This two-part study will include a dose escalation part to determine the recommended dose for expansion of DS8201a and pembrolizumab and a dose expansion part to evaluate efficacy, safety, and tolerability of the combination.
Name: Trastuzumab deruxtecan (DS-8201a)
Name: Trastuzumab deruxtecan (DS-8201a)
Name: Pembrolizumab
Description: Maximum Tolerated Dose (MTD) or recommended dose expansion (RDE) of DS-8201a (Part1) are based on the occurrence of DLTs.
Measure: Dose-limiting toxicities (DLTs), Part 1 Time: Within two 3-week cycles (6 weeks)Allocation: Non-Randomized
Parallel Assignment
There is one SNP
- Adequate organ function - Adequate treatment washout period before enrollment Inclusion Criteria Specific to Part 1 - Participants in Part 1 should meet the additional inclusion criteria listed for 1 of the 4 cohorts in Part 2. Inclusion Criteria Specific to Part 2 Inclusion Criteria for Cohort 1 - Pathologically documented, locally advanced/metastatic breast cancer that has centrally determined HER2-positive expression as per American Society of Clinical Oncology-College of American Pathologists (ASCO-CAP) Guidelines - Received prior trastuzumab emtansine (T-DM1) therapy with documented progression Inclusion Criteria for Cohort 2 - Pathologically documented, locally advanced/metastatic breast cancer that has centrally determined HER2-low expression (immunohistochemistry [IHC] 1+ or IHC 2+/in situ hybridization [ISH-]) - Participants must have exhausted treatments that can confer any clinically meaningful benefit (eg, other therapies such as hormonal therapy for participants who are hormone receptor positive) Inclusion Criteria for Cohort 3 - Pathologically documented, locally advanced/metastatic NSCLC that has centrally determined HER2-expression (IHC 1+, 2+, or 3+) - Participants who have known epidermal growth factor receptor (EGFR) mutation, anaplastic lymphoma kinase (ALK), BRAF V600E mutation, or ROS1 fusion should have disease progression after treatment with at least one genomically-targeted therapy for metastatic disease that are known to confer clinical benefit, or are intolerant to treatment, or refuse standard treatment Inclusion Criteria for Cohort 4 - Pathologically documented, locally advanced/metastatic HER2-mutant NSCLC - Participants who have known EGFR mutation, ALK, BRAF V600E mutation, or ROS1 fusion should have disease progression after treatment with available targeted therapies for metastatic disease that are known to confer clinical benefit, or are intolerant to treatment, or refuse standard treatment Exclusion Criteria: - Prior treatment with pembrolizumab or DS-8201a - Medical history of myocardial infarction within 6 months before enrollment, symptomatic congestive heart failure (New York Heart Association Class II to IV), troponin levels consistent with myocardial infarction as defined according to the manufacturer within 28 days prior to enrollment - Corrected QT interval (QTc) prolongation to >470 ms (females) or >450 ms (males) - History of (non-infectious) interstitial lung disease (ILD)/pneumonitis that required steroids, has current ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be ruled out by imaging at screening - Spinal cord compression or clinically active central nervous system metastases - Clinically significant corneal disease - Active, known or suspected autoimmune disease - Condition requiring systemic treatment with either corticosteroids (>10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 days of start of study treatment - Prior therapy with an anti-PD-1 or anti-PD-L1 agent - Prior therapy with an agent directed to another stimulatory or coinhibitory T-cell receptor (eg, CTLA-4, OX 40, CD137) and was discontinued from that treatment due to a Grade 3 or higher immune-related adverse event (irAE) - Prior anti-HER2 therapy is not allowed for participants with HER2 low-expressing breast cancer or participants with NSCLC (Cohorts 2, 3, or 4). --- V600E ---
- Adequate organ function - Adequate treatment washout period before enrollment Inclusion Criteria Specific to Part 1 - Participants in Part 1 should meet the additional inclusion criteria listed for 1 of the 4 cohorts in Part 2. Inclusion Criteria Specific to Part 2 Inclusion Criteria for Cohort 1 - Pathologically documented, locally advanced/metastatic breast cancer that has centrally determined HER2-positive expression as per American Society of Clinical Oncology-College of American Pathologists (ASCO-CAP) Guidelines - Received prior trastuzumab emtansine (T-DM1) therapy with documented progression Inclusion Criteria for Cohort 2 - Pathologically documented, locally advanced/metastatic breast cancer that has centrally determined HER2-low expression (immunohistochemistry [IHC] 1+ or IHC 2+/in situ hybridization [ISH-]) - Participants must have exhausted treatments that can confer any clinically meaningful benefit (eg, other therapies such as hormonal therapy for participants who are hormone receptor positive) Inclusion Criteria for Cohort 3 - Pathologically documented, locally advanced/metastatic NSCLC that has centrally determined HER2-expression (IHC 1+, 2+, or 3+) - Participants who have known epidermal growth factor receptor (EGFR) mutation, anaplastic lymphoma kinase (ALK), BRAF V600E mutation, or ROS1 fusion should have disease progression after treatment with at least one genomically-targeted therapy for metastatic disease that are known to confer clinical benefit, or are intolerant to treatment, or refuse standard treatment Inclusion Criteria for Cohort 4 - Pathologically documented, locally advanced/metastatic HER2-mutant NSCLC - Participants who have known EGFR mutation, ALK, BRAF V600E mutation, or ROS1 fusion should have disease progression after treatment with available targeted therapies for metastatic disease that are known to confer clinical benefit, or are intolerant to treatment, or refuse standard treatment Exclusion Criteria: - Prior treatment with pembrolizumab or DS-8201a - Medical history of myocardial infarction within 6 months before enrollment, symptomatic congestive heart failure (New York Heart Association Class II to IV), troponin levels consistent with myocardial infarction as defined according to the manufacturer within 28 days prior to enrollment - Corrected QT interval (QTc) prolongation to >470 ms (females) or >450 ms (males) - History of (non-infectious) interstitial lung disease (ILD)/pneumonitis that required steroids, has current ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be ruled out by imaging at screening - Spinal cord compression or clinically active central nervous system metastases - Clinically significant corneal disease - Active, known or suspected autoimmune disease - Condition requiring systemic treatment with either corticosteroids (>10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 days of start of study treatment - Prior therapy with an anti-PD-1 or anti-PD-L1 agent - Prior therapy with an agent directed to another stimulatory or coinhibitory T-cell receptor (eg, CTLA-4, OX 40, CD137) and was discontinued from that treatment due to a Grade 3 or higher immune-related adverse event (irAE) - Prior anti-HER2 therapy is not allowed for participants with HER2 low-expressing breast cancer or participants with NSCLC (Cohorts 2, 3, or 4). --- V600E --- --- V600E ---