Breast Cancer, Urothelial Carcinoma
Conditions
Keywords
Human epidermal growth factor receptor-2, HER2, Refractory, Metastatic, Urothelial cancer, Breast Cancer
Brief summary
This is a study of trastuzumab deruxtecan for the treatment of HER2-positive unresectable or metastatic breast cancer following two or more prior anti-HER2 based regimens. Participants will receive this study drug along with a cancer drug, an immune checkpoint inhibitor, anti-PD1, called nivolumab. The study will be done in two parts: * Part 1 is to identify the recommended dose to use for treatment. * Part 2 is to find out how well the combination works, and how safe and tolerable it is.
Detailed description
The purpose of this phase 1b (Part 1, Part 2) study is to assess the combination of a test drug (trastuzumab deruxtecan) with nivolumab in participants with HER2-expressing breast and urothelial cancer who had disease progression during or after prior therapies, did not respond to standard therapies, or for whom no standard therapy is available. The study will be performed in 2 parts. * Part 1 is to test different doses of trastuzumab deruxtecan when given along with a fixed dose of nivolumab, and establish the maximum tolerated dose/recommended dose for expansion, when used in combination with nivolumab * Part 2 is to assess the efficacy and safety of this dose combination.
Interventions
DRUGTrastuzumab deruxtecan
The investigational product is a sterile lyophilized powder, which is made into solution for intravenous administration.
DRUGNivolumab
Nivolumab is an aqueous solution formulated at 10 mg/mL to be administered at a flat dose of 360 mg IV over 30 minutes. Protocol-defined thyroid testing is required while taking nivolumab.
Sponsors
Bristol-Myers Squibb
AstraZeneca
Daiichi Sankyo
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Part 1 will be a sequential dose-finding (dose escalation) study, Part 2 will consist of a single group of four cohorts who receive the recommended dose (determined during Part 1)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Is the age of majority (adulthood) in their country 2. Has an Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 to 1 3. Has pathologically documented breast cancer or urothelial cancer that is unresectable or metastatic, and refractory to or intolerant of existing therapy(ies) known to provide clinical benefit, and as specified in each study cohort 4. Has an adequate archival tumor sample available for the central laboratory to determine eligibility to participate 5. Has at least 1 measurable lesion per RECIST version 1.1 6. Has cardiac, bone marrow, kidney, liver, blood and clotting test results required per protocol 7. Has had an adequate washout period before enrollment since previous surgery and other treatment 8. If reproduction is possible, agrees to use protocol-defined methods of contraception (or completely abstain from heterosexual intercourse) from screening to at least 7 months for females and males after the last dose of study drug 9. Agrees to avoid harvesting sperm or ova for any reason from screening to at least 7 months for females and males after the last dose of study drug 10. Has a life expectancy of at least 3 months
Exclusion criteria
1. Has received prior treatment with nivolumab or trastuzumab deruxtecan 2. Has medical history of myocardial infarction (MI) within 6 months before enrollment, symptomatic congestive heart failure (CHF) (New York Heart Association classes II-IV). Troponin levels above upper limit of normal (ULN) at screening (as defined by the manufacturer) and without any MI-related symptoms should have a cardiologic consultation before enrollment to rule out MI. 3. Has a corrected QT interval by Fredericia (QTcF) prolongation to \> 470 ms (females) or \> 450 ms (males) based on an average of the screening triplicate 12-lead electrocardiogram 4. Has history of non-infectious interstitial lung disease (ILD/pneumonitis) (that required steroids), has ILD/pneumonitis currently, or it cannot be ruled out by imaging at screening 5. Has a condition (other than active autoimmune disease) that requires systemic treatment with either corticosteroids (\>10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 days of starting study treatment 6. Is pregnant or breastfeeding, or planning to become pregnant
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Dose-Limiting Toxicities at 3.2 mg/kg and 5.4 mg/kg Dose Level in Participants With HER2-expressing Advanced Breast Cancer in Dose Escalation | Cycles 1 and 2 (each cycle is 21 days) | A Dose-Limiting Toxicity (DLT) is defined as any Treatment Emergent Adverse Event not attributable to disease or disease-related processes that occurs during the DLT evaluation period (2 complete cycles during Part 1) and is Grade 3 or above according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0. Each cycle is 21 days. Low dose was set at 3.2 mg/kg and high dose was set at 5.4 mg/kg. |
| Percentage of Participants With Objective Response Rate (ORR) Based on Independent Central Review in Participants With HER2-expressing Advanced Breast Cancer or Urothelial Cancer | Every 6 weeks in the first year after Day 1 of Cycle 1 and thereafter every 12 weeks until disease progression or initiation of additional anticancer therapy and survival, up to 2 years 11.5 months (each cycle is 21 days) | The Objective Response Rate (ORR) was the defined as the percentage of participants who achieved a best overall response of confirmed Complete Response (CR) or Partial Response (PR), assessed by independent central review (ICR) committee based on RECIST version 1.1. CR was defined as a disappearance of all target lesions and PR was defined as at least a 30% decrease in the sum of diameters of target lesions. Confirmed ORR based on ICR is reported. As prespecified in the protocol, participants enrolled in Part 1 were pooled according to their trastuzumab deruxtecan dose and HER2 expressing levels (HER2 positive or HER2 low) for efficacy analyses. Participants who were dosed at 5.4 mg/kg of trastuzumab deruxtecan and have HER2-positive expression Breast Cancer (IHC score 3+ or IHC score 2+/ISH+) in Part 1 were pooled with the same participants from Part 2 (in this case, participants enrolled in Cohort 1). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression-Free Survival (PFS) in Participants With HER2-expressing Advanced Breast Cancer or Urothelial Cancer | Every 6 weeks in the first year after Day 1 of Cycle 1 and thereafter every 12 weeks until disease progression or initiation of additional anticancer therapy and survival, up to 5 years (each cycle is 21 days) | Progression-free survival (PFS) was defined as the time from the date of enrollment to the earlier of the dates of the first objective documentation of disease progression (as per RECIST v1.1) or death due to any cause. Progressive disease was defined as at least a 20% increase in the sum of diameters of target lesions. PFS based on independent central review and investigator assessment is reported. As prespecified in the protocol, participants enrolled in Part 1 were pooled according to their trastuzumab deruxtecan dose and HER2 expressing levels (HER2 positive or HER2 low) for efficacy analyses. Participants who were dosed at 5.4 mg/kg of trastuzumab deruxtecan and have HER2-positive expression Breast Cancer (IHC score 3+ or IHC score 2+/ISH+) in Part 1 were pooled with the same participants from Part 2 (in this case, participants enrolled in Cohort 1). |
| Time to Response (TTR) Based on Independent Central Review in Participants With HER2-expressing Advanced Breast Cancer or Urothelial Cancer | Every 6 weeks in the first year after Day 1 of Cycle 1 and thereafter every 12 weeks until disease progression or initiation of additional anticancer therapy and survival, up to 5 years (each cycle is 21 days) | Time to response (TTR) is defined as the time from the date of first dose of study treatment to the date of the first documented objective response (CR or PR). CR was defined as a disappearance of all target lesions and PR was defined as at least a 30% decrease in the sum of diameters of target lesions. Confirmation of CR/PR was required. TTR based on independent central review and investigator assessment is reported. As prespecified in the protocol, participants enrolled in Part 1 were pooled according to their trastuzumab deruxtecan dose and HER2 expressing levels (HER2 positive or HER2 low) for efficacy analyses. Participants who were dosed at 5.4 mg/kg of trastuzumab deruxtecan and have HER2-positive expression Breast Cancer (IHC score 3+ or IHC score 2+/ISH+) in Part 1 were pooled with the same participants from Part 2 (in this case, participants enrolled in Cohort 1). |
| Duration of Response (DoR) in Participants With HER2-expressing Advanced Breast Cancer or Urothelial Cancer | Every 6 weeks in the first year after Day 1 of Cycle 1 and thereafter every 12 weeks until disease progression or initiation of additional anticancer therapy and survival, up to 5 years (each cycle is 21 days) | Duration of Response (DoR) was defined as the time from the date of the first documentation of objective response (complete response \[CR\] or partial response \[PR\]) to the date of the first objective documentation of progressive disease (PD) or death due to any cause. CR was defined as a disappearance of all target lesions and PR was defined as at least a 30% decrease in the sum of diameters of target lesions. DoR in participants with confirmed CR/PR based on independent central review and investigator assessment is reported. As prespecified in the protocol, participants enrolled in Part 1 were pooled according to their trastuzumab deruxtecan dose and HER2 expressing levels (HER2 positive or HER2 low) for efficacy analyses. Participants who were dosed at 5.4 mg/kg of trastuzumab deruxtecan and have HER2-positive expression Breast Cancer (IHC score 3+ or IHC score 2+/ISH+) in Part 1 were pooled with the same participants from Part 2 (in this case, participants enrolled in Cohort 1). |
| Percentage of Participants With Objective Response Rate (ORR) Based on Investigator Assessment in Participants With HER2-expressing Advanced Breast Cancer or Urothelial Cancer | Every 6 weeks in the first year after Day 1 of Cycle 1 and thereafter every 12 weeks until disease progression or initiation of additional anticancer therapy and survival, up to 5 years (each cycle is 21 days) | The Objective Response Rate (ORR) was the defined as the percentage of participants who achieved a best overall response of confirmed Complete Response (CR) or Partial Response (PR), assessed by investigator assessment (IA) based on RECIST version 1.1. CR was defined as a disappearance of all target lesions and PR was defined as at least a 30% decrease in the sum of diameters of target lesions. Confirmed ORR based on IA is reported. As prespecified in the protocol, participants enrolled in Part 1 were pooled according to their trastuzumab deruxtecan dose and HER2 expressing levels (HER2 positive or HER2 low) for efficacy analyses. Participants who were dosed at 5.4 mg/kg of trastuzumab deruxtecan and have HER2-positive expression Breast Cancer (IHC score 3+ or IHC score 2+/ISH+) in Part 1 were pooled with the same participants from Part 2 (in this case, participants enrolled in Cohort 1). |
| Number of Participants With Treatment Emergent Adverse Events (TEAEs) | Date of signing the informed consent form up to 100 days after last dose of study drug or start of a new anticancer drug (whichever occurs first), up to 5 years | A treatment-emergent adverse event (TEAE) was defined as an AE that occurred, having been absent before the first dose of study drug, or had worsened in severity or seriousness after initiating the study drug until 47 days after last dose of study drug. |
| Overall Survival (OS) in Participants With HER2-expressing Advanced Breast Cancer or Urothelial Cancer | Date of first dose of study drug to the date of death due to any cause, up to 5 years | Overall survival (OS) was defined as the time from the date of first dose of study drug to the date of death due to any cause. As prespecified in the protocol, participants enrolled in Part 1 were pooled according to their trastuzumab deruxtecan dose and HER2 expressing levels (HER2 positive or HER2 low) for efficacy analyses. Participants who were dosed at 5.4 mg/kg of trastuzumab deruxtecan and have HER2-positive expression Breast Cancer (IHC score 3+ or IHC score 2+/ISH+) in Part 1 were pooled with the same participants from Part 2 (in this case, participants enrolled in Cohort 1). |
| Percentage of Participants With Disease Control Rate (DCR) in Participants With HER2-expressing Advanced Breast Cancer or Urothelial Cancer | Every 6 weeks in the first year after Day 1 of Cycle 1 and thereafter every 12 weeks until disease progression or initiation of additional anticancer therapy and survival, up to 5 years (each cycle is 21 days) | Disease Control Rate (DCR) was defined as the percentage of participants who achieved a best overall response of CR, PR, or stable disease (SD) during study treatment. CR was defined as a disappearance of all target lesions, PR as at least a 30% decrease in the sum of diameters of target lesions, and SD as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease. Confirmation of CR/PR was required. DCR based on independent central review and investigator assessment is reported. As prespecified in the protocol, participants enrolled in Part 1 were pooled according to their trastuzumab deruxtecan dose and HER2 expressing levels (HER2 positive or HER2 low) for efficacy analyses. Participants who were dosed at 5.4 mg/kg of trastuzumab deruxtecan and have HER2-positive expression Breast Cancer (IHC score 3+ or IHC score 2+/ISH+) in Part 1 were pooled with the same participants from Part 2 (in this case, participants enrolled in Cohort 1). |
Countries
Belgium, France, Germany, Italy, Spain, United Kingdom, United States
Participant flow
Recruitment details
A total of 86 participants were enrolled and treated at 21 study sites in US and Europe. Final study results are reported for all outcome measures.
Pre-assignment details
The Dose Escalation was intended to identify the maximum tolerated dose (MTD) of T-DXd in combination with a fixed dose of nivolumab.
Participants by arm
| Arm | Count |
|---|---|
| Dose Escalation (3.2 mg/kg) Participants with HER2-expressing breast cancer who received starting intravenous dose of trastuzumab deruxtecan at 3.2 mg/kg and a fixed intravenous dose of 360mg of nivolumab every 3 weeks (Q3W).
Escalating/de-escalating doses of trastuzumab deruxtecan in combination with a flat dose of nivolumab was administered on Day 1 of each 21-day cycle. | 4 |
| Dose Escalation (5.4 mg/kg) Participants with HER2-expressing breast cancer who received starting intravenous dose of trastuzumab deruxtecan at 5.4 mg/kg and a fixed intravenous dose of 360mg of nivolumab every 3 weeks (Q3W).
Escalating/de-escalating doses of trastuzumab deruxtecan in combination with a flat dose of nivolumab was administered on Day 1 of each 21-day cycle. | 3 |
| Expansion Cohort 1 (5.4 mg/kg): HER2 Positive BC Participants with pathologically documented advanced/metastatic breast cancer (BC) that has centrally-determined positive HER2 expression (IHC 3+ or IHC 2+/ISH+) \[as defined by American Society of Clinical Oncology/College of American Pathologists (ASCO-CAP) guidelines\] and have received prior ado-trastuzumab emtansine (T-DM1) who received starting intravenous dose of trastuzumab deruxtecan at 5.4 mg/kg and a fixed intravenous dose of 360mg of nivolumab every 3 weeks (Q3W). | 29 |
| Dose Expansion Cohort 2 (5.4 mg/kg): HER2 Low BC Participants with pathologically documented advanced/metastatic breast cancer (BC) that has centrally-determined low HER2 expression (IHC 1+ or IHC 2+/ISH-) who have exhausted treatments that can confer any clinically meaningful benefit (e.g. other therapies such as hormonal therapy for patients who are hormone receptor positive) who received starting intravenous dose of trastuzumab deruxtecan at 5.4 mg/kg and a fixed intravenous dose of 360mg of nivolumab every 3 weeks (Q3W). | 16 |
| Dose Expansion Cohort 3 (5.4 mg/kg): HER2 High Expressing (IHC 2+/3+) UC Participants with pathologically documented advanced/metastatic urothelial carcinoma (UC) that has centrally-determined HER2 expression of IHC 2+ or 3+, who received prior platinum-based therapy with documented progression who received starting intravenous dose of trastuzumab deruxtecan at 5.4 mg/kg and a fixed intravenous dose of 360mg of nivolumab every 3 weeks (Q3W). | 30 |
| Dose Expansion Cohort 4 (5.4 mg/kg): HER2 Low Expressing (IHC 1+) UC Participants with pathologically documented advanced/metastatic urothelial carcinoma (UC) that has centrally-determined HER2 expression of IHC 1+, who received prior platinum-based therapy with documented progression who received starting intravenous dose of trastuzumab deruxtecan at 5.4 mg/kg and a fixed intravenous dose of 360mg of nivolumab every 3 weeks (Q3W). | 4 |
| Total | 86 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Dose Escalation | Adverse Event | 2 | 0 | 0 | 0 | 0 | 0 |
| Dose Escalation | Clinical Progression | 0 | 1 | 0 | 0 | 0 | 0 |
| Dose Escalation | Physician Decision | 1 | 1 | 0 | 0 | 0 | 0 |
| Dose Escalation | Progressive disease | 1 | 0 | 0 | 0 | 0 | 0 |
| Dose Expansion | Adverse Event | 0 | 0 | 10 | 1 | 5 | 2 |
| Dose Expansion | Clinical Progression | 0 | 0 | 2 | 2 | 2 | 0 |
| Dose Expansion | Miscellaneous | 0 | 0 | 0 | 0 | 3 | 0 |
| Dose Expansion | Physician Decision | 0 | 0 | 1 | 0 | 1 | 0 |
| Dose Expansion | Progressive Disease | 0 | 0 | 9 | 11 | 15 | 2 |
| Dose Expansion | Withdrawal by Subject | 0 | 0 | 1 | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | Dose Escalation (3.2 mg/kg) | Dose Escalation (5.4 mg/kg) | Expansion Cohort 1 (5.4 mg/kg): HER2 Positive BC | Dose Expansion Cohort 2 (5.4 mg/kg): HER2 Low BC | Dose Expansion Cohort 3 (5.4 mg/kg): HER2 High Expressing (IHC 2+/3+) UC | Dose Expansion Cohort 4 (5.4 mg/kg): HER2 Low Expressing (IHC 1+) UC | Total |
|---|---|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 2 Participants | 2 Participants | 5 Participants | 0 Participants | 22 Participants | 2 Participants | 33 Participants |
| Age, Categorical Between 18 and 65 years | 2 Participants | 1 Participants | 24 Participants | 16 Participants | 8 Participants | 2 Participants | 53 Participants |
| Age, Continuous | 60.73 years STANDARD_DEVIATION 10.978 | 63.99 years STANDARD_DEVIATION 16.995 | 56.37 years STANDARD_DEVIATION 9.799 | 48.11 years STANDARD_DEVIATION 8.781 | 69.29 years STANDARD_DEVIATION 10.352 | 59.71 years STANDARD_DEVIATION 13.308 | 59.48 years STANDARD_DEVIATION 12.672 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 0 Participants | 5 Participants | 0 Participants | 0 Participants | 0 Participants | 6 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) White | 3 Participants | 3 Participants | 23 Participants | 14 Participants | 28 Participants | 4 Participants | 75 Participants |
| Region of Enrollment Belgium | 0 participants | 0 participants | 2 participants | 0 participants | 3 participants | 2 participants | 7 participants |
| Region of Enrollment France | 0 participants | 0 participants | 0 participants | 0 participants | 2 participants | 0 participants | 2 participants |
| Region of Enrollment Germany | 0 participants | 0 participants | 0 participants | 0 participants | 4 participants | 1 participants | 5 participants |
| Region of Enrollment Italy | 0 participants | 0 participants | 3 participants | 1 participants | 7 participants | 1 participants | 12 participants |
| Region of Enrollment Spain | 0 participants | 0 participants | 4 participants | 7 participants | 6 participants | 0 participants | 17 participants |
| Region of Enrollment United Kingdom | 0 participants | 0 participants | 3 participants | 1 participants | 1 participants | 0 participants | 5 participants |
| Region of Enrollment United States | 4 participants | 3 participants | 17 participants | 7 participants | 7 participants | 0 participants | 38 participants |
| Sex: Female, Male Female | 4 Participants | 3 Participants | 29 Participants | 16 Participants | 27 Participants | 3 Participants | 82 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 3 Participants | 1 Participants | 4 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 2 / 4 | 1 / 3 | 7 / 29 | 8 / 16 | 17 / 30 | 0 / 4 |
| other Total, other adverse events | 4 / 4 | 3 / 3 | 29 / 29 | 16 / 16 | 30 / 30 | 4 / 4 |
| serious Total, serious adverse events | 3 / 4 | 2 / 3 | 12 / 29 | 4 / 16 | 17 / 30 | 3 / 4 |
Outcome results
Primary
Number of Participants With Dose-Limiting Toxicities at 3.2 mg/kg and 5.4 mg/kg Dose Level in Participants With HER2-expressing Advanced Breast Cancer in Dose Escalation
A Dose-Limiting Toxicity (DLT) is defined as any Treatment Emergent Adverse Event not attributable to disease or disease-related processes that occurs during the DLT evaluation period (2 complete cycles during Part 1) and is Grade 3 or above according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0. Each cycle is 21 days. Low dose was set at 3.2 mg/kg and high dose was set at 5.4 mg/kg.
Time frame: Cycles 1 and 2 (each cycle is 21 days)
Population: DLT was assessed in the DLT evaluable set.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Dose Escalation (3.2 mg/kg) | Number of Participants With Dose-Limiting Toxicities at 3.2 mg/kg and 5.4 mg/kg Dose Level in Participants With HER2-expressing Advanced Breast Cancer in Dose Escalation | 0 Participants |
| Dose Escalation (5.4 mg/kg) | Number of Participants With Dose-Limiting Toxicities at 3.2 mg/kg and 5.4 mg/kg Dose Level in Participants With HER2-expressing Advanced Breast Cancer in Dose Escalation | 0 Participants |
Primary
Percentage of Participants With Objective Response Rate (ORR) Based on Independent Central Review in Participants With HER2-expressing Advanced Breast Cancer or Urothelial Cancer
The Objective Response Rate (ORR) was the defined as the percentage of participants who achieved a best overall response of confirmed Complete Response (CR) or Partial Response (PR), assessed by independent central review (ICR) committee based on RECIST version 1.1. CR was defined as a disappearance of all target lesions and PR was defined as at least a 30% decrease in the sum of diameters of target lesions. Confirmed ORR based on ICR is reported. As prespecified in the protocol, participants enrolled in Part 1 were pooled according to their trastuzumab deruxtecan dose and HER2 expressing levels (HER2 positive or HER2 low) for efficacy analyses. Participants who were dosed at 5.4 mg/kg of trastuzumab deruxtecan and have HER2-positive expression Breast Cancer (IHC score 3+ or IHC score 2+/ISH+) in Part 1 were pooled with the same participants from Part 2 (in this case, participants enrolled in Cohort 1).
Time frame: Every 6 weeks in the first year after Day 1 of Cycle 1 and thereafter every 12 weeks until disease progression or initiation of additional anticancer therapy and survival, up to 2 years 11.5 months (each cycle is 21 days)
Population: Objective response rate was assessed in the Full Analysis Set. Participants who were dosed at 5.4 mg/kg of trastuzumab deruxtecan and have HER2-positive expression Breast Cancer (IHC score 3+ or IHC score 2+/ISH+) in Part 1 were pooled with the same participants from Part 2 (in this case, participants enrolled in Cohort 1).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dose Escalation (3.2 mg/kg) | Percentage of Participants With Objective Response Rate (ORR) Based on Independent Central Review in Participants With HER2-expressing Advanced Breast Cancer or Urothelial Cancer | 25.0 Percentage of Participants |
| Dose Escalation (5.4 mg/kg) | Percentage of Participants With Objective Response Rate (ORR) Based on Independent Central Review in Participants With HER2-expressing Advanced Breast Cancer or Urothelial Cancer | 65.6 Percentage of Participants |
| Dose Expansion Cohort 2 (5.4 mg/kg): HER2 Low BC | Percentage of Participants With Objective Response Rate (ORR) Based on Independent Central Review in Participants With HER2-expressing Advanced Breast Cancer or Urothelial Cancer | 50.0 Percentage of Participants |
| Dose Expansion Cohort 3 (5.4 mg/kg): HER2 High Expressing (IHC 2+/3+) UC | Percentage of Participants With Objective Response Rate (ORR) Based on Independent Central Review in Participants With HER2-expressing Advanced Breast Cancer or Urothelial Cancer | 36.7 Percentage of Participants |
| Dose Expansion Cohort 4 (5.4 mg/kg): HER2 Low Expressing (IHC 1+) UC | Percentage of Participants With Objective Response Rate (ORR) Based on Independent Central Review in Participants With HER2-expressing Advanced Breast Cancer or Urothelial Cancer | 50.0 Percentage of Participants |
Secondary
Duration of Response (DoR) in Participants With HER2-expressing Advanced Breast Cancer or Urothelial Cancer
Duration of Response (DoR) was defined as the time from the date of the first documentation of objective response (complete response \[CR\] or partial response \[PR\]) to the date of the first objective documentation of progressive disease (PD) or death due to any cause. CR was defined as a disappearance of all target lesions and PR was defined as at least a 30% decrease in the sum of diameters of target lesions. DoR in participants with confirmed CR/PR based on independent central review and investigator assessment is reported. As prespecified in the protocol, participants enrolled in Part 1 were pooled according to their trastuzumab deruxtecan dose and HER2 expressing levels (HER2 positive or HER2 low) for efficacy analyses. Participants who were dosed at 5.4 mg/kg of trastuzumab deruxtecan and have HER2-positive expression Breast Cancer (IHC score 3+ or IHC score 2+/ISH+) in Part 1 were pooled with the same participants from Part 2 (in this case, participants enrolled in Cohort 1).
Time frame: Every 6 weeks in the first year after Day 1 of Cycle 1 and thereafter every 12 weeks until disease progression or initiation of additional anticancer therapy and survival, up to 5 years (each cycle is 21 days)
Population: Duration of Response (DoR) was assessed in the Full Analysis Set of participants with available data with confirmed CR/PR. Participants who were dosed at 5.4 mg/kg of trastuzumab deruxtecan and have HER2-positive expression Breast Cancer (IHC score 3+ or IHC score 2+/ISH+) in Part 1 were pooled with the same participants from Part 2 (in this case, participants enrolled in Cohort 1).
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Dose Escalation (5.4 mg/kg) | Duration of Response (DoR) in Participants With HER2-expressing Advanced Breast Cancer or Urothelial Cancer | Independent Central Review | NA months |
| Dose Escalation (5.4 mg/kg) | Duration of Response (DoR) in Participants With HER2-expressing Advanced Breast Cancer or Urothelial Cancer | Investigator Assessment | 20.2 months |
| Dose Expansion Cohort 2 (5.4 mg/kg): HER2 Low BC | Duration of Response (DoR) in Participants With HER2-expressing Advanced Breast Cancer or Urothelial Cancer | Investigator Assessment | 5.8 months |
| Dose Expansion Cohort 2 (5.4 mg/kg): HER2 Low BC | Duration of Response (DoR) in Participants With HER2-expressing Advanced Breast Cancer or Urothelial Cancer | Independent Central Review | 5.5 months |
| Dose Expansion Cohort 3 (5.4 mg/kg): HER2 High Expressing (IHC 2+/3+) UC | Duration of Response (DoR) in Participants With HER2-expressing Advanced Breast Cancer or Urothelial Cancer | Investigator Assessment | 8.7 months |
| Dose Expansion Cohort 3 (5.4 mg/kg): HER2 High Expressing (IHC 2+/3+) UC | Duration of Response (DoR) in Participants With HER2-expressing Advanced Breast Cancer or Urothelial Cancer | Independent Central Review | 13.1 months |
| Dose Expansion Cohort 4 (5.4 mg/kg): HER2 Low Expressing (IHC 1+) UC | Duration of Response (DoR) in Participants With HER2-expressing Advanced Breast Cancer or Urothelial Cancer | Investigator Assessment | NA months |
| Dose Expansion Cohort 4 (5.4 mg/kg): HER2 Low Expressing (IHC 1+) UC | Duration of Response (DoR) in Participants With HER2-expressing Advanced Breast Cancer or Urothelial Cancer | Independent Central Review | NA months |
Secondary
Number of Participants With Treatment Emergent Adverse Events (TEAEs)
A treatment-emergent adverse event (TEAE) was defined as an AE that occurred, having been absent before the first dose of study drug, or had worsened in severity or seriousness after initiating the study drug until 47 days after last dose of study drug.
Time frame: Date of signing the informed consent form up to 100 days after last dose of study drug or start of a new anticancer drug (whichever occurs first), up to 5 years
Population: TEAEs were assessed in the Safety Analysis Set.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Dose Escalation (3.2 mg/kg) | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | 4 Participants |
| Dose Escalation (5.4 mg/kg) | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | 3 Participants |
| Dose Expansion Cohort 2 (5.4 mg/kg): HER2 Low BC | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | 29 Participants |
| Dose Expansion Cohort 3 (5.4 mg/kg): HER2 High Expressing (IHC 2+/3+) UC | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | 16 Participants |
| Dose Expansion Cohort 4 (5.4 mg/kg): HER2 Low Expressing (IHC 1+) UC | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | 30 Participants |
| Dose Expansion Cohort 4 (5.4 mg/kg): HER2 Low Expressing (IHC 1+) UC | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | 4 Participants |
Secondary
Overall Survival (OS) in Participants With HER2-expressing Advanced Breast Cancer or Urothelial Cancer
Overall survival (OS) was defined as the time from the date of first dose of study drug to the date of death due to any cause. As prespecified in the protocol, participants enrolled in Part 1 were pooled according to their trastuzumab deruxtecan dose and HER2 expressing levels (HER2 positive or HER2 low) for efficacy analyses. Participants who were dosed at 5.4 mg/kg of trastuzumab deruxtecan and have HER2-positive expression Breast Cancer (IHC score 3+ or IHC score 2+/ISH+) in Part 1 were pooled with the same participants from Part 2 (in this case, participants enrolled in Cohort 1).
Time frame: Date of first dose of study drug to the date of death due to any cause, up to 5 years
Population: Overall survival (OS) was assessed in the Full Analysis Set. Participants who were dosed at 5.4 mg/kg of trastuzumab deruxtecan and have HER2-positive expression Breast Cancer (IHC score 3+ or IHC score 2+/ISH+) in Part 1 were pooled with the same participants from Part 2 (in this case, participants enrolled in Cohort 1).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Dose Escalation (3.2 mg/kg) | Overall Survival (OS) in Participants With HER2-expressing Advanced Breast Cancer or Urothelial Cancer | NA months |
| Dose Escalation (5.4 mg/kg) | Overall Survival (OS) in Participants With HER2-expressing Advanced Breast Cancer or Urothelial Cancer | NA months |
| Dose Expansion Cohort 2 (5.4 mg/kg): HER2 Low BC | Overall Survival (OS) in Participants With HER2-expressing Advanced Breast Cancer or Urothelial Cancer | 19.5 months |
| Dose Expansion Cohort 3 (5.4 mg/kg): HER2 High Expressing (IHC 2+/3+) UC | Overall Survival (OS) in Participants With HER2-expressing Advanced Breast Cancer or Urothelial Cancer | 11.0 months |
| Dose Expansion Cohort 4 (5.4 mg/kg): HER2 Low Expressing (IHC 1+) UC | Overall Survival (OS) in Participants With HER2-expressing Advanced Breast Cancer or Urothelial Cancer | NA months |
Secondary
Percentage of Participants With Disease Control Rate (DCR) in Participants With HER2-expressing Advanced Breast Cancer or Urothelial Cancer
Disease Control Rate (DCR) was defined as the percentage of participants who achieved a best overall response of CR, PR, or stable disease (SD) during study treatment. CR was defined as a disappearance of all target lesions, PR as at least a 30% decrease in the sum of diameters of target lesions, and SD as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease. Confirmation of CR/PR was required. DCR based on independent central review and investigator assessment is reported. As prespecified in the protocol, participants enrolled in Part 1 were pooled according to their trastuzumab deruxtecan dose and HER2 expressing levels (HER2 positive or HER2 low) for efficacy analyses. Participants who were dosed at 5.4 mg/kg of trastuzumab deruxtecan and have HER2-positive expression Breast Cancer (IHC score 3+ or IHC score 2+/ISH+) in Part 1 were pooled with the same participants from Part 2 (in this case, participants enrolled in Cohort 1).
Time frame: Every 6 weeks in the first year after Day 1 of Cycle 1 and thereafter every 12 weeks until disease progression or initiation of additional anticancer therapy and survival, up to 5 years (each cycle is 21 days)
Population: Disease control rate was assessed in the Full Analysis Set. Participants who were dosed at 5.4 mg/kg of trastuzumab deruxtecan and have HER2-positive expression Breast Cancer (IHC score 3+ or IHC score 2+/ISH+) in Part 1 were pooled with the same participants from Part 2 (in this case, participants enrolled in Cohort 1).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Dose Escalation (3.2 mg/kg) | Percentage of Participants With Disease Control Rate (DCR) in Participants With HER2-expressing Advanced Breast Cancer or Urothelial Cancer | Investigator Assessment | 50 Percentage of Participants |
| Dose Escalation (3.2 mg/kg) | Percentage of Participants With Disease Control Rate (DCR) in Participants With HER2-expressing Advanced Breast Cancer or Urothelial Cancer | Independent Central Review | 50 Percentage of Participants |
| Dose Escalation (5.4 mg/kg) | Percentage of Participants With Disease Control Rate (DCR) in Participants With HER2-expressing Advanced Breast Cancer or Urothelial Cancer | Investigator Assessment | 93.8 Percentage of Participants |
| Dose Escalation (5.4 mg/kg) | Percentage of Participants With Disease Control Rate (DCR) in Participants With HER2-expressing Advanced Breast Cancer or Urothelial Cancer | Independent Central Review | 93.8 Percentage of Participants |
| Dose Expansion Cohort 2 (5.4 mg/kg): HER2 Low BC | Percentage of Participants With Disease Control Rate (DCR) in Participants With HER2-expressing Advanced Breast Cancer or Urothelial Cancer | Independent Central Review | 75.0 Percentage of Participants |
| Dose Expansion Cohort 2 (5.4 mg/kg): HER2 Low BC | Percentage of Participants With Disease Control Rate (DCR) in Participants With HER2-expressing Advanced Breast Cancer or Urothelial Cancer | Investigator Assessment | 87.5 Percentage of Participants |
| Dose Expansion Cohort 3 (5.4 mg/kg): HER2 High Expressing (IHC 2+/3+) UC | Percentage of Participants With Disease Control Rate (DCR) in Participants With HER2-expressing Advanced Breast Cancer or Urothelial Cancer | Independent Central Review | 76.7 Percentage of Participants |
| Dose Expansion Cohort 3 (5.4 mg/kg): HER2 High Expressing (IHC 2+/3+) UC | Percentage of Participants With Disease Control Rate (DCR) in Participants With HER2-expressing Advanced Breast Cancer or Urothelial Cancer | Investigator Assessment | 73.3 Percentage of Participants |
| Dose Expansion Cohort 4 (5.4 mg/kg): HER2 Low Expressing (IHC 1+) UC | Percentage of Participants With Disease Control Rate (DCR) in Participants With HER2-expressing Advanced Breast Cancer or Urothelial Cancer | Investigator Assessment | 50 Percentage of Participants |
| Dose Expansion Cohort 4 (5.4 mg/kg): HER2 Low Expressing (IHC 1+) UC | Percentage of Participants With Disease Control Rate (DCR) in Participants With HER2-expressing Advanced Breast Cancer or Urothelial Cancer | Independent Central Review | 75.0 Percentage of Participants |
Secondary
Percentage of Participants With Objective Response Rate (ORR) Based on Investigator Assessment in Participants With HER2-expressing Advanced Breast Cancer or Urothelial Cancer
The Objective Response Rate (ORR) was the defined as the percentage of participants who achieved a best overall response of confirmed Complete Response (CR) or Partial Response (PR), assessed by investigator assessment (IA) based on RECIST version 1.1. CR was defined as a disappearance of all target lesions and PR was defined as at least a 30% decrease in the sum of diameters of target lesions. Confirmed ORR based on IA is reported. As prespecified in the protocol, participants enrolled in Part 1 were pooled according to their trastuzumab deruxtecan dose and HER2 expressing levels (HER2 positive or HER2 low) for efficacy analyses. Participants who were dosed at 5.4 mg/kg of trastuzumab deruxtecan and have HER2-positive expression Breast Cancer (IHC score 3+ or IHC score 2+/ISH+) in Part 1 were pooled with the same participants from Part 2 (in this case, participants enrolled in Cohort 1).
Time frame: Every 6 weeks in the first year after Day 1 of Cycle 1 and thereafter every 12 weeks until disease progression or initiation of additional anticancer therapy and survival, up to 5 years (each cycle is 21 days)
Population: Objective response rate was assessed in the Full Analysis Set. Participants who were dosed at 5.4 mg/kg of trastuzumab deruxtecan and have HER2-positive expression Breast Cancer (IHC score 3+ or IHC score 2+/ISH+) in Part 1 were pooled with the same participants from Part 2 (in this case, participants enrolled in Cohort 1).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dose Escalation (3.2 mg/kg) | Percentage of Participants With Objective Response Rate (ORR) Based on Investigator Assessment in Participants With HER2-expressing Advanced Breast Cancer or Urothelial Cancer | 25 Percentage of Participants |
| Dose Escalation (5.4 mg/kg) | Percentage of Participants With Objective Response Rate (ORR) Based on Investigator Assessment in Participants With HER2-expressing Advanced Breast Cancer or Urothelial Cancer | 71.9 Percentage of Participants |
| Dose Expansion Cohort 2 (5.4 mg/kg): HER2 Low BC | Percentage of Participants With Objective Response Rate (ORR) Based on Investigator Assessment in Participants With HER2-expressing Advanced Breast Cancer or Urothelial Cancer | 43.8 Percentage of Participants |
| Dose Expansion Cohort 3 (5.4 mg/kg): HER2 High Expressing (IHC 2+/3+) UC | Percentage of Participants With Objective Response Rate (ORR) Based on Investigator Assessment in Participants With HER2-expressing Advanced Breast Cancer or Urothelial Cancer | 40.0 Percentage of Participants |
| Dose Expansion Cohort 4 (5.4 mg/kg): HER2 Low Expressing (IHC 1+) UC | Percentage of Participants With Objective Response Rate (ORR) Based on Investigator Assessment in Participants With HER2-expressing Advanced Breast Cancer or Urothelial Cancer | 25.0 Percentage of Participants |
Secondary
Progression-Free Survival (PFS) in Participants With HER2-expressing Advanced Breast Cancer or Urothelial Cancer
Progression-free survival (PFS) was defined as the time from the date of enrollment to the earlier of the dates of the first objective documentation of disease progression (as per RECIST v1.1) or death due to any cause. Progressive disease was defined as at least a 20% increase in the sum of diameters of target lesions. PFS based on independent central review and investigator assessment is reported. As prespecified in the protocol, participants enrolled in Part 1 were pooled according to their trastuzumab deruxtecan dose and HER2 expressing levels (HER2 positive or HER2 low) for efficacy analyses. Participants who were dosed at 5.4 mg/kg of trastuzumab deruxtecan and have HER2-positive expression Breast Cancer (IHC score 3+ or IHC score 2+/ISH+) in Part 1 were pooled with the same participants from Part 2 (in this case, participants enrolled in Cohort 1).
Time frame: Every 6 weeks in the first year after Day 1 of Cycle 1 and thereafter every 12 weeks until disease progression or initiation of additional anticancer therapy and survival, up to 5 years (each cycle is 21 days)
Population: Progression-free survival (PFS) was assessed in the Full Analysis Set. Participants who were dosed at 5.4 mg/kg of trastuzumab deruxtecan and have HER2-positive expression Breast Cancer (IHC score 3+ or IHC score 2+/ISH+) in Part 1 were pooled with the same participants from Part 2 (in this case, participants enrolled in Cohort 1).
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Dose Escalation (5.4 mg/kg) | Progression-Free Survival (PFS) in Participants With HER2-expressing Advanced Breast Cancer or Urothelial Cancer | Investigator Assessment | 18.0 months |
| Dose Escalation (5.4 mg/kg) | Progression-Free Survival (PFS) in Participants With HER2-expressing Advanced Breast Cancer or Urothelial Cancer | Independent Central Review | 11.6 months |
| Dose Expansion Cohort 2 (5.4 mg/kg): HER2 Low BC | Progression-Free Survival (PFS) in Participants With HER2-expressing Advanced Breast Cancer or Urothelial Cancer | Investigator Assessment | 7.8 months |
| Dose Expansion Cohort 2 (5.4 mg/kg): HER2 Low BC | Progression-Free Survival (PFS) in Participants With HER2-expressing Advanced Breast Cancer or Urothelial Cancer | Independent Central Review | 7.0 months |
| Dose Expansion Cohort 3 (5.4 mg/kg): HER2 High Expressing (IHC 2+/3+) UC | Progression-Free Survival (PFS) in Participants With HER2-expressing Advanced Breast Cancer or Urothelial Cancer | Investigator Assessment | 5.5 months |
| Dose Expansion Cohort 3 (5.4 mg/kg): HER2 High Expressing (IHC 2+/3+) UC | Progression-Free Survival (PFS) in Participants With HER2-expressing Advanced Breast Cancer or Urothelial Cancer | Independent Central Review | 6.9 months |
| Dose Expansion Cohort 4 (5.4 mg/kg): HER2 Low Expressing (IHC 1+) UC | Progression-Free Survival (PFS) in Participants With HER2-expressing Advanced Breast Cancer or Urothelial Cancer | Investigator Assessment | NA months |
| Dose Expansion Cohort 4 (5.4 mg/kg): HER2 Low Expressing (IHC 1+) UC | Progression-Free Survival (PFS) in Participants With HER2-expressing Advanced Breast Cancer or Urothelial Cancer | Independent Central Review | NA months |
Secondary
Time to Response (TTR) Based on Independent Central Review in Participants With HER2-expressing Advanced Breast Cancer or Urothelial Cancer
Time to response (TTR) is defined as the time from the date of first dose of study treatment to the date of the first documented objective response (CR or PR). CR was defined as a disappearance of all target lesions and PR was defined as at least a 30% decrease in the sum of diameters of target lesions. Confirmation of CR/PR was required. TTR based on independent central review and investigator assessment is reported. As prespecified in the protocol, participants enrolled in Part 1 were pooled according to their trastuzumab deruxtecan dose and HER2 expressing levels (HER2 positive or HER2 low) for efficacy analyses. Participants who were dosed at 5.4 mg/kg of trastuzumab deruxtecan and have HER2-positive expression Breast Cancer (IHC score 3+ or IHC score 2+/ISH+) in Part 1 were pooled with the same participants from Part 2 (in this case, participants enrolled in Cohort 1).
Time frame: Every 6 weeks in the first year after Day 1 of Cycle 1 and thereafter every 12 weeks until disease progression or initiation of additional anticancer therapy and survival, up to 5 years (each cycle is 21 days)
Population: Time to response was assessed in the Full Analysis Set. Participants who were dosed at 5.4 mg/kg of trastuzumab deruxtecan and have HER2-positive expression Breast Cancer (IHC score 3+ or IHC score 2+/ISH+) in Part 1 were pooled with the same participants from Part 2 (in this case, participants enrolled in Cohort 1).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Dose Escalation (3.2 mg/kg) | Time to Response (TTR) Based on Independent Central Review in Participants With HER2-expressing Advanced Breast Cancer or Urothelial Cancer | 1.41 months |
| Dose Escalation (5.4 mg/kg) | Time to Response (TTR) Based on Independent Central Review in Participants With HER2-expressing Advanced Breast Cancer or Urothelial Cancer | 1.61 months |
| Dose Expansion Cohort 2 (5.4 mg/kg): HER2 Low BC | Time to Response (TTR) Based on Independent Central Review in Participants With HER2-expressing Advanced Breast Cancer or Urothelial Cancer | 3.73 months |
| Dose Expansion Cohort 3 (5.4 mg/kg): HER2 High Expressing (IHC 2+/3+) UC | Time to Response (TTR) Based on Independent Central Review in Participants With HER2-expressing Advanced Breast Cancer or Urothelial Cancer | 1.87 months |
| Dose Expansion Cohort 4 (5.4 mg/kg): HER2 Low Expressing (IHC 1+) UC | Time to Response (TTR) Based on Independent Central Review in Participants With HER2-expressing Advanced Breast Cancer or Urothelial Cancer | 3.25 months |