Precision medicine has transformed cancer treatment by targeting shared genetic markers across tumor types. Fam-trastuzumab deruxtecan-nxki (Enhertu; T-DXd) received FDA approval on April 5, 2024, for adult patients with unresectable or metastatic HER2-positive (immunohistochemistry [IHC] score of 3+) solid tumors, expanding its treatment landscape beyond metastatic breast, colorectal, gastric, and non–small cell lung cancers. This approval underscores the importance of understanding and managing the risks associated with targeted therapies to optimize patient outcomes.
Clinical Efficacy Across Tumor Types
The recognition of HER2 as a therapeutic target across tumor sites dates back to 2015. Studies analyzing HER2 expression have found overexpression and/or amplification in various cancers, including bladder, biliary tract, cervical, endometrial, and ovarian cancers. Several clinical trials have since demonstrated the efficacy of HER2-directed therapies, including those used as the basis for T-DXd’s site-agnostic approval: DESTINY-PanTumor02, DESTINY-Lung01, and DESTINY-CRC02.
DESTINY-PanTumor02 Trial
The open-label phase 2 DESTINY-PanTumor02 study (NCT04482309) evaluated T-DXd (5.4 mg/kg every 3 weeks) in patients with HER2-expressing (IHC 3+/2+) local or metastatic disease after at least one prior systemic treatment. The primary endpoint was objective response rate (ORR). The overall ORR was 37.1% (95% CI, 31.3%-43.2%), with responses in all tumor cohorts. The median duration of response (DOR) was 11.3 months (95% CI, 9.6-17.8), the median progression-free survival (PFS) was 6.9 months (95% CI, 5.6-8.0), and the median overall survival (OS) was 13.4 months (95% CI, 11.9-15.5). Participants with HER2 IHC 3+ expression experienced the greatest benefit.
DESTINY-Lung01 Trial
DESTINY-Lung01 (NCT03505710) was a multicenter, 2-cohort, phase 2 study of T-DXd (6.4 mg/kg every 3 weeks) in patients with unresectable or metastatic, HER2-mutated, nonsquamous NSCLC refractory to standard therapy. Among the 91 participants, the ORR was 55% (95% CI, 44%-65%). The median DOR was 9.3 months (95% CI, 5.7-14.7), the median PFS was 8.2 months (95% CI, 6.0-11.9), and the median OS was 17.8 months (95% CI, 13.8-22.1). The DESTINY-Lung02 trial (NCT04644237) evaluated a 5.4 mg/kg dose, demonstrating comparable efficacy with a lower rate of ILD/pneumonitis, establishing the recommended T-DXd dose of 5.4 mg/kg every 3 weeks.
DESTINY-CRC02 Trial
The multicenter, phase 2 DESTINY-CRC02 study (NCT04744831) assessed the efficacy of T-DXd (5.4 and 6.4 mg/kg) in patients with metastatic colorectal cancer and centrally confirmed HER2 expression. Confirmed ORR was 37.8% (95% CI, 27.3%-49.2%) in the 5.4 mg/kg arm and 27.5% (95% CI, 14.6%-43.9%) in the 6.4 mg/kg arm. The median DOR was 5.5 months in both arms, and the median PFS was 5.8 months and 5.5 months, respectively. Safety favored the lower dose.
Safety and Monitoring
Treatment with T-DXd is associated with unique adverse events (AEs) such as interstitial lung disease (ILD), nausea, vomiting, cytopenias, and cardiotoxicity. In a pooled analysis of 9 T-DXd monotherapy studies, the overall incidence of drug-related ILD/pneumonitis was 15.4%, with a median time to onset of 5.4 months and a fatal event rate of 2.2%. Monitoring and management strategies are crucial to avoid irreversible complications. Recommendations include baseline ejection fraction studies, consideration for high-resolution CT (HRCT) scans, and patient education on ILD symptoms.
DEBBRAH Trial: T-DXd in Breast Cancer with Leptomeningeal Disease
The phase 2 DEBBRAH trial (NCT04420598) demonstrated promising antitumor activity of T-DXd in patients with HER2+ and HER2-low advanced breast cancer (ABC) with previously untreated leptomeningeal disease (LMD). The trial met its primary endpoint with an OS of 13.3 months (95% confidence interval [CI], 5.7–NA, P < .001), with a median PFS of 8.9 months (95% CI, 2.1–NA). The safety was consistent with the known profile of T-DXd, and no treatment-related deaths occurred.
Future Directions
Future studies will elucidate the safety and efficacy of T-DXd in other settings, such as for earlier-stage treatment of patients with HER2-positive breast cancer and in patients with HER2-positive breast cancer and active brain metastases. Combination therapies are of particular interest, with phase 1 trials underway of T-DXd in combination with other types of medications, such as immunotherapy and PARP inhibitors. As more targeted therapies emerge with site-agnostic FDA approvals, it is imperative to familiarize ourselves with the risks of these treatments to proactively and effectively mitigate negative safety outcomes and maximize treatment effects.
