Summary

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• Enhertu (fam-trastuzumab deruxtecan-nxki) is indicated for the treatment of adult patients with unresectable or metastatic HER2-positive breast cancer who have received two or more prior anti-HER2-based regimens either in the metastatic setting, or in the neoadjuvant or adjuvant setting and have developed disease recurrence during or within six months of completing therapy. It is also indicated for the treatment of adult patients with unresectable or metastatic HER2-low (IHC 1+ or IHC 2+/ISH-) breast cancer, as determined by an FDA-approved test, who have received prior chemotherapy in the metastatic setting or developed disease recurrence during or within six months of completing adjuvant chemotherapy. Additionally, it is used for the treatment of adult patients with unresectable or metastatic non-small cell lung cancer (NSCLC) whose tumors have activating HER2 (ERBB2) mutations, as detected by an FDA-approved test, and who have received prior systemic therapy. Furthermore, it is indicated for the treatment of adult patients with locally advanced or metastatic HER2-positive gastric or gastroesophageal junction adenocarcinoma who have received a prior trastuzumab-based regimen. Finally, it is used for the treatment of adult patients with unresectable or metastatic HER2-positive (IHC 3+) solid tumors who have received prior systemic treatment and have no satisfactory alternative treatment options.
• This summary is based on the review of 51 systematic review(s)/meta-analysis(es). ^[1-51]
• Objective Response Rate (ORR) and Pathological Complete Response (pCR): Trastuzumab deruxtecan (T-DXd) demonstrated an ORR between 37% and 79.9% across various studies in HER2-positive breast cancer and other solid tumors. Comparatively, pyrotinib with trastuzumab and chemotherapy achieved a pCR rate of 57%.
• Progression-Free Survival (PFS) and Overall Survival (OS): In HER2-positive patients with brain metastases, T-DXd showed a median PFS of 15 months with an ORR of 61%. Additionally, meta-analysis results indicated that T-DXd improved PFS (OR: 0.38) and OS (OR: 0.61) across various solid tumors.
• Health-Related Quality of Life (HRQoL): Trastuzumab-containing regimens were associated with improved HRQoL during treatment, with post-treatment HRQoL being comparable to chemotherapy but showing better functional status and reduced fatigue.
• Subgroup Efficacy: T-DXd demonstrated effectiveness in HER2-low expressing tumors, with ORRs of 46% in HER2-low and 64% in HER2-positive expressions. In hormone receptor-positive/HER2-positive breast cancer, dual HER2 blockade combined with endocrine therapy provided superior PFS benefits.
• Common adverse events (AEs) associated with enhertu (fam-trastuzumab deruxtecan-nxki) included gastrointestinal toxicities such as nausea, vomiting, and diarrhea, as well as hematologic toxicities including neutropenia, anemia, and fatigue.
• Interstitial lung disease (ILD) was a significant safety concern, with incidences reported up to 10.9% in clinical trials.
• In comparison to other HER2-targeted therapies, T-DXd demonstrated similar or slightly higher incidences of AEs, particularly neutropenia and anemia.
• Serious adverse events (SAEs) were significant, with grade ≥3 AEs such as severe neutropenia and anemia being the most common in patients treated with T-DXd.
• T-DXd demonstrated significant effectiveness in specific subgroups, including patients with breast cancer brain metastases (BCBM), hormone receptor-positive/HER2-positive tumors, and HER2-low expressing tumors, with notable improvements in ORR and PFS.
• Clinical management should focus on monitoring ILD/pneumonitis and cardiotoxicity, particularly in patients receiving T-DXd or combination regimens involving trastuzumab and anthracyclines, due to the increased risks observed in these subgroups.