Abstract
The anti-HER2–drug conjugate trastuzumab deruxtecan (T-DXd) was effective in HER2-low breast cancer.
Major Finding: The anti-HER2–drug conjugate trastuzumab deruxtecan (T-DXd) was effective in HER2-low breast cancer.
Concept: Prior work hinted that T-DXd may be effective even in HER2-low disease due to a bystander effect.
Impact: Studies to find predictors of serious side effects and a phase III clinical trial are now under way.
Trastuzumab deruxtecan (T-DXd), a drug–antibody conjugate that combines the HER2 antibody trastuzumab with the topoisomerase I inhibitor deruxtecan, is approved to treat patients with HER2-positive breast cancer who have not responded to other HER2-targeted therapies. Counterintuitively, preclinical studies have indicated that T-DXd may also be effective against breast cancers with low overall HER2 expression, possibly because the high payload of cell membrane–permeable deruxtecan can affect low-HER2 cells neighboring those with higher HER2 expression, reflecting a bystander effect. In a first-in-human, nonrandomized, open-label, phase Ib clinical trial, Modi and colleagues investigated the use of T-DXd at two dose levels in 54 patients with advanced HER2-low breast cancer. Patients had been heavily pretreated, with a median number of prior therapies of 7.5, and 10 patients (19%) had already received HER2-targeted therapies. According to an independent central review, all responses were partial, and the objective response rate was 37%, with the median duration of response being 10.4 months. Treatment-emergent adverse events—most commonly gastrointestinal disturbances, fatigue, alopecia, and anemia—occurred in 53 patients (98%) and led to treatment discontinuation in 11 patients (20%). Notably, three patients (all in the cohort receiving the higher dose) died of effects deemed to be due to study treatment, two of pneumonitis and one of interstitial lung disease (ILD). Due to the greater potential for adverse effects with the higher dose, the lower dose was recommended for further study, and predictors of drug-related ILD are currently being evaluated in other studies. Some limitations of this study include its small size, lack of randomization, and lack of prospective evaluation of HER2 status. The results of this early study demonstrate the potential value of T-DXd treatment in a patient population with poor prognosis and few treatment options remaining, and a randomized, phase III clinical trial of T-DXd in patients with advanced HER2-negative breast cancer is now being conducted.
Note: Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/CDNews.
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