Neoplasms

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Breast Diseases

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Trastuzumab

Docetaxel

Ado-Trastuzumab Emtansine

Maytansine

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Patients received trastuzumab emtansine 3.6 mg/kg intravenously (IV) administered over 30-90 minutes every 3 weeks on Day 1 of each 21-day cycle.

Patients received a loading dose of trastuzumab 8 mg/kg IV + docetaxel 75 or 100 mg/m\^2 IV on Day 1 of Cycle 1 followed by trastuzumab 6 mg/kg IV + docetaxel 75 or 100 mg/m\^2 IV on Day 1 of all subsequent 21-day cycles.

The total dose depended on the patient's weight on Day 1 of each cycle. Trastuzumab emtansine was administered every 3 weeks until investigator-assessed radiographic or clinical progressive disease (or until second disease progression for patients who crossed over), unacceptable toxicity, or study closure, whichever occurred first.

Trastuzumab emtansine [Kadcyla]

The dose of trastuzumab was recalculated if body weight changed by more than ±10% from baseline. Trastuzumab was administered every 3 weeks until investigator-assessed radiographic or clinical progressive disease, or unmanageable toxicity. Patients in the trastuzumab + docetaxel arm who discontinued study treatment because of progressive disease were eligible to cross-over to trastuzumab emtansine treatment until a second progressive disease event, clinical deterioration, and/or intolerance.

Docetaxel was given at a dose of 75 or 100 mg/m\^2 based on the investigator's decision. Patients in the trastuzumab + docetaxel arm who discontinued study treatment because of progressive disease were eligible to cross-over to trastuzumab emtansine treatment until a second progressive disease event, clinical deterioration, and/or intolerance.

Ellie Guardino, MD/PhD

This was a Phase II, randomized, multicenter, international, 2-arm, open-label clinical trial designed to explore the efficacy and safety of trastuzumab emtansine (T-DM1) relative to the combination of trastuzumab and docetaxel in patients with human epidermal growth factor receptor 2 (HER2)-positive, unresectable, locally advanced breast cancer and/or metastatic breast cancer who have not received prior chemotherapy for metastatic disease.

A Study of the Efficacy and Safety of Trastuzumab Emtansine (Trastuzumab-MCC-DM1) vs. Trastuzumab (Herceptin®) and Docetaxel (Taxotere®) in Patients With Metastatic HER2-positive Breast Cancer Who Have Not Received Prior Chemotherapy for Metastatic Disease

A Randomized, Multicenter, Phase ii Study of the Efficacy and Safety of Trastuzumab-MCC-DM1 vs. Trastuzumab (Herceptin®) and Docetaxel (Taxotere®) in Patients With Metastatic HER2-positive Breast Cancer Who Have Not Received Prior Chemotherapy for Metastatic Disease

PFS was defined as the time from randomization (R) to first documented investigator-assessed radiographic or clinical disease progression (PD) or death due to any cause, whichever occurred first. For target lesions (TL), PD was defined as at least a 20% increase in the sum of the longest diameter (SLD) of TLs, taking as reference the SLD recorded since treatment started or the appearance of 1 or more new lesions. For non-TLs, PD was defined as the appearance of 1 or more new lesions and/or unequivocal progression of existing non-TLs. Data for patients without PD or death were censored at the last date of tumor assessment prior to crossover (or, if no tumor assessment was performed after Baseline, at the R date +1 day). Data for patients who were lost to follow-up were censored at the last date of tumor assessment prior to crossover at which the patient was known to be progression free. Data for patients with no post-baseline tumor assessment were censored at the R date +1 day.

Overall survival was defined as the time from randomization to the date of death from any cause. Patients who were alive at the time of analysis were censored at the date on which they were last known to be alive. Patients with no post-baseline were censored at the date of randomization plus 1 day.

A patient had an objective response if they had a complete response or a partial response on 2 consecutive occasions ≥ 4 weeks apart. For target lesions, a complete response was defined as the disappearance of all target lesions; a partial response was defined as at least a 30% decrease in the sum of the longest diameter of target lesions, taking as reference the baseline sum longest diameter. For non-target lesions, a complete response was defined as the disappearance of all non-target lesions; a partial response was defined as the persistence of 1 or more non-target lesions.

Duration of objective response was defined as the time from initial response to investigator-assessed radiographic or clinical disease progression or death on study from any cause. For target lesions, disease progression was defined as at least a 20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum of the longest diameter recorded since treatment started or the appearance of 1 or more new lesions. For non-target lesions, disease progression was defined as the appearance of 1 or more new lesions and/or unequivocal progression of existing non-target lesions. Target lesions should be selected on the basis of their size (those with the longest diameter) and their suitability for accurate repeated measurements by imaging techniques or clinically. All measurable lesions up to a maximum of 5 lesions per organ and 10 lesions in total, representative of all involved organs, should be identified as target lesions.

CB was defined as an objective response (complete response \[CR\], partial response \[PR\]) or stable disease (SD) for 6 months after randomization. For target lesions (TL), CR=the disappearance of all TL; PR=at least a 30% decrease in the sum of the longest diameter (LD) of TL, taking as reference the baseline sum LD; SD=neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD), taking as reference the smallest sum LD since the treatment started; PD=at least a 20% increase in the sum of the LD of TL, taking as reference the smallest sum of the LD recorded since the treatment started or the appearance of 1 or more new lesions. For non-TL, CR=the disappearance of all non-TL; PR=the persistence of 1 or more non-TL; SD=the persistence of 1 or more non-target lesion(s) and/or the maintenance of tumor marker level above the normal limits; PD=the appearance of 1 or more new lesions and/or unequivocal progression of existing non-TL.

Time to symptom progression was defined as the time from randomization to the first documentation of a ≥ 5-point decrease from baseline in the Trial Outcome Index-Physical/Functional/Breast (TOI-PFB) subscale score of the Functional Assessment of Cancer Therapy-Breast (FACT-B) questionnaire. The FACT-B questionnaire is a valid and reliable measure of symptoms associated with breast cancer. The TOI-PFB is a 24-item subscale generated using 3 subsections (Physical Well-Being \[7 items\], Functional Well-Being \[7 items\], and Additional Concerns \[10 items\]) from the FACT-B questionnaire. Patients responded to each item on a scale of 0-4 (Not at all-Very much). The total score ranged from 0 to 96. A higher score indicates fewer symptoms. A positive change score indicates improvement.

Serum samples were collected from all 67 patients enrolled in the trastuzumab emtansine arm using sparse pharmacokinetic sampling. Blood samples were collected prior to dosing and 30 minutes post-infusion of trastuzumab emtansine at Cycles 1 and 5. Serum samples were assayed for trastuzumab emtansine and total trastuzumab (sum of unconjugated trastuzumab and emtansine conjugated to trastuzumab) in indirect sandwich ELISAs. The area under the concentration-time curve (AUC) was estimated based on non-compartmental analysis using WinNonlin (Version 5.2.1) software.

Plasma samples were collected from all 67 patients in the trastuzumab emtansine group 30 minutes post-infusion of trastuzumab emtansine at Cycles 1 and 5. The plasma samples were assayed for free emtansine in a mass-spectrometric assay.

Hoffmann-La Roche

Safety population: All randomized patients who received at least 1 dose of study treatment. In the trastuzumab + docetaxel (T+D) group, 2 patients received no treatment and 2 patients received a dose of trastuzumab emtansine (TE) and were included in that group for safety analyses, resulting in 66 patients in the T+D group and 69 in the TE group.

Trastuzumab Emtansine

Trastuzumab + Docetaxel

Total

Age, Continuous

Sex: Female, Male

Medical Communications

Intent-to-treat population: All randomized patients.

Progression-free Survival (PFS) by the Investigator Using Modified Response Evaluation Criteria In Solid Tumors (RECIST)

Overall Survival

All randomized patients with measureable disease at Baseline.

Objective Response Assessed by the Investigator Using Response Evaluation Criteria in Solid Tumors (RECIST)

All randomized patients with measureable disease at Baseline. Only patients with an objective response were included in the analysis.

Duration of Objective Response Assessed by the Investigator Using Response Evaluation Criteria in Solid Tumors (RECIST)

All randomized patients with measurable disease at Baseline.

Clinical Benefit (CB) Assessed by the Investigator Using Response Evaluation Criteria in Solid Tumors (RECIST)

All randomized patients with a Baseline and at least 1 post-Baseline valid score.

Time to Symptom Progression

Trastuzumab emtansine Cycle 1 (n=62)

Trastuzumab emtansine Cycle 5 (n=39)

Total trastuzumab Cycle 1 (n=60)

Total trastuzumab Cycle 5 (n=38)

Trastuzumab Emtansine 3.6 mg/kg

Pharmacokinetic evaluable population: Patients who had adequate concentration-time data to estimate at least 1 pharmacokinetic parameter.

Spots Global Cancer Trial Database for trastuzumab dm1