Inclusion Criteria
- Histologically and/or cytologically documented adenocarcinoma of the colon or rectum
that is metastatic and/or unresectable
- Unless contraindicated, participants must have received and failed regimens containing
the following agents: fluoropyrimidine (e.g., 5-fluorouracil or capecitabine),
oxaliplatin, irinotecan, an anti-VEGF monoclonal antibody (bevacizumab, ramucirumab,
or ziv-aflibercept), and an anti-PD-(L)1 therapy (nivolumab or pembrolizumab) if tumor
has deficient mismatch repair proteins or is MSI-High.
- Have progression of unresectable or metastatic CRC after the last systemic therapy, or
be intolerant of last systemic therapy
- Have RAS wild-type in primary or metastatic tumor tissue, based on expanded RAS
testing
- Willing and able to provide the most recently available tissue blocks obtained prior
to treatment initiation. If archival tissue is not available, then a newly-obtained
baseline biopsy of an accessible tumor
- Have confirmed HER2-positive mCRC, as defined by having tumor tissue tested at a
Clinical Laboratory Improvement Act (CLIA)-certified or International Organization for
Standardization (ISO)-accredited laboratory, meeting at least one of the following
criteria:
- HER2+ overexpression (3+ immunohistochemistry [IHC]) by an FDA-approved or
Conformité Européene (CE)-marked HER2 ICH test
- HER2 2+ IHC is eligible if the tumor is amplified by an FDA-approved or CE-marked
HER2 in situ hybridization assay (FISH or chromogenic in situ hybridization
[CISH]))
- HER2 (ERBB2) amplification by CLIA-certified or ISO-accredited next generation
sequencing (NGS) sequencing assay
- Have radiographically measurable disease assessable by RECIST 1.1, with at least one
site of disease that is measurable and that has not been previously irradiated; or, if
the participant has had previous radiation to the target lesion(s), there must be
evidence of progression since the radiation
- Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0, 1, or 2
- Life expectancy greater than 3 months
- Have adequate hematological, hepatic, renal, coagulation, and cardiac function
Exclusion Criteria
- Previous treatment with anti-HER2 targeting therapy
- Previous treatment with any systemic anticancer therapy, non-central nervous system
radiation, or experimental agent within 3 weeks of first dose of study treatment
- Toxicity related to prior cancer therapies that has not resolved to ≤ Grade 1, with
the following exceptions:
- Alopecia and neuropathy, which must have resolved to ≤ Grade 2
- Congestive heart failure (CHF), which must have been ≤ Grade 1 in severity at the
time of occurrence, and must have resolved completely
- Anemia, which must have resolved to ≤ Grade 2
- Decreased ANC, which must have resolved to ≤ Grade 2
- Have clinically significant cardiopulmonary disease
- Have known myocardial infarction, unstable angina, cardiac or other vascular stenting,
angioplasty, or cardiac surgery within 6 months prior to first dose of study treatment
- Major surgical procedure, open biopsy, or significant traumatic injury ≤28 days prior
to enrollment (≤56 days for hepatectomy, open thoracotomy, or major neurosurgery) or
anticipation of need for major surgical procedure during the study
- Serious, non-healing wound, ulcer, or bone fracture
- Known to be positive for hepatitis B by surface antigen expression
- Known to have active hepatitis C infection
- Exception for participants with a documented sustained virologic response of 12
weeks
- Known to be positive for human immunodeficiency virus (HIV)
- Subjects who are pregnant, breastfeeding, or planning a pregnancy
- Inability to swallow pills or any significant gastrointestinal disease which would
preclude the adequate oral absorption of medications
- Have used strong CYP2C8 inhibitor within 5 half-lives of the inhibitor, or have used a
strong CYP2C8 or CYP3A4 inducer within 5 days prior to first dose of study treatment
- History of another malignancy within 3 years before the first dose of study drug, or
any evidence of residual disease from a previously diagnosed malignancy.
- Exceptions are malignancies with a negligible risk of metastasis or death
- Subjects with known active CNS metastasis
- Irradiated or resected lesions are permitted, provided the lesions are fully
treated and inactive, subject is asymptomatic, and no steroids have been
administered for at least 30 days
