In a retrospective analysis of the EMILIA study, the rate of central nervous system (CNS) progression in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer was similar for trastuzumab emtansine (T-DM1) and for capecitabine–lapatinib. In patients with treated, asymptomatic CNS metastases at baseline, T-DM1 was associated with significantly improved overall survival versus capecitabine–lapatinib.

Purpose HER2-positive breast cancer is heterogeneous. Some tumors express mutations, like activating PIK3CA mutations or reduced PTEN expression, that negatively correlate with response to HER2-targeted therapies. In this exploratory analysis, we investigated whether the efficacy of trastuzumab emtansine (T-DM1), an antibody–drug conjugate comprised of the cytotoxic agent DM1 linked to the HER2-targeted antibody trastuzumab, was correlated with the expression of specific biomarkers in the phase III EMILIA study. Experimental Design Tumors were evaluated for HER2 (n = 866), EGFR (n = 832), and HER3 (n = 860) mRNA expression by quantitative reverse transcriptase PCR; for PTEN protein expression (n = 271) by IHC; and for PIK3CA mutations (n = 259) using a mutation detection kit. Survival outcomes were analyzed by biomarker subgroups. T-DM1 was also tested on cell lines and in breast cancer xenograft models containing PIK3CA mutations. Results Longer progression-free survival (PFS) and overall survival (OS) were observed with T-DM1 compared with capecitabine plus lapatinib in all biomarker subgroups. PIK3CA mutations were associated with shorter median PFS (mutant vs. wild type: 4.3 vs. 6.4 months) and OS (17.3 vs. 27.8 months) in capecitabine plus lapatinib–treated patients, but not in T-DM1-treated patients (PFS, 10.9 vs. 9.8 months; OS, not reached in mutant or wild type). T-DM1 showed potent activity in cell lines and xenograft models with PIK3CA mutations. Conclusions Although other standard HER2-directed therapies are less effective in tumors with PI3KCA mutations, T-DM1 appears to be effective in both PI3KCA-mutated and wild-type tumors.

A B S T R A C T PurposeSevere (grade Ն 3) pulmonary hemorrhage (PH) in advanced non-small-cell lung cancer was observed in two prospective, randomized, phase II (N ϭ 99) and phase III (N ϭ 878) trials of bevacizumab plus carboplatin and paclitaxel. Retrospective case-control and cohort analyses were conducted to identify associated radiographic and clinical risk factors for PH. Patients and MethodsSix patients with PH from the phase II trial, 15 potential PH patients with hemorrhage at any site from the phase III trial, and their matched controls were evaluated with review of baseline and on-treatment radiographs by an independent radiology facility, blinded to patient/control status. Patients with severe (grade Ն 3) PH from each trial were matched with up to three controls based on sex, age group, histology (phase II), or sex and age group (phase III). ResultsSeven PH patients in the phase III trial were identified as severe PH. Six of the patients were early onset (occurred Ͻ 150 days of initiating bevacizumab) and one was late onset. Baseline tumor cavitation, not tumor location, was identified as the only potential risk factor for patients with early onset. Combined analysis of severe PH patients from the phase II and phase III trials (n ϭ 13), compared with their pooled matched controls (n ϭ 42), did not identify any additional baseline radiographic or clinical variables associated with PH. ConclusionPH was an uncommon event. Based on these analyses, baseline tumor cavitation may be a potential risk factor for PH. No other baseline clinical variables were predictive for PH although the number of events was small.

In this analysis of 884 T-DM1-exposed patients, grade 3 or greater AEs were infrequent and typically asymptomatic and manageable. This favorable safety profile makes T-DM1 treatment suitable for exploration in other breast cancer settings.

Purpose Trastuzumab emtansine (T-DM1) is an antibody–drug conjugate comprising the humanized monoclonal antibody trastuzumab linked to DM1, a highly potent cytotoxic agent. A population pharmacokinetic (PK) analysis was performed to estimate typical values and interindividual variability of T-DM1 PK parameters and the effects of clinically relevant covariates.MethodsSerum samples were collected from 671 patients with human epidermal growth factor receptor 2-positive locally advanced or metastatic breast cancer (MBC) who received single-agent T-DM1 in five phase I to phase III studies. Nonlinear mixed-effects modeling with the first-order conditional estimation method was used.ResultsA linear two-compartment model with first-order elimination from the central compartment described T-DM1 PKs in the clinical dose range. T-DM1 elimination clearance was 0.676 L/day, volume of distribution in the central compartment (Vc) was 3.127 L, and terminal elimination half-life was 3.94 days. Age, race, region, and renal function did not influence T-DM1 PK. Given the low-to-moderate effect of all statistically significant covariates on T-DM1 exposure, none of these covariates is expected to result in a clinically meaningful change in T-DM1 exposure.ConclusionsT-DM1 PK properties are consistent and predictable in patients. A further refinement of dose based on baseline covariates other than body weight for the current 3.6 mg/kg regimen would not yield clinically meaningful reductions in interindividual PK variability in patients with MBC.Electronic supplementary materialThe online version of this article (doi:10.1007/s00280-014-2500-2) contains supplementary material, which is available to authorized users.

ABSTRACT

Exposure-response relationships for efficacy were inconsistent across exposure metrics; model-predicted cycle 1 C showed the strongest exposure-response trend. The Q1 subgroup based on model-predicted cycle 1 C had numerically similar or better OS and PFS versus control following covariate adjustment. The approved T-DM1 dose (3.6 mg/kg every 3 weeks) has a positive benefit-risk ratio versus control, even for the T-DM1 Q1 subgroup.

Development of effective therapies for recurrent glioblastoma multiforme (GBM) and reliable, timely evaluation of their benefit are needed. Understanding the relationship between objective response (OR) and survival is important for determining whether OR can provide an early signal of treatment activity in clinical trials. We performed a landmark analysis to evaluate the association between OR and survival at 9, 18, and 26 weeks for 167 patients with recurrent GBM who participated in BRAIN, a phase II trial that evaluated efficacy of bevacizumab alone or in combination with irinotecan, using the Cox regression models adjusted for age, baseline Karnofsky performance score, first vs second relapse, and treatment arm. Hazard ratios (HRs) and P-values for survival between responders and nonresponders were calculated. Additional analyses were performed to test robustness, validity, fit, and accuracy of the models. The relationships between progression-free survival (PFS) and survival and between OR and PFS were also explored. There were 55 responders and 112 nonresponders across the 2 treatment arms in BRAIN. OR status at 9, 18, and 26 weeks was a statistically significant predictor of survival (HR ≤ 0.52, P < .01). PFS was also a statistically significant predictor of survival at each landmark (HR ≤ 0.25, P < .0001). The association between OR and PFS was not statistically significant, likely due to inadequate statistical power for the analysis. Clarifying the relationship of OR and survival is important for determining whether OR can be a reliable predictor of the benefit of a therapeutic agent in patients with recurrent GBM.