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)

S-2

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

S-3

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.

S-4

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

S-5

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

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

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

S-6

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

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

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

S-7

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

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

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

S-8

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

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

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

S-9

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

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

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

S-10

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

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

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

S-11

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

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

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

S-12

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

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

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

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

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

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

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

S-15

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

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

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

S-16

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

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

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

S-17

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

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

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

S-18

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

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

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).

S-19