Exposure–Response Relationship of T-DM1: Insight Into Dose Optimization for Patients With HER2-Positive Metastatic Breast Cancer

Abstract

Exposure-response (E-R) analyses for ado-trastuzumab emtansine (T-DM1, Kadcyla) were performed using data from a randomized, active control (lapatinib plus capecitabine) trial in patients with human epidermal growth factor 2-positive metastatic breast cancer. Kaplan-Meier survival analyses stratified by T-DM1 trough concentration on day 21 of cycle 1 (Cmin,C1D21) were performed for overall survival (OS) and progression-free survival (PFS). E-R analyses indicated that after adjusting for baseline risk factors, higher T-DM1 exposure is associated with improved efficacy. T-DM1-treated patients with Cmin,C1D21 lower than the median value had values of OS and PFS comparable to those of the active control arm. The percentage of patients who received T-DM1 dose adjustments was similar across the exposure range and was lower than that of the active control arm. Our findings suggest that there may be an opportunity to optimize Kadcyla dose in the patient subgroup with low T-DM1 exposure for improved efficacy with acceptable tolerability.

Population pharmacokinetics and exposure–response of trastuzumab emtansine in advanced breast cancer previously treated with ≥2 HER2‐targeted regimens

“…In Kaplan–Meier analysis, patients with higher model‐predicted C min at cycle 1 and AUC ss (Q2–Q4) exhibited a numerically longer median OS and PFS (lower HR estimates) than patients in the lowest T‐DM1 exposure (Q1). A similar relationship was seen in the exposure–response analyses of EMILIA data . Although the distribution of most covariates was comparable across T‐DM1 exposure quartiles, patients in the Q1 subgroup had a numerically higher tumour burden, AST and alkaline phosphatase, and were more likely to have an ECOG PS ≥1 relative to patients in the Q2–Q4 subgroups.…”

“…Overall, the exposure–response relationships for ORR were consistent with the analyses of OS and PFS. For the exposure–response analyses of safety endpoints, irrespective of exposure metric (model‐predicted C max at cycle 1, C min at cycle 1 or AUC ss ), no exposure–response relationship was evident for grade ≥3 thrombocytopenia, grade ≥3 hepatotoxicity or any grade ≥3 adverse event, which is consistent with the exposure–response analyses of EMILIA study data .…”

Exposure–Response Analysis of Overall Survival for Tremelimumab in Unresectable Malignant Mesothelioma: The Confounding Effect of Disease Status

“…When a single‐dose experimental arm fails to demonstrate superiority over standard of care (as in the tremelimumab confirmatory trial in melanoma), post hoc analysis of E‐R is generally conducted to delineate whether a higher dose could have resulted in survival benefit, provided that the maximum tolerated dose was not yet tested. When the single‐dose experimental arm shows a clinically relevant benefit over standard of care, as in the case of trastuzumab in gastric cancer or trastuzumab‐DM1 in breast cancer, a post hoc analysis of E‐R was also conducted to decide whether nonresponders could have benefited from a higher dose. In both cases, this can result in further confirmatory trials with a higher dose (as in tremelimumab in mesothelioma) or in postapproval commitment trials, as exemplified by the HELOISE trial evaluating higher dose of trastuzumab and by the TH3RESA trial for trastuzumab‐DM1 .…”

Exposure-Response Analysis of Necitumumab Efficacy in Squamous Non-Small Cell Lung Cancer Patients

“…The underlying principle stems from the chemotherapy era, where the more drug that is tolerated by the patient, the more efficacy you achieved, but needed to be balanced by safety. With targeted agents, however, it is possible that the exposure–response for safety and efficacy may be separated, and several examples have been presented by academia and regulators on the need for dose optimization on therapeutic proteins in the oncology area 19, 20, 21, 22. This work aims at presenting the exposure–response modeling of safety and efficacy performed with data obtained in squamous NSCLC patients, given gemcitabine‐cisplatin with or without necitumumab 12…”