Non-Small Cell Lung Cancer
Conditions
Brief summary
This is a Phase 2, multicenter study designed to evaluate the efficacy and safety of trastuzumab emtansine administered as a single-agent in participants with HER2-positive (HER2 IHC 2+ or HER2 IHC 3+) advanced or metastatic NSCLC. Participants will be treated with trastuzumab emtansine administered intravenously at a dose of 3.6 milligrams per kilogram (mg/kg) on Day 1 of 21-day cycles until disease progression (as assessed by the investigator), unmanageable toxicity, or study termination by the Sponsor, whichever occurs first.
Interventions
DRUGTrastuzumab Emtansine
Trastuzumab emtansine will be administered intravenously (IV) at a dose of 3.6 mg/kg on Day 1 of every 21-day cycle until disease progression (as assessed by the investigator), unmanageable toxicity, or study termination by the sponsor, whichever occurs first.
Sponsors
Hoffmann-La Roche
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Histologically or cytologically documented diagnosis of Stage IIIB not amenable to radical treatment or Stage IV NSCLC (pathological characterization must determine the non-squamous or squamous histological subtype as well as adenocarcinoma subtype classification) * HER2 status of IHC 2+ or 3+ as determined by a Sponsor-designated central laboratory * Prior treatment with at least one regimen of platinum-based (cisplatin or carboplatin) chemotherapy in the locally advanced or metastatic setting/recurrent NSCLC with documented disease progression by investigator assessment * Participants with a known anaplastic lymphoma kinase (ALK) fusion oncogene (must be documented in the participant's chart) must have also experienced disease progression or intolerance with a first-line ALK Tyrosine Kinase Inhibitor (TKI) approved for the treatment of ALK fusion oncogene NSCLC (for example, crizotinib). Disease progression or intolerance must be documented * Participants with a known mutation in the epidermal growth factor receptor (EGFR) gene (must be documented in the participant's chart) must have also experienced disease progression or intolerance with an EGFR TKI approved for the treatment of EGFR-mutant NSCLC (for example, gefitinib, erlotinib, afatinib). Disease progression or intolerance must be documented * Measurable disease determined as per the RECIST v1.1 * Life expectancy of at least (\>/=) 12 weeks * Adequate organ function * Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 * Left ventricular ejection fraction (LVEF) \>/= 50 percent (%) by either echocardiogram (ECHO) or multiple-gated acquisition (MUGA) scan * Use of highly effective contraception
Exclusion criteria
Cancer-Related Criteria: * Any approved anti-cancer therapy less than or equal to (\</=) 21 days (including chemotherapy or hormonal therapy) before the first study treatment; the following exceptions are allowed: (1) TKIs approved for the treatment of NSCLC must be discontinued greater than (\>) 7 days prior to the first study treatment on D1C1 (The baseline computed tomography \[CT\] scan must be completed after discontinuation of TKIs); (2) Hormone-replacement therapy or oral contraceptives; (3) Anti-emetics, Granulocyte-colony stimulating factor (GCS-F), and prophylactic antibiotics according to local standards * Investigational therapy participation in another clinical study with therapeutic intent \</= 21 days before first study treatment * Previous irradiation is permitted if \>/=14 days since the last fraction of radiotherapy have elapsed before the first study treatment on Day 1 as long as a sufficient number of target lesions remain to allow for measurable disease as per RECIST v1.1 * Participants who have untreated brain metastases or are symptomatic; participants with treated brain metastases must have discontinued corticosteroid therapy and not have any neurological symptoms * History of intolerance (including Grade 3 or 4 infusion reaction) or hypersensitivity to trastuzumab or murine proteins or any excipient of the product * History of exposure to the following cumulative doses of anthracyclines: Doxorubicin or liposomal doxorubicin \> 500 milligram per meter-square (mg/m\^2); Epirubicin \> 900 mg/m\^2; Mitoxantrone \> 120 mg/m\^2. If another anthracycline, or more than one anthracycline, has been used, the cumulative dose must not exceed the equivalent of 500 mg/m\^2 doxorubicin * Peripheral neuropathy of Grade \>/= 3 per the National Cancer Institute Common Toxicity Criteria for Adverse Events Version 4.0 (NCI CTCAE v. 4.0) * History of other malignancy within the last 5 years, except for appropriately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, Stage I uterine cancer, or other cancers with a similar outcome as those mentioned above Cardiopulmonary Function Criteria: * Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures * Severe dyspnea at rest due to complications of advanced malignancy or requiring current continuous oxygen therapy * Clinical history of active hemoptysis * Evidence of active pneumonitis during screening * Current unstable ventricular arrhythmia requiring treatment * History of symptomatic congestive heart failure (CHF) New York Heart Association (NYHA) classes II-IV * History of myocardial infarction or unstable angina within 6 months of enrollment * History of a decrease in LVEF to \<50% General Criteria: * Current severe, uncontrolled systemic disease (for example, clinically significant cardiovascular, pulmonary, or metabolic disease) * Major surgical procedure or significant traumatic injury within 28 days before enrollment or anticipation of the need for major surgery during the course of study treatment * Current pregnancy or lactation * Current known active infection with human immunodeficiency virus (HIV), hepatitis B virus (HBV), or hepatitis C virus (HCV)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Objective Response as Per Investigator Assessment According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v. 1.1) | From Day 1 to disease progression (PD) or death from any cause, up to the clinical cutoff date (approximately 22 months) | Objective response is defined as a complete response (CR) or partial response (PR) determined on two consecutive assessments ≥ 4 weeks apart, based on investigator assessment according to RECIST, Version 1.1. CR: disappearance of all target lesions; and any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \< 10 millimeters (mm). PR: at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) | From Day 1 to death from any cause, up to the study completion date (approximately 43 months) | OS is defined as the time from first study drug administration to death from any cause. |
| Percentage of Participants With PFS Event of Disease Progression, as Per Investigator Assessment According to RECIST v. 1.1, or Death | From Day 1 to PD or death from any cause, up to the study completion date (approximately 43 months) | PFS is defined as the time from first study drug administration to first documented disease progression, based on investigator assessment using RECIST, v1.1, or death from any cause during the study, whichever occurs first. Disease progression is defined as: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study, including baseline; an absolute increase of at least 5 mm in the sum of diameters of target lesions; the appearance of one or more new lesions. |
| Progression-Free Survival (PFS) as Per Investigator Assessment According to RECIST v. 1.1 | From Day 1 to PD or death from any cause, up to the study completion date (approximately 43 months) | PFS is defined as the time from first study drug administration to first documented disease progression, based on investigator assessment using RECIST, v1.1, or death from any cause during the study, whichever occurs first. Disease progression is defined as: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study, including baseline; an absolute increase of at least 5 mm in the sum of diameters of target lesions; the appearance of one or more new lesions. |
| Percentage of Participants With DOR Event of Disease Progression, Assessed According to RECIST v1.1 | From first documented objective response to PD or death from any cause, up to the study completion date (approximately 43 months) | DOR is defined as the time from the initial documentation of response (CR or PR using RECIST, v1.1) to documented disease progression using RECIST v1.1 or death from any cause during the study. CR: disappearance of all target lesions; and any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \< 10 mm. PR: at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters. Disease progression: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study, including baseline; an absolute increase of at least 5 mm in the sum of diameters of target lesions; the appearance of one or more new lesions. |
| Duration of Objective Response (DOR) Assessed According to RECIST v1.1 | From first documented objective response to PD or death from any cause, up to the study completion date (approximately 43 months) | DoR is defined as the time from the initial documentation of response (CR or PR using RECIST, v1.1) to documented disease progression using RECIST v1.1 or death from any cause during the study. CR: disappearance of all target lesions; and any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \< 10 mm. PR: at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters. Disease progression: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study, including baseline; an absolute increase of at least 5 mm in the sum of diameters of target lesions; the appearance of one or more new lesions. |
| Percentage of Participants With Clinical Benefit as Per Investigator Assessment According to RECIST, v1.1 | From Day 1 to PD or death from any cause, up to the study completion date (approximately 43 months) | Clinical benefit is defined as having a CR or PR or stable disease (using RECIST, v1.1) at 6 months. Participants with no post-baseline response assessment are considered as experiencing no clinical benefit. CR: disappearance of all target lesions; and any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \< 10 mm. PR: at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters. Stable disease: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for disease progression, taking as reference the smallest sum while in the study. Disease progression: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study, including baseline; an absolute increase of at least 5 mm in the sum of diameters of target lesions; the appearance of one or more new lesions. |
| Percentage of Participants With Adverse Events (AEs) and Serious AEs (SAEs) | From Day 1 to 30 days after last dose of study drug, up to the study completion date (approximately 43 months) | An AE is any untoward medical occurrence in a clinical investigation participant administered a pharmaceutical product, whether or not considered related to the study drug. A SAE is any experience that: results in death, is life-threatening, requires in-patient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, or is medically significant. |
| Percentage of Participants Who Died | From Day 1 to death from any cause, up to the study completion date (approximately 43 months) | — |
| AUCinf for Trastuzumab Emtansine and Total Trastuzumab | Pre-dose & 30 minutes (min) post-infusion (inf.) on Day (D) 1 of Cycles (C) 1 & 3; post- inf. on D 2, 3, 4 or 5, 8, & 15 of C 1, & pre- inf. on D1 of C2 & D1 of C 4 (C=21 D); at discontin./termination, up to primary analysis, approx. 22 months | AUC (from zero to infinity) represents the total drug exposure over time in blood serum. |
| Elimination Half-Life (t1/2) for Trastuzumab Emtansine and Total Trastuzumab | Pre-dose & 30 minutes (min) post-infusion (inf.) on D 1 of C 1 & 3; post- inf. on D 2, 3, 4 or 5, 8, & 15 of C 1, & pre- inf. on D 1 of C 2 & D 1 of C 4 (C=21 days); at treatment discontin./early termination, up to primary analysis, approx. 22 months | t1/2 is the time required for the drug serum concentration to be reduced to half. |
| Volume of Distribution (Vss) for Trastuzumab Emtansine and Total Trastuzumab | Pre-dose & 30 minutes (min) post-infusion (inf.) on D1 of C1 & 3; post- inf. on D2, 3, 4 or 5, 8, & 15 of C 1, & pre- inf. on D 1 of C 2 & D1 of C 4 (C=21 days); at treatment discontin/early termination, up to primary analysis, approx. 22 months | Vss is the volume of distribution of study drug at steady state. |
| Clearance (CL) for Trastuzumab Emtansine and Total Trastuzumab | Pre-dose & 30 minutes (min) post-infusion (inf.) on D 1 of C 1 & 3; post- inf. on D 2, 3, 4 or 5, 8, & 15 of C 1, & pre- inf. on D 1 of C 2 & D 1 of C 4 (C=21 days); at treatment discontin/early termination, up to primary analysis, approx. 22 months | CL is a measure of the body's elimination of a drug from blood serum over time. |
| Maximum Observed Concentration (Cmax) for N2'- Deacetyl-N2'-(3-mercapto-1-oxopropyl)-Maytansine (DM1) | Pre-dose (within 2 days) and 30 minutes (min) after end of infusion (infusion length= 100 min or less) on Day 1 of Cycle 1 (one cycle=21 days); at treatment discontinuation/early termination,up to primary analysis, approx. 22 months | Cmax is the maximum observed concentration of a drug and was measured in blood plasma. |
| Percentage of Participants With Treatment-Emergent Anti-Drug Antibodies (ADAs) | Pre-dose (within 2 days) on Day 1 of Cycles 1 and 3; at treatment discontinuation/early termination,up to primary analysis, approx. 22 months | The presence of ADAs in blood serum is an indication of the body's immune response to a drug. |
| Maximum Observed Concentration (Cmax) for Trastuzumab Emtansine and Total Trastuzumab | Pre-dose (within 2 days) and 30 minutes (min) after end of infusion (infusion length= 100 min or less) on Day 1 of Cycles 1 and 3 (one cycle=21 days); at treatment discontinuation/early termination, up to primary analysis, approx. 22 months | Cmax is the 0-21 day maximum observed concentration of a drug and was measured in blood serum. |
Countries
Germany, Italy, Poland, South Korea, Spain, Switzerland, United States
Participant flow
Recruitment details
Subjects were screened centrally for HER2 status, using archived tumor specimens from previously collected tissue, if available.
Participants by arm
| Arm | Count |
|---|---|
| Cohort IHC2+ Participants with HER2 IHC2-positive (IHC 2+) locally advanced or metastatic NSCLC, who had received at least one prior platinum-based chemotherapy regimen, will receive trastuzumab emtansine. | 29 |
| Cohort IHC3+ Participants with HER2 IHC3-positive (IHC 3+) locally advanced or metastatic NSCLC, who had received at least one prior platinum-based chemotherapy regimen, will receive trastuzumab emtansine. | 20 |
| Total | 49 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 23 | 16 |
| Overall Study | Lost to Follow-up | 4 | 0 |
| Overall Study | Study discontinuation | 0 | 1 |
Baseline characteristics
| Characteristic | Cohort IHC2+ | Cohort IHC3+ | Total |
|---|---|---|---|
| Age, Continuous | 63.1 years STANDARD_DEVIATION 10.3 | 61.4 years STANDARD_DEVIATION 8.6 | 62.4 years STANDARD_DEVIATION 9.6 |
| Sex: Female, Male Female | 13 Participants | 7 Participants | 20 Participants |
| Sex: Female, Male Male | 16 Participants | 13 Participants | 29 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 23 / 29 | 16 / 20 |
| other Total, other adverse events | 24 / 29 | 19 / 20 |
| serious Total, serious adverse events | 5 / 29 | 5 / 20 |
Outcome results
Primary
Percentage of Participants With Objective Response as Per Investigator Assessment According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v. 1.1)
Objective response is defined as a complete response (CR) or partial response (PR) determined on two consecutive assessments ≥ 4 weeks apart, based on investigator assessment according to RECIST, Version 1.1. CR: disappearance of all target lesions; and any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \< 10 millimeters (mm). PR: at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters.
Time frame: From Day 1 to disease progression (PD) or death from any cause, up to the clinical cutoff date (approximately 22 months)
Population: The efficacy-evaluable population included participants who received at least one dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort IHC2+ | Percentage of Participants With Objective Response as Per Investigator Assessment According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v. 1.1) | 0 percentage of participants |
| Cohort IHC3+ | Percentage of Participants With Objective Response as Per Investigator Assessment According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v. 1.1) | 20.0 percentage of participants |
Secondary
AUCinf for Trastuzumab Emtansine and Total Trastuzumab
AUC (from zero to infinity) represents the total drug exposure over time in blood serum.
Time frame: Pre-dose & 30 minutes (min) post-infusion (inf.) on Day (D) 1 of Cycles (C) 1 & 3; post- inf. on D 2, 3, 4 or 5, 8, & 15 of C 1, & pre- inf. on D1 of C2 & D1 of C 4 (C=21 D); at discontin./termination, up to primary analysis, approx. 22 months
Population: The pharmacokinetic (PK) population included participants who had received at least one dose of study treatment and had at least one serum or plasma concentration result available at clinical data cut-off. Data are reported for evaluable participants who consented to intense sampling.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort IHC2+ | AUCinf for Trastuzumab Emtansine and Total Trastuzumab | Trastuzumab Emtansine | 324 days times ug/mL (day* ug/mL) | Standard Deviation 49.9 |
| Cohort IHC2+ | AUCinf for Trastuzumab Emtansine and Total Trastuzumab | Total Trastuzumab | 436 days times ug/mL (day* ug/mL) | Standard Deviation 83.4 |
Secondary
Clearance (CL) for Trastuzumab Emtansine and Total Trastuzumab
CL is a measure of the body's elimination of a drug from blood serum over time.
Time frame: Pre-dose & 30 minutes (min) post-infusion (inf.) on D 1 of C 1 & 3; post- inf. on D 2, 3, 4 or 5, 8, & 15 of C 1, & pre- inf. on D 1 of C 2 & D 1 of C 4 (C=21 days); at treatment discontin/early termination, up to primary analysis, approx. 22 months
Population: The pharmacokinetic (PK) population included participants who had received at least one dose of study treatment and had at least one serum or plasma concentration result available at clinical data cut-off. Data are reported for evaluable participants who consented to intense sampling.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort IHC2+ | Clearance (CL) for Trastuzumab Emtansine and Total Trastuzumab | Trastuzumab Emtansine | 11.35 mL/day/kg | Standard Deviation 1.99 |
| Cohort IHC2+ | Clearance (CL) for Trastuzumab Emtansine and Total Trastuzumab | Total Trastuzumab | 8.54 mL/day/kg | Standard Deviation 1.99 |
Secondary
Duration of Objective Response (DOR) Assessed According to RECIST v1.1
DoR is defined as the time from the initial documentation of response (CR or PR using RECIST, v1.1) to documented disease progression using RECIST v1.1 or death from any cause during the study. CR: disappearance of all target lesions; and any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \< 10 mm. PR: at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters. Disease progression: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study, including baseline; an absolute increase of at least 5 mm in the sum of diameters of target lesions; the appearance of one or more new lesions.
Time frame: From first documented objective response to PD or death from any cause, up to the study completion date (approximately 43 months)
Population: The efficacy-evaluable population included participants who received at least one dose of study drug. Data are reported for participants with response.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort IHC3+ | Duration of Objective Response (DOR) Assessed According to RECIST v1.1 | 7.3 months |
Secondary
Elimination Half-Life (t1/2) for Trastuzumab Emtansine and Total Trastuzumab
t1/2 is the time required for the drug serum concentration to be reduced to half.
Time frame: Pre-dose & 30 minutes (min) post-infusion (inf.) on D 1 of C 1 & 3; post- inf. on D 2, 3, 4 or 5, 8, & 15 of C 1, & pre- inf. on D 1 of C 2 & D 1 of C 4 (C=21 days); at treatment discontin./early termination, up to primary analysis, approx. 22 months
Population: The pharmacokinetic (PK) population included participants who had received at least one dose of study treatment and had at least one serum or plasma concentration result available at clinical data cut-off. Data are reported for evaluable participants who consented to intense sampling.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort IHC2+ | Elimination Half-Life (t1/2) for Trastuzumab Emtansine and Total Trastuzumab | Trastuzumab Emtansine | 3.2 days | Standard Deviation 0.51 |
| Cohort IHC2+ | Elimination Half-Life (t1/2) for Trastuzumab Emtansine and Total Trastuzumab | Total Trastuzumab | 5.6 days | Standard Deviation 1.14 |
Secondary
Maximum Observed Concentration (Cmax) for N2'- Deacetyl-N2'-(3-mercapto-1-oxopropyl)-Maytansine (DM1)
Cmax is the maximum observed concentration of a drug and was measured in blood plasma.
Time frame: Pre-dose (within 2 days) and 30 minutes (min) after end of infusion (infusion length= 100 min or less) on Day 1 of Cycle 1 (one cycle=21 days); at treatment discontinuation/early termination,up to primary analysis, approx. 22 months
Population: The pharmacokinetic (PK) population included participants who had received at least one dose of study treatment and had at least one serum or plasma concentration result available at clinical data cut-off. Data are reported for evaluable participants.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort IHC2+ | Maximum Observed Concentration (Cmax) for N2'- Deacetyl-N2'-(3-mercapto-1-oxopropyl)-Maytansine (DM1) | 4.3 nanograms per milliliter (ng/mL) | Standard Deviation 3.36 |
Secondary
Maximum Observed Concentration (Cmax) for Trastuzumab Emtansine and Total Trastuzumab
Cmax is the 0-21 day maximum observed concentration of a drug and was measured in blood serum.
Time frame: Pre-dose (within 2 days) and 30 minutes (min) after end of infusion (infusion length= 100 min or less) on Day 1 of Cycles 1 and 3 (one cycle=21 days); at treatment discontinuation/early termination, up to primary analysis, approx. 22 months
Population: The pharmacokinetic (PK) population included participants who had received at least one dose of study treatment and had at least one serum or plasma concentration result available at clinical data cut-off. Data are reported for evaluable participants.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort IHC2+ | Maximum Observed Concentration (Cmax) for Trastuzumab Emtansine and Total Trastuzumab | Trastuzumab Emtansine | 78.7 micrograms per milliliter (ug/mL) | Standard Deviation 19.6 |
| Cohort IHC2+ | Maximum Observed Concentration (Cmax) for Trastuzumab Emtansine and Total Trastuzumab | Total Trastuzumab | 79.9 micrograms per milliliter (ug/mL) | Standard Deviation 21.3 |
Secondary
Overall Survival (OS)
OS is defined as the time from first study drug administration to death from any cause.
Time frame: From Day 1 to death from any cause, up to the study completion date (approximately 43 months)
Population: The efficacy-evaluable population included participants who received at least one dose of study drug. Data are reported for participants with events.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort IHC2+ | Overall Survival (OS) | 12.2 months |
| Cohort IHC3+ | Overall Survival (OS) | 13.7 months |
Secondary
Percentage of Participants Who Died
Time frame: From Day 1 to death from any cause, up to the study completion date (approximately 43 months)
Population: The efficacy-evaluable population included participants who received at least one dose of study drug. Data are reported for participants with events.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort IHC2+ | Percentage of Participants Who Died | 79.3 percentage of participants |
| Cohort IHC3+ | Percentage of Participants Who Died | 80.0 percentage of participants |
Secondary
Percentage of Participants With Adverse Events (AEs) and Serious AEs (SAEs)
An AE is any untoward medical occurrence in a clinical investigation participant administered a pharmaceutical product, whether or not considered related to the study drug. A SAE is any experience that: results in death, is life-threatening, requires in-patient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, or is medically significant.
Time frame: From Day 1 to 30 days after last dose of study drug, up to the study completion date (approximately 43 months)
Population: The safety-evaluable population included participants who received at least one dose of study treatment.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Cohort IHC2+ | Percentage of Participants With Adverse Events (AEs) and Serious AEs (SAEs) | AEs | 93.1 percentage of participants |
| Cohort IHC2+ | Percentage of Participants With Adverse Events (AEs) and Serious AEs (SAEs) | SAEs | 17.2 percentage of participants |
| Cohort IHC3+ | Percentage of Participants With Adverse Events (AEs) and Serious AEs (SAEs) | AEs | 95.0 percentage of participants |
| Cohort IHC3+ | Percentage of Participants With Adverse Events (AEs) and Serious AEs (SAEs) | SAEs | 25.0 percentage of participants |
Secondary
Percentage of Participants With Clinical Benefit as Per Investigator Assessment According to RECIST, v1.1
Clinical benefit is defined as having a CR or PR or stable disease (using RECIST, v1.1) at 6 months. Participants with no post-baseline response assessment are considered as experiencing no clinical benefit. CR: disappearance of all target lesions; and any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \< 10 mm. PR: at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters. Stable disease: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for disease progression, taking as reference the smallest sum while in the study. Disease progression: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study, including baseline; an absolute increase of at least 5 mm in the sum of diameters of target lesions; the appearance of one or more new lesions.
Time frame: From Day 1 to PD or death from any cause, up to the study completion date (approximately 43 months)
Population: The efficacy-evaluable population included participants who received at least one dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort IHC2+ | Percentage of Participants With Clinical Benefit as Per Investigator Assessment According to RECIST, v1.1 | 6.9 percentage of participants |
| Cohort IHC3+ | Percentage of Participants With Clinical Benefit as Per Investigator Assessment According to RECIST, v1.1 | 30.0 percentage of participants |
Secondary
Percentage of Participants With DOR Event of Disease Progression, Assessed According to RECIST v1.1
DOR is defined as the time from the initial documentation of response (CR or PR using RECIST, v1.1) to documented disease progression using RECIST v1.1 or death from any cause during the study. CR: disappearance of all target lesions; and any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \< 10 mm. PR: at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters. Disease progression: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study, including baseline; an absolute increase of at least 5 mm in the sum of diameters of target lesions; the appearance of one or more new lesions.
Time frame: From first documented objective response to PD or death from any cause, up to the study completion date (approximately 43 months)
Population: The efficacy-evaluable population included participants who received at least one dose of study drug. Data are reported for participants with response.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort IHC3+ | Percentage of Participants With DOR Event of Disease Progression, Assessed According to RECIST v1.1 | 75.0 percentage of participants |
Secondary
Percentage of Participants With PFS Event of Disease Progression, as Per Investigator Assessment According to RECIST v. 1.1, or Death
PFS is defined as the time from first study drug administration to first documented disease progression, based on investigator assessment using RECIST, v1.1, or death from any cause during the study, whichever occurs first. Disease progression is defined as: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study, including baseline; an absolute increase of at least 5 mm in the sum of diameters of target lesions; the appearance of one or more new lesions.
Time frame: From Day 1 to PD or death from any cause, up to the study completion date (approximately 43 months)
Population: The efficacy-evaluable population included participants who received at least one dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort IHC2+ | Percentage of Participants With PFS Event of Disease Progression, as Per Investigator Assessment According to RECIST v. 1.1, or Death | 100 percentage of participants |
| Cohort IHC3+ | Percentage of Participants With PFS Event of Disease Progression, as Per Investigator Assessment According to RECIST v. 1.1, or Death | 95.0 percentage of participants |
Secondary
Percentage of Participants With Treatment-Emergent Anti-Drug Antibodies (ADAs)
The presence of ADAs in blood serum is an indication of the body's immune response to a drug.
Time frame: Pre-dose (within 2 days) on Day 1 of Cycles 1 and 3; at treatment discontinuation/early termination,up to primary analysis, approx. 22 months
Population: The pharmacokinetic (PK) population included participants who had received at least one dose of study treatment and had at least one serum or plasma concentration result available at clinical data cut-off. Data are reported for evaluable participants with post-dose sample available for ADA analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort IHC2+ | Percentage of Participants With Treatment-Emergent Anti-Drug Antibodies (ADAs) | 0 percentage of participants |
Secondary
Progression-Free Survival (PFS) as Per Investigator Assessment According to RECIST v. 1.1
PFS is defined as the time from first study drug administration to first documented disease progression, based on investigator assessment using RECIST, v1.1, or death from any cause during the study, whichever occurs first. Disease progression is defined as: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study, including baseline; an absolute increase of at least 5 mm in the sum of diameters of target lesions; the appearance of one or more new lesions.
Time frame: From Day 1 to PD or death from any cause, up to the study completion date (approximately 43 months)
Population: The efficacy-evaluable population included participants who received at least one dose of study drug. Data are reported for participants with events.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort IHC2+ | Progression-Free Survival (PFS) as Per Investigator Assessment According to RECIST v. 1.1 | 2.6 months |
| Cohort IHC3+ | Progression-Free Survival (PFS) as Per Investigator Assessment According to RECIST v. 1.1 | 2.7 months |
Secondary
Volume of Distribution (Vss) for Trastuzumab Emtansine and Total Trastuzumab
Vss is the volume of distribution of study drug at steady state.
Time frame: Pre-dose & 30 minutes (min) post-infusion (inf.) on D1 of C1 & 3; post- inf. on D2, 3, 4 or 5, 8, & 15 of C 1, & pre- inf. on D 1 of C 2 & D1 of C 4 (C=21 days); at treatment discontin/early termination, up to primary analysis, approx. 22 months
Population: The pharmacokinetic (PK) population included participants who had received at least one dose of study treatment and had at least one serum or plasma concentration result available at clinical data cut-off. Data are reported for evaluable participants who consented to intense sampling.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort IHC2+ | Volume of Distribution (Vss) for Trastuzumab Emtansine and Total Trastuzumab | Trastuzumab Emtansine | 51.1 milliliters kilogram (mL/kg) | Standard Deviation 1.81 |
| Cohort IHC2+ | Volume of Distribution (Vss) for Trastuzumab Emtansine and Total Trastuzumab | Total Trastuzumab | 60.7 milliliters kilogram (mL/kg) | Standard Deviation 4.23 |