Targeted Treatment for ALK Positive Patients Who Have Previously Been Treated for Non-squamous Non-small Cell Lung Cancer

Stage IV Lung Cancer AJCC v8 Clinical Trial

Official title:

A Biomarker-Driven Protocol for Previously Treated ALK-Positive Non-Squamous NSCLC Patients: The NCI-NRG ALK Protocol

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT03737994
• Other study ID #: NCI-2018-02486
• Secondary ID: NCI-2018-02486NR
• Status: Active, not recruiting
• Phase: Phase 2
• Start date: July 25, 2019
• Est. completion date: September 21, 2024

Study information

• Verified date: March 2024
• Source: National Cancer Institute (NCI)
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This National Cancer Institute (NCI)-NRG ALK Protocol phase II trial studies how well a combination of different biomarker/ALK inhibitors work in treating patients with stage IV ALK positive non-squamous non-small cell lung cancer. Lorlatinib, ceritinib, alectinib, brigatinib, ensartinib, and crizotinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as pemetrexed, cisplatin, and carboplatin, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. It is not yet known whether a combination of biomarker/ALK inhibitors or chemotherapy may work better in treating patients with ALK positive non-squamous non-small cell lung cancer.

Description:

PRIMARY OBJECTIVES:

I. To assess whether ALK kinase domain mutations (G1202/C1156Y/I1171/L1196/ V1180/ F1174/compound mutation) associated with drug resistance are prognostic for objective response to subsequent ALK inhibitor therapy.

II. To assess whether subsequent pemetrexed based chemotherapy improves objective response comparing to ALK inhibitor therapy for no ALK mutation patients.

III. To evaluate objective responses of patients with specific genetic alterations (ALKL1198F/MET double mutation or high-level MET gene amplification) treated with crizotinib.

SECONDARY OBJECTIVES:

I. Progression-free survival (PFS). II. Duration of response (DOR). III. Overall survival (OS). IV. Intracranial objective response rate (ORR). V. Safety and tolerability.

CORRELATIVE SCIENCE OBJECTIVE:

I. Establish concordance between tumor and liquid biopsies.

OUTLINE:

Patients with a G1202R or G1202del mutation receive either lorlatinib orally (PO) once daily (QD) or brigatinib PO QD. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.

Patients with a C1156Y mutation receive either lorlatinib PO QD, brigatinib PO QD, or alectinib PO twice daily (BID). Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.

Patients with a I1171 mutation receive either lorlatinib PO QD, ceritinib PO QD, or brigatinib PO QD. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.

Patients with a L1196 mutation receive either lorlatinib PO QD, brigatinib PO QD, ensartinib PO QD, alectinib PO BID, or ceritinib PO QD. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.

Patients with a V1180 mutation receive either lorlatinib PO QD, brigatinib PO QD, or ceritinib PO QD. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.

Patients with a F1174 mutation receive either alectinib PO BID, lorlatinib PO QD, or brigatinib PO QD. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.

Patients with a compound mutation receive lorlatinib PO QD. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.

Patients with an ALK L1198F mutation alone or with another mutation, and patients with high level MET amplification receive crizotinib PO BID. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.

Patients with no ALK-resistant mutations receive either lorlatinib PO QD, ceritinib PO QD, alectinib PO BID, brigatinib PO QD, or ensartinib PO QD, or pemetrexed intravenously (IV) over 10 minutes on day 1 and either cisplatin IV or carboplatin IV on day 1. ALK inhibitor cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Pemetrexed-based treatment repeats every 21 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Maintenance treatment of pemetrexed may continue until disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 30 days, every 3 months for 2 years, every 6 months for 3 years, and annually thereafter.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 10
• Est. completion date: September 21, 2024
• Est. primary completion date: July 21, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• PRIOR TO STEP 1 REGISTRATION

• Patients must have histologically or cytologically confirmed stage IV ALK-positive non-squamous non-small cell lung carcinoma (NSCLC) (includes M1a, M1b, M1c stage disease, American Joint Committee on Cancer [AJCC] 8th edition). ALK rearrangement must have been demonstrated by a Food and Drug Administration (FDA) approved assay (Vysis fluorescence in situ hybridization [FISH] or Ventana immunohistochemistry [IHC]) or by next generation sequencing (NGS)

• Patient must be willing and able to undergo a fresh biopsy or if patient has a biopsy after progression on current tyrosine-kinase inhibitor (TKI) within 3 months of study enrollment (and has continued TKI for clinical benefit per treating physician) this tissue may be used. Must have sufficient tissue

• Patient must have progressive disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 after one second generation ALK inhibitor, including LDK378 (ceritinib), alectinib, ensartinib, and brigatinib (may not have received more than one second-generation ALK inhibitor). Patient may have received prior crizotinib; however, the second generation ALK inhibitor received must be the last treatment given prior to study enrollment

• Prior lorlatinib (third-generation ALK inhibitor) is not allowed

• Prior chemotherapy is not allowed except for one prior cycle received at the time of original diagnosis of metastatic NSCLC with no evidence of disease progression following the cycle. NOTE: prior adjuvant or neoadjuvant chemotherapy is allowed if last dose was received more than 12 months prior to enrollment

• The patient or a legally authorized representative must provide study-specific informed consent prior to Step 1 Registration

• PRIOR TO STEP 2 REGISTRATION

• Absolute neutrophil count (ANC) >= 1500 cells/mm^3 (within 28 days prior to step 2 registration)

• Platelets >= 100,000 cells/mm^3 (within 28 days prior to step 2 registration)

• Estimated creatinine clearance >= 60 mL/min by the Cockcroft Gault formula (within 28 days prior to step 2 registration)

• Total bilirubin =< 1.5 x upper limit of normal (ULN) (except for patients with documented Gilbert's syndrome) (within 28 days prior to step 2 registration)

• Aspartate aminotransferase (AST) =< 2.5 x ULN; =< 5 x ULN if liver metastases are present (within 28 days prior to step 2 registration)

• Alanine aminotransferase (ALT) =< 2.5 x ULN; =< 5 x ULN if liver metastases are present (within 28 days prior to step 2 registration)

• Patients with asymptomatic treated or untreated brain metastases are eligible. Treated brain metastases are eligible as long as patients have measurable disease outside the brain according to RECIST 1.1. Patients must be on a stable or decreasing dose of steroids for at least 7 days prior to step 2 registration. Anticonvulsants are allowed as long as the patient is neurologically stable and not deteriorating

• Patients enrolled with asymptomatic brain metastases (mets) must have at least one measurable target extracranial lesion according to RECIST 1.1

• Eastern Cooperative Oncology Group (ECOG) performance status 0-2

• Acute effects of any prior therapy resolved to baseline severity or to Common Terminology Criteria for Adverse Events (CTCAE) grade =< 1 (except for alopecia, hearing loss)

• Not taking any medications that may interact with selected study medication based on stratification

• Patients must be able to take oral medications (i.e. swallow whole tablets/capsules)

• All females of childbearing potential must have a blood test or urine study within 14 days prior to Step 2 Registration to rule out pregnancy. A female of childbearing potential is any woman, regardless of sexual orientation or whether they have undergone tubal ligation, who meets the following criteria:

• Has not undergone a hysterectomy or bilateral oophorectomy; or

• Has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months)

• Women must not be pregnant or breast-feeding due to potential harm to the fetus or infant from ALK inhibitors and the unknown risk. Women of childbearing potential and sexually active males must agree to use an accepted and effective method of contraception or to abstain from sexual intercourse for the duration of their participation in the study

Exclusion Criteria:

• Major surgery within 2 weeks of study entry. Minor surgical procedures (e.g., port insertion, pleurex catheter placement) are allowed and all wounds must not show signs of infection or draining

• Palliative RT (< 10 fractions) must have been completed at least 48 hours prior to study entry. Stereotactic or small field brain irradiation must have completed at least 1 week prior to study entry. Whole brain RT or other palliative RT must have been completed at least 2 weeks prior to study entry

• Prior dose of next generation ALK inhibitor (LDK378 [ceritinib], alectinib, ensartinib, lorlatinib) within 5 days prior to step 2 registration. Prior dose of brigatinib within 7 days prior to step 2 registration

• History of interstitial lung disease or interstitial fibrosis, including a history of pneumonitis, obliterative bronchiolitis, pulmonary fibrosis. Patients with a history of prior radiation pneumonitis are not excluded

• Active inflammatory gastrointestinal disease (such as Crohns, ulcerative colitis), chronic diarrhea, symptomatic diverticular disease, or any gastrointestinal disease that would affect the absorption of oral medications or increase the risk of toxicity

• Clinically significant cardiovascular abnormalities, as determined by the treating/registering physician, such as uncontrolled hypertension, congestive heart failure New York Heart Association (NYHA) classification of 3, unstable angina or poorly controlled arrhythmia, or myocardial infarction within 6 months

• Active and clinically significant bacterial, fungal, or viral infection

• Patients with active or chronic pancreatitis based on lipase elevation, symptoms, and radiographic findings

• Other concomitant serious illness or organ system dysfunction that in the opinion of the investigator would either compromise patient safety or interfere with the evaluation of the safety of the study drug

• Patients must not plan to receive any other investigational agents during the course of therapy

• Patients with active malignancy other than ALK-positive non-squamous NSCLC within the last 2 years are excluded (note: adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, papillary thyroid cancer treated with curative intent, adequately treated stage I or II cancer from which the patient is currently in complete remission, or any other cancer from which the patient has been disease free for 2 years are eligible)

• No chemotherapy and/or immunotherapy allowed after step 1 registration

Related Conditions & MeSH terms

• Carcinoma, Non-Small-Cell Lung
• Lung Neoplasms
• Lung Non-Squamous Non-Small Cell Carcinoma
• Stage IV Lung Cancer AJCC v8
• Stage IVA Lung Cancer AJCC v8
• Stage IVB Lung Cancer AJCC v8

Intervention

Drug:
• Alectinib
Given PO
• Brigatinib
Given PO
• Carboplatin
Given IV
• Ceritinib
Given PO
• Cisplatin
Given IV
• Crizotinib
Given PO
• Ensartinib
Given PO
• Lorlatinib
Given PO
• Pemetrexed
Given IV

Locations

Country	Name	City	State
United States	Hawaii Cancer Care - Westridge	'Aiea	Hawaii
United States	Pali Momi Medical Center	'Aiea	Hawaii
United States	Queen's Cancer Center - Pearlridge	'Aiea	Hawaii
United States	The Cancer Center of Hawaii-Pali Momi	'Aiea	Hawaii
United States	Riverwood Healthcare Center	Aitkin	Minnesota
United States	Lehigh Valley Hospital-Cedar Crest	Allentown	Pennsylvania
United States	UPMC Altoona	Altoona	Pennsylvania
United States	Mary Greeley Medical Center	Ames	Iowa
United States	McFarland Clinic - Ames	Ames	Iowa
United States	Community Hospital of Anaconda	Anaconda	Montana
United States	Kaiser Permanente-Anaheim	Anaheim	California
United States	Trinity Health Saint Joseph Mercy Hospital Ann Arbor	Ann Arbor	Michigan
United States	Kaiser Permanente-Deer Valley Medical Center	Antioch	California
United States	Mission Hope Medical Oncology - Arroyo Grande	Arroyo Grande	California
United States	Duluth Clinic Ashland	Ashland	Wisconsin
United States	Northwest Wisconsin Cancer Center	Ashland	Wisconsin
United States	Emory Saint Joseph's Hospital	Atlanta	Georgia
United States	Emory University Hospital Midtown	Atlanta	Georgia
United States	Emory University Hospital/Winship Cancer Institute	Atlanta	Georgia
United States	Grady Health System	Atlanta	Georgia
United States	Northside Hospital	Atlanta	Georgia
United States	Rush - Copley Medical Center	Aurora	Illinois
United States	UCHealth University of Colorado Hospital	Aurora	Colorado
United States	GenesisCare USA - Aventura FP	Aventura	Florida
United States	Saint Alphonsus Cancer Care Center-Baker City	Baker City	Oregon
United States	Kaiser Permanente-Baldwin Park	Baldwin Park	California
United States	Saint Louis Cancer and Breast Institute-Ballwin	Ballwin	Missouri
United States	Johns Hopkins University/Sidney Kimmel Cancer Center	Baltimore	Maryland
United States	Saint Agnes Hospital	Baltimore	Maryland
United States	Eastern Maine Medical Center	Bangor	Maine
United States	Flaget Memorial Hospital	Bardstown	Kentucky
United States	Indu and Raj Soin Medical Center	Beavercreek	Ohio
United States	Kaiser Permanente-Bellflower	Bellflower	California
United States	Strecker Cancer Center-Belpre	Belpre	Ohio
United States	Sanford Joe Lueken Cancer Center	Bemidji	Minnesota
United States	UPMC Cancer Center-Bethel Park	Bethel Park	Pennsylvania
United States	Lehigh Valley Hospital - Muhlenberg	Bethlehem	Pennsylvania
United States	Billings Clinic Cancer Center	Billings	Montana
United States	Sanford Bismarck Medical Center	Bismarck	North Dakota
United States	Illinois CancerCare-Bloomington	Bloomington	Illinois
United States	Saint Elizabeth Boardman Hospital	Boardman	Ohio
United States	GenesisCare USA - Boca Ration FP06	Boca Raton	Florida
United States	GenesisCare USA - Boca Raton FP02	Boca Raton	Florida
United States	Saint Alphonsus Cancer Care Center-Boise	Boise	Idaho
United States	Parkland Health Center-Bonne Terre	Bonne Terre	Missouri
United States	McFarland Clinic - Boone	Boone	Iowa
United States	Massachusetts General Hospital Cancer Center	Boston	Massachusetts
United States	Bozeman Health Deaconess Hospital	Bozeman	Montana
United States	Essentia Health Saint Joseph's Medical Center	Brainerd	Minnesota
United States	Cox Cancer Center Branson	Branson	Missouri
United States	Harrison HealthPartners Hematology and Oncology-Bremerton	Bremerton	Washington
United States	Lafayette Family Cancer Center-EMMC	Brewer	Maine
United States	Trinity Health IHA Medical Group Hematology Oncology - Brighton	Brighton	Michigan
United States	Trinity Health Medical Center - Brighton	Brighton	Michigan
United States	Henry Ford Cancer Institute-Downriver	Brownstown	Michigan
United States	Saint Joseph Regional Cancer Center	Bryan	Texas
United States	Bryn Mawr Hospital	Bryn Mawr	Pennsylvania
United States	Highline Medical Center-Main Campus	Burien	Washington
United States	Fairview Ridges Hospital	Burnsville	Minnesota
United States	Minnesota Oncology - Burnsville	Burnsville	Minnesota
United States	Saint Alphonsus Cancer Care Center-Caldwell	Caldwell	Idaho
United States	Cambridge Medical Center	Cambridge	Minnesota
United States	Illinois CancerCare-Canton	Canton	Illinois
United States	Trinity Health IHA Medical Group Hematology Oncology - Canton	Canton	Michigan
United States	Trinity Health Medical Center - Canton	Canton	Michigan
United States	Saint Francis Medical Center	Cape Girardeau	Missouri
United States	Southeast Cancer Center	Cape Girardeau	Missouri
United States	Memorial Hospital of Carbondale	Carbondale	Illinois
United States	Caro Cancer Center	Caro	Michigan
United States	SIH Cancer Institute	Carterville	Illinois
United States	Illinois CancerCare-Carthage	Carthage	Illinois
United States	Dayton Physicians LLC-Miami Valley South	Centerville	Ohio
United States	Miami Valley Hospital South	Centerville	Ohio
United States	Centralia Oncology Clinic	Centralia	Illinois
United States	Christiana Care Health System-Concord Health Center	Chadds Ford	Pennsylvania
United States	University of Virginia Cancer Center	Charlottesville	Virginia
United States	Memorial Hospital	Chattanooga	Tennessee
United States	Chelsea Hospital	Chelsea	Michigan
United States	Trinity Health IHA Medical Group Hematology Oncology - Chelsea Hospital	Chelsea	Michigan
United States	University of Illinois	Chicago	Illinois
United States	Adena Regional Medical Center	Chillicothe	Ohio
United States	Bethesda North Hospital	Cincinnati	Ohio
United States	Good Samaritan Hospital - Cincinnati	Cincinnati	Ohio
United States	Oncology Hematology Care Inc-Kenwood	Cincinnati	Ohio
United States	TriHealth Cancer Institute-Anderson	Cincinnati	Ohio
United States	TriHealth Cancer Institute-Westside	Cincinnati	Ohio
United States	University of Cincinnati Cancer Center-UC Medical Center	Cincinnati	Ohio
United States	Hematology Oncology Consultants-Clarkston	Clarkston	Michigan
United States	Michigan Healthcare Professionals Clarkston	Clarkston	Michigan
United States	Newland Medical Associates-Clarkston	Clarkston	Michigan
United States	Cleveland Clinic Foundation	Cleveland	Ohio
United States	Henry Ford Macomb Hospital-Clinton Township	Clinton Township	Michigan
United States	Mercy Cancer Center-West Lakes	Clive	Iowa
United States	Mission Cancer and Blood - West Des Moines	Clive	Iowa
United States	Billings Clinic-Cody	Cody	Wyoming
United States	Kootenai Health - Coeur d'Alene	Coeur d'Alene	Idaho
United States	Memorial Hospital North	Colorado Springs	Colorado
United States	Penrose-Saint Francis Healthcare	Colorado Springs	Colorado
United States	Rocky Mountain Cancer Centers-Penrose	Colorado Springs	Colorado
United States	UCHealth Memorial Hospital Central	Colorado Springs	Colorado
United States	Columbus Oncology and Hematology Associates Inc	Columbus	Ohio
United States	Doctors Hospital	Columbus	Ohio
United States	Grant Medical Center	Columbus	Ohio
United States	Mount Carmel East Hospital	Columbus	Ohio
United States	Mount Carmel Health Center West	Columbus	Ohio
United States	Ohio State University Comprehensive Cancer Center	Columbus	Ohio
United States	Riverside Methodist Hospital	Columbus	Ohio
United States	The Mark H Zangmeister Center	Columbus	Ohio
United States	Mercy Hospital	Coon Rapids	Minnesota
United States	Commonwealth Cancer Center-Corbin	Corbin	Kentucky
United States	Alegent Health Mercy Hospital	Council Bluffs	Iowa
United States	Greater Regional Medical Center	Creston	Iowa
United States	Siteman Cancer Center at West County Hospital	Creve Coeur	Missouri
United States	Parkland Memorial Hospital	Dallas	Texas
United States	UT Southwestern/Simmons Cancer Center-Dallas	Dallas	Texas
United States	Carle at The Riverfront	Danville	Illinois
United States	Geisinger Medical Center	Danville	Pennsylvania
United States	Dayton Physician LLC - Englewood	Dayton	Ohio
United States	Good Samaritan Hospital - Dayton	Dayton	Ohio
United States	Miami Valley Hospital	Dayton	Ohio
United States	Miami Valley Hospital North	Dayton	Ohio
United States	Henry Ford Medical Center-Fairlane	Dearborn	Michigan
United States	Cancer Care Specialists of Illinois - Decatur	Decatur	Illinois
United States	Decatur Memorial Hospital	Decatur	Illinois
United States	Essentia Health - Deer River Clinic	Deer River	Minnesota
United States	Delaware Health Center-Grady Cancer Center	Delaware	Ohio
United States	Grady Memorial Hospital	Delaware	Ohio
United States	Porter Adventist Hospital	Denver	Colorado
United States	Mercy Medical Center - Des Moines	Des Moines	Iowa
United States	Mission Cancer and Blood - Laurel	Des Moines	Iowa
United States	Ascension Saint John Hospital	Detroit	Michigan
United States	Henry Ford Hospital	Detroit	Michigan
United States	Essentia Health Saint Mary's - Detroit Lakes Clinic	Detroit Lakes	Minnesota
United States	Illinois CancerCare-Dixon	Dixon	Illinois
United States	Dublin Methodist Hospital	Dublin	Ohio
United States	Kaiser Permanente Dublin	Dublin	California
United States	Essentia Health Cancer Center	Duluth	Minnesota
United States	Essentia Health Saint Mary's Medical Center	Duluth	Minnesota
United States	Miller-Dwan Hospital	Duluth	Minnesota
United States	Northside Hospital - Duluth	Duluth	Georgia
United States	Mercy Medical Center	Durango	Colorado
United States	Southwest Oncology PC	Durango	Colorado
United States	Great Lakes Cancer Management Specialists-Doctors Park	East China Township	Michigan
United States	Pocono Medical Center	East Stroudsburg	Pennsylvania
United States	Marshfield Medical Center-EC Cancer Center	Eau Claire	Wisconsin
United States	Fairview Southdale Hospital	Edina	Minnesota
United States	Carle Physician Group-Effingham	Effingham	Illinois
United States	Crossroads Cancer Center	Effingham	Illinois
United States	21st Century Oncology - El Segundo	El Segundo	California
United States	Walter Knox Memorial Hospital	Emmett	Idaho
United States	Saint Elizabeth Hospital	Enumclaw	Washington
United States	Illinois CancerCare-Eureka	Eureka	Illinois
United States	NorthShore University HealthSystem-Evanston Hospital	Evanston	Illinois
United States	Essentia Health Cancer Center-South University Clinic	Fargo	North Dakota
United States	Sanford Broadway Medical Center	Fargo	North Dakota
United States	Sanford Medical Center Fargo	Fargo	North Dakota
United States	Sanford Roger Maris Cancer Center	Fargo	North Dakota
United States	Sanford South University Medical Center	Fargo	North Dakota
United States	Southpointe-Sanford Medical Center Fargo	Fargo	North Dakota
United States	Parkland Health Center - Farmington	Farmington	Missouri
United States	Michigan Healthcare Professionals Farmington	Farmington Hills	Michigan
United States	Saint Francis Hospital	Federal Way	Washington
United States	Lake Region Healthcare Corporation-Cancer Care	Fergus Falls	Minnesota
United States	Armes Family Cancer Center	Findlay	Ohio
United States	Blanchard Valley Hospital	Findlay	Ohio
United States	Orion Cancer Care	Findlay	Ohio
United States	Genesee Cancer and Blood Disease Treatment Center	Flint	Michigan
United States	Genesee Hematology Oncology PC	Flint	Michigan
United States	Genesys Hurley Cancer Institute	Flint	Michigan
United States	Hurley Medical Center	Flint	Michigan
United States	Kaiser Permanente-Fontana	Fontana	California
United States	McFarland Clinic - Trinity Cancer Center	Fort Dodge	Iowa
United States	Holy Cross Hospital	Fort Lauderdale	Florida
United States	Mercy Hospital Fort Smith	Fort Smith	Arkansas
United States	Essentia Health - Fosston	Fosston	Minnesota
United States	Beebe South Coastal Health Campus	Frankford	Delaware
United States	Atrium Medical Center-Middletown Regional Hospital	Franklin	Ohio
United States	Dayton Physicians LLC-Atrium	Franklin	Ohio
United States	Kaiser Permanente-Fremont	Fremont	California
United States	Fresno Cancer Center	Fresno	California
United States	Kaiser Permanente-Fresno	Fresno	California
United States	Unity Hospital	Fridley	Minnesota
United States	Central Ohio Breast and Endocrine Surgery	Gahanna	Ohio
United States	Illinois CancerCare-Galesburg	Galesburg	Illinois
United States	Western Illinois Cancer Treatment Center	Galesburg	Illinois
United States	NorthShore University HealthSystem-Glenbrook Hospital	Glenview	Illinois
United States	Mountain Blue Cancer Care Center	Golden	Colorado
United States	CTCA at Western Regional Medical Center	Goodyear	Arizona
United States	Nebraska Cancer Specialists/Oncology Hematology West PC	Grand Island	Nebraska
United States	Benefis Sletten Cancer Institute	Great Falls	Montana
United States	Great Falls Clinic	Great Falls	Montana
United States	Dayton Physicians LLC-Wayne	Greenville	Ohio
United States	Wayne Hospital	Greenville	Ohio
United States	Legacy Mount Hood Medical Center	Gresham	Oregon
United States	Academic Hematology Oncology Specialists	Grosse Pointe Woods	Michigan
United States	Great Lakes Cancer Management Specialists-Van Elslander Cancer Center	Grosse Pointe Woods	Michigan
United States	Michigan Breast Specialists-Grosse Pointe Woods	Grosse Pointe Woods	Michigan
United States	Mount Carmel Grove City Hospital	Grove City	Ohio
United States	Kaiser Permanente - Harbor City	Harbor City	California
United States	UPMC Pinnacle Cancer Center/Community Osteopathic Campus	Harrisburg	Pennsylvania
United States	Geisinger Medical Center-Cancer Center Hazleton	Hazleton	Pennsylvania
United States	Lehigh Valley Hospital-Hazleton	Hazleton	Pennsylvania
United States	Saint Peter's Community Hospital	Helena	Montana
United States	Essentia Health Hibbing Clinic	Hibbing	Minnesota
United States	NorthShore University HealthSystem-Highland Park Hospital	Highland Park	Illinois
United States	Pulmonary Medicine Center of Chattanooga-Hixson	Hixson	Tennessee
United States	Hawaii Cancer Care Inc - Waterfront Plaza	Honolulu	Hawaii
United States	Hawaii Cancer Care Inc-Liliha	Honolulu	Hawaii
United States	Island Urology	Honolulu	Hawaii
United States	Kaiser Permanente Moanalua Medical Center	Honolulu	Hawaii
United States	Kapiolani Medical Center for Women and Children	Honolulu	Hawaii
United States	Kuakini Medical Center	Honolulu	Hawaii
United States	Queen's Cancer Cenrer - POB I	Honolulu	Hawaii
United States	Queen's Cancer Center - Kuakini	Honolulu	Hawaii
United States	Queen's Medical Center	Honolulu	Hawaii
United States	Straub Clinic and Hospital	Honolulu	Hawaii
United States	The Cancer Center of Hawaii-Liliha	Honolulu	Hawaii
United States	University of Hawaii Cancer Center	Honolulu	Hawaii
United States	CHI Saint Vincent Cancer Center Hot Springs	Hot Springs	Arkansas
United States	M D Anderson Cancer Center	Houston	Texas
United States	Indiana University/Melvin and Bren Simon Cancer Center	Indianapolis	Indiana
United States	Kaiser Permanente-Irvine	Irvine	California
United States	Allegiance Health	Jackson	Michigan
United States	Mayo Clinic in Florida	Jacksonville	Florida
United States	Essentia Health - Jamestown Clinic	Jamestown	North Dakota
United States	McFarland Clinic - Jefferson	Jefferson	Iowa
United States	MU Health Care Goldschmidt Cancer Center	Jefferson City	Missouri
United States	Emory Johns Creek Hospital	Johns Creek	Georgia
United States	Freeman Health System	Joplin	Missouri
United States	Mercy Hospital Joplin	Joplin	Missouri
United States	Kalispell Regional Medical Center	Kalispell	Montana
United States	CHI Health Good Samaritan	Kearney	Nebraska
United States	Heartland Hematology and Oncology	Kearney	Nebraska
United States	ECU Health Oncology Kenansville	Kenansville	North Carolina
United States	First Dayton Cancer Care	Kettering	Ohio
United States	Greater Dayton Cancer Center	Kettering	Ohio
United States	Kettering Medical Center	Kettering	Ohio
United States	Illinois CancerCare-Kewanee Clinic	Kewanee	Illinois
United States	GenesisCare USA - Key West	Key West	Florida
United States	ECU Health Oncology Kinston	Kinston	North Carolina
United States	UC San Diego Moores Cancer Center	La Jolla	California
United States	Rocky Mountain Cancer Centers-Lakewood	Lakewood	Colorado
United States	Saint Anthony Hospital	Lakewood	Colorado
United States	Saint Clare Hospital	Lakewood	Washington
United States	GenesisCare USA - Lakewood Ranch	Lakewood Ranch	Florida
United States	Fairfield Medical Center	Lancaster	Ohio
United States	University of Michigan Health - Sparrow Lansing	Lansing	Michigan
United States	Northside Hospital - Gwinnett	Lawrenceville	Georgia
United States	Beebe Medical Center	Lewes	Delaware
United States	Geisinger Medical Oncology-Lewisburg	Lewisburg	Pennsylvania
United States	Lewistown Hospital	Lewistown	Pennsylvania
United States	Saint Joseph Hospital East	Lexington	Kentucky
United States	Saint Joseph Radiation Oncology Resource Center	Lexington	Kentucky
United States	Wilcox Memorial Hospital and Kauai Medical Clinic	Lihue	Hawaii
United States	Saint Elizabeth Regional Medical Center	Lincoln	Nebraska
United States	Littleton Adventist Hospital	Littleton	Colorado
United States	Hope Cancer Clinic	Livonia	Michigan
United States	Trinity Health Saint Mary Mercy Livonia Hospital	Livonia	Michigan
United States	Loma Linda University Medical Center	Loma Linda	California
United States	Saint Joseph London	London	Kentucky
United States	Longmont United Hospital	Longmont	Colorado
United States	Rocky Mountain Cancer Centers-Longmont	Longmont	Colorado
United States	Kaiser Permanente Los Angeles Medical Center	Los Angeles	California
United States	Kaiser Permanente West Los Angeles	Los Angeles	California
United States	Jewish Hospital	Louisville	Kentucky
United States	Saints Mary and Elizabeth Hospital	Louisville	Kentucky
United States	UofL Health Medical Center Northeast	Louisville	Kentucky
United States	Great Lakes Cancer Management Specialists-Macomb Medical Campus	Macomb	Michigan
United States	Illinois CancerCare-Macomb	Macomb	Illinois
United States	Michigan Breast Specialists-Macomb Township	Macomb	Michigan
United States	Michigan Healthcare Professionals Macomb	Macomb	Michigan
United States	Michigan Healthcare Professionals Madison Heights	Madison Heights	Michigan
United States	OhioHealth Mansfield Hospital	Mansfield	Ohio
United States	Fairview Clinics and Surgery Center Maple Grove	Maple Grove	Minnesota
United States	Minnesota Oncology Hematology PA-Maplewood	Maplewood	Minnesota
United States	Saint John's Hospital - Healtheast	Maplewood	Minnesota
United States	Marietta Memorial Hospital	Marietta	Ohio
United States	OhioHealth Marion General Hospital	Marion	Ohio
United States	Saint Mary's Oncology/Hematology Associates of Marlette	Marlette	Michigan
United States	McFarland Clinic - Marshalltown	Marshalltown	Iowa
United States	Marshfield Medical Center-Marshfield	Marshfield	Wisconsin
United States	Carle Physician Group-Mattoon/Charleston	Mattoon	Illinois
United States	UPMC Cancer Center at UPMC McKeesport	McKeesport	Pennsylvania
United States	Riddle Memorial Hospital	Media	Pennsylvania
United States	Baptist Memorial Hospital and Cancer Center-Memphis	Memphis	Tennessee
United States	Idaho Urologic Institute-Meridian	Meridian	Idaho
United States	Medical College of Wisconsin	Milwaukee	Wisconsin
United States	Abbott-Northwestern Hospital	Minneapolis	Minnesota
United States	Health Partners Inc	Minneapolis	Minnesota
United States	Hennepin County Medical Center	Minneapolis	Minnesota
United States	Marshfield Clinic-Minocqua Center	Minocqua	Wisconsin
United States	Community Medical Center	Missoula	Montana
United States	Kaiser Permanente-Modesto	Modesto	California
United States	Monticello Cancer Center	Monticello	Minnesota
United States	Good Samaritan Regional Health Center	Mount Vernon	Illinois
United States	Knox Community Hospital	Mount Vernon	Ohio
United States	ProHealth D N Greenwald Center	Mukwonago	Wisconsin
United States	Arnold Palmer Cancer Center Medical Oncology Norwin	N. Huntingdon	Pennsylvania
United States	Saint Alphonsus Cancer Care Center-Nampa	Nampa	Idaho
United States	Cancer Center of Western Wisconsin	New Richmond	Wisconsin
United States	New Ulm Medical Center	New Ulm	Minnesota
United States	Mount Sinai Chelsea	New York	New York
United States	Mount Sinai Hospital	New York	New York
United States	Christiana Care Health System-Christiana Hospital	Newark	Delaware
United States	Delaware Clinical and Laboratory Physicians PA	Newark	Delaware
United States	Helen F Graham Cancer Center	Newark	Delaware
United States	Licking Memorial Hospital	Newark	Ohio
United States	Medical Oncology Hematology Consultants PA	Newark	Delaware
United States	Newark Radiation Oncology	Newark	Ohio
United States	CTCA at Southeastern Regional Medical Center	Newnan	Georgia
United States	Henry Ford Medical Center-Columbus	Novi	Michigan
United States	Cancer Care Center of O'Fallon	O'Fallon	Illinois
United States	Kaiser Permanente Oakland-Broadway	Oakland	California
United States	Kaiser Permanente-Oakland	Oakland	California
United States	ProHealth Oconomowoc Memorial Hospital	Oconomowoc	Wisconsin
United States	Mercy Hospital Oklahoma City	Oklahoma City	Oklahoma
United States	University of Oklahoma Health Sciences Center	Oklahoma City	Oklahoma
United States	Alegent Health Bergan Mercy Medical Center	Omaha	Nebraska
United States	Alegent Health Immanuel Medical Center	Omaha	Nebraska
United States	Alegent Health Lakeside Hospital	Omaha	Nebraska
United States	Creighton University Medical Center	Omaha	Nebraska
United States	Hematology and Oncology Consultants PC	Omaha	Nebraska
United States	Nebraska Methodist Hospital	Omaha	Nebraska
United States	Kaiser Permanente-Ontario	Ontario	California
United States	Saint Alphonsus Cancer Care Center-Ontario	Ontario	Oregon
United States	Memorial GYN Plus	Ooltewah	Tennessee
United States	Illinois CancerCare-Ottawa Clinic	Ottawa	Illinois
United States	GenesisCare USA - Palm Beach Gardens	Palm Beach Gardens	Florida
United States	Kaiser Permanente - Panorama City	Panorama City	California
United States	Paoli Memorial Hospital	Paoli	Pennsylvania
United States	Midlands Community Hospital	Papillion	Nebraska
United States	Essentia Health - Park Rapids	Park Rapids	Minnesota
United States	Parker Adventist Hospital	Parker	Colorado
United States	Rocky Mountain Cancer Centers-Parker	Parker	Colorado
United States	Illinois CancerCare-Pekin	Pekin	Illinois
United States	Illinois CancerCare-Peoria	Peoria	Illinois
United States	Methodist Medical Center of Illinois	Peoria	Illinois
United States	Illinois CancerCare-Peru	Peru	Illinois
United States	Valley Radiation Oncology	Peru	Illinois
United States	Eastern Regional Medical Center	Philadelphia	Pennsylvania
United States	Fox Chase Cancer Center	Philadelphia	Pennsylvania
United States	Mayo Clinic Hospital in Arizona	Phoenix	Arizona
United States	Oncology Hematology Association	Pittsburgh	Pennsylvania
United States	Saint Clair Hospital	Pittsburgh	Pennsylvania
United States	University of Pittsburgh Cancer Institute (UPCI)	Pittsburgh	Pennsylvania
United States	UPMC-Mercy Hospital	Pittsburgh	Pennsylvania
United States	UPMC-Passavant Hospital	Pittsburgh	Pennsylvania
United States	GenesisCare USA - Plantation	Plantation	Florida
United States	Hope Cancer Center	Pontiac	Michigan
United States	Michigan Healthcare Professionals Pontiac	Pontiac	Michigan
United States	Newland Medical Associates-Pontiac	Pontiac	Michigan
United States	Trinity Health Saint Joseph Mercy Oakland Hospital	Pontiac	Michigan
United States	Legacy Good Samaritan Hospital and Medical Center	Portland	Oregon
United States	Southern Ohio Medical Center	Portsmouth	Ohio
United States	Kootenai Clinic Cancer Services - Post Falls	Post Falls	Idaho
United States	Geisinger Cancer Services-Pottsville	Pottsville	Pennsylvania
United States	Harrison HealthPartners Hematology and Oncology-Poulsbo	Poulsbo	Washington
United States	Fairview Northland Medical Center	Princeton	Minnesota
United States	Illinois CancerCare-Princeton	Princeton	Illinois
United States	Rocky Mountain Cancer Centers - Pueblo	Pueblo	Colorado
United States	Saint Mary Corwin Medical Center	Pueblo	Colorado
United States	Kaiser Permanente-Rancho Cordova Cancer Center	Rancho Cordova	California
United States	Kaiser Permanente-Redwood City	Redwood City	California
United States	Beebe Health Campus	Rehoboth Beach	Delaware
United States	Marshfield Medical Center-Rice Lake	Rice Lake	Wisconsin
United States	ECU Health Oncology Richlands	Richlands	North Carolina
United States	Kaiser Permanente-Richmond	Richmond	California
United States	Reid Health	Richmond	Indiana
United States	Kaiser Permanente-Riverside	Riverside	California
United States	North Memorial Medical Health Center	Robbinsdale	Minnesota
United States	Mayo Clinic in Rochester	Rochester	Minnesota
United States	University of Rochester	Rochester	New York
United States	Great Lakes Cancer Management Specialists-Rochester Hills	Rochester Hills	Michigan
United States	Rohnert Park Cancer Center	Rohnert Park	California
United States	Delbert Day Cancer Institute at PCRMC	Rolla	Missouri
United States	Mercy Clinic-Rolla-Cancer and Hematology	Rolla	Missouri
United States	Kaiser Permanente-Roseville	Roseville	California
United States	The Permanente Medical Group-Roseville Radiation Oncology	Roseville	California
United States	Kaiser Permanente - Sacramento	Sacramento	California
United States	Kaiser Permanente Downtown Commons	Sacramento	California
United States	Kaiser Permanente-South Sacramento	Sacramento	California
United States	South Sacramento Cancer Center	Sacramento	California
United States	Ascension Saint Mary's Hospital	Saginaw	Michigan
United States	Oncology Hematology Associates of Saginaw Valley PC	Saginaw	Michigan
United States	Heartland Regional Medical Center	Saint Joseph	Missouri
United States	Mercy Hospital Saint Louis	Saint Louis	Missouri
United States	Mercy Hospital South	Saint Louis	Missouri
United States	Missouri Baptist Medical Center	Saint Louis	Missouri
United States	Saint Louis Cancer and Breast Institute-South City	Saint Louis	Missouri
United States	Siteman Cancer Center at Christian Hospital	Saint Louis	Missouri
United States	Siteman Cancer Center-South County	Saint Louis	Missouri
United States	Washington University School of Medicine	Saint Louis	Missouri
United States	Park Nicollet Clinic - Saint Louis Park	Saint Louis Park	Minnesota
United States	Regions Hospital	Saint Paul	Minnesota
United States	United Hospital	Saint Paul	Minnesota
United States	Siteman Cancer Center at Saint Peters Hospital	Saint Peters	Missouri
United States	Sainte Genevieve County Memorial Hospital	Sainte Genevieve	Missouri
United States	Huntsman Cancer Institute/University of Utah	Salt Lake City	Utah
United States	Kaiser Permanente-San Diego Mission	San Diego	California
United States	Kaiser Permanente-San Diego Zion	San Diego	California
United States	Kaiser Permanente-San Francisco	San Francisco	California
United States	Kaiser Permanente-Santa Teresa-San Jose	San Jose	California
United States	Kaiser Permanente San Leandro	San Leandro	California
United States	Pacific Central Coast Health Center-San Luis Obispo	San Luis Obispo	California
United States	Kaiser Permanente-San Marcos	San Marcos	California
United States	Kaiser Permanente-San Rafael	San Rafael	California
United States	Kaiser San Rafael-Gallinas	San Rafael	California
United States	Kootenai Clinic Cancer Services - Sandpoint	Sandpoint	Idaho
United States	Essentia Health Sandstone	Sandstone	Minnesota
United States	Kaiser Permanente Medical Center - Santa Clara	Santa Clara	California
United States	Mission Hope Medical Oncology - Santa Maria	Santa Maria	California
United States	Kaiser Permanente-Santa Rosa	Santa Rosa	California
United States	Mayo Clinic in Arizona	Scottsdale	Arizona
United States	Community Medical Center	Scranton	Pennsylvania
United States	TidalHealth Nanticoke / Allen Cancer Center	Seaford	Delaware
United States	Geisinger Medical Oncology-Selinsgrove	Selinsgrove	Pennsylvania
United States	Saint Francis Regional Medical Center	Shakopee	Minnesota
United States	Henry Ford Macomb Health Center - Shelby Township	Shelby	Michigan
United States	Jewish Hospital Medical Center South	Shepherdsville	Kentucky
United States	Welch Cancer Center	Sheridan	Wyoming
United States	Saint Michael Cancer Center	Silverdale	Washington
United States	Sanford Cancer Center Oncology Clinic	Sioux Falls	South Dakota
United States	Sanford USD Medical Center - Sioux Falls	Sioux Falls	South Dakota
United States	Suburban Hematology Oncology Associates - Snellville	Snellville	Georgia
United States	Kaiser Permanente Cancer Treatment Center	South San Francisco	California
United States	Kaiser Permanente-South San Francisco	South San Francisco	California
United States	Baptist Memorial Hospital and Cancer Center-Desoto	Southhaven	Mississippi
United States	CoxHealth South Hospital	Springfield	Missouri
United States	Memorial Medical Center	Springfield	Illinois
United States	Mercy Hospital Springfield	Springfield	Missouri
United States	Mercy Medical Center	Springfield	Massachusetts
United States	Southern Illinois University School of Medicine	Springfield	Illinois
United States	Springfield Clinic	Springfield	Illinois
United States	Springfield Regional Cancer Center	Springfield	Ohio
United States	Springfield Regional Medical Center	Springfield	Ohio
United States	Geisinger Medical Group	State College	Pennsylvania
United States	Bhadresh Nayak MD PC-Sterling Heights	Sterling Heights	Michigan
United States	Marshfield Medical Center-River Region at Stevens Point	Stevens Point	Wisconsin
United States	Lakeview Hospital	Stillwater	Minnesota
United States	Kaiser Permanente-Stockton	Stockton	California
United States	Missouri Baptist Sullivan Hospital	Sullivan	Missouri
United States	BJC Outpatient Center at Sunset Hills	Sunset Hills	Missouri
United States	Southwest Illinois Health Services LLP	Swansea	Illinois
United States	Franciscan Research Center-Northwest Medical Plaza	Tacoma	Washington
United States	Northwest Medical Specialties PLLC	Tacoma	Washington
United States	Ascension Saint Joseph Hospital	Tawas City	Michigan
United States	Sanford Thief River Falls Medical Center	Thief River Falls	Minnesota
United States	Rocky Mountain Cancer Centers-Thornton	Thornton	Colorado
United States	Dayton Physicians LLC - Troy	Troy	Ohio
United States	Michigan Healthcare Professionals Troy	Troy	Michigan
United States	Upper Valley Medical Center	Troy	Ohio
United States	Cancer Treatment Centers of America	Tulsa	Oklahoma
United States	Oklahoma Cancer Specialists and Research Institute-Tulsa	Tulsa	Oklahoma
United States	Carle Cancer Center	Urbana	Illinois
United States	The Carle Foundation Hospital	Urbana	Illinois
United States	Kaiser Permanente Medical Center-Vacaville	Vacaville	California
United States	Kaiser Permanente-Vallejo	Vallejo	California
United States	Legacy Salmon Creek Hospital	Vancouver	Washington
United States	Essentia Health Virginia Clinic	Virginia	Minnesota
United States	Ridgeview Medical Center	Waconia	Minnesota
United States	Kaiser Permanente-Walnut Creek	Walnut Creek	California
United States	Advanced Breast Care Center PLLC	Warren	Michigan
United States	Great Lakes Cancer Management Specialists-Macomb Professional Building	Warren	Michigan
United States	Macomb Hematology Oncology PC	Warren	Michigan
United States	Michigan Breast Specialists-Warren	Warren	Michigan
United States	Saint John Macomb-Oakland Hospital	Warren	Michigan
United States	Saint Joseph Warren Hospital	Warren	Ohio
United States	Mercy Hospital Washington	Washington	Missouri
United States	Sibley Memorial Hospital	Washington	District of Columbia
United States	UPMC Cancer Center-Washington	Washington	Pennsylvania
United States	ProHealth Waukesha Memorial Hospital	Waukesha	Wisconsin
United States	UW Cancer Center at ProHealth Care	Waukesha	Wisconsin
United States	Henry Ford West Bloomfield Hospital	West Bloomfield	Michigan
United States	Saint Mary's Oncology/Hematology Associates of West Branch	West Branch	Michigan
United States	University of Cincinnati Cancer Center-West Chester	West Chester	Ohio
United States	Mercy Medical Center-West Lakes	West Des Moines	Iowa
United States	Good Samaritan Medical Center	West Palm Beach	Florida
United States	Saint Ann's Hospital	Westerville	Ohio
United States	Marshfield Medical Center - Weston	Weston	Wisconsin
United States	Geisinger Wyoming Valley/Henry Cancer Center	Wilkes-Barre	Pennsylvania
United States	Rice Memorial Hospital	Willmar	Minnesota
United States	Christiana Care Health System-Wilmington Hospital	Wilmington	Delaware
United States	Minnesota Oncology Hematology PA-Woodbury	Woodbury	Minnesota
United States	Kaiser Permanente-Woodland Hills	Woodland Hills	California
United States	Sanford Cancer Center Worthington	Worthington	Minnesota
United States	Lankenau Medical Center	Wynnewood	Pennsylvania
United States	Fairview Lakes Medical Center	Wyoming	Minnesota
United States	Rush-Copley Healthcare Center	Yorkville	Illinois
United States	Saint Elizabeth Youngstown Hospital	Youngstown	Ohio
United States	Huron Gastroenterology PC	Ypsilanti	Michigan
United States	Trinity Health IHA Medical Group Hematology Oncology Ann Arbor Campus	Ypsilanti	Michigan
United States	Genesis Healthcare System Cancer Care Center	Zanesville	Ohio

Sponsors (2)

Lead Sponsor	Collaborator
National Cancer Institute (NCI)	NRG Oncology

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Agreement of Biopsy Mutation and Circulating Free Deoxyribonucleic Acid (cfDNA) Mutation Results	For each mutation, the agreement of the biopsy result (present, absent, unavailable) and the cfDNA result (present, absent, unavailable) would be assessed. Agreement of cfDNA and biopsy results will be considered separately for MET amplification and for the gene mutations. This outcome measure was to be contingent upon FDA approval of the outcome measure analysis plan, which was not pursued due to the early accrual closure.	Baseline
Primary	Objective Response Rate (ORR), Per Investigator Assessment Using the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 Criteria	ORR= number of subjects with best overall response (BOR) of complete or partial response (CR, PR) divided by number of evaluable subjects. BOR= best response recorded from start of treatment to first progression (PD)/new anticancer therapy, otherwise last follow-up.; CR: disappearance of target and non-target lesions; no new lesions; pathological lymph nodes < 10mm.; PR: 30% decrease in target lesions; non-target lesions not progressed or not evaluated; no new lesions.; PD: 20% increase of target lesions and/or new lesion(s).; ORR was to be compared using Fisher's exact test within each ALK inhibitor treatment arm (each mutation vs. no mutation) and also within the subset of subjects with no mutation comparing each experimental arm vs. pemetrexed. Due to early accrual closure (few subjects), only the number of subjects with BOR of CR or PR are provided, by mutation, no statistical testing. Analysis was to occur after each patient was potentially followed = 24 weeks.	Baseline to 24 weeks
Secondary	Progression-free Survival (PFS), Per Investigator Assessment Using RECIST v1.1 Criteria	Progression-free survival time is defined as the time from second step registration to the date of the first disease progression / progressive disease (PD), death, or last known follow-up (censored). Progressive disease is defined as a 20% increase of target lesions and/or new lesion(s). Percentage of participants progression-free at a given time (PFS) was to be estimated by the Kaplan-Meier method. Median PFS and PFS at specific time points was to be reported, with 95% confidence intervals, for each mutation (or no mutation)/regimen combination. Due to early accrual closure resulting in few participants, only the number of participants who progressed or died, by mutation, with no statistical testing.	Baseline to the date of the first disease progression / progressive disease, death, or last known follow-up. Maximum follow-up time was 33.6 months, median 8.9 months.
Secondary	Duration of Overall Response, Per Investigator Assessment Using RECIST v1.1	Duration of overall response (DOR) is defined as the time from the first occurrence of a documented BOR of CR or PR to the first date of recorded disease progression (PD) or death from any cause (whichever occurs first). BOR is the best response recorded from the start of treatment to first progression (PD)/new anticancer therapy, otherwise last follow-up.; CR: disappearance of target and non-target lesions; no new lesions; pathological lymph nodes < 10mm.; PR: 30% decrease in target lesions; non-target lesions not progressed or not evaluated; no new lesions.; PD: 20% increase of target lesions and/or new lesion(s).; Median DOR was to be estimated, with 95% confidence intervals, for each mutation/regimen combination using the Kaplan-Meier method. Due to early accrual closure resulting in few subjects, only the mean and range DOR are provided, by mutation, and no statistical testing was done.	Baseline to the date of the first disease progression / progressive disease, death, or last known follow-up. Maximum follow-up time was 33.6 months, median 8.9 months.
Secondary	Overall Survival (OS)	Survival time is defined as the time from second step registration to the date of death, or last known follow-up (censored). Percentage of participants alive at a given time (OS) was to be estimated by the Kaplan-Meier method. Median OS and OS at specific time points was to be reported, with 95% confidence intervals, for each mutation/regimen combination. Due to early accrual closure resulting in few patients, only the number of participants who died are provided, by mutation, and no statistical testing was done.	Baseline to the date of death or last known follow-up. Maximum follow-up time was 33.6 months, median 8.9 months.
Secondary	Intracranial Objective Response Rate, Per Investigator Assessment Using RECIST v1.1	Intracranial objective response rate (IORR) is defined as the number of participants with central nervous system (CNS) metastasis complete or partial response (CR, PR) divided by the number of evaluable participants with baseline CNS metastasis and no prior CNS radiation therapy. Participants who required additional treatment (for their non-cranial systemic disease) would be considered as non-responders (if they have not previously had an intracranial response).; CR: disappearance of target and non-target lesions; no new lesions; pathological lymph nodes < 10mm.; PR: 30% decrease in target lesions; non-target lesions not progressed or not evaluated; no new lesions.; IORR was to be estimated for each mutation/regimen combination, with the associated 95% confidence intervals (using Clapper-Pearson method). Due to early accrual closure resulting in few subjects, only the number of subjects with CR or PR are provided, by mutation, with no statistical testing.	Baseline to 24 weeks
Secondary	Number of Participants by Highest Grade Adverse Event Reported	Common Terminology Criteria for Adverse Events (version 4.0) grades adverse event severity from 1=mild to 5=death. Summary data is provided in this outcome measure; see Adverse Events Module for specific adverse event data.	Baseline to the date of last known follow-up. Maximum follow-up time was 33.6 months, median 8.9 months.