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.

Conflict of interest statement

O.Y., T.G., M.A.T., L.Z., J.S., and F.L. report employment with and equity ownership in Daiichi Sankyo. C.L. reports employment with Daiichi Sankyo. H.I. reports honoraria from AstraZeneca, Chugai/Roche, Daiichi Sankyo, Eisai, Lilly, Novartis, Pfizer, and Taiho, and consulting fees from AbbVie, AstraZeneca, Chugai/Roche, Daiichi Sankyo, Kyowa Hakko Kirin, Lilly, Novartis, Odonate, and Pfizer. C.‐C.L. reports travel support from BeiGene and Daiichi Sankyo, advisory fees from Blueprint Medicines, Boehringer Ingelheim, Daiichi Sankyo, and Novartis, and honoraria from Boehringer Ingelheim, Lilly, Novartis, and Roche. K.T. reports receiving research funding from Daiichi Sankyo, Eisai, Lilly, and Pfizer. J.W. reports personal fees from Daiichi Sankyo related to the current work and lecture fees from AstraZeneca, Chugai, Eisai, Eli Lilly, Novartis, and Pfizer outside of the submitted work. R.W. and H.K. report consulting fees from Daiichi Sankyo related to the current work and consulting fees from undisclosed sponsors outside of the submitted work.

© 2021 The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.

Figures

Figure 1

Exposure‐response plot (a) and forest plot of confirmed central ORR by Cavg (b) and exposure‐response plot of confirmed central ORR by Cmin (c). In panels a and c, numbers in red represent n/N; horizontal bars below the plot illustrate the 5th, 50th, and 95th percentiles of exposures. Cavg, average concentration; Cmin, minimum concentration; ORR, objective response rate.

Figure 2

Kaplan‐Meier curves of duration of response (a) and progression‐free survival (b) stratified by intact T‐DXd exposure. Cavg, average concentration; ORR, objective response rate; PFS, progression‐free survival; Q, quartile; T‐DXd, trastuzumab deruxtecan.

Figure 3

Logistic regression plots of discontinuations associated with AEs (a) and anemia (b) and Cox regression plots of ILD (c). In panels a and b, numbers in red represent n/N; horizontal bars below the plot illustrate the 5th, 50th, and 95th percentiles of exposures. In panel c, the solid black line represents the estimated Kaplan‐Meier curves, the dashed lines are 95% CIs, and the solid green line represents the estimated Kaplan‐Meier curve determined using multivariate Cox regression. AE, adverse event; AUC, area under the concentration‐time curve; Cavg, average concentration; CI, confidence interval; Cmax, maximum concentration; ILD, interstitial lung disease; Q, quartile.

Figure 4

Forest plots of probability of discontinuations associated with AEs (a), anemia (b), and ILD (c). AE, adverse event; AUCSS, area under the concentration‐time curve at steady state; Cavg, average concentration; ECOG PS, Eastern Cooperative Oncology Group performance status; ILD, interstitial lung disease.

Figure 5

Model‐projected event rates for T‐DXd 5.4‐ and 6.4‐mg/kg doses in the overall population (all patients), non‐Asian group, Asian‐Japan group, and Asian–non‐Japan group. Error bars represent 90% CI. No effect of race‐country was observed on ORR; therefore, the ORR on all race‐country plots represents the ORR for the overall population. Discontinuations, dose interruptions, and dose reductions plotted are those due to adverse events. Anemia, neutropenia, and thrombocytopenia are laboratory test based. ECHO, echocardiogram; ILD; interstitial lung disease; LVEF, left ventricular ejection fraction; ORR, objective response rate; SAE, serious adverse event.