Approval Probability
TA Base Rate
Adjusted LOA
ML Risk
Also known as trastuzumab emtansine [Kadcyla], Trastuzumab emtansine [Kadcyla], trastuzumab-emtansine
Trastuzumab Emtansine · 16 trials · 10 indications
PFS is defined as the time from randomization to the first occurrence of disease progression as determined by the investigator using Response Evaluation Criteria in Solid Tumors (RECIST) Version (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 with an absolute increase of at least 5 millimeter (mm) taking as reference the smallest sum during the study including baseline or the appearance of one or more new lesions. Tumor assessments will be performed with computed tomography (CT) or magnetic resonance imaging (MRI) scans.
IDFS event was defined as the time from randomization until the date of first occurrence of one of the following: Ipsilateral invasive breast tumor recurrence (an invasive breast cancer \[bc\] involving the same breast parenchyma as the original primary lesion); Ipsilateral local-regional invasive bc recurrence (an invasive bc in the axilla, regional lymph nodes, chest wall, and/or skin of the ipsilateral breast); Contralateral or ipsilateral second primary invasive bc; Distant recurrence (evidence of bc in any anatomic site \[other than the three sites mentioned above\]) that has either been histologically confirmed or clinically/radiographically diagnosed as recurrent invasive bc; Death attributable to any cause, including bc, non-bc, or unknown cause. 3-year IDFS event-free rate per randomized treatment arms in the ITT population was estimated using the Kaplan-Meier method and estimated the probability of a participant being event-free after 3 years after randomization.
IDFS event was defined as the time from randomization until the date of first occurrence of one of the following: Ipsilateral invasive breast tumor recurrence (an invasive breast cancer \[bc\] involving the same breast parenchyma as the original primary lesion); Ipsilateral local-regional invasive bc recurrence (an invasive bc in the axilla, regional lymph nodes, chest wall, and/or skin of the ipsilateral breast); Contralateral or ipsilateral second primary invasive bc; Distant recurrence (evidence of bc in any anatomic site \[other than the three sites mentioned above\]) that has either been histologically confirmed or clinically/radiographically diagnosed as recurrent invasive bc; Death attributable to any cause, including bc, non-bc, or unknown cause. 3-year IDFS event-free rate per randomized treatment arms in the ITT population were estimated using the Kaplan-Meier method and estimated the probability of a patient being event-free after 3 years after randomization.
The AEPIs in this study were defined as the following: adverse events (AEs) Grade \>/= 3, specifically, hepatic events, allergic reactions, thrombocytopenia and hemorrhage events, all Grade \>/= 3 AEs related to trastuzumab emtansine and pneumonitis events of all grades.
Progression-free survival was defined as the time from randomization to the first documented disease progression by investigator assessment using Response Evaluation Criteria In Solid Tumors (RECIST) v1.1 or death from any cause, whichever occurred first. Progression-free survival was a co-primary endpoint.
Overall survival (OS) was defined as the time from randomization to death from any cause. Overall survival was a co-primary endpoint.
PD was assessed by an IRC using modified Response Evaluation Criteria in Solid Tumors (RECIST). All measurable lesions up to a maximum of 5 per organ and 10 in total were identified as target lesions (TLs) and recorded at baseline. TLs should be selected on the basis of their size (those with the longest diameter) and their suitability for accurate repeated measurements either by imaging or clinically. A sum of the longest diameter for all TLs was calculated as baseline sum longest diameter (SLD). All other lesions (or sites of disease) should be identified as non-TLs and recorded at baseline. PD for TLs was defined as greater than or equal to (\>/=) 20 percent (%) increase in SLD, taking as reference smallest SLD recorded since treatment started or appearance of 1 or more new lesions. PD for non-TLs was defined as appearance of 1 or more new lesions and/or unequivocal progression of existing non-TLs. Percentage of Participants with PD by IRC or death from any cause was reported.
Tumor response was assessed by an IRC according to modified RECIST. All measurable lesions up to a maximum of 5 per organ and 10 in total were identified as TLs (on the basis of their size and their suitability for accurate repeated measurements either by imaging or clinically) and recorded at baseline. A sum of the longest diameter for all TLs was calculated as baseline SLD. All other lesions were identified as non-TLs and recorded at baseline. PD for TLs: \>/= 20% increase in the SLD, taking as reference the smallest SLD recorded since treatment started or appearance of 1 or more new lesions. PD for non-TLs: appearance of 1 or more new lesions and/or unequivocal progression of existing non-TLs. PFS: time from randomization to first documented PD by IRC or death from any cause (whichever occurred earlier). The median duration of PFS was estimated using Kaplan-Meier method. The 95% confidence interval (CI) was computed using the method of Brookmeyer and Crowley.
The percentage of participants who died from any cause was reported. The results are reported from second interim analysis, which deemed to be the confirmatory.
OS was defined as the time from the date of randomization to the date of death from any cause. The median duration of OS was estimated using Kaplan-Meier method. The 95% CI was computed using the method of Brookmeyer and Crowley. The results are reported from second interim analysis, which deemed to be the confirmatory.
The percentage of participants who died from any cause was reported. The results reported are from the final analysis. The final analysis is descriptive.
OS was defined as the time from the date of randomization to the date of death from any cause. The median duration of OS was estimated using Kaplan-Meier method. The 95% CI was computed using the method of Brookmeyer and Crowley. The results reported are from the final analysis. The final analysis is descriptive.
1 year survival was defined as the percentage of participants alive 1 year after starting treatment. The results reported are from the final analysis.
2 year survival was defined as the percentage of participants alive 2 years after starting treatment. The results reported are from the final analysis.
To characterize the tumour landscape (molecular alterations on tissue and HER2 expression and its heterogeneity) in HER2-positive mBC after at least 1 line of systemic therapy for advanced disease in order to better inform the oncologist and the subject regarding next treatment options.
The time to treatment failure (TTF), defined as the time from T-DM1 start to discontinuation for any reason, including disease progression (clinical or image-based on 18FDG-PET/CT), treatment toxicity or death in participants classified as "positive" (per metabolic response). Time to Treatment Failure (TTF) of subjects classified as "positive" and its survival probability measures (median survival, survival rate at month 6) will be estimated using Kaplan-Meier method
Compare the incidence of clinically relevant toxicities (CRT) in patients with Stage I HER2-positive breast cancer treated with trastuzumab emtansine followed by trastuzumab SC to the incidence in those treated with paclitaxel in combination with trastuzumab SC as assessed by PRO-CTCAE
Evaluate disease-free survival in the T-DM1 followed by trastuzumab SC arm
BOR was defined as having best objective response as complete response (CR) or partial response (PR), as assessed by investigator and confirmed at least 28 days after initial response, according to the Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST 1.1). CR was defined as the disappearance of all target and non-target lesions. Any pathological lymph nodes (whether target or non-target) must decrease to normal (short axis less than \[\<\] 10 millimeter \[mm\]). PR was defined as a 30% decrease in the sum of the diameters of the target lesions taking as a reference the baseline sum diameter. Percentage of participants with best overall response of CR or PR are reported.
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.
A cardiac event was defined as death from a cardiac cause or severe congestive failure (New York Heart Association \[NYHA\] Class III or IV) with a decrease in left ventricular ejection fraction (LVEF) of ≥ 10% from Baseline to an LVEF of \< 50%.
The following percentages of participants are reported: At least 1 adverse event while receiving T-DM1; at least 1 serious adverse event while receiving T-DM1; an adverse event leading to discontinuation, dose delay, or dose reduction of trastuzumab emtansine treatment; symptomatic cardiac dysfunction; and asymptomatic decline in left ventricular ejection fraction (LVEF). An asymptomatic LVEF decline was defined as a LVEF \< 50% and a maximum decrease ≥ 10% from Baseline. The percentage of participants who died is reported.
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.
Objective response was defined as a complete response (CR) or partial response (PR) determined on two consecutive occasions ≥ 4 weeks apart, assessed using Response Evaluation Criteria in Solid Tumors (RECIST). CR: the disappearance of all target lesions and all nontarget lesions and normalization of tumor marker level and no new lesions. PR: disappearance of all target lesions and persistence of ≥ 1 nontarget lesion(s) and/or the maintenance of tumor marker level above the normal limits, or, at least a 30% decrease in the sum of the longest diameter of target lesions, and no new lesions or unequivocal progression of existing nontarget lesions. The primary data cut-off date was 17 September 2009 (approximately 6 months after the last patient was enrolled). The final efficacy analysis was performed using a data cut-off date of 1 January 2010 (approximately 9 months after the last patient was enrolled).
Objective response was defined as a complete response (CR) or partial response (PR) determined on 2 consecutive occasions ≥ 4 weeks apart, using Response Evaluation Criteria in Solid Tumors (RECIST). CR: The disappearance of all target lesions and all non-target lesions, normalization of tumor marker level, and no new lesions. PR: Disappearance of all target lesions and persistence of ≥ 1 non-target lesions and/or the maintenance of tumor marker level above the normal limits, or, at least a 30% decrease in the sum of the longest diameter of target lesions, and no new lesions or unequivocal progression of existing non-target lesions.
AUC will be evaluated and reported for trastuzumab emtansine and its metabolites.
Maximum serum concentration (Cmax) immediately after dosing will be evaluated and reported for trastuzumab emtansine and its metabolites.
Minimum (Trough) Concentration (Cmin) will be evaluated and reported for trastuzumab emtansine and its metabolites.
Clearance (CL) will be evaluated and reported for trastuzumab emtansine and its metabolites.
Volume of distribution at steady-state (Vss) will be evaluated and reported.
Half-life (t1/2) will be evaluated and reported.
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.
| Arm | Type | Description |
|---|---|---|
| Trastuzumab Emtansine | EXPERIMENTAL | Participants with HER2-positive, unresectable LABC or MBC who have experienced disease progression after treatment with trastuzumab and a taxane will be treated with trastuzumab emtansine. Participants may continue to receive study treatment until disease progression (as assessed by the investigator), unmanageable toxicity, or study termination by the Sponsor. |
| Control (lapatinib + capecitabine) | ACTIVE_COMPARATOR | Participants with HER2-positive, unresectable LABC or MBC who have experienced disease progression after treatment with trastuzumab and a taxane will be treated with lapatinib plus capecitabine. Participants may continue to receive study treatment until disease progression (as assessed by the investigator), unmanageable toxicity, or study termination by the Sponsor. |
| Anthracycline Followed by Trastuzumab, Pertuzumab, and Taxane | ACTIVE_COMPARATOR | Trastuzumab and pertuzumab will be administered concurrently for up to a total duration of 1 year (up to 18 cycles \[1 Cycle = 21 days\]) with the taxane (docetaxel or paclitaxel) component of chemotherapy following anthracycline \[5 fluorouracil, epirubicin, and cyclophosphamide (FEC) or epirubicin and cyclophosphamide (EC) or doxorubicin and cyclophosphamide (AC)\] based chemotherapy. |
| Anthracycline Followed by Trastuzumab Emtansine and Pertuzumab | EXPERIMENTAL | Trastuzumab emtansine and pertuzumab will continue for up to a total duration of 1 year (up to 18 cycles \[1 Cycle = 21 days\]) following anthracycline \[5 fluorouracil, epirubicin, and cyclophosphamide (FEC) or epirubicin and cyclophosphamide (EC) or doxorubicin and cyclophosphamide (AC)\] based chemotherapy. |
| Trastuzumab Emtansine (All Participants) | EXPERIMENTAL | This cohort will enroll all participants with HER2-positive, unresectable, LABC or mBC who have received prior anti-HER2 and chemotherapy treatment and have progressed on or after the most recent treatment for LABC or mBC, or within 6 months of completing adjuvant therapy. Participants will receive trastuzumab emtansine every 3 weeks until unacceptable toxicity, withdrawal of consent, or disease progression. |
| Trastuzumab Emtansine (Asian Participants) | EXPERIMENTAL | This cohort will enroll Asian race participants with HER2-positive, unresectable, LABC or mBC who have received prior anti-HER2 and chemotherapy treatment and have progressed on or after the most recent treatment for LABC or mBC, or within 6 months of completing adjuvant therapy. Participants will receive trastuzumab emtansine every 3 weeks until unacceptable toxicity, withdrawal of consent, or disease progression. |
| Treatment of physician's choice | ACTIVE_COMPARATOR | Treatment of physician's choice until disease progression (as assessed by the investigator) or unmanageable toxicity. The treatments included single-agent chemotherapy, single-agent or dual-agent hormonal therapy for hormone receptor positive-disease, and HER2-directed therapy. |
| Lapatinib + Capecitabine | ACTIVE_COMPARATOR | Participants will receive lapatinib 1250 mg (five 250 mg tablets) orally once daily during each 21-day cycle + capecitabine 1000 milligrams per square meter (mg/m\^2) orally twice daily on Days 1-14 of each 21-day treatment cycle until PD (as assessed by the investigator), unmanageable toxicity, or study termination. Eligible participants will cross over to receive trastuzumab emtansine if second interim analysis demonstrates statistically significant overall survival benefit in favor of trastuzumab emtansine. |
| HER2 PET/CT "positive" | EXPERIMENTAL | Subjects classified as HER2-PET/CT positive will receive T-DM1, IV 3.6mg/kg every 3 weeks, as monotherapy. HER2-PET/CT positive pattern: The entire or majority of the tumour load shows significant tracer uptake. |
| HER2 PET/CT "negative" | NO_INTERVENTION | Subjects classified as HER2 PET/CT negative will receive treatment of physician's choice (TPC) as per the best local clinical practice. Subsequent treatment will be collected and the subject will enter survival follow-up. HER2-PET/CT negative pattern: The dominant part or all of the tumour load lacks significant tracer uptake. |
| Arm A. T-DM1 followed by Trastuzumab SC | EXPERIMENTAL | Randomized participants will receive intravenous T-DM1 every 3 weeks for 6 cycles (18 weeks) and then Trastuzumab SC (subcutaneous) every 3 weeks for 11 cycles |
| Arm B: Paclitaxel with Trastuzumab SC, followed by Trastuzumab SC alone | EXPERIMENTAL | Randomized participants will receive weekly intravenous Paclitaxel for 12 weeks (4 cycles) and Trastuzumab SC (subcutaneous) every 3 weeks for 17 cycles. The first 4 doses Trastuzumab SC are given with Paclitaxel. |
| Cohort 1 (UBC) | EXPERIMENTAL | First six participants with locally advanced (unresectable and not treatable with curative intent) or metastatic UBC will initially receive Regimen A (trastuzumab emtansine at a dose of 2.4 mg/kg qw). An iDMC will assess the safety among the first six participants and decide whether dose will be switched to Regimen B (trastuzumab emtansine at a dose of 3.6 mg/kg q3w). |
| Cohort 2 (Pancreatic cancer/cholangiocarcinoma) | EXPERIMENTAL | First six participants with metastatic pancreatic cancer/cholangiocarcinoma will receive Regimen A (trastuzumab emtansine at a dose of 2.4 mg/kg qw). An iDMC will assess the safety among the first six participants and decide whether dose will be switched to Regimen B (trastuzumab emtansine at a dose of 3.6 mg/kg q3w). |
| Cohort IHC2+ | EXPERIMENTAL | 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. |
| Cohort IHC3+ | EXPERIMENTAL | 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. |
| Trastuzumab + docetaxel | ACTIVE_COMPARATOR | 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. |
| Trastuzumab emtansine 3.6 mg/kg | EXPERIMENTAL | Patients received trastuzumab emtansine 3.6 mg/kg intravenously on Day 1 of each 21 day cycle for a maximum of 1 year. The total dose was dependent on the patient's weight on Day 1 of each cycle. |
| Mild hepatic dysfunction | EXPERIMENTAL | - |
| Moderate hepatic dysfunction | EXPERIMENTAL | - |
| Normal hepatic function | EXPERIMENTAL | - |
| Trastuzumab emtansine 3.0 mg/kg + pertuzumab 420 mg | EXPERIMENTAL | Patients received trastuzumab emtansine 3.0 mg/kg intravenously (IV) on Day 1 of every 3 week cycle until progressive disease, intolerable toxicity, initiation of another anti-cancer therapy, or patient discontinuation. Patients also received a loading dose of 840 mg of pertuzumab IV on Day 1 of Cycle 1 followed by pertuzumab 420 mg IV on Day 1 of every subsequent 3 week cycle. |
| Trastuzumab emtansine 3.6 mg/kg + pertuzumab 420 mg | EXPERIMENTAL | Patients received trastuzumab emtansine 3.6 mg/kg intravenously (IV) on Day 1 of every 3 week cycle until progressive disease, intolerable toxicity, initiation of another anti-cancer therapy, or patient discontinuation. Patients also received a loading dose of 840 mg of pertuzumab IV on Day 1 of Cycle 1 followed by pertuzumab 420 mg IV on Day 1 of every subsequent 3 week cycle. |
| Name | Type | Description |
|---|---|---|
| Trastuzumab Emtansine | BIOLOGICAL | Trastuzumab emtansine 3.6 milligrams per kilogram (mg/kg) was administered intravenously on Day 1 of each 21-day cycle. |
| Lapatinib | DRUG | Lapatinib 1250 mg was administered orally once per day of each 21-day cycle. |
| Capecitabine | DRUG | Capecitabine 1000 milligrams per square meter (mg/m\^2) was administered orally twice daily on Days 1-14 of each 21-day cycle. |
| Trastuzumab | DRUG | Trastuzumab IV infusion (duration 90 minutes) will be administered at 8 mg/kg loading dose followed by 6 mg/kg IV q3w for up to 18 cycles (1 cycle = 21 days). |
| Pertuzumab | DRUG | Pertuzumab infusion (duration 60 minutes) will be administered at 840 mg loading dose followed by 420 mg IV q3w for up to 18 cycles (1 cycle = 21 days). |
| Paclitaxel | DRUG | IV infusion of paclitaxel 80 mg/m\^2 once weekly may be administered concurrently with trastuzumab in combination with pertuzumab for 12 weeks. |
| Epirubicin | DRUG | 3 to 4 cycles (1 cycle = 21 days) of standard of care anthracycline-based chemotherapy using epirubicin may be administered in both Arms 1 and 2 as per discretion of the investigator and local prescribing information/institutional guidelines. |
| Doxorubicin | DRUG | 3 to 4 cycles (1 cycle = 21 days) of standard of care anthracycline-based chemotherapy using doxorubicin may be administered in both Arms 1 and 2 as per discretion of the investigator and local prescribing information/institutional guidelines. |
| Docetaxel | DRUG | IV infusion either docetaxel every 3 weeks (q3w) (at 100 milligram per square meter \[mg/m\^2\] for 3 cycles (1 cycle = 21 days); at 75 mg/m2 for 4 cycles; or start at 75 mg/m\^2 in the first cycle and escalate to 100 mg/m\^2 if no dose limiting toxicity occurs, for a total of 3 cycles at minimum) may be administered concurrently with trastuzumab in combination with pertuzumab. |
| Cyclophosphamide | DRUG | 3 to 4 cycles (1 cycle = 21 days) of standard of care anthracycline-based chemotherapy using cyclophosphamide (FEC) may be administered in both Arms 1 and 2 as per discretion of the investigator and local prescribing information/institutional guidelines. |
| 5-Fluorouracil | DRUG | 3 to 4 cycles (1 cycle = 21 days) of standard of care anthracycline-based chemotherapy using 5-fluorouracil, may be administered in both Arms 1 and 2 as per discretion of the investigator and local prescribing information/institutional guidelines. |
| Treatment of physician's choice | DRUG | The treatment of physician's choice (TPC) was a protocol-specified approved or standard of care therapy or combination of therapies, based on frequently used regimens for late-line HER2-positive metastatic breast cancer treatment after receipt of both trastuzumab- and lapatinib-containing regimens. The therapies included single-agent chemotherapy, single-agent (e.g., tamoxifen or aromatase inhibitor) or dual-agent (e.g., aromatase inhibitor with luteinizing hormone releasing hormone \[LHRH\] agonist) hormonal therapy for hormone receptor positive-disease, and HER2-directed therapy. Participants who had documented progressive disease (PD) were eligible to switch treatment to receive trastuzumab emtansine 3.6 mg/kg. Participants who switched treatment remained on trastuzumab emtansine treatment until another PD event or unmanageable toxicity. The formulation, storage, and preparation of all TPC were as per the appropriate package insert or national prescribing information. |
| trastuzumab-emtansine | DRUG | intravenous infusion |
| Trastuzumab SC | DRUG | Muscular injection |
| Trastuzumab emtansine [Kadcyla] | DRUG | 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] 3.0 mg/kg | DRUG | Trastuzumab emtansine was provided as a single-use lyophilized formulation. |
| Trastuzumab emtansine [Kadcyla] 3.6 mg/kg | DRUG | Trastuzumab emtansine was provided as a single-use lyophilized formulation. |
| Pertuzumab 420 mg | DRUG | Pertuzumab was provided as a single-use formulation. |
Inclusion Criteria: * Aged \>/= 18 years * Prospective centrally assessed HER2-positive disease (i.e., immunohistochemistry \[IHC\] 3+ and/or gene amplified \[HER2 to Chromosome 17 \[CEP 17\] ratio \>/= 2\]) by in situ hybridization (ISH) through use of archival paraffin-embedded tumor tissue * His...
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