A Study of Tucatinib vs. Placebo in Combination With Capecitabine & Trastuzumab in Patients With Advanced HER2+ Breast Cancer

HER2 Positive Breast Cancer Clinical Trial

— HER2CLIMB  

Official title:

Phase 2 Randomized, Double-Blinded, Controlled Study of Tucatinib vs Placebo in Combination With Capecitabine and Trastuzumab in Patients With Pretreated Unresectable Locally Advanced or Metastatic HER2+ Breast Carcinoma

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02614794
• Other study ID #: ONT-380-206
• Secondary ID: 2015-002801-12
• Status: Completed
• Phase: Phase 2
• Start date: January 28, 2016
• Est. completion date: August 11, 2022

Study information

• Verified date: July 2023
• Source: Seagen Inc.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This study is being done to see if tucatinib works better than placebo to help patients who have a specific type of breast cancer called HER2 positive breast carcinoma. The breast cancer in this study is either metastatic (spread into other parts of the body) or cannot be removed completely with surgery. All patients in the study will get capecitabine and trastuzumab, two drugs that are often used to treat this cancer.

There are two parts to this study. The first part of the study is already complete. Patients were randomly assigned to get either tucatinib or placebo (a pill with no medicine). Since this part was "blinded," neither patients nor their doctors knew whether a patient got tucatinib or placebo.

The second part of the study is called the Unblinded Phase. In this part of the study, participants and their doctors know which drugs are being given. Participants who used to get or are currently getting placebo may be able to start taking tucatinib instead.

Each treatment cycle lasts 21 days. Patients will swallow tucatinib pills two times every day. They will swallow capecitabine pills two times a day during the first two weeks of each cycle. Patients will get trastuzumab injections from the study site staff on the first day of every cycle.

Description:

This is a randomized, international, multi-center study in patients with progressive unresectable locally advanced or metastatic HER2+ breast cancer who have had prior treatment with trastuzumab, pertuzumab and T-DM1. There are two phases to this trial: the Double-blind Phase and the Unblinded Phase. In the Double-blind phase, participants were randomized in a 2:1 ratio to receive tucatinib or placebo in combination with capecitabine and trastuzumab. In the Unblinded Phase, patients on placebo may be offered tucatinib.

Stratification factors include presence or history of treated or untreated brain metastases or brain lesions of equivocal significance (yes/no), Eastern Cooperative Oncology Group (ECOG) Performance Status (0 vs. 1), and region of world (US vs. Canada vs. Rest of World).

Safety assessments will be performed at a minimum of once every three weeks throughout study treatment and 30 days after the last dose of study drugs. Laboratory assessments will be performed locally at sites. Left ventricular ejection fraction will be assessed by MUGA or ECHO at screening and once every 12 weeks thereafter.

For the blinded phase, contrast brain MRI was performed at baseline. Efficacy assessments (CT of chest, abdomen and pelvis at a minimum) utilized RECIST 1.1 and included patients with evaluable tumors defined as measurable target lesions and non-measurable non-target lesions. RECIST assessment was performed at baseline, every 6 weeks for the first 24 weeks, and then every 9 weeks thereafter. Repeat MRI of the brain was required on this same schedule only in those patients with brain metastases identified at baseline. All treatment decisions were made based upon investigator assessment. All patients underwent a repeat MRI of the brain within 30 days of the end of treatment unless previously performed at time of disease progression.

For the unblinded phase, RECIST assessments will be performed per standard clinical practice as determined by investigator with a maximum interval of 12 weeks.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 612
• Est. completion date: August 11, 2022
• Est. primary completion date: September 4, 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Double-blind Phase Inclusion Criteria

• Histologically confirmed HER2+ breast carcinoma, with HER2+ defined by in situ hybridization (ISH), immunohistochemistry (IHC), or fluorescence in situ hybridization (FISH) methodology

• Received previous treatment with trastuzumab, pertuzumab, and T-DM1

• Progression of unresectable locally advanced or metastatic breast cancer after last systemic therapy (as confirmed by investigator), or be intolerant of last systemic therapy

• Have measurable or non-measurable disease assessable by RECIST 1.1

• Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1

• Adequate hepatic and renal function and hematologic parameters

• Left ventricular ejection fraction (LVEF) = 50%

• CNS Inclusion - Based on screening brain magnetic resonance imaging (MRI), patients must have one of the following:

1. No evidence of brain metastases

2. Untreated brain metastases not needing immediate local therapy

3. Previously treated brain metastases not needing immediate local therapy

1. Brain metastases previously treated with local therapy may either be stable since treatment or may have progressed since prior local CNS therapy

2. Patients treated with CNS local therapy for newly identified lesions found on contrast brain MRI performed during screening for this study may be eligible to enroll if the following criteria are met:

i. Time since whole brain radiation therapy (WBRT) is = 21 days prior to first dose of study treatment, time since stereotactic radiosurgery (SRS) is = 7 days prior to first dose of study treatment, or time since surgical resection is = 28 days.

ii. Other sites of disease assessable by RECIST 1.1 are present

4. Relevant records of any CNS treatment must be available to allow for classification of target and non-target lesions

Double-blind Phase Exclusion Criteria

• Previously been treated with:

1. lapatinib within 12 months of starting study treatment (except in cases where lapatinib was given for = 21 days and was discontinued for reasons other than disease progression or toxicity)

2. neratinib, afatinib, or other investigational HER2/epidermal growth factor receptor (EGFR) or HER2 tyrosine kinase inhibitor (TKI) at any time previously

3. capecitabine (or other fluoropyrimidine) for metastatic disease except in cases where capecitabine was given for < 21 days and was discontinued for reasons other than disease progression or toxicity. Patients who have received capecitabine for adjuvant or neoadjuvant treatment at least 12 months prior to starting study treatment are eligible.

• Clinically significant cardiopulmonary disease

• Carriers of Hepatitis B or Hepatitis C or have other known chronic liver disease

• Positive for human immunodeficiency virus (HIV)

• Unable for any reason to undergo MRI of the brain

• Have used a strong CYP3A4 or CYP2C8 inhibitor within 5 half-lives of the inhibitor, or a strong CYP3A4 or CYP2C8 inducer within 5 days prior to first dose of study treatment

• Have known dihydropyrimidine dehydrogenase deficiency (DPD)

• CNS Exclusion - Based on screening brain MRI, patients must not have any of the following:

1. Any untreated brain lesions > 2.0 cm in size, unless approved by medical monitor

2. Ongoing use of systemic corticosteroids for control of symptoms of brain metastases at a total daily dose of > 2 mg of dexamethasone (or equivalent)

3. Any brain lesion thought to require immediate local therapy. Patients who undergo local treatment for such lesions identified by screening contrast brain MRI may still be eligible for the study based on criteria described under CNS inclusion criteria

4. Known or suspected leptomeningeal disease (LMD)

5. Poorly controlled seizures Unblinded Phase Crossover Inclusion Criteria - Participants who were randomized to the control arm (placebo + trastuzumab + capecitabine) must meet the following criteria to be eligible to crossover to the experimental arm.

• Have measurable or non-measurable disease assessable by RECIST 1.1

• For patients who were randomized to the control arm and on the long-term follow-up period at the time of crossover screening: have progression of unresectable locally advanced or metastatic breast cancer after last systemic therapy (as confirmed by investigator), or be intolerant of last systemic therapy.

• Have an ECOG Performance Status of 0 or 1

• Have a life expectancy of at least 6 months

• Have adequate hepatic and renal function and hematologic parameters

• Left ventricular ejection fraction (LVEF) = 50%

• CNS Inclusion - Based on screening brain magnetic resonance imaging (MRI), patients must have one of the following:

i. No evidence of brain metastases ii. Untreated brain metastases not needing immediate local therapy iii. Previously treated brain metastases not needing immediate local therapy

• Brain metastases previously treated with local therapy may either be stable since treatment or may have progressed since prior local CNS therapy

• Patients treated with CNS local therapy for newly identified lesions found on contrast brain MRI performed during screening for this study may be eligible to enroll if the following criteria are met:

1. Time since whole brain radiation therapy (WBRT) is = 21 days prior to first dose of study treatment, time since stereotactic radiosurgery (SRS) is = 7 days prior to first dose of study treatment, or time since surgical resection is = 28 days.

2. Other sites of disease assessable by RECIST 1.1 are present Unblinded Phase Crossover Exclusion Criteria - Participants who were randomized to the control arm (placebo + trastuzumab + capecitabine) will be excluded from the crossover to the experimental arm for any of the following reasons.

• Discontinuation of study treatment due to an adverse event while on the double-blind phase of the study. If the adverse event leading to discontinuation of study treatment has resolved, the patient may be allowed to crossover with approval from the medical monitor.

• History of exposure to the following cumulative doses of anthracyclines:

• Doxorubicin > 360 mg/m^2

• Epirubicin > 720 mg/m^2

• Mitoxantrone > 120 mg/m^2

• Idarubicin > 90 mg/m^2

• Liposomal doxorubicin > 550 mg/m^2

• History of allergic reactions to trastuzumab, capecitabine, or compounds chemically or biologically similar to tucatinib

o Exceptions for Grade 1 or 2 infusion related reactions to trastuzumab that were successfully managed, or known allergy to one of the excipients in the study drugs

• Have received treatment with any systemic anti-cancer therapy, non-CNS radiation, or experimental agent within 3 weeks prior to start of crossover therapy

• Any toxicity related to prior cancer therapies that has not resolved to = Grade 1, with the following exceptions:

• Alopecia and neuropathy (must have resolved to = Grade 2)

• CHF (must have been = Grade 1 in severity at the time of occurrence and must have resolved completely)

• Anemia (must have resolved to = Grade 2)

• Have clinically significant cardiopulmonary disease

• Have known myocardial infarction or unstable angina within 6 months prior to start of crossover therapy

• Require therapy with warfarin or other coumarin derivatives

• Inability to swallow pills or significant gastrointestinal disease which would preclude the adequate oral absorption of medications

• Have used a strong CYP2C8 inhibitor within 5 half-lives of the inhibitor or have used a strong CYP2C8 or CYP34A inducer within 5 days prior to start of the crossover (tucatinib) treatment.

• Known dihydropyrimidine dehydrogenase deficiency

• Unable to undergo contract MRI of the brain

• Have evidence within 2 years prior to start of crossover therapy of another malignancy that required systemic treatment

• CNS Exclusion:

• CNS Exclusion - Based on screening brain MRI, patients must not have any of the following:

• Any untreated brain lesions > 2.0 cm in size, unless approved by medical monitor

• Ongoing use of systemic corticosteroids for control of symptoms of brain metastases at a total daily dose of > 2 mg of dexamethasone (or equivalent)

• Any brain lesion thought to require immediate local therapy. Patients who undergo local treatment for such lesions identified by screening contrast brain MRI may still be eligible for the study based on criteria described under CNS inclusion criteria

• Known or suspected leptomeningeal disease (LMD)

• Poorly controlled seizures

Related Conditions & MeSH terms

• Breast Neoplasms
• HER2 Positive Breast Cancer

Intervention

Drug:
• tucatinib
300 mg orally twice daily
• capecitabine
1000 mg/m2 orally twice daily on Days 1-14 of each 21-day cycle
• trastuzumab
8 mg/kg intravenously (IV) on Day 1 of Cycle 1, followed by 6 mg/kg on Day1 of each 21-day cycle. In regions where approved, trastuzumab may be given at 600mg subcutaneously once every 3-weeks at either study initiation or crossing over from previous IV trastuzumab.
• placebo
Oral dose twice daily

Locations

Country	Name	City	State
Australia	Austin Hospital	Heidelberg
Australia	Cabrini Education and Research Precinct	Malvern
Australia	Peter MacCallum Cancer Centre	Melbourne
Australia	Breast Cancer Research Centre	Nedlands
Australia	Mater Hospital	North Sydney
Australia	Icon Cancer Care South Brisbane	South Brisbane
Australia	Mater Health Services	South Brisbane
Australia	Sunshine Hospital	St Albans
Australia	Westmead Hospital	Westmead
Austria	LKH- Universitat Klinikum Graz	Graz
Austria	Medizinische Universitat Innsbruck	Innsbruck
Austria	KH d. Barmherzigen Schwestern Linz	Linz
Austria	LKH Salzburg, Universitatsklinikum der PMU	Salzburg
Belgium	AZ Klina	Brasschaat
Belgium	Cliniques Universitaires Saint Luc	Brussels
Belgium	Grand Hopital de Charleroi	Charleroi
Belgium	Centre Hospitalier de l'Ardenne	Libramont
Belgium	CHU UCL Namur-Site de Saint Elisabeth	Namur
Canada	Tom Baker Cancer Centre	Calgary
Canada	University of Alberta / Cross Cancer Institute	Edmonton
Canada	Queen Elizabeth II Health Sciences Centre	Halifax
Canada	Jewish General Hospital	Montreal
Canada	Hopital du Saint-Sacrement, CHU de Quebec-Universite Laval	Quebec
Canada	Allan Blair Cancer Centre	Regina
Canada	Saskatoon Cancer Centre	Saskatoon
Canada	H. Bliss Murphy Cancer Centre	St John's
Canada	Sunnybrook Health Sciences Centre	Toronto
Canada	University Health Network, Princess Margaret Hospital	Toronto
Canada	British Columbia Cancer Agency - Vancouver Centre	Vancouver
Czechia	Fakultni nemocnice Hradec Kralove-oddeleni klinicke hematologie	Hradec Kralove
Czechia	Fakultni Nemocnice Olomouc (Fnol) - Onkologicka Klinika	Olomouc
Denmark	Aalborg Universitetshospital	Aalborg
Denmark	Rigs Hospiltalet	Copenhagen
Denmark	Herlev Hospital	Herlev
Denmark	Odense University Hospital	Odense C
Denmark	Sygehus Lillebaelt - Vejle Sygehus	Vejle
France	University Hospital of Besancon	Besancon cedex
France	Clinique Victor Hugo	Le Mans
France	Centre Leon Berard - Centre regional de lutte contre le cancer Rhone-Alpes	Lyon
France	Institut Paoli Calmettes	Marseille
France	Institute Curie - Centre de Lutte Contre Le Cancer CLCC de Paris	Paris
France	Centre Hospitalier Lyon Sud	Pierre Bénite Cedex
France	Institut Jean Godinot	REIMS Cedex
France	Centre Eugene Marquis	Rennes Cedex
France	Hopitaux Universitaires de Strasbourg	Strasbourg
France	Institut Claudius Regaud	Toulouse Cedex 9
France	CHU Tours - Hopital Bretonneau	TOURS Cedex 09
Germany	Charite Universitatsmedizin Berlin	Berlin
Germany	Kliniken Essen-Mitte - Evang. Huyssens-Stiftung	Essen
Germany	Universitaetsklinikum Hamburg-Eppendorf (UKE) - Onkologisches Zentrum - Interdisziplinaere Klinik und Poliklinik fuer Stammzelltransplantation	Hamburg
Germany	Medizinische Hochschule Hannover	Hannover
Germany	Universitatsklinikum Schleswig-Holstein	Kiel
Germany	InVO- Institut fUr Versorgungsforschung in der onkologie GbR	Koblenz
Germany	Universitatsklinikum Koln	Köln
Germany	HOPE- Onkologisches Zentrum Rotkreuzklinikum	Munchen
Germany	Sana Klinikum Offenbach GmbH	Offenbach am Main
Israel	Rambam Health Corp.	Haifa
Israel	Hadassah Medical Center	Jerusalem
Israel	Meir Medical Center	Kfar Saba
Israel	Rabin Medical Center	Petach Tikva
Israel	Kaplan Medical Center	Rehovot
Israel	Tel Aviv Sourasky Medical Center	Tel Aviv
Israel	Sheba Medical Center	Tel Hashomer
Italy	Azienda Ospedaliero-Universitaria di Bologna Policlinico S. Orsola-Malpighi	Bologna
Italy	Ospedale di Bolzano	Bolzano
Italy	Presido Ospedaliero- Senatore Antonio Perrino	Brindisi
Italy	Ospedale Ramazzini di Carpi	Carpi
Italy	Ospedale Policlinico San Martino	Genova
Italy	Istituto Europeo di Oncologia	Milano
Italy	IRCSS Policlinico San Matteo	Pavia
Italy	Azienda Ospedaliera S. Maria di Terni	Terni
Italy	A.O.U. - Ospedali Riuniti di Ancona	Torrette
Portugal	Hospital Cuf Descobertas R. Mario Botas Parque das Nacoes	Lisboa
Portugal	Centro Hospitalar do Porto - Hospital Santo Antonio	Porto
Spain	Hospital Clinic i Provincial de Barcelona	Barcelona
Spain	Hospital Universitario Vall d'Hebron	Barcelona
Spain	Hospital San Pedro de Alcantara	Caceres
Spain	Complejo Asistencial Universitario de Leon	Leon
Spain	Hospital General Universitario Gregorio Marañon	Madrid
Spain	Hospital Universitario 12 de Octubre	Madrid
Spain	Hospital Son Espases	Palma de Mallorca
Spain	Hospital Clinico Univ De Santiago De Compostela	Santiago de Compostela
Spain	Hospital Arnau De Vilanova	Valencia
Spain	Hospital Clinico Universitario Lozano Blesa de Zaragoza	Zaragoza
Switzerland	Institute of Oncology of Southern Switzerland	Bellinzona
United Kingdom	Colchester Hospital University NHS Foundation Trust	Colchester
United Kingdom	Sarah Cannon Research Institute UK	London
United Kingdom	The Royal Marsden Hospital	London
United Kingdom	The Christie NHS Foundation Trust	Manchester
United Kingdom	Mount Vernon Hospital, UK	Northwood
United Kingdom	Nottingham University Hospitals NHS Trust	Nottingham
United Kingdom	Peterborough City Hospital	Peterborough
United Kingdom	Weston Park Hospital- UK	Sheffield
United Kingdom	The Royal Marsden Hospital (Surrey)	Sutton
United Kingdom	Royal Cornwall Hospitals NHS Trust	Truro
United States	Northside Hospital	Atlanta	Georgia
United States	Winship Cancer Institute / Emory University School of Medicine	Atlanta	Georgia
United States	Augusta University	Augusta	Georgia
United States	University of Colorado Hospital / University of Colorado	Aurora	Colorado
United States	Texas Oncology - Austin Midtown	Austin	Texas
United States	University of Maryland	Baltimore	Maryland
United States	University of Alabama at Birmingham	Birmingham	Alabama
United States	Dana Farber Cancer Institute	Boston	Massachusetts
United States	Montefiore Medical Center	Bronx	New York
United States	UNC Lineberger Comprehensive Cancer Center / University of North Carolina	Chapel Hill	North Carolina
United States	Medical University of South Carolina/Hollings Cancer Center	Charleston	South Carolina
United States	Roper St. Francis Healthcare	Charleston	South Carolina
United States	Rush University Medical Center	Chicago	Illinois
United States	University of Chicago	Chicago	Illinois
United States	James Cancer Hospital / Ohio State University	Columbus	Ohio
United States	Texas Oncology Methodist	Dallas	Texas
United States	Texas Oncology - Denton South	Denton	Texas
United States	Henry Ford Health System	Detroit	Michigan
United States	City of Hope National Medical Center	Duarte	California
United States	Duke University Medical Center	Durham	North Carolina
United States	Virginia Cancer Specialists, PC	Fairfax	Virginia
United States	Florida Cancer Specialists - South Region	Fort Myers	Florida
United States	The Center for Cancer and Blood Disorders: Fortworth	Fort Worth	Texas
United States	Cancer Treatment Centers of America - Phoenix	Goodyear	Arizona
United States	Leo W. Jenkins Cancer Services / Brody School of Medicine East Carolina University	Greenville	North Carolina
United States	Hackensack University Medical Center	Hackensack	New Jersey
United States	Memorial Regional Hospital TRIO	Hollywood	Florida
United States	Baylor Clinic	Houston	Texas
United States	MD Anderson Cancer Center / University of Texas	Houston	Texas
United States	Texas Oncology - Houston Memorial City	Houston	Texas
United States	Baptist MD Anderson Cancer Center	Jacksonville	Florida
United States	Saint Luke's Cancer Institute LLC	Kansas City	Missouri
United States	Wellmont Cancer Institute	Kingsport	Tennessee
United States	Dartmouth-Hitchcock Medical Center/ Norris Cotton Cancer Center	Lebanon	New Hampshire
United States	TRIO - Central Regulatory Office	Los Angeles	California
United States	UCLA Medical Center / David Geffen School of Medicine	Los Angeles	California
United States	Joe Arrington Cancer Research and Treatment Center	Lubbock	Texas
United States	Carbone Cancer Center / University of Wisconsin	Madison	Wisconsin
United States	University of Miami	Miami	Florida
United States	Mount Sinai Medical Center / Florida	Miami Beach	Florida
United States	Virginia Piper Cancer Institute	Minneapolis	Minnesota
United States	University of South Alabama - Mitchell Cancer Institute	Mobile	Alabama
United States	Tennessee Oncology - Nashville	Nashville	Tennessee
United States	Vanderbilt University Medical Center	Nashville	Tennessee
United States	Yale Cancer Center	New Haven	Connecticut
United States	Mount Sinai Beth Israel	New York	New York
United States	New York University (NYU) Cancer Institute	New York	New York
United States	Cancer Treatment Centers of America	Newnan	Georgia
United States	Illinois Cancer Specialists / Advocate Lutheran General Hospital	Niles	Illinois
United States	Nebraska Cancer Specialists	Omaha	Nebraska
United States	Orlando Health, Inc. TRIO	Orlando	Florida
United States	Paris Regional Medical Center / US Oncology	Paris	Texas
United States	Cancer Treatment Centers of America / Eastern Regional Medical Center	Philadelphia	Pennsylvania
United States	University of Pennsylvania / Perelman Center for Advanced Medicine	Philadelphia	Pennsylvania
United States	Arizona Oncology Associates, PC - HAL	Phoenix	Arizona
United States	Texas Oncology - Plano East	Plano	Texas
United States	Oregon Health and Science University	Portland	Oregon
United States	Providence Portland Medical Center	Portland	Oregon
United States	Torrance Memorial Physician Network - TRIO	Redondo Beach	California
United States	Maryland Oncology Hematology, P.A.	Rockville	Maryland
United States	William Beaumont Hospital	Royal Oak	Michigan
United States	Florida Cancer Specialists - North Region	Saint Petersburg	Florida
United States	University of Utah	Salt Lake City	Utah
United States	Texas Oncology - San Antonio Medical Center Northeast	San Antonio	Texas
United States	University of Texas Health Science Center at San Antonio	San Antonio	Texas
United States	University of California at San Francisco	San Francisco	California
United States	Kaiser Permanente San Marcos Medical Offices	San Marcos	California
United States	Central Coast Medical Oncology Corporation TRIO	Santa Maria	California
United States	Seattle Cancer Care Alliance / University of Washington	Seattle	Washington
United States	Swedish Cancer Institute	Seattle	Washington
United States	Stony Brook University Cancer Center	Stony Brook	New York
United States	H. Lee Moffitt Cancer Center and Research Institute	Tampa	Florida
United States	US Oncology Central Regulatory	The Woodlands	Texas
United States	Northwest Cancer Specialists, P.C.	Tualatin	Oregon
United States	Carle Cancer Center	Urbana	Illinois
United States	Kaiser Permanente Medical Center Northern California	Vallejo	California
United States	Lombardi Cancer Center / Georgetown University Medical Center	Washington	District of Columbia
United States	Texas Oncology - Deke Slayton Cancer Center	Webster	Texas
United States	Florida Cancer Specialists - East West Palm Beach, FL (SCRI)	West Palm Beach	Florida
United States	University of Kansas Cancer Center	Westwood	Kansas
United States	Shenandoah Oncology P.C.	Winchester	Virginia

Sponsors (1)

Lead Sponsor	Collaborator
Seagen Inc.

Countries where clinical trial is conducted

United States,  Australia,  Austria,  Belgium,  Canada,  Czechia,  Denmark,  France,  Germany,  Israel,  Italy,  Portugal,  Spain,  Switzerland,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Progression-free Survival (PFS) Per RECIST 1.1 as Determined by Blinded Independent Central Review (BICR)	Defined as the time from the date of randomization to the date of documented disease progression.	34.6 months
Secondary	PFS in Patients With Brain Metastases at Baseline Using RECIST 1.1 as Determined by BICR	Defined as the time from the date of randomization to the date of documented disease progression.	34.6 months
Secondary	Overall Survival (OS) at Time of Primary Analysis	Defined as time from randomization to death from any cause	35.9 months
Secondary	Confirmed Objective Response Rate (ORR) Per RECIST 1.1 as Determined by BICR	Defined as achieving a best overall response of confirmed complete response (CR) or confirmed partial response (PR).	34.6 months
Secondary	ORR Per RECIST 1.1 as Determined by Investigator Assessment	Defined as achieving a best overall response of confirmed CR or confirmed PR.	34.6 months
Secondary	PFS Per RECIST 1.1 as Determined by Investigator Assessment at Time of Primary Analysis	Defined as the time from the date of randomization to the date of documented disease progression	34.6 months
Secondary	Duration of Response (DOR) Per RECIST 1.1 as Determined by BICR	Defined as the time from the first objective response to documented disease progression or death from any cause, whichever occurred first.	24.6 months
Secondary	DOR Per RECIST 1.1 as Determined by Investigator Assessment	Defined as the time from the first objective response to documented disease progression or death from any cause, whichever occurred first.	33.2 months
Secondary	Clinical Benefit Rate (CBR) as Determined by BICR Per RECIST 1.1	Clinical benefit was defined as achieving stable disease (SD) or non-complete response (CR)/non-progressive disease (PD) for at least 6 months or a best overall response of confirmed CR or confirmed partial response (PR).	34.6 months
Secondary	CBR Per RECIST 1.1 as Determined by Investigator Assessment	Clinical benefit was defined as achieving stable disease (SD) or non-CR/non-PD for at least 6 months or a best overall response of confirmed CR or confirmed PR.	34.6 months
Secondary	Incidence of Adverse Events (AEs) at Time of Primary Analysis	As determined by assessment of AEs, clinical laboratory tests, and vital signs measurements. AEs were classified by system organ class (SOC) and preferred term using the Medical Dictionary for Regulatory Activities (MedDRA) Version 22.0 or higher; AE severities were classified using Version 4.03 of the (Common Terminology Criteria for Adverse Events) CTCAE criteria.	36.1 months
Secondary	Frequency of Dose Modifications		35.1 months
Secondary	Incidence of Health Resources Utilization	Cumulative incidence of health resource utilization, including length of stay, hospitalizations, and ER visits using the EQ-5D-5L questionnaire.	36.1 months
Secondary	Pharmacokinetic Measure: Ctrough of Tucatinib	Individual plasma tucatinib concentrations at each sampling time	3.5 months
Secondary	Pharmacokinetic Measure: ONT-993	Individual plasma primary metabolite concentrations at each sampling time	3.5 months
Secondary	Overall Survival (OS) at Time of Final Analysis	Defined as time from randomization to death from any cause	Up to 60.1 months
Secondary	PFS Per RECIST 1.1 as Determined by Investigator Assessment at Time of Final Analysis	Defined as the time from the date of randomization to the date of documented disease progression	Up to 58.0 months
Secondary	Incidence of Adverse Events (AEs) at Time of Final Analysis	As determined by assessment of AEs, clinical laboratory tests, and vital signs measurements. AEs were classified by system organ class (SOC) and preferred term using the Medical Dictionary for Regulatory Activities (MedDRA) Version 22.0 or higher; AE severities were classified using Version 4.03 of the (Common Terminology Criteria for Adverse Events) CTCAE criteria.	Up to 60.1 months
Secondary	Frequency of Dose Modifications at Time of Final Analysis		Up to 60.1 months