Exposure‐Response Relationships in Patients With HER2‐Positive Metastatic Breast Cancer and Other Solid Tumors Treated With Trastuzumab Deruxtecan

Abstract

Trastuzumab deruxtecan (T-DXd) is a HER2-targeting antibody-drug conjugate composed of a novel enzyme-cleavable linker and membrane-permeable topoisomerase I inhibitor payload. T-DXd has been approved for HER2-positive metastatic breast cancer and for HER2-positive metastatic gastric cancer. The approval in breast cancer was based on results from the DESTINY-Breast01 (U201; NCT03248492) and J101 (NCT02564900) trials. Here, we present dose justification for the approved 5.4 mg/kg every-3-weeks (Q3W) dose based on exposure-efficacy evaluated in patients with HER2-positive breast cancer (N = 337) from these 2 trials. Exposure-safety was assessed in patients with all tumor types (N = 639, n = 512 with breast cancer) across 5 trials, including J101 and DESTINY-Breast01. T-DXd doses ranged from 0.8-8.0 mg/kg Q3W; most patients received 5.4 (n = 312) or 6.4 mg/kg (n = 291). For each end point, multivariate logistic or Cox regression analysis was performed using various exposure metrics of T-DXd and released drug. A statistically significant association was observed between intact T-DXd area under the concentration-time curve (AUC) and confirmed objective response rate (ORR; P = 0.028). No significant exposure-response relationships were observed between intact T-DXd or released drug and duration of response or progression-free survival; however, follow-up was limited. All evaluated safety end points demonstrated a significant (P < 0.05) relationship with either intact T-DXd or released drug, with higher adverse event (AE) rates projected at higher exposures. Dose-response projections suggested an increase in ORR (67.5% vs. 62.9%) and toxicity (e.g., grade ≥ 3 all-cause treatment-emergent AEs: 61% vs. 54%) with T-DXd 6.4 vs. 5.4 mg/kg. Results demonstrate the benefit-risk profile at different doses and guide clinicians in the use of the 5.4-mg/kg Q3W dose in patients with HER2-positive metastatic breast cancer.

Multidisciplinary clinical guidance on trastuzumab deruxtecan (T-DXd)–related interstitial lung disease/pneumonitis—Focus on proactive monitoring, diagnosis, and management

“…These analyses should be interpreted with caution because they were performed in heavily pretreated and heterogeneous patients with different tumor types who received different doses and treatment durations [66,69]. These results support the established benefit-risk profile of T-DXd and do not warrant exclusion from using T-DXd or amended T-DXd dosing for any of these factors [66,69]. Further research is needed to validate these findings.…”

“…While several studies have found ILD/pneumonitis to be more common in Japan, [66,67,[69][70][71] reasons underlying this association are uncertain. Population pharmacokinetic analyses suggested that T-DXd clearance was slightly lower in Japanese patients; however, there were no clinically meaningful differences in T-DXd steady-state exposure or released DXd based on patient race/country [72].…”

“…Pooled analyses of T-DXd trials have identified factors of interest potentially associated with T-DXd-related ILD/pneumonitis, including treatment in Japan, T-DXd dose, baseline oxygen saturation (SpO 2 ), moderate/severe renal impairment, presence of certain lung comorbidities, and time since initial diagnosis (Table 2) [66,69]. These analyses should be interpreted with caution because they were performed in heavily pretreated and heterogeneous patients with different tumor types who received different doses and treatment durations [66,69]. These results support the established benefit-risk profile of T-DXd and do not warrant exclusion from using T-DXd or amended T-DXd dosing for any of these factors [66,69].…”

“…Another possible reason is increased toxicity in general with T-DXd in Japan. In an exposure-safety analysis of T-DXd, an analysis of covariates found that modeled event rates for eight endpoints (discontinuations due to AEs, dose interruptions due to AEs, grade ≥ 3 anemia, any-grade neutropenia, grade ≥ 3 neutropenia, any-grade thrombocytopenia, grade ≥ 3 thrombocytopenia, and any-grade ILD) were significantly higher in patients in the Asian-Japan group than those in the non-Asian group [69]. However, whether increased toxicity in general with T-DXd in Japanese patients can explain the increased ILD/pneumonitis rate is not known; further research is needed to address this possibility.…”

CT Findings From Interstitial Lung Diseases in Patients With Metastatic Breast Cancer Treated With Fam-Trastuzumab Deruxtecan: A Single Institutional Experience

“…Unlike previous studies, both the onset and recovery times for ILD in our cohort were long. However, a pooled analysis of eight single-arm phase 1 and 2 studies examining trastuzumab deruxtecan use showed that 88% of the patients who developed ILD experienced onset within 12 months of treatment [ 13 ]. In 48% of the confirmed cases, the onset time identified by the investigators was later than that identified by the ILD adjudication committee.…”