Adverse effect of trastuzumab deruxtecan in solid tumours: A systematic review and meta-analysis.

Introduction: Trastuzumab deruxtecan (T-DXd) is approved for use in numerous solid tumours. Here we summarize its safety and tolerability profile.

Methods: Studies were identified from MEDLINE, EMBASE and recent conference proceedings. Analysis comprised clinical trials (phases 1 [dose-expansion], 2 or 3) reporting safety and tolerability of T-DXd. Data were pooled as the mean weighted by individual study sample size from single arm studies. Randomized studies were analyzed separately to compare T-DXd to chemotherapy and to trastuzumab emtansine. Meta regression comprised linear regression weighted by sample size was performed.

Results: A total of 35 studies with 48 distinct cohorts were included in the analysis. All grade adverse effects (AEs) and grade ≥ 3 AEs occurred in 97.2 % and 54.9 % of patients respectively. Most common all grade AEs included: nausea (66.2 %), fatigue (41.8 %) and anemia (33.8 %). Common grade ≥ 3 AEs included anemia (12.9 %), thrombocytopenia (6.7 %) and fatigue (5.3 %). Pooled incidence rate of interstitial lung disease (ILD) and grade≥ 3 ILD were 13.2 % and 2.3 % respectively, and 2 % had febrile neutropenia. Cardiotoxicity was rare. Treatment- and ILD- related deaths were reported in 5 % and ILD 1.4 %, respectively. Compared to chemotherapy, T-DXd had higher odds of AEs and treatment discontinuation. Higher dose, non-Caucasian ethnicity and cancer sites other than breast were associated with grade ≥ 3 AE, grade ≥ 3 ILD, AE- and ILD- related deaths and serious AEs.

Conclusions: T-DXd has a safety and tolerability profile less favorable than classical chemotherapy. Dose, ethnicity and cancer site are associated with differential safety and tolerability.