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Ado-Trastuzumab Emtansine

Trastuzumab

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Trastuzumab emtansine 3.6 mg/kg intravenously every 3 weeks until disease progression (as assessed by the investigator) or unmanageable toxicity.

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.

The dose was calculated based on the patient's Baseline weight on Day 1 of each 3-week treatment cycle. The same dose was administered in subsequent cycles if the patient's weight stayed within 10% of the Baseline weight. If there was a weight change \> 10%, the dose was adjusted accordingly and the recorded weight became the new Baseline weight. Trastuzumab emtansine was provided as a single-use lyophilized formulation.

Trastuzumab emtansine

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.

Treatment of physician's choice

Clinical Trials

This randomized, multicenter, 2-arm, open-label study (TH3RESA) will evaluate the efficacy and safety of trastuzumab emtansine (T-DM1) in comparison with treatment of the physician's choice in participants with metastatic or unresectable locally advanced/recurrent human epidermal growth factor receptor 2 (HER2)-positive breast cancer. Eligible participants will be randomized to receive either trastuzumab emtansine 3.6 mg/kg intravenously every 21 days or treatment of the physician's choice. Participants continue to receive study treatment until disease progression or unacceptable toxicity occurs. This study is also known under Roche study protocol number BO25734.

A Study of Trastuzumab Emtansine in Comparison With Treatment of Physician's Choice in Participants With HER2-positive Breast Cancer Who Have Received at Least Two Prior Regimens of HER2-directed Therapy

A Phase III Randomized, Multicenter, Two Arm, Open-label Trial to Evaluate the Efficacy of Trastuzumab Emtansine Compared With Treatment of Physician's Choice in Patients With HER2-positive Metastatic Breast Cancer Who Have Received at Least Two Prior Regimens of HER2 Directed Therapy

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.

An objective response was defined as a complete or partial response determined on 2 consecutive occasions ≥ 4 weeks apart using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Complete response was defined as the disappearance of all target and non-target lesions. Any pathological lymph nodes (whether target or non-target) must be \< 10 mm on the short axis. Partial response was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum. Participants who had no post-baseline tumor assessment were counted as non-responders.

Duration of the objective response was defined as the time from the first tumor assessment that was judged to indicate that the patient had an objective response to the time of first documented disease progression using RECIST v1.1 per investigator assessment or death from any cause, whichever occurred first.

6-month and 1-year survival were defined as the percentage of participants who were alive at 6 months and 1 year, respectively, as estimated using Kaplan-Meier method.

Time to pain symptom progression was defined as the time from randomization to the first documentation of an increase in narcotic use and/or a 10 point increase from Baseline in the pain score as measured by the European Organisation for Research and Treatment of Cancer, Quality of Life Questionnaire for patients with bone metastases (EORTC QLQ-BM22). The EORTC QLQ-BM22 assesses the symptoms of bone metastases using 22 items: 5 items for sites of pain, 3 pain characteristics, 8 functional interference aspects, and 6 psychosocial aspects. The pain score was derived from the 3 pain characteristic items. Each item was rated on a 4-point scale, where 1=Not at all to 4=Very much. The pain score was the sum of the 3 pain characteristic scores and was normalized to a scale of 0 to 100. A higher score indicates greater pain.

The EORTC QLQ-BM22 assesses the symptoms of bone metastases using 22 items: 5 items for sites of pain, 3 pain characteristics, 8 functional interference aspects, and 6 psychosocial aspects. The pain score was derived from the 3 pain characteristic items. Each item was rated on a 4-point scale, where 1=Not at all to 4=Very much. The pain score was the sum of the 3 pain characteristic scores and was normalized to a scale of 0 to 100. A higher score indicates greater pain. A negative change score indicates improvement.

Overall survival was defined as the time from randomization to death from any cause.

Hoffmann-La Roche

Safety population: All participants who received any amount of planned study treatment, according to treatment actually received. Data for participants in the Treatment of Physicians Choice (TPC) arm who switched treatment to receive trastuzumab emtansine (TE) following disease progression on TPC are presented separately. Median treatment duration of trastuzumab emtansine: 5.2 months (range 0.03-40.7),TPC: 2.7 months (range 0.03-31.0) and TE - Post TPC Treatment Switch: 4.5 months (range 1-43).

Trastuzumab Emtansine

Treatment of Physician's Choice (TPC)

Participants, who switched treatment in the Treatment of Physician's Choice arm to trastuzumab emtansine, were administered trastuzumab emtansine 3.6 mg/kg intravenously every 3 weeks until disease progression (as assessed by the investigator) or unmanageable toxicity.

Trastuzumab Emtansine - Post TPC Treatment Switch

Treatment of Physician's Choice

Total

Age, Continuous

Sex: Female, Male

Randomized population: All participants who were randomized to the study.

Medical Communications

The analysis was stratified for 1) World region (United States, Western Europe, or Other); 2) Number of prior regimens, excluding single-agent hormones, for treatment of metastatic or unresectable locally advanced/recurrent disease (≤ 3 or \> 3); and 3) Presence of visceral disease (any visceral disease vs no visceral disease).

Randomized population: All participants who were randomized to the study. Participants were included in the treatment group to which they were randomized.

Progression-free Survival

Overall Survival

Randomized population: All participants who were randomized to the study. Only participants with measurable disease at Baseline were included in the analysis. Participants were included in the treatment group to which they were randomized.

Percentage of Participants With an Objective Response

Randomized population: All participants who were randomized to the study. Only participants with an objective response were included in the analysis. Participants were included in the treatment group to which they were randomized.

Duration of the Objective Response

6-Month Survival

1-Year Survival

6-month and 1-year Survival

Randomized population: All participants who were randomized to the study. Only participants with a Baseline pain score and at least 1 post-baseline pain score were included in the analysis. Participants were included in the treatment group to which they were randomized.

Time to Pain Symptom Progression

Cycle 2 (n=282,98)

Cycle 3 (n=257,86)

Cycle 4 (n=236,74)

Cycle 5 (n=224,54)

Cycle 6 (n=195,42)

Cycle 7 (n=163,30)

Cycle 8 (n=130,20)

Cycle 9 (n=97,15)

Cycle 10 (n=80,7)

Cycle 11 (n=56,8)

Cycle 12 (n=48,7)

Cycle 13 (n=40,5)

Cycle 14 (n=33,5)

Cycle 15 (n=27,3)

Cycle 16 (n=19,3)

Cycle 17 (n=15,2)

Cycle 18 (n=11,0)

Cycle 19 (n=8,0)

Cycle 20 (n=4,0)

Cycle 21 (n=3,0)

Termination Visit (n=84,37)

Change From Baseline in the EORTC QLQ-BM22 Pain Score on Day 1 of Each Cycle

The analysis was stratified for 1) World region (United States, Western Europe, or Other); 2) Number of prior regimens, excluding single-agent hormones, for treatment of metastatic or unresectable locally advanced/recurrent disease (≤ 3 or \> 3); and 3) Presence of visceral disease (any visceral disease versus no visceral disease).

Overall Survival (Final Analysis)

6-month and 1-year Survival (Final Analysis)

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 human epidermal growth factor receptor 2 (HER2)-directed therapy.

Overall Study

Vinorelbine

Maleic acid

pyrotinib 320mg tablets administered daily by mouth, vinorelbine 80 mg/m2 weekly (following a first cycle at 60 mg/m2) administered OV on day 1 and day 8 of 21 day cycle. Treatment lasts for two cycles

pyrotinib 400mg tablets administered daily by mouth, vinorelbine 80 mg/m2 weekly (following a first cycle at 60 mg/m2) administered OV on day 1 and day 8 of 21 day cycle. Treatment lasts for two cycles

pyrotinib administered daily by mouth（MTD）, vinorelbine 80 mg/m2 weekly (following a first cycle at 60 mg/m2) administered OV on day 1 and day 8 of 21 day cycle. Treatments will lasts until disease progression (as assessed by the investigator) or unmanageable toxicity.

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 single-agent HER2-directed therapy.

Pyrotinib Maleate combine with vinorelbine as the second-line treatment to HER2-positive Metastatic Breast Cancer

Pyrotinib

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 second-line HER2-positive metastatic breast cancer treatment after receipt of trastuzumab-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 single-agent HER2-directed therapy.

vinorelbine

The purpose of this study is to identify the highest tolerable dose of pyrotinib in combination with vinorelbine and to assess the safety and efficacy of the combination in Patients With HER2-Positive Locally Advanced or Metastatic Breast Cancer.

The study will be conducted in two parts. In the first part, testing will be done on up to 12 subjects to determine the highest tolerable dose of pyrotinib and vinorelbine in patients with advanced solid tumors. In the second part of the study, we will compare the safety and efficacy of Pyrotinib + vinorelbine vs. Treatment of Physician's Choice in Patients With HER2-Positive Locally Advanced or Metastatic Breast Cancer Who Have Received Prior Trastuzumab-Based Therapy.Participants will be treated until disease progression (PD), unmanageable toxicity, or study termination.

A Study of Pyrotinib Plus Vinorelbine in Comparison With Treatment of Physician's Choice in Participants With HER2-positive Locally Advanced or Metastatic Breast Cancer

A Randomized, Multicenter, Phase II Open-label Study of the Efficacy and Safety of Pyrotinib + Vinorelbine vs. Treatment of Physician's Choice in Patients With HER2-Positive Locally Advanced or Metastatic Breast Cancer Who Have Received Prior Trastuzumab-Based Therapy

The maximum-tolerated dose (MTD) will be defined as the maximum dose level at which no more than one subject out of three experiences has a dose-limiting toxicity (DLT) upon completing two treatment cycle.

OS was defined as the time from the date of randomization to the date of death from any cause

Jiangsu HengRui Medicine Co., Ltd.

Sun Yat-sen University

clinical professor

Capecitabine

Antimetabolites

Pyrotinib 400mg, qd, po, day 1-21, q3w, Capecitabine 1000mg/m2, bid po d1-14, q3w

pyrotinib combined with Capecitabine

treatment of physician's choice

Xuefei Wang

Xuefei Wang, Dr.

This is a prospective, multicenter, registry-based cohort study to explore the efficacy and safety of Pyrotinib combined with Capecitabine for adjuvant treatment of HER2 positive early breast cancer compared with treatment of physician's choice. Pyrotinib is a small molecule tyrosine kinase inhibitor which can irreversibly inhibit HER1, HER2, and HER4.

Pyrotinib Plus Capecitabine for Adjuvant Treatment of HER2 Positive Early-stage Breast Cancer

A Prospective, Multicenter and Registry-based Cohort Study of Pyrotinib Plus Capecitabine for Adjuvant Treatment of HER2 Positive Early-stage Breast Cancer

The 3-year IDFS (invasive disease-free survival) is defined as the time from the date of enrollment to the first occurrence of recurrent diseases. Recurrent diseases include ipsilateral or contralateral recurrent breast cancer, local or regional recurrence, remote recurrence and death caused by any reason. The observation period is from enrollment to 3 years after enrollment.

The incidence and severity of adverse events (AEs) and serious adverse events (SAEs) are recorded according to the NCI CTCAE v5.0.

The quality of life (QoL) of the participants is assessed according to the EORTC QLQ-C30 quality of life questionnaire.

Peking Union Medical College Hospital

Professor

Immune System Diseases

Hypersensitivity

aromatase inhibitors with or without GnRHa plus 3-year lower dose (100mg bid) abemaciclib without chemotherapy.

treatment of physician's choice, including whether to receive chemotherapy, the chemotherapy regimen and the endocrine therapy regimen.

aromatase inhibitors (± ovarian suppression) plus 3-year abemaciclib (100mg bid) without chemotherapy.

3-year abemaciclib without chemo

treatment of physician's choice including whether to receive chemotherapy, chemotherapy regimen and endocrine therapy regimen.

Zhimin Shao, MD, PhD

Yin Liu, MD

This is a prospective, randomized, open-label, multicenter phase III study to explore chemotherapy omission in ER+/HER2-endocrine-sensitive breast cancer with 1-3 positive lymph nodes receiving extended (3 year) adjuvant abemaciclib

This is a prospective, randomized, open-label, multicenter phase III study to explore chemotherapy omission in estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative endocrine-sensitive breast cancer with 1-3 positive lymph nodes receiving extended (3 year) adjuvant abemaciclib. In this study, patient eligible will be randomized into either endocrine drug plus 3-year adjuvant abemaciclib without chemotherapy or treatment of physician's choice (TPC).The safety and efficacy of each group will be assessed through invasive disease free survival (iDFS), disease-free survival (DFS), distant disease free survival (DDFS), overall survival (OS) and adverse effects (AE) as graded by Common Terminology Criteria for Adverse Events (CTCAE) 5.0.

Arm 1# endocrine drug plus 3-year abemaciclib without chemotherapy Arm 2# treatment of physician's choice

Chemotherapy Omission in ER+/HER2- Breast Cancer With 1-3 Positive Lymph Nodes Receiving Extended Adjuvant Abemaciclib

A Prospective, Randomized, Open-label, Multicenter Phase III Study to Explore Chemotherapy Omission in ER+/HER2-endocrine-sensitive Breast Cancer With 1-3 Positive Lymph Nodes Receiving Extended Adjuvant Abemaciclib

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
A Study of Trastuzumab Emtansine in Comparison With Treatment of Physician's Choice in Participants With HER2-positive Breast Cancer Who Have Received at Least Two Prior Regimens of HER2-directed Therapy	NCT01419197	Breast Cancer	Trastuzumab emt... Treatment of ph...	18 Years -	Hoffmann-La Roche
A Study of Pyrotinib Plus Vinorelbine in Comparison With Treatment of Physician's Choice in Participants With HER2-positive Locally Advanced or Metastatic Breast Cancer	NCT03997539	Metastatic Brea...	Pyrotinib Treatment of ph... vinorelbine	18 Years - 70 Years	Sun Yat-sen University
A Study of Pyrotinib Plus Vinorelbine in Comparison With Treatment of Physician's Choice in Participants With HER2-positive Locally Advanced or Metastatic Breast Cancer	NCT03997539	Metastatic Brea...	Pyrotinib Treatment of ph... vinorelbine	18 Years - 70 Years	Sun Yat-sen University
Pyrotinib Plus Capecitabine for Adjuvant Treatment of HER2 Positive Early-stage Breast Cancer	NCT06035016	HER2-positive B... Early-stage Bre...	pyrotinib combi... treatment of ph...	18 Years - 75 Years	Peking Union Medical College Hospital
Pyrotinib Plus Capecitabine for Adjuvant Treatment of HER2 Positive Early-stage Breast Cancer	NCT06035016	HER2-positive B... Early-stage Bre...	pyrotinib combi... treatment of ph...	18 Years - 75 Years	Peking Union Medical College Hospital
Chemotherapy Omission in ER+/HER2- Breast Cancer With 1-3 Positive Lymph Nodes Receiving Extended Adjuvant Abemaciclib	NCT06341621	Breast Cancer	3-year abemacic... treatment of ph...	18 Years - 80 Years	Fudan University

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