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Supplementary Material
Systematic Review of Sequencing of Anaplastic Lymphoma Kinase Inhibitors in ALK-Positive Non–Small Cell Lung Cancer
Barrows et al.
Lung Cancer: Targets and Therapy
List of TablesSupplementary eTable 1. PubMed Literature Search Strategy
Supplementary eTable 2. Inclusion and Exclusion Criteria
Supplementary eTable 3. List of 80 Studies Included in Review
Systematic Review of Sequencing of Anaplastic Lymphoma Kinase Inhibitors in ALK-Positive Non–Small Cell Lung Cancer
Supplementary eTable 1. PubMed Literature Search Strategy
Search No. Search Terms
Disease#1 (“Carcinoma, Non-Small-Cell Lung”[Majr] OR “non-small-cell lung cancer”[Title] OR “non-
small-cell lung carcinoma”[Title] OR “nonsmall cell lung cancer”[Title] OR “nonsmall cell lung carcinoma”[Title] OR “NSCLC”[Title]) AND (“ALK”[Title/Abstract] OR “anaplastic lymphoma kinase”[Title/Abstract])
Treatment#2 #1 AND (“crizotinib”[Supplementary Concept] OR crizotinib[Title/Abstract] OR
xalkori[Title/Abstract] OR “PF-02341066”[Title/Abstract] OR “PF02341066”[Title/Abstract] OR “PF-2341066”[Title/Abstract] OR “ceritinib”[Supplementary Concept] OR ceritinib[Title/Abstract] OR zykadia[Title/Abstract] OR “LDK378”[Title/Abstract] OR “CH5424802”[Supplementary Concept] OR “CH5424802”[Title/Abstract] OR alectinib[Title/Abstract] OR “RO5424802”[Title/Abstract] OR alecensa[Title/Abstract] OR ALK inhibitor*[Title/Abstract] OR anaplastic lymphoma kinase inhibitor*[Title/Abstract] OR “brigatinib”[Title/Abstract] OR “AP26113”[Title/Abstract] OR "AP26113"[Supplementary Concept])
Study Types#3 #2 AND (“Prospective Studies”[Majr] OR “Retrospective Studies”[Majr] OR “Longitudinal
Studies”[Majr] OR “Follow-Up Studies”[Majr] OR “Clinical Trials as Topic”[Majr] OR “Observational Studies as Topic”[Majr] OR “Multicenter Studies as Topic”[Majr] OR “Randomized Controlled Trials as Topic”[Majr] OR prospective stud*[Title/Abstract] OR retrospective stud*[Title/Abstract] OR retrospective analys*[Title/Abstract] OR retrospectively[Title/Abstract] OR longitudinal stud*[Title/Abstract] OR follow-up stud*[Title/Abstract] OR “phase IV”[Title/Abstract] OR “phase 4”[Title/Abstract] OR “phase four”[Title/Abstract] OR observational stud*[Title/Abstract] OR “real world”[Title/Abstract] OR multicenter stud*[Title/Abstract] OR multicentre stud*[Title/Abstract] OR multicenter trial*[Title/Abstract] OR multicentre trial*[Title/Abstract] OR randomized trial*[Title/Abstract] OR randomized clinical trial*[Title/Abstract] OR randomized controlled trial*[Title/Abstract] OR randomized controlled clinical trial*[Title/Abstract] OR “Clinical Trial”[Publication Type] OR “Observational Study”[Publication Type] OR “Multicenter Study” [Publication Type] OR “Randomized Controlled Trial”[Publication Type] OR “phase III”[Title/Abstract] OR “phase 3”[Title/Abstract] OR “phase three”[Title/Abstract] OR “phase 2”[Title/Abstract] OR “phase II”[Title/Abstract] OR “phase two”[Title/Abstract] OR “phase 1”[Title/Abstract] OR “phase I”[Title/Abstract] OR “phase one”[Title/Abstract])
Practice Patterns and Guidelines#4 #2 AND (“Practice Patterns, Physicians’”[Majr] OR “Guidelines as Topic”[Majr] OR “Drug
Resistance, Neoplasm”[Majr] OR practice pattern*[Title/Abstract] OR prescribing pattern*[Title/Abstract] OR treatment pattern*[Title/Abstract] OR best practice*[Title/Abstract] OR guideline*[Title/Abstract] OR sequen*[Title/Abstract] OR “drug resistance”[Title/Abstract] OR “Practice Guideline”[Publication Type])
Exclusions#5 “Animals”[Mesh] NOT “Humans”[Mesh]#6 “Comment”[Publication Type] OR “Letter”[Publication Type] OR “Editorial”[Publication
Type]Total#7 (#3 OR #4) NOT (#5 OR #6)
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Systematic Review of Sequencing of Anaplastic Lymphoma Kinase Inhibitors in ALK-Positive Non–Small Cell Lung Cancer
Supplementary eTable 2. Inclusion and Exclusion Criteria
Criteria Included ExcludedPopulation Adult patients with ALK-positive NSCLC
Patients who received at least one ALK inhibitor (any line of therapy)
Population: children Studies in which the primary
focus is ROS or MET or anything other than ALK
Interventions ALK inhibitor used in any line of therapy (1st, 2nd, and subsequent)
ALK inhibitors of interest:–Crizotinib (Xalkori), PF-02341066–Ceritinib (Zykadia), LDK378, CH5424802–Alectinib (Alecensa)–Brigatinib (Alunbrig), AP26113
Studies that do not contain intervention of interest
Studies where the primary intervention is surgery or radiotherapy
Outcomes Impact on outcome following ALK inhibitor use Impact of treatment using 1st and 2nd ALK
inhibitors on the outcomes listed–Does the order in which the ALK inhibitors are
used affect the outcome, such as progression-free survival or overall survival?
Impact of variations of treatment sequencing (e.g., 1st-line chemotherapy followed by 2nd-line ALK inhibitor; 1st-line ALK inhibitor followed by 2nd-line ALK inhibitor, etc.)
Overall cumulative outcome across multiple lines of therapy
Outcomes of interest:–Overall response rate–Complete response–Partial response–Stable disease–Progression rate–Progression-free survival–Time to progression–Overall survival–Duration of treatment–Time from ALK inhibitor use to initiation of
chemotherapy Patterns of resistance (e.g., time frame, patient
characteristics)
Studies that do not report any of the outcomes of interest
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Systematic Review of Sequencing of Anaplastic Lymphoma Kinase Inhibitors in ALK-Positive Non–Small Cell Lung Cancer
Criteria Included ExcludedStudy design Randomized controlled trials
Prospective cohort studies Retrospective cohort studies (e.g., case-control
studies, historical control studies) Longitudinal studies Clinical trials Registry studies Observational or open-label trials Literature reviews and meta-analysesa
Phase 1 studies with one or more of the specific outcomes of interest
Case reports Commentaries and letters
(publication type) Consensus reports Phase 1 studies in healthy
volunteers
ALK = anaplastic lymphoma kinase; MET = mesenchymal-epithelial transition factor; NSCLC = non–small cell lung cancer; ROS = c-ros oncogene1.a Literature reviews and meta-analyses were not included in their own right, but were used to identify primary studies not previously identified.
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Systematic Review of Sequencing of Anaplastic Lymphoma Kinase Inhibitors in ALK-Positive Non–Small Cell Lung Cancer
Supplementary eTable 3. List of 80 Studies Included in Review
ALK
Naï
ve
ALK
Afte
r In
itia
l ALK
2nd
Gen
Aft
er
CRZ
CER
Afte
r In
itia
l CRZ
ALEC
Aft
er In
itia
l CRZ
BRIG
Aft
er In
itia
l CRZ
CRZ
Afte
r 2n
d G
en
2nd
Gen
Aft
er
2nd
Gen
Oth
er
Reference, Country, Study Name (if Known), NCT #
Study Type (CT or Obs)
Primary Tx or Tx Sequence(s) Studied N/(n) Pr
esen
t?
Pres
ent?
Pres
ent?
Resu
lts?
a
Pres
ent?
Resu
lts?
Pres
ent?
Resu
lts?
a
1 Tamura et al. (2017)J Clinic OncolJapanJapicCTI-101264
CT N = 46Chemo followed by ALEC (N = 46)
X
2 Hida et al. (2017b)LancetJapanJ-ALEX
CT N = 207Chem-naïve or prior chemo followed by ALEC (n = 103)Chemo-naïve or prior chemo followed by CRZ(n = 104)
X
3 Peters et al. (2017)N Engl J MedMultinationalALEXNCT02075840
CT N = 303ALEC (n = 152)CRZ (n = 151)
X
4 Takiguchi et al, (2017)ABSTR; ASCOJapanJ-ALEX
CT N = 207ALEC (N = 207)
X
5 Tan et al, (2016)ABSTR; IASLCASCEND-1NCT01283516
CT N = 246CER (n = 16)
X
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Systematic Review of Sequencing of Anaplastic Lymphoma Kinase Inhibitors in ALK-Positive Non–Small Cell Lung Cancer
ALK
Naï
ve
ALK
Afte
r In
itia
l ALK
2nd
Gen
Aft
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CRZ
CER
Afte
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itia
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ALEC
Aft
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itia
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BRIG
Aft
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itia
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CRZ
Afte
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en
2nd
Gen
Aft
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2nd
Gen
Oth
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Reference, Country, Study Name (if Known), NCT #
Study Type (CT or Obs)
Primary Tx or Tx Sequence(s) Studied N/(n) Pr
esen
t?
Pres
ent?
Pres
ent?
Resu
lts?
a
Pres
ent?
Resu
lts?
Pres
ent?
Resu
lts?
a
6 Felip et al, (2016) ABSTR; Ann OncolMultinationalASCEND-3NCT01685138
CT N = 124Chemo followed by CER (N = 124)
X
7 De Castro et al, (2017)ABSTR; IASLCASCEND 4NCT01828099
CT N = 376CER (n = 189)Chemo (n = 187)
X
8 Soria et al. (2017)LancetMultinationalASCEND-4NCT01828099
CT N = 376CER (n = 189)Chemo (n = 187)
X
9 Camidge et al. (2012)Lancet OncolUSNCT00585195
CT N = 149CRZ (n = 143)
X
10
Kim et al. (2012)ABSTR; J Clin OncolPROFILE 1005
CT N = 255Chemo followed by CRZ (N = 255)
X
11
Shaw et al. (2016b)ABSTR; J Clin OncolPROFILE 1007NCT00932893
CT N = 347Chemo followed by CRZ (n = 173)Chemo (PEM or DOC) (n = 174)
X
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Systematic Review of Sequencing of Anaplastic Lymphoma Kinase Inhibitors in ALK-Positive Non–Small Cell Lung Cancer
ALK
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ALK
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2nd
Gen
Aft
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CRZ
CER
Afte
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itia
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ALEC
Aft
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itia
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BRIG
Aft
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itia
l CRZ
CRZ
Afte
r 2n
d G
en
2nd
Gen
Aft
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2nd
Gen
Oth
er
Reference, Country, Study Name (if Known), NCT #
Study Type (CT or Obs)
Primary Tx or Tx Sequence(s) Studied N/(n) Pr
esen
t?
Pres
ent?
Pres
ent?
Resu
lts?
a
Pres
ent?
Resu
lts?
Pres
ent?
Resu
lts?
a
12
Costa et al. (2015)J Clin OncolPooled data analysis of PROFILE 1005 and 1007
CT N = 888Previously untreated asymptomatic baseline BM: (n = 109)Previously treated asymptomatic baseline BM: (n = 166)No detected baseline BM: (n = 613)
X
13
Nishio et al. (2017) Caner Res Treat MultinationalSubgroup analysis: pooled data from PROFILE 1007 and PROFILE 1014Asian patients
CT N = 314PROFILE 1007 (n = 157)PROFILE 1014 (n = 157)
X
14
Lei et al. (2015)J Thorac DisChina
CT N = 120Patients with BM (n = 38)Patients without BM (n = 82)
X
15
Shaw et al. (2013)N Engl J MedNCT00932893
CT N = 347CRZ (n = 173)Chemo (n = 174)
X
16
Solomon et al. (2016)J Clin OncolMultinationalPROFILE 1014NCT01154140
CT N = 343CRZ (n = 172) Chemo (PEM + CIS or PEM + CBP) (n = 171)
X
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Systematic Review of Sequencing of Anaplastic Lymphoma Kinase Inhibitors in ALK-Positive Non–Small Cell Lung Cancer
ALK
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ALK
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2nd
Gen
Aft
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CRZ
CER
Afte
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itia
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ALEC
Aft
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itia
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BRIG
Aft
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itia
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CRZ
Afte
r 2n
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en
2nd
Gen
Aft
er
2nd
Gen
Oth
er
Reference, Country, Study Name (if Known), NCT #
Study Type (CT or Obs)
Primary Tx or Tx Sequence(s) Studied N/(n) Pr
esen
t?
Pres
ent?
Pres
ent?
Resu
lts?
a
Pres
ent?
Resu
lts?
Pres
ent?
Resu
lts?
a
17
Solomon et al. (2014)N Engl J MedMultinationalPROFILE 1014NCT01154140
CT N = 343CRZ (n = 172)Chemo (PEM + CIS or PEM + CBP) (n = 171)
X
18
Shaw et al. (2011b)Lancet OncolSubgroup analysis of NCT00585195MultinationalUS/Australia/Korea subgroup
CT N = 82CRZ after initial chemo or tx naïve (N = 82)
X
19
Kwak et al. (2010)N Engl J MedUS, Australia, and Korea
CT N = 82CRZ after initial chemo or tx naïve (N = 82)
X
20
Murakami et al. (2017)ABSTRJapan
Obs N = 14ALEC or CRZ after initial chemo (N = 14)
X
21
Barlesi et al. (2016)ABSTR; Ann OncolMultinationalNCT01801111
CT N = 138ALEC after initial CRZ (N = 138)
X X mPFSmOS
X
22
Ou et al. (2016)J Clin OncolMultinationalNCT01801111
CT N = 138ALEC after initial CRZ (N = 138)
X X mPFSTx Dur
X
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Systematic Review of Sequencing of Anaplastic Lymphoma Kinase Inhibitors in ALK-Positive Non–Small Cell Lung Cancer
ALK
Naï
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ALK
Afte
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2nd
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Aft
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CRZ
CER
Afte
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itia
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ALEC
Aft
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itia
l CRZ
BRIG
Aft
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itia
l CRZ
CRZ
Afte
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en
2nd
Gen
Aft
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2nd
Gen
Oth
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Reference, Country, Study Name (if Known), NCT #
Study Type (CT or Obs)
Primary Tx or Tx Sequence(s) Studied N/(n) Pr
esen
t?
Pres
ent?
Pres
ent?
Resu
lts?
a
Pres
ent?
Resu
lts?
Pres
ent?
Resu
lts?
a
23
Shaw et al. (2016a)Lancet OncolUS and CanadaNCT01871805
CT N = 87ALEC after initial CRZ (N = 87)
X X mPFSSurvival
X
24
Camidge et al. (2016)ABSTR IASLCUS and CanadaNCT01871805
CT N = 87ALEC after initial CRZ (N = 87)
X X mPFSmOS
X
25
Yang et al. (2017)J Thorac OncolMultinationalPooled analysis of NCT01801111 and NCT01871805
CT N = 225ALEC after initial CRZ (N = 225)
X X mPFSmOS
X
26
Gandhi et al. (2017)Eur J CancerMultinationalPooled analysis of NCT01801111 and NCT01871805
CT N = 225ALEC after initial CRZ (N = 225)
X X NR X
27
Gandhi et al. (2016)ABSTR; ESMOPooled analysis of NCT01801111 and NCT01871805
CT N = 225ALEC after initial CRZ (N = 225)
X X NR X
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Systematic Review of Sequencing of Anaplastic Lymphoma Kinase Inhibitors in ALK-Positive Non–Small Cell Lung Cancer
ALK
Naï
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ALK
Afte
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itia
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2nd
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Aft
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CRZ
CER
Afte
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itia
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ALEC
Aft
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itia
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BRIG
Aft
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itia
l CRZ
CRZ
Afte
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2nd
Gen
Aft
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2nd
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Reference, Country, Study Name (if Known), NCT #
Study Type (CT or Obs)
Primary Tx or Tx Sequence(s) Studied N/(n) Pr
esen
t?
Pres
ent?
Pres
ent?
Resu
lts?
a
Pres
ent?
Resu
lts?
Pres
ent?
Resu
lts?
a
28
Gadgeel et al. (2016)J Clin OncolMultinationalPooled subanalysis of NCT01801111 and NCT01871805
CT N =136ALEC after initial CRZ patients with baseline BM (N = 136)
X X mPFS X
29
Gadgeel et al. (2014)Lancet OncolUSNCT01588028
CT N = 47ALEC after initial CRZ (any dose) (N = 47)
X X NR X
30
Ahn et al. (2017)ABSTR; ASCOALTANCT02094573
CT N = 222BRIG 90 mg after initial CRZ (n = 112)BRIG 180 mg after initial CRZ (n = 110)
X X mPFSSurvival
X
31
Camidge et al. (2015)ABSTR; ESMOALTANCT01449461Intracranial response
CT N = 45BRIG after initial CRZ or chemo (N = 45)
X X mPFS X
32
Gettinger et al. (2016b)ABSTR; IASLCPooled analysisPhase 1/2 and ALTA studies
CT N = 50BRIG after initial CRZ or Chemo(N = 50)
X X mPFS X
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Systematic Review of Sequencing of Anaplastic Lymphoma Kinase Inhibitors in ALK-Positive Non–Small Cell Lung Cancer
ALK
Naï
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ALK
Afte
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2nd
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CRZ
CER
Afte
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itia
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ALEC
Aft
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itia
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BRIG
Aft
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CRZ
Afte
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2nd
Gen
Aft
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2nd
Gen
Oth
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Reference, Country, Study Name (if Known), NCT #
Study Type (CT or Obs)
Primary Tx or Tx Sequence(s) Studied N/(n) Pr
esen
t?
Pres
ent?
Pres
ent?
Resu
lts?
a
Pres
ent?
Resu
lts?
Pres
ent?
Resu
lts?
a
33
Kim et al. (2017)J Clin OncolMultinationalALTANCT02094573
CT N = 222BRIG 90 mg after chemo and/or CRZ (n = 112)BRIG 180 mg after prior chemo and/or CRZ (n = 110)
X X mPFSSurvival
X
34
Ou et al. (2017)ABSTR; ASCOALTANCT02094573Subanalysis intracranial response
CT N = 154BRIG 90 mg after initial CRZ (n = 80)BRIG 180 mg after initial CRZ (n = 74)
X X mPFS X
35
Crino et al. (2016)J Clin OncolMultinationalASCEND-2NCT01685060
CT N = 140CER after initial CRZ (N = 140)
X X mPFSmOS
Survival
X
36
Hida et al. (2017a)Jpn J Clin OncolMultinationalSubgroup analysis of ASCEND-2NCT01685060Japanese patients
CT N = 24CER after initial chemo and/or CRZ (N = 24)
X X mPFS X
37
Ou et al. (2014)Ann OncolPooled data analysis of PROFILE 1001 and PROFILE 1005
CT N = 194CRZ continued post PD (n = 120)BSC after CRZ (n = 74)
X
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Systematic Review of Sequencing of Anaplastic Lymphoma Kinase Inhibitors in ALK-Positive Non–Small Cell Lung Cancer
ALK
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ALK
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2nd
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CRZ
CER
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ALEC
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BRIG
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CRZ
Afte
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Aft
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2nd
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Reference, Country, Study Name (if Known), NCT #
Study Type (CT or Obs)
Primary Tx or Tx Sequence(s) Studied N/(n) Pr
esen
t?
Pres
ent?
Pres
ent?
Resu
lts?
a
Pres
ent?
Resu
lts?
Pres
ent?
Resu
lts?
a
38
Shaw et al. (2017)Lancet OncolASCEND-5NCT01828112
CT N = 231CER after initial CRZ (n = 115)Chemo after initial CRZ (n = 116)
X X mPFSmOS
Tx dur
X
39
Ito et al. (2017)J Thorac OncolJapan
Obs N = 61ALEC or CRZ after initial chemo (n = 46)ALEC after initial CRZ (n = 13)
X X X mPFSmOS
Survival
X
40
Bendaly et al. (2017b)Adv TherUS
Obs N = 74CRZ (any line; N = 74)
X Tx dur X
41
Bendaly et al. (2017a)Adv TherUS
Obs N = 58CER after initial CRZ (N = 58)
X mPFSmOS
Survival
X
42
Chiari et al. (2015)Lung CancerItaly
Obs N = 69ALK after initial chemo or ALK (N = 69)
X X mPFSmOS
X X
43
Gainor et al. (2015)Clin Cancer resMultinational
Obs N = 73CER after initial CRZ (any line of therapy) (N = 73)
X X mPFSmOS
X
44
Roeper et al. (2017)ABSTR; J Clin Oncol
Obs N = 24 CRZ alone; CER or BRIG or osimertinib after initial CRZ(n = 22)
X X mOS X X
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Systematic Review of Sequencing of Anaplastic Lymphoma Kinase Inhibitors in ALK-Positive Non–Small Cell Lung Cancer
ALK
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Reference, Country, Study Name (if Known), NCT #
Study Type (CT or Obs)
Primary Tx or Tx Sequence(s) Studied N/(n) Pr
esen
t?
Pres
ent?
Pres
ent?
Resu
lts?
a
Pres
ent?
Resu
lts?
Pres
ent?
Resu
lts?
a
45
Hong et al. (2017)OncotargetChina
Obs N = 33CRZ beyond PD (N = 33)
X
46
Hongmei et al. (2016)Ann OncolChinaABSTR
Obs N = 53CRZ patients with PD (N = 53)
X
47
Watanabe et al. (2016)Clin Lung CancerJapan
Obs N = 11ALEC after initial CRZ (N = 11)
X X mPFS X X mPFS X
48
Hida et al. (2016)Cancer SciJapanJapicCTI-132186
CT N = 35ALEC after initial ALKi or chemo or both: ALEC (n = 35)ALEC after initial CRZ (n = 23)
X X mPFS X
49
Iwama et al. (2017)ABSTR; J Thorac OncolALEC
CT N = 18ALEC after CRZ or ALK naïve (N = 18)
X X X mPFS X
50
Gettinger et al. (2016a)Lancet Oncol(US and Spain)NCT01449461
CT N = 137BRIG after initial CRZ or chemo or ALK naïve
X X X mPFSSurvival
X
S-13
Systematic Review of Sequencing of Anaplastic Lymphoma Kinase Inhibitors in ALK-Positive Non–Small Cell Lung Cancer
ALK
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ALK
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CRZ
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Reference, Country, Study Name (if Known), NCT #
Study Type (CT or Obs)
Primary Tx or Tx Sequence(s) Studied N/(n) Pr
esen
t?
Pres
ent?
Pres
ent?
Resu
lts?
a
Pres
ent?
Resu
lts?
Pres
ent?
Resu
lts?
a
51
Kim et al. (2016)Lancet OncolASCEND-1NCT01283516
CT N = 246ALKi-naïve patients (n = 83)ALKi-pretreated patients (n = 163)
X X X mPFSmOS
Survival Tx Dur
X
52
Felip et al. (2016a)ABSTR; J Clin OncolMultinationalPooled intracranial data from ASCEND-1 (NCT01283516) and ASCEND-3 (NCT01685138)
CT N = 76ASCEND-1: May have had prior Chemo followed by CER (n = 26)ASCEND-3: Chemo followed by CER (n = 50)
X
53
Liu et al. (2016)Curr Med Res OpinMultinationalPooled analysisASCEND-1 (NCT01283516) and ASCEND-2(NCT01685060)
CT N = 181CER after initial CRZ (N = 181)
X X mOS X
54
Tan et al. (2016b)J Thorac OncolMultinationalCER data from ASCEND-1 and ASCEND-3 compared with pooled CRZ data from PROFILE 1001, 1005, and 1007
CT N = 746CER after initial tx (n = 189)CRZ after initial tx (n = 557)
X
S-14
Systematic Review of Sequencing of Anaplastic Lymphoma Kinase Inhibitors in ALK-Positive Non–Small Cell Lung Cancer
ALK
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Reference, Country, Study Name (if Known), NCT #
Study Type (CT or Obs)
Primary Tx or Tx Sequence(s) Studied N/(n) Pr
esen
t?
Pres
ent?
Pres
ent?
Resu
lts?
a
Pres
ent?
Resu
lts?
Pres
ent?
Resu
lts?
a
55
Nishio et al. (2015)J Thorac OncolJapanNCT01634763
CT N = 20CER 300/450/600/750 mg after initial ALKi or ALK naïve
X X X Tx dur X
56
Shaw et al. (2014)N Engl J MedNCT01283516
CT N = 130CER after initial CRZ or chemo (N = 130)
X X X mPFSmOS
X
57
Felip et al. (2017)ABSTR; ASCOCER + NIVO
CT N = 36NIVO + CER 450 mg daily (n = 14)NIVO + CER 300 mg daily (n = 22)
X X X X X
58
Asao et al. (2017)Clin Lung CancerJapan
Obs N = 37CRZ or ALEC monotherapy or ALEC after initial CRZ (n = 34)Chemotherapy (n = 3)
X X X mPFSSurvival
X
59
Nosaki et al. (2017)ABSTR; J Clin OncolJapan
Obs N = 60CRZ (any line of therapy) (n = NR)ALEC or CER after initial CRZ (n = NR)CER after initial ALEC (n = NR)
X X mOS X X X mOS (not
reached)
60
Kayaniyil et al. (2016)Curr OncolCanada
Obs N = 97CRZ (n = 39)CRZ-naïve (n = 9)CER after CRZ (n = 21)
X X X mPFSmOS
Survival
X
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Systematic Review of Sequencing of Anaplastic Lymphoma Kinase Inhibitors in ALK-Positive Non–Small Cell Lung Cancer
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Reference, Country, Study Name (if Known), NCT #
Study Type (CT or Obs)
Primary Tx or Tx Sequence(s) Studied N/(n) Pr
esen
t?
Pres
ent?
Pres
ent?
Resu
lts?
a
Pres
ent?
Resu
lts?
Pres
ent?
Resu
lts?
a
61
Berge et al. (2013)US and Australia
Obs N = 38CRZ after initial PEM (n = 29)PEM after initial CRZ (n = 9)
X
62
Cadranel et al. (2016)Lung CancerMultinational
Obs N = 158CER or BRIG or ALEC after initial CRZ (n = 32)
X X Xc mOS (not
reached)
Survival
X X X
63
Cao et al. (2014)China
Obs N = 40CRZ after initial chemo or EGFR TKI (N = 40)
X
64
Cui et al. (2016)Cancer MedicineChina
Obs N = 80 CRZ 1L (1st tx received) (n = 30)Chemo 1L (n = 50)
X
65
Cui et al. (2015)Med OncolChina
Obs N = 72CRZ after initial tx(n = 67 evaluable)
X
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Systematic Review of Sequencing of Anaplastic Lymphoma Kinase Inhibitors in ALK-Positive Non–Small Cell Lung Cancer
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Reference, Country, Study Name (if Known), NCT #
Study Type (CT or Obs)
Primary Tx or Tx Sequence(s) Studied N/(n) Pr
esen
t?
Pres
ent?
Pres
ent?
Resu
lts?
a
Pres
ent?
Resu
lts?
Pres
ent?
Resu
lts?
a
66
Duruisseaux et al. (2017)OncotargetFrance
Obs N = 318CRZ after initial tx or ALK naïve (n = 105)Agent other than ALK after initial CRZ (n = 74)2nd Gen ALK after initial CRZ(n = 84)
X X Xd mOSSurvival
X X X
67
Lim et al. (2017)Korea
Obs N = 55CRZ after initial tx or tx naïve CRZ (n = 30)Patients who discontinued CRZ (n = 25)
X
68
Chen et al. (2017)China
Obs N = 97CRZ (al lines) (n = 52)Chemo (only tx received) (n = 36)BSC (n = 9)
X
69
Davis et al. (2015)US and CanadaABSTR IASLC
Obs N = 212CRZ 1L or 2L (n = 212)
X
70
DiBonaventura et al. (2016)ABSTR A711Multinational
Obs N = 1,471CRZ (n = 336)Non-CRZ(n = 1,135)
X
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Systematic Review of Sequencing of Anaplastic Lymphoma Kinase Inhibitors in ALK-Positive Non–Small Cell Lung Cancer
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Reference, Country, Study Name (if Known), NCT #
Study Type (CT or Obs)
Primary Tx or Tx Sequence(s) Studied N/(n) Pr
esen
t?
Pres
ent?
Pres
ent?
Resu
lts?
a
Pres
ent?
Resu
lts?
Pres
ent?
Resu
lts?
a
71
Kasan et al. (2015)Slovak RepublicABSTR IASLC
Obs N = 20CRZ after initial tx (N = 20)
X
72
Kolek et al. (2015)Czech RepublicABSTR IASLC
Obs N = 26CRZ (n = 14 evaluable)
X
73
Noronha et al. (2016)India
Obs N = 94CRZ (any line of therapy) (n = 69)No CRZ (n = 25)
X X
74
Reynolds et al. (2016)USABSTR IASLC
Obs N = 199CRZ (any line of therapy) (N = 199)
X
75
Yoshida et al. (2016)Japan
Obs N = 59May or may not have had prior tx/CRZ (regardless of line of therapy) (N = 59)
X X X NR X X
76
Xing et al. (2016)China
Obs N = 34CRZ any line of therapy (N = 34)
X
77
Zhang et al. (2016)China
Obs N = 19CRZ (n = 7)Chemo (n = 12)
X
78
Kang et al. (2016)ChinaABSTR IASLC
Obs N = 171CRZ with PD: Secondary resistance (n = 81)
X
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Systematic Review of Sequencing of Anaplastic Lymphoma Kinase Inhibitors in ALK-Positive Non–Small Cell Lung Cancer
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Reference, Country, Study Name (if Known), NCT #
Study Type (CT or Obs)
Primary Tx or Tx Sequence(s) Studied N/(n) Pr
esen
t?
Pres
ent?
Pres
ent?
Resu
lts?
a
Pres
ent?
Resu
lts?
Pres
ent?
Resu
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79
Kang et al. (2017)ABSTR ASCOChina
Obs N = 171CRZ with PD/primary resistance (n = 18)CRZ with PD/secondary (acquired) resistance (n = 82)
X
80
Guerin et al. (2015)US
Obs N = 119Chemo after initial CRZ (N = 119)
X
ABSTR = abstract; ALEC = alectinib; ALK = anaplastic lymphoma kinase; ALKi = anaplastic lymphoma kinase inhibitor; BM = brain metastases; BRIG = brigatinib; BSC = best supportive care; CER = ceritinib; chemo = chemotherapy; CIS = cisplatin; CRZ = crizotinib; CT = clinical trial; DOC = docetaxel; mos = months; mOS = median overall survival; mPFS = median progression-free survival; NA = not applicable; NIVO = nivolumab; NR = not reported; Obs = observational; PD = progressive disease; PEM = pemetrexed; Tx = treatment.
Note: No published information was identified for the treatment sequence: second-generation ALKi followed by crizotinib. a Results of interest included: mPFS, mOS, survival rate, and treatment duration.b Specific treatment sequence not specified.c Results reported from pooled data (i.e., patient population includes any of the following treatment sequences: ceritinib after initial crizotinib or alectinib after initial crizotinib, or brigatinib after initial crizotinib). d Results reported from pooled data (i.e., patient population includes any of the following treatment sequences: ceritinib after initial crizotinib or alectinib after initial crizotinib or lorlatinib after initial crizotinib or crizotinib after crizotinib, or crizotinib and anti-HSP90 after initial crizotinib).
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