Colorectal Neoplasms

Primary Objective: To compare progression-free survival (PFS) between treatment groups according to Response Evaluation Criteria in Solid Tumors 1.1 (RECIST v1.1) as assessed by blinded central independent review (BICR) Secondary Objectives: • To compare overall survival (OS) between treatment groups • To compare confirmed objective response rate (cORR) between treatment groups according to RECIST v1.1 as assessed by BICR • To assess PFS according to RECIST v1.1 as assessed by the trial sponsor (INV) • To assess cORR according to RECIST v1.1 as assessed by INV • To assess duration of response (DOR) according to RECIST v1.1 as assessed by BICR • To assess DOR as assessed by INV • To assess disease progression or death from any cause from randomization to next line of therapy (PFS2) time • Evaluate the overall safety of each treatment group • Evaluate the pharmacokinetics (PK) of tucatinib • Evaluate the changes from baseline in selected items of overall health status/quality of life (QoL), physical function, and appetite loss in each treatment group using the European Organization for Research and Treatment of Cancer Cancer Quality of Life 30 Core Questionnaire (EORTC QLQ-C30)

Tucatinib

Tucatinib

Film-coated tablet

50, 150

The primary efficacy endpoint of the trial is PFS per RECIST v1.1 as assessed by BICR. Key secondary efficacy endpoints are OS and cORR per RECIST v1.1 as assessed by BICR; other secondary efficacy endpoints will include PFS per RECIST v1.1 as assessed by INV, cORR per RECIST v1.1 as assessed by INV, DOR per BICR and INV, PFS2, safety, PK, and change from baseline and time to meaningful change in global health status/QoL, physical function, and decreased appetite as measured by EORTC QLQ-C30. Exploratory endpoints include biomarker assessments, assessment of the incidence and/or worsening of CNS metastases, PK of trastuzumab, and HRQoL as measured by EQ-5D-5L and the rest of the EORTC QLQ-C30 scales.

Inclusion Criteria:

Histologically and/or cytologically confirmed adenocarcinoma of the colon or rectum which is locally advanced unresectable or metastatic
Able to provide the most recently available formalin-fixed paraffin-embedded (FFPE) tumor tissue blocks (or freshly sectioned slides) obtained prior to treatment initiation to a central laboratory

If archival tissue is not available, a newly-obtained baseline biopsy of an accessible tumor lesion is required within 35 days prior to start of study treatment
HER2+ disease as determined by a tissue based assay performed at a central laboratory.
Participant has rat sarcoma viral oncogene homolog wild-type (RAS WT) disease as determined by local or central testing. For central RAS analysis, tissue sample must be analyzed within 1 year of biopsy date.
Radiographically measurable disease per RECIST v1.1 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 of 0 or 1
CNS Inclusion - based on contrast brain magnetic resonance imaging, participants may have any of the following:

No evidence of brain metastases
Previously treated brain metastases which are asymptomatic

Exclusion Criteria:

Prior systemic anticancer therapy for colorectal cancer (CRC) in the locally advanced unresectable or metastatic setting; note that participants may have received a maximum of 2 doses of mFOLFOX6 in the locally advanced/unresectable or metastatic setting prior to randomization.

Note: May have received chemotherapy for CRC in the adjuvant setting if it was completed >6 months prior to enrollment
Radiation therapy within 14 days prior to enrollment (or within 7 days in the setting of stereotactic radiosurgery)
Previous treatment with anti-HER2 therapy
Ongoing Grade 3 or higher neuropathy
Active or untreated gastrointestinal (GI) perforation at the time of screening.