples (n = 3) presented no or very few T-DXd staining (Pearson correlation coefficient r = 0.75, P = 0.053). Among patients with HER2 immunohistochemistry 0 metastatic breast cancer, 5 of 14 (35.7%, 95% CI 12.8–64.9) with ERBB2 expression below the median presented a confirmed objective response as compared to 3 of 10 (30%, 95% CI 6.7–65.2) with ERBB2 expression above the median. Although HER2 expression is a determinant of T-DXd efficacy, our study suggests that additional mechanisms may also be involved. (ClinicalTrials.gov identifier NCT04132960.)

In Vivo Biorthogonal Antibody Click for Dual Targeting and Augmented Efficacy in Cancer Treatment

“…T-DXd shows clinical benefit in patients with HER2-high and HER2-low tumors ( 39, 43 ), but most of the patients will ultimately experience disease progression. Additionally, T-DXd does not accumulate in high levels in HER2 - cancer cells ( 43 ).…”

“…T-DXd shows clinical benefit in patients with HER2-high and HER2-low tumors ( 39, 43 ), but most of the patients will ultimately experience disease progression. Additionally, T-DXd does not accumulate in high levels in HER2 - cancer cells ( 43 ). To determine if antibody-ADC click could extend the potential benefit of an ADC to non-HER2 expressing tumors, we performed therapeutic studies in a bilateral model of HER2 + NCIN87 and HER2 - A431 cancer cells ( Fig.…”

Real‐world effectiveness and safety of RC48‐ADC alone or in combination with PD‐1 inhibitors for patients with locally advanced or metastatic urothelial carcinoma: A multicenter, retrospective clinical study

“…The results showed that the mPFS was longer in Cohort 1 at 11.1 months, Cohort 2 had an median PFS of 6.7 months, and Cohort 3 had an median PFS of 4.2 months. 31 The interim results of the DESTINY-PanTumor02 (DP-02) trial included 41 patients with urothelial cancer, with an overall response rate (ORR) of 56.3% in 16 patients with HER2 3+ compared to an ORR of 35.0% in 20 patients with HER2 2+. 32 Additionally, Klümper et al's study showed that the clinical benefit of EV strongly depends on membranous NECTIN-4 expression, and the lack or low expression of NECTIN-4 is significantly associated with shortened PFS of EV.…”

Antibody–drug conjugates transform the outcome of individuals with low‐HER2‐expression advanced breast cancer

“…The DESTINY-Breast06 study brings forward the application of T-DXd in HRþ/HER2-low-expressing BC patients as the first-line chemotherapy stage after endocrine-targeted therapy and further extends to patients with ultra-low expression of HER2 with 0 < IHC <1þ, a group that may also benefit, as demonstrated in the recent phase 2 DAISY trial. There was no significant difference in the PFS and the probability of ORR between two cohorts (37.5% in HER2-low and 29.7% in HER2-0; 6.7 months in HER2-low and 4.2 months in HER2 0) 62. Regardless of the underlying mechanism, these findings suggest the following thought-provoking hypothesis: if T-DXd proves to be clinically advantageous in HER2-0 tumors, the definition of HER2-low may potentially broaden to encompass tumors that do not exhibit HER2 amplification, aligning with the definition of HER2-negative.…”