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Meta-Analysis
. 2022 Jan 7;1(1):CD013453.
doi: 10.1002/14651858.CD013453.pub2.

Targeted therapy for advanced anaplastic lymphoma kinase (<I>ALK</I>)-rearranged non-small cell lung cancer

Laird B Cameron  1 , Nadia Hitchen  1 , Elias Chandran  1 , Tessa Morris  2   3 , Renée Manser  4   5   6 , Benjamin J Solomon  7 , Vanessa Jordan  8
Affiliations
Meta-Analysis

Targeted therapy for advanced anaplastic lymphoma kinase (<I>ALK</I>)-rearranged non-small cell lung cancer

Laird B Cameron et al. Cochrane Database Syst Rev. .

Abstract

Background: Targeted therapies directed at specific driver oncogenes have improved outcomes for individuals with advanced non-small cell lung cancer (NSCLC). Approximately 5% of lung adenocarcinomas, the most common histologic subtype of NSCLC, harbour rearrangements in the anaplastic lymphoma kinase (ALK) gene leading to constitutive activity of the ALK kinase. Crizotinib was the first tyrosine kinase inhibitor (TKI) demonstrated to be effective in advanced NSCLC. Next-generation ALK TKIs have since been developed including ceritinib, alectinib, brigatinib, ensartinib, and lorlatinib, and have been compared with crizotinib or chemotherapy in randomised controlled trials (RCTs). These ALK-targeted therapies are currently used in clinical practice and are endorsed in multiple clinical oncology guidelines.

Objectives: To evaluate the safety and efficacy of ALK inhibitors given as monotherapy to treat advanced ALK-rearranged NSCLC.

Search methods: We conducted electronic searches in the Cochrane Lung Cancer Group Specialised Register, Cochrane Central Register of Controlled Trials, MEDLINE, and Embase. We also searched conference proceedings from the American Society for Clinical Oncology (ASCO), European Society of Medical Oncology (ESMO), and International Association for the Study of Lung Cancer (IASLC) World Conference on Lung Cancer, as well as the reference lists of retrieved articles. All searches were conducted from 2007 until 7 January 2021.

Selection criteria: We included RCTs comparing ALK inhibitors with cytotoxic chemotherapy or another ALK inhibitor in individuals with incurable locally advanced or metastatic pathologically confirmed ALK-rearranged NSCLC.

Data collection and analysis: Two review authors independently assessed studies for eligibility, extracted study characteristics and outcome data, and assessed risk of bias using the Cochrane risk of bias tool for each included study. We assessed the certainty of evidence using GRADE. Primary outcomes were progression-free survival (PFS) and adverse events (AE); secondary outcomes were overall survival (OS), OS at one year, overall response rate (ORR) by RECIST (Response Evaluation Criteria in Solid Tumours) criteria, and health-related quality of life (HRQoL). We performed a meta-analysis for all outcomes, where appropriate, using the fixed-effect model. We reported hazard ratios (HR) for PFS, OS, and a composite HRQoL of life outcome (time to deterioration), and risk ratios (RR) for AE, ORR, and one-year OS. We presented 95% confidence intervals (95% CIs) and used the I² statistic to investigate heterogeneity. We planned comparisons of 'ALK inhibitor versus chemotherapy' and 'next-generation ALK inhibitor versus crizotinib' with subgroup analysis by type of ALK inhibitor, line of treatment, and baseline central nervous system involvement.

Main results: Eleven studies (2874 participants) met our inclusion criteria: six studies compared an ALK inhibitor (crizotinib, ceritinib, and alectinib) to chemotherapy, and five studies compared a next-generation ALK inhibitor (alectinib, brigatinib, and lorlatinib) to crizotinib. We assessed the evidence for most outcomes as of moderate to high certainty. Most studies were at low risk for selection, attrition, and reporting bias; however, no RCTs were blinded, resulting in a high risk of performance and detection bias for outcomes reliant on subjective measurement. ALK inhibitor versus chemotherapy Treatment with ALK inhibitors resulted in a large increase in PFS compared to chemotherapy (HR 0.45, 95% CI 0.40 to 0.52, 6 RCTs, 1611 participants, high-certainty evidence). This was found regardless of line of treatment. ALK inhibitors may result in no difference in overall AE rate when compared to chemotherapy (RR 1.01, 95% CI 1.00 to 1.03, 5 RCTs, 1404 participants, low-certainty evidence). ALK inhibitors slightly improved OS (HR 0.84, 95% CI 0.72 to 0.97, 6 RCTs, 1611 participants, high-certainty evidence), despite most included studies having a significant number of participants crossing over from chemotherapy to receive an ALK inhibitor after the study period. ALK inhibitors likely increase ORR (RR 2.43, 95% CI 2.16 to 2.75, 6 RCTs, 1611 participants, moderate-certainty evidence) including in measurable baseline brain metastases (RR 4.88, 95% CI 2.18 to 10.95, 3 RCTs, 108 participants) when compared to chemotherapy. ALK inhibitors result in a large increase in the HRQoL measure, time to deterioration (HR 0.52, 95% CI 0.44 to 0.60, 5 RCTs, 1504 participants, high-certainty evidence) when compared to chemotherapy. Next-generation ALK inhibitor versus crizotinib Next-generation ALK inhibitors resulted in a large increase in PFS (HR 0.39, 95% CI 0.33 to 0.46, 5 RCTs, 1263 participants, high-certainty evidence), particularly in participants with baseline brain metastases. Next-generation ALK inhibitors likely result in no difference in overall AE (RR 1.00, 95% CI 0.98 to 1.01, 5 RCTs, 1263 participants, moderate-certainty evidence) when compared to crizotinib. Next-generation ALK inhibitors likely increase OS (HR 0.71, 95% CI 0.56 to 0.90, 5 RCTs, 1263 participants, moderate-certainty evidence) and slightly increase ORR (RR 1.18, 95% CI 1.10 to 1.25, 5 RCTs, 1229 participants, moderate-certainty evidence) including a response in measurable brain metastases (RR 2.45, 95% CI 1.7 to 3.54, 4 RCTs, 138 participants) when compared to crizotinib. Studies comparing ALK inhibitors were conducted exclusively or partly in the first-line setting.

Authors' conclusions: Next-generation ALK inhibitors including alectinib, brigatinib, and lorlatinib are the preferred first systemic treatment for individuals with advanced ALK-rearranged NSCLC. Further trials are ongoing including investigation of first-line ensartinib. Next-generation inhibitors have not been compared to each other, and it is unknown which should be used first and what subsequent treatment sequence is optimal.

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Conflict of interest statement

Laird B Cameron: none known. LC is a member of the Thoracic Oncology Group Australasia (formerly Australasian Lung Cancer Trials Group) and chairperson of the New Zealand Lung Oncology Special Interest Group.

Nadia Hitchen: none known.

Elias Chandran: none known.

Tessa Morris: none known

Renée Manser: none known.

Benjamin J Solomon is an author on phase III clinical studies of crizotinib, ceritinib, and lorlatinib. He has served on advisory boards for Pfizer, Novartis, Roche‐Genentech, AstraZeneca, Merck, Bristol Myers Squibb, Gritstone Oncology, and Loxo Oncology, and he has spoken at meetings where costs were sponsored by industry.

Vanessa Jordan: none known.

Figures

1
1
Study flow diagram.
2
2
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
3
3
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
4
4
Forest plot of comparison: 1 ALK inhibitor versus chemotherapy, outcome: 1.1 Progression‐free survival subgrouped by line of treatment.
5
5
Forest plot of comparison: 1 ALK inhibitor versus chemotherapy, outcome: 1.4 Overall adverse events subgrouped by line of treatment.
6
6
Forest plot of comparison: 1 ALK inhibitor versus chemotherapy, outcome: 1.9 Grade 5 adverse events (excluding progressive disease) subgrouped by line of treatment.
7
7
Forest plot of comparison: 1 ALK inhibitor versus chemotherapy, outcome: 1.16 Overall survival subgrouped by line of treatment.
8
8
Forest plot of comparison: 2 Next‐generation ALK inhibitor versus crizotinib, outcome: 2.1 Progression‐free survival subgrouped by type of ALK inhibitor.
9
9
Forest plot of comparison: 2 Next‐generation ALK inhibitor versus crizotinib, outcome: 2.3 Overall adverse events subgrouped by type of ALK inhibitor.
10
10
Forest plot of comparison: 2 Next‐generation ALK inhibitor versus crizotinib, outcome: 2.5 Grade 5 adverse events (excluding progressive disease) subgrouped by type of ALK inhibitor.
11
11
Forest plot of comparison: 2 Next‐generation ALK inhibitor versus crizotinib, outcome: 2.11 Overall survival subgrouped by type of ALK inhibitor.
1.1
1.1. Analysis
Comparison 1: ALK inhibitor versus chemotherapy, Outcome 1: Progression‐free survival subgrouped by line of treatment
1.2
1.2. Analysis
Comparison 1: ALK inhibitor versus chemotherapy, Outcome 2: Progression‐free survival subgrouped by type of ALK inhibitor
1.3
1.3. Analysis
Comparison 1: ALK inhibitor versus chemotherapy, Outcome 3: Progression‐free survival in people with CNS disease
1.4
1.4. Analysis
Comparison 1: ALK inhibitor versus chemotherapy, Outcome 4: Overall adverse events subgrouped by line of treatment
1.5
1.5. Analysis
Comparison 1: ALK inhibitor versus chemotherapy, Outcome 5: Overall adverse events subgrouped by type of ALK inhibitor
1.6
1.6. Analysis
Comparison 1: ALK inhibitor versus chemotherapy, Outcome 6: Grade 3/4 adverse events subgrouped by line of treatment
1.7
1.7. Analysis
Comparison 1: ALK inhibitor versus chemotherapy, Outcome 7: Grade 3/4 adverse events subgrouped by type of ALK inhibitor
1.8
1.8. Analysis
Comparison 1: ALK inhibitor versus chemotherapy, Outcome 8: Total Grade 5 adverse events subgrouped by line of treatment
1.9
1.9. Analysis
Comparison 1: ALK inhibitor versus chemotherapy, Outcome 9: Grade 5 adverse events (excluding progressive disease) subgrouped by line of treatment
1.10
1.10. Analysis
Comparison 1: ALK inhibitor versus chemotherapy, Outcome 10: Grade 5 adverse events (excluding progressive disease) subgrouped by ALK inhibitor
1.11
1.11. Analysis
Comparison 1: ALK inhibitor versus chemotherapy, Outcome 11: Dose intensity
1.12
1.12. Analysis
Comparison 1: ALK inhibitor versus chemotherapy, Outcome 12: Gastrointestinal adverse events
1.13
1.13. Analysis
Comparison 1: ALK inhibitor versus chemotherapy, Outcome 13: Haematological adverse events
1.14
1.14. Analysis
Comparison 1: ALK inhibitor versus chemotherapy, Outcome 14: Hepatic adverse events
1.15
1.15. Analysis
Comparison 1: ALK inhibitor versus chemotherapy, Outcome 15: General any grade adverse events
1.16
1.16. Analysis
Comparison 1: ALK inhibitor versus chemotherapy, Outcome 16: Overall survival subgrouped by line of treatment
1.17
1.17. Analysis
Comparison 1: ALK inhibitor versus chemotherapy, Outcome 17: Overall survival subgrouped by type of ALK inhibitor
1.18
1.18. Analysis
Comparison 1: ALK inhibitor versus chemotherapy, Outcome 18: Overall survival at 1 year
1.19
1.19. Analysis
Comparison 1: ALK inhibitor versus chemotherapy, Outcome 19: Overall response rate by line of treatment
1.20
1.20. Analysis
Comparison 1: ALK inhibitor versus chemotherapy, Outcome 20: Overall response rate subgrouped by type of ALK inhibitor
1.21
1.21. Analysis
Comparison 1: ALK inhibitor versus chemotherapy, Outcome 21: Partial and complete response rate
1.22
1.22. Analysis
Comparison 1: ALK inhibitor versus chemotherapy, Outcome 22: Overall and complete response rate in people with measurable baseline CNS disease
1.23
1.23. Analysis
Comparison 1: ALK inhibitor versus chemotherapy, Outcome 23: Quality of life: time to deterioration in composite endpoint (cough, dyspnoea, and chest pain)
2.1
2.1. Analysis
Comparison 2: Next‐generation ALK inhibitor versus crizotinib, Outcome 1: Progression‐free survival subgrouped by type of ALK inhibitor
2.2
2.2. Analysis
Comparison 2: Next‐generation ALK inhibitor versus crizotinib, Outcome 2: Progression‐free survival in people with CNS disease
2.3
2.3. Analysis
Comparison 2: Next‐generation ALK inhibitor versus crizotinib, Outcome 3: Overall adverse events subgrouped by type of ALK inhibitor
2.4
2.4. Analysis
Comparison 2: Next‐generation ALK inhibitor versus crizotinib, Outcome 4: Grade 3/4 adverse events subgrouped by type of ALK inhibitor
2.5
2.5. Analysis
Comparison 2: Next‐generation ALK inhibitor versus crizotinib, Outcome 5: Grade 5 adverse events (excluding progressive disease) subgrouped by type of ALK inhibitor
2.6
2.6. Analysis
Comparison 2: Next‐generation ALK inhibitor versus crizotinib, Outcome 6: Dose intensity
2.7
2.7. Analysis
Comparison 2: Next‐generation ALK inhibitor versus crizotinib, Outcome 7: Gastrointestinal adverse events
2.8
2.8. Analysis
Comparison 2: Next‐generation ALK inhibitor versus crizotinib, Outcome 8: Haematological adverse events
2.9
2.9. Analysis
Comparison 2: Next‐generation ALK inhibitor versus crizotinib, Outcome 9: Hepatic adverse events
2.10
2.10. Analysis
Comparison 2: Next‐generation ALK inhibitor versus crizotinib, Outcome 10: General adverse events
2.11
2.11. Analysis
Comparison 2: Next‐generation ALK inhibitor versus crizotinib, Outcome 11: Overall survival subgrouped by type of ALK inhibitor
2.12
2.12. Analysis
Comparison 2: Next‐generation ALK inhibitor versus crizotinib, Outcome 12: Overall survival at 1 year subgrouped by type of ALK inhibitor
2.13
2.13. Analysis
Comparison 2: Next‐generation ALK inhibitor versus crizotinib, Outcome 13: Overall response rate subgrouped by type of ALK inhibitor
2.14
2.14. Analysis
Comparison 2: Next‐generation ALK inhibitor versus crizotinib, Outcome 14: Partial and complete response rate
2.15
2.15. Analysis
Comparison 2: Next‐generation ALK inhibitor versus crizotinib, Outcome 15: Overall and complete response rate in people with measurable baseline CNS disease
2.16
2.16. Analysis
Comparison 2: Next‐generation ALK inhibitor versus crizotinib, Outcome 16: Quality of life: time to deterioration in composite endpoint (cough, dyspnoea, and chest pain)
See this image and copyright information in PMC

Update of

  • doi: 10.1002/14651858.CD013453

References

References to studies included in this review

ALESIA 2019 {published data only}
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ALEX 2017 {published data only}
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ALTA‐1L 2019 {published data only}
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ALUR 2018 {published data only}
    1. De Castro J, Novello S, Mazieres J, Oh IJ, Migliorino MR, Helland A, et al.CNS efficacy results from the phase III ALUR study of alectinib versus chemotherapy in previously treated ALK1 NSCLC. Annals of Oncology 2017;28(Suppl 5):v481. [DOI: 10.1093/annonc/mdx380.048] - DOI
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    1. NCT02604342.Alectinib versus pemetrexed or docetaxel in anaplastic lymphoma kinase (ALK)-Positive advanced non-small cell lung cancer (NSCLC) participants previously treated with platinum-based chemotherapy and crizotinib. clinicaltrials.gov/ct2/show/NCT02604342.
ASCEND‐4 2017 {published data only}
    1. De Castro G, Shao-Weng Tan D, Crino L, Wu YL, Paz-Ares L, Wolf J, et al.First-line ceritinib versus chemotherapy in patients with ALK-rearranged (ALK+) NSCLC: a randomized, phase 3 study (ASCEND-4). Journal of Thoracic Oncology 2017;12(1):S7.
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ASCEND‐5 2017 {published data only}
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CROWN 2020 {published data only}
    1. CTRI/2018/01/011325.Study with investigational drug PF-06463922 and comparator crizotinib in patients with a specific type of advanced lung cancer. www.ctri.nic.in/Clinicaltrials/pdf_generate.php?trialid=22321&EncHid....
    1. EUCTR2016-003315-35-PL.Study with investigational drug PF-06463922 and comparator crizotinib in patients with a specific type of advanced lung cancer. clinicaltrialsregister.eu/ctr-search/search?query=2016-003315-35.
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    1. NCT03052608.A study of lorlatinib versus crizotinib in first line treatment of patients with ALK-positive NSCLC. clinicaltrials.gov/ct2/show/NCT03052608.
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J‐ALEX 2017 {published data only}
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    1. JPRN-JapicCTI-132316.Open-label randomized phase III study of the efficacy and safety of CH5424802(AF802) in ALK-positive advanced or recurrent non-small cell lung cancer with crizotinib control. www.clinicaltrials.jp/user/showCteDetailE.jsp?japicId=JapicCTI-132316.
    1. Kim Y, Hida T, Nokihara H, Kondo M, Azuma K, Seto T, et al.Alectinib (ALC) versus crizotinib (CRZ) in ALK-positive non-small cell lung cancer (ALK+ NSCLC): primary results from phase III study (J-ALEX). Journal of Thoracic Oncology 2017;12(1):S378‐9.
    1. Nakagawa K, Hida T, Nokihara H, Morise M, Azuma K, Kim YH, et al.Final progression-free survival results from the J-ALEX study of alectinib versus crizotinib in ALK-positive non-small-cell lung cancer. Lung Cancer 2020;139:195-9. - PubMed
PROFILE 1007 2013 {published data only}
    1. Blackhall F, Hirsh V, Kim DW, Besse B, Nokihara H, Han JY, et al .Impact of crizotinib on patient-reported general health status compared with single-agent chemotherapy in a phase III study of advanced ALK-positive non-small cell lung cancer (NSCLC). European Journal of Cancer 2013;49(Suppl 2):S799‐800. [DOI: 10.1016/S0959-8049%2813%2970065-0] - DOI
    1. Blackhall F, Kim DW, Besse B, Nokihara H, Han JY, Wilner KD, et al.Patient-reported outcomes and quality of life in PROFILE 1007: a randomized trial of crizotinib compared with chemotherapy in previously treated patients with ALK-positive advanced non-small-cell lung cancer. Journal of Thoracic Oncology 2014;9(11):1625‐33. [DOI: 10.1097/JTO.0000000000000318] - DOI - PubMed
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    1. EUCTR2009-012595-27-BG.Phase 3, randomized, open-label study of the efficacy and safety of pf 02341066 versus standard of care chemotherapy (pemetrexed or docetaxel) in patients with advanced non-small cell lung cancer (Nsclc) harboring a translocation or inversion event involving the anaplastic lymphoma kinase (Alk) gene locus. trialsearch.who.int/Trial2.aspx?TrialID=NCT00932893 (first received 30 June 2009).
    1. NCT00932893.An investigational drug, PF-02341066 is being studied versus standard of care in patients with advanced non-small cell lung cancer with a specific gene profile involving the anaplastic lymphoma kinase (ALK) gene. clinicaltrials.gov/ct2/show/NCT00932893.
PROFILE 1014 2014 {published data only}
    1. EUCTR2010-021336-33-PT.Cancer of the lung with special characteristics (nonsquamous histology and ALK fusion gene event). trialsearch.who.int/Trial2.aspx?TrialID=NCT01154140.
    1. Felip E, Blackhall FH, Mok T, Cappuzzo F, Wilner KD, Reisman A, et al.Impact of crizotinib on patient-reported general health status compared with chemotherapy in patients with no prior systemic treatment for advanced non-squamous ALK-positive non-small cell lung cancer (NSCLC). Journal of Clinical Oncology 2015;33(15 Suppl):8101.
    1. Lu Y, Zhou J, Chung CH, Masters E, Wilner K, Selaru P, et al.Patient-reported symptoms and quality of life (QOL) in East Asian patients with ALK+ NSCLC treated with crizotinib versus chemotherapy. Journal of Thoracic Oncology 2017;12(1):S1167.
    1. Mok TSK, Kim DW, Wu YL, Nakagawa K, Mekhail T, Felip E, et al.Overall survival (OS) for first-line crizotinib versus chemotherapy in ALK1 lung cancer: updated results from PROFILE 1014. Annals of Oncology 2017;28(Suppl 5):v605-49. [DOI: 10.1093/annonc/mdx440.053] - DOI
    1. Nakagawa K, Kim DW, Wu YL, Solomon BJ, Mekhail T, Felip E, et al.First-line crizotinib versus pemetrexed + cisplatin/carboplatin in Asian patients with advanced ALK+ NSCLC in PROFILE 1014. Annals of Oncology 2014;25(Suppl 5):v2. [DOI: 10.1093/annonc/mdu395.1] - DOI
PROFILE 1029 2018 {published data only}
    1. NCT01639001.A study of crizotinib versus chemotherapy in previously untreated ALK positive East Asian non-small cell lung cancer patients. clinicaltrials.gov/ct2/show/NCT01639001.
    1. Wu YL, Lu S, Lu Y, Zhou J, Shi YK, Sriuranpong V, et al.Results of PROFILE 1029, a phase III comparison of first-line crizotinib versus chemotherapy in East Asian patients with ALK-positive advanced non–small cell lung cancer. Journal of Thoracic Oncology 2018;13(10):1539‐48. [DOI: 10.1016/j.jtho.2018.06.012] - DOI - PubMed
    1. Zhou J, Lu Y, Chung CH, Masters E, Wilner K, Tang Y, Wu YL.Patient reported general health status in a study of crizotinib versus chemotherapy in patients with non-small cell lung cancer (NSCLC). Journal of Thoracic Oncology 2017;12(1):S1169.

References to studies excluded from this review

Blackhall 2017 {published data only}
    1. Blackhall F, Ross Camidge D, Shaw AT, Soria JC, Solomon BJ, et al.Final results of the large-scale multinational trial PROFILE 1005: efficacy and safety of crizotinib in previously treated patients with advanced/metastatic ALK-positive non-small-cell lung cancer. ESMO Open 2017;2(3):e000219. [DOI: 10.1136/esmoopen-2017-000219] - DOI - PMC - PubMed
Cho 2017 {published data only}
    1. Cho BC, Kim DW, Bearz A, Laurie SA, McKeage M, Borra G, et al.ASCEND-8: a randomized phase 1 study of ceritinib, 450 mg or 600 mg, taken with a low-fat meal versus 750 mg in fasted state in patients with anaplastic lymphoma kinase (ALK)-rearranged metastatic non-small cell lung cancer (NSCLC). Journal of Thoracic Oncology 2017;12(9):1357‐67. [DOI: 10.1016/j.jtho.2017.07.005] - DOI - PubMed
    1. Cho BC, Obermannova R, Bearz A, Kim D, Orlov S, Borra G, et al.Efficacy and updated safety of ceritinib (450 mg or 600 mg) with low-fat meal vs 750 mg fasted in ALK+ metastatic NSCLC. Journal of Thoracic Oncology 2017;12(11):S1757.
    1. Cho BC, Obermannova R, Bearz A, McKeage M, Kim DW, Batra U, et al.Efficacy and safety of ceritinib (450 mg/d or 600 mg/d) with food versus 750-mg/d fasted in patients with ALK receptor tyrosine kinase (ALK)–positive NSCLC: primary efficacy results from the ASCEND-8 study. Journal of Thoracic Oncology 2019;14(7):1255-65. [DOI: 10.1016/j.jtho.2019.03.002] - DOI - PubMed
Chow 2019 {published data only}
    1. Chow LQ, Barlesi F, Bertino EM, den Bent MJ, Wakelee H, Wen PY, et al.Results of the ASCEND-7 phase II study evaluating ALK inhibitor (ALKi) ceritinib in patients (pts) with ALK+ non-small cell lung cancer (NSCLC) metastatic to the brain. Annals of Oncology 2019;30(Suppl 5):v602‐3.
EUCTR2012‐003474‐36‐BE {published data only}
    1. EUCTR2012-003474-36-BE.A clinical study of oral LDK378 in adult patients with ALK-activated non-small cell lung cancer and who have not been previously treated with crizotinib. www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:201... (first received 25 October 2012).
Felip 2016 {published data only}
    1. Felip E, Orlov S, Park K, Yu C, Tsai CM, Nishio M, et al.Phase 2 study of ceritinib in ALKi-naive patients (pts) with ALK-rearranged (ALK+) non-small cell lung cancer (NSCLC): whole body responses in the overall pt group and in pts with baseline brain metastases (BM). In: Annals of Oncology. Vol. 27. 2016. [DOI: 10.1093/annonc/mdw383.3] - DOI
Gao 2016 {published data only}
    1. Gao L, Zhang Y, Hu B, Liu J, Kong P, Lou S, et al.Phase II multicenter, randomized, double-blind controlled study of efficacy and safety of umbilical cord–derived mesenchymal stromal cells in the prophylaxis of chronic graft-versus-host disease after HLA-haploidentical stem-cell transplantation. Journal of Clinical Oncology 2016;34(24):2843-50. - PubMed
JPRN‐JapicCTI‐184073 {published data only}
    1. JPRN-JapicCTI-184073.A study comparing adjuvant alectinib versus adjuvant platinum-based chemotherapy in patients with ALK positive non-small cell lung cancer. trialsearch.who.int/Trial2.aspx?TrialID=JPRN-JapicCTI-184073.
Kim 2016 {published data only}
    1. Ahn M, Camidge DR, Tiseo M, Reckamp K, Hansen K, Kim S, et al.Brigatinib in crizotinib-refractory ALK+ NSCLC: updated efficacy and safety results from ALTA, a randomized phase 2 trial. Journal of Thoracic Oncology 2017;12(11):S1755‐6.
    1. Ahn MJ, Camidge DR, Tiseo M, Reckamp KL, Hansen KH, Kim SW, et al.Brigatinib (BRG) in crizotinib (CRZ)-refractory ALK+ non-small cell lung cancer (NSCLC): updates from ALTA, a pivotal randomized phase 2 trial. Journal of Clinical Oncology 2017;35(15 Suppl):e20503.
    1. Camidge DR, Kim DW, Tiseo M, Langer CJ, Ahn MJ, Shaw AT, et al.Exploratory analysis of brigatinib activity in patients with anaplastic lymphoma kinase-positive non-small-cell lung cancer and brain metastases in two clinical trials. Journal of Clinical Oncology 2018;36(26):2693‐701. [DOI: 10.1200/JCO.2017.77.5841] - DOI - PubMed
    1. Camidge DR, Tiseo M, Ahn M, Reckamp K, Hansen K, Kim S, et al.Depth of target lesion response to brigatinib and its association with outcomes in patients with ALK+ NSCLC in the ALTA trial. Journal of Thoracic Oncology 2017;12(11):S1892.
    1. Camidge DR, Tiseo M, Ahn MJ, Reckamp K, Hansen K, Kim SW, et al.Brigatinib in crizotinib-refractory ALK+ NSCLC: central assessment and updates from ALTA, a pivotal randomized phase 2 trial. Journal of Thoracic Oncology 2017;12(1):S1167‐9.
Lenderking 2017 {published data only}
    1. Lenderking WR, Speck RM, Huang JT, Huang H, Kerstein D, Reichmann W, et al.Evaluating clinically meaningful change of the EORTC QLQ-C30 in patients with NSCLC. Value in Health 2017;20(5):A120.
Liang 2019 {published data only}
    1. Liang F, Shen D.EP1.14-02 comparative efficacy of first-line ceritinib at a dose of 450mg with food and alectinib in advanced ALK+ NSCLC. Journal of Thoracic Oncology 2019;14(10):S1032. [DOI: 10.1016/j.jtho.2019.08.2287] - DOI
NCT02134912 {published data only}
    1. NCT02134912.S1300: Pemetrexed Disodium With or Without Crizotinib in Treating Patients With Stage IV Non-Small Cell Lung Cancer That Has Progressed After Crizotinib. clinicaltrials.gov/ct2/show/NCT02134912.
Park 2020 {published data only}
    1. Park S, Lee YG, Park JH, Lee GW, Kang EJ, Choi YJ, et al.A phase III, open-label, randomized study of atezolizumab in combination with carboplatin + paclitaxel + bevacizumab compared with pemetrexed + cisplatin or carboplatin with stage IV non-squamous non-small cell lung cancer (NSCLC) with activating EGFR mutation or ALK translocation (ATLAS Trial). Journal of Clinical Oncology 2020;38(15 Suppl):TPS9636.
Reckamp 2019 {published data only}
    1. Reckamp K, Lin HM, Huang J, Proskorovsky I, Reichmann W, Krotneva S, et al.Comparative efficacy of brigatinib versus ceritinib and alectinib in patients with crizotinib-refractory anaplastic lymphoma kinase-positive non-small cell lung cancer. Current Medicine Respiratory Opinion 2019;35(4):569-76. [DOI: 10.1080/03007995.2018.1520696] - DOI - PubMed
Wolf 2015 {published data only}
    1. Wolf J, Schneider CP, Potzner M, Cazorla Arratia P, Shen J, Branle F, et al.The phase II ASCEND-7 (CLDK378A2205) trial: ceritinib in patients (pts) with ALK-rearranged (ALK+) non-small cell lung cancer (NSCLC) metastatic to the brain and/or leptomeninges. Oncology Research and Treatment 2015;38:138. [DOI: 10.1159/000439070] - DOI
Zhao 2015 {published data only}
    1. Zhao J, Zhang K, Zhang L, Wang H.Clinical efficacy of crizotinib in advanced ALK positive non-small cell lung cancer. Zhongguo fei ai za zhi [Chinese Journal of Lung Cancer] 2015;18(10):616‐20. [DOI: 10.3779/j.issn.1009-3419.2015.10.03] - DOI - PMC - PubMed

References to ongoing studies

eXalt3 2020 {published data only}
    1. EUCTR2015-004147-40-NL.A clinical trial comparing ensartinib (study drug) to crizotinib in lung cancer patients. trialsearch.who.int/Trial2.aspx?TrialID=NCT02767804.
    1. Horn L, Wu Y, Reck M, Wakelee H, Liang C, Harrow K, et al.eXalt3: phase 3 randomized study comparing ensartinib to crizotinib in anaplastic lymphoma kinase positive non-small cell lung cancer patients. Journal of Thoracic Oncology 2018;13(10):S582. [DOI: 10.1016/j.jtho.2018.08.858] - DOI
    1. Horn L, Wu YL, Reck M, Liang C, Tan F, Harrow K, et al.EXalt3: a phase III study of ensartinib (X-396) in anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC). Journal of Clinical Oncology 2017;35(15):TPS8578.
    1. Horn L, Wu YL, Reck M, Liang C, Tan F, Harrow K, et al.EXalt3: phase 3 randomized study comparing ensartinib to crizotinib in anaplastic lymphoma kinase (ALK) positive non-small cell lung cancer (NSCLC) patients. Journal of Thoracic Oncology 2018;13(4):S116.
    1. Horn L, Wu YL, Reck M, Liang C, Tan F, Harrow K et al.EXalt3: a phase III study of ensartinib (X-396) in anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC). Annals of Oncology 2017;28:iii51. [DOI: 10.1093/annonc/mdx085] - DOI
NCT03737994 {published data only}
    1. NCT03737994.Biomarker/ALK inhibitor combinations in treating patients with stage IV ALK positive non-small cell lung cancer (The NCI-NRG ALK master protocol). clinicaltrials.gov/ct2/show/NCT03737994.
NCT04009317 {published data only}
    1. NCT04009317.Study of TQ-B3139 versus crizotinib in the first line treatment of subjects with anaplastic lymphoma kinase (ALK) positive non-small cell lung cancer (NSCLC). clinicaltrials.gov/ct2/show/NCT04009317.
NCT04318938 {published data only}
    1. NCT04318938.Advancing brigatinib properties in ALK+ NSCLC patients by deep phenotyping. clinicaltrials.gov/ct2/show/NCT04318938.
NCT04632758 {published data only}
    1. NCT04632758.Study comparing WX-0593 to crizotinib in ALK positive non-small cell lung cancer (NSCLC) patients. clinicaltrials.gov/ct2/show/NCT04632758.
Popat 2019 {published data only}
    1. NCT03596866.An efficacy study comparing brigatinib versus alectinib in advanced anaplastic lymphoma kinase-positive non-small-cell lung cancer participants who have progressed on crizotinib. clinicaltrials.gov/ct2/show/NCT03596866.
    1. Popat S, Liu G, Lu S, Song G, Samnotra V, Yang JCH.Phase III ALTA-3 study of brigatinib (BRG) versus alectinib (ALC) in patients (pts) with advanced anaplastic lymphoma kinase (ALK)−positive non–small cell lung cancer (NSCLC) that progressed on crizotinib (CRZ). Annals of Oncology 2019;30:v653-4. [DOI: 10.1093/annonc/mdz260.108] - DOI

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