ALK-positive Advanced NSCLC PatientsNCT07045610
Primary Resistance Mechanisms of ALK TKIs
An observational study of ALK-positive Advanced NSCLC Patients and Primary Resistance, run by National Taiwan University Hospital at 1 site in Taiwan.
Trial summary
Anaplastic lymphoma kinase (ALK) gene rearrangement is a known oncogenic driver in non-small cell lung cancer (NSCLC). ALK tyrosine kinase inhibitors (TKIs) have been clearly shown to produce excellent therapeutic effects and prolong survival in patients with this gene mutation. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- ALK-positive Advanced NSCLC Patients, Primary Resistance, NGS
- What is being tested?
- re-biopsy tumor with primary ALK tKI resistance for NGS
- How many people
- 20 participants
- Where
- 1 siteTaiwan
- Study dates
- 1 Jul 2025to 1 Jul 2028
- Phase
- Observational
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Study population: ALK-positive advanced NSCLC patients who develop primary resistance or rapid progression (within 3-6 months) during ALK inhibitor treatment.
Who may be able to join
- Age ≥ 18 years old.
- Histologically or cytologically diagnosed NSCLC
- ALK gene fusion detected at initial diagnosis of NSCLC
- Patients exhibiting primary resistance to ALK-TKI therapy, defined as the absence of initial response or progression within 3 to 6 months of treatment initiation, were included.
- Able and willing to provide written informed consent prior to performing any study related procedures and to comply with the study protocol.
Who cannot join
- Unable to provide written inform consent
- The patients had received other systemic treatments except ALK TKI.
- Unable to undergo tumor biopsy or venipuncture
Trial locations and contacts
1 site in 1 country. Contact the study team or a site near you to ask about taking part.
Taiwan1 site
National Taiwan University Hospital
Taipei, 10099
Shang-Gin Wu, 0972651242, b8501091@gmail.com
About this study
Official title: Explore the Primary Resistance Mechanisms of Anaplastic Lymphoma Kinase Inhibitors
Anaplastic lymphoma kinase (ALK) gene rearrangement is a known oncogenic driver in non-small cell lung cancer (NSCLC). ALK tyrosine kinase inhibitors (TKIs) have been clearly shown to produce excellent therapeutic effects and prolong survival in patients with this gene mutation. According to current treatment guidelines, ALK inhibitors are the first-line treatment of choice for ALK-positive advanced NSCLC patients. However, although ALK TKIs are very effective, there is still a small group of patients who do not achieve good treatment outcomes, developing resistance and tumor progression within 3 to 6 months of initial ALK TKI use. This is called primary resistance. Intrinsic resistance to ALK inhibition occurs when the best clinical response after first-generation and second/third-generation TKI treatment is disease progression. Approximately 5-7% of cases after crizotinib treatment, 9% after ceritinib treatment, and 25% after lorlatinib treatment show no response to treatment, and no specific ALK mutation has been found to explain the occurrence of primary resistance. Currently, many different resistance mechanisms are known, some of which are still ALK-related, while others are ALK-independent alternative survival pathways. However, most research focuses on acquired resistance, with very few studies on primary resistance, only a few case reports. Therefore, this study aims to explore the primary ALK TKI resistance mechanisms.
The investigators plan to explore the incidence and mechanisms of primary ALK TKI resistance in ALK-positive advanced NSCLC patients who develop primary resistance or rapid progression (within 3-6 months) during ALK inhibitor treatment by re-obtaining tumor samples for genetic analysis.
Read the detailed description
Lung cancer is the most common cause of cancer death in Taiwan and worldwide [1]. The traditional chemotherapy, platinum-doublet chemotherapy, provided limited survival benefit. In the recent decades, the major evolution in lung cancer is the molecular subtyping of NSCLC, especially lung adenocarcinoma, which has resulted in a paradigm shift in the management of patients in advanced disease. The target therapy provided better treatment response and longer overall survival. For example, patients with NSCLC harboring Epidermal growth factor receptor (EGFR) mutations can get remarkable benefit and longer survival from EGFR tyrosine kinase inhibitors (TKIs) treatment comparing with the traditional platinum-base chemotherapy [2].
Anaplastic lymphoma kinase (ALK) gene rearrangements define a distinct molecular subset of NSCLC, typically occurring in younger, non-smoking individuals with adenocarcinoma histology [3]. The discovery of ALK fusions, particularly EML4-ALK, revolutionized the treatment of these patients with the development of ALK TKIs. First-generation ALK inhibitors, such as crizotinib, demonstrated remarkable initial responses, significantly improving progression-free survival (PFS) compared to standard chemotherapy [4]. However, the emergence of resistance, both primary and acquired, remains a major clinical challenge.
Primary resistance, defined as the lack of initial response or early progression within the first few months of ALK TKI therapy, occurs in a subset of patients and represents a significant obstacle to optimal treatment outcomes [5]. Primary resistance to ALK inhibition occurs, even with advanced TKI therapies, when the best clinical outcome is disease progression. Notably, approximately 5-7% of patients following crizotinib, 9% following ceritinib, and 25% following lorlatinib demonstrated a lack of response, and in these cases, no identifiable ALK mutations were detected [6]. Unlike acquired resistance, which typically arises from secondary mutations within the ALK kinase domain or activation of bypass signaling pathways, the mechanisms underlying primary resistance are less well understood.
Several potential factors contribute to primary resistance. One key aspect involves inherent tumor heterogeneity. NSCLC tumors are complex ecosystems with diverse subclones, some of which may harbor pre-existing genetic alterations that confer resistance to ALK inhibition [7]. These alterations might include co-occurring mutations in genes involved in cell signaling pathways, such as KRAS, EGFR, or TP53, which can bypass ALK dependence [6]. Furthermore, variations in ALK fusion isoforms or copy number alterations may also influence initial drug sensitivity. For example, some less common ALK fusion variants might possess distinct structural properties that reduce their affinity for ALK TKIs.
Another potential mechanism involves the tumor microenvironment (TME). The TME, composed of stromal cells, immune cells, and extracellular matrix, plays a critical role in tumor growth and drug response [8]. Components of the TME, such as cancer-associated fibroblasts (CAFs) and immunosuppressive cells, can secrete growth factors and cytokines that activate alternative signaling pathways, thereby promoting resistance to ALK inhibition. Additionally, the TME can create a physical barrier that limits drug penetration and efficacy.
Furthermore, the complexity of ALK signaling networks and the potential for activation of bypass pathways contribute to primary resistance. For example, activation of the EGFR or MET signaling pathways can provide alternative growth signals, bypassing the need for ALK activation [9]. Understanding these bypass pathways is crucial for developing combination therapies that can overcome primary resistance.
Investigating primary resistance requires a comprehensive approach that integrates genomic, transcriptomic, and proteomic analyses. Next-generation sequencing (NGS) can identify pre-existing genetic alterations that confer resistance. Single-cell RNA sequencing can dissect tumor heterogeneity and identify resistant subclones. Proteomic profiling can reveal activation of bypass signaling pathways. Clinical studies analyzing pre-treatment tumor samples and correlating genomic and clinical data are essential for identifying predictive biomarkers of primary resistance.
In summary, primary resistance to ALK TKIs in NSCLC is a complex phenomenon driven by multiple factors, including tumor heterogeneity, TME interactions, pharmacokinetic variations, and activation of bypass signaling pathways. Further research is needed to elucidate the precise mechanisms underlying primary resistance and to develop strategies to overcome this clinical challenge, ultimately improving outcomes for patients with ALK-positive NSCLC.
- Being tested
- re-biopsy tumor with primary ALK tKI resistance for NGS
- Keywords
- lung cancer, Anaplastic lymphoma kinase (ALK) gene rearrangement, gene mutation, Primary resistance, Next-generation sequencing, Target therapy
- Medical subject headings
- Lung Neoplasms
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
re-biopsy tumor with primary ALK tKI resistance for NGSDiagnostic test
Lung cancer patients who initially use ALK TKI as first-line treatment will be invited to enroll and sign the consent form. Only those who meet the criteria for primary resistance or rapid progression will proceed with tumor sample collection for genetic analysis. Alternatively, patients who develop primary resistance or rapid progression after using ALK TKI and are about to undergo tumor re-biopsy can also sign the subject consent form to be included in this study.
| Study group | Role | What they receive |
|---|---|---|
| Patients who develop primary resistance or rapid progression after using ALK TKI. | Lung cancer patients who initially use ALK TKI as first-line treatment will be invited to enroll and sign the consent form. Only those who meet the criteria for primary resistance or rapid progression will proceed with tumor sample collection for genetic analysis. Alternatively, patients who develop primary resistance or rapid progression after using ALK TKI and are about to undergo tumor re-biopsy can also sign the subject consent form to be included in this study. Receives: Diagnostic Test: re-biopsy tumor with primary ALK tKI resistance for NGS |
What is being measured
The primary outcome is the main question the study is designed to answer.
resistance mechanism
Lung cancer patients who initially use ALK TKI as first-line treatment will be invited to enroll and sign the consent form. Only those who meet the criteria for primary resistance or rapid progression will proceed with tumor sample collection for NGS analysis. Alternatively, patients who develop primary resistance or rapid progression after using ALK TKI and are about to undergo tumor re-biopsy can also sign the subject consent form to be included in this study.
Measured: From ALK TKI treatment to primary resistance or rapid progression for less than 6 months.
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted1 Jul 2025
- Study start1 Jul 2025 (estimated)
- Primary completion1 Jul 2027 (estimated)
- Study completion1 Jul 2028 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (10)Papers the sponsor has linked to this study.
- Other trials for ALK-positive Advanced NSCLC PatientsStudies of the same condition, open and under way.
- More trials run by National Taiwan University HospitalThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Observational
- Observational model
- Case only
- Time perspective
- Prospective
- Enrolment
- 20 participants (estimated)
Sponsor and investigators
- Lead sponsor
- National Taiwan University Hospital
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, National Taiwan University Clinical Trial Center, National Taiwan University Hospital
- Investigators
- Chin-Shing Chen, Professor, Principal investigator, Taiwan Society of Thoracic Surgeons
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT07045610
- Sponsor's protocol ID
- 202504068RINB
- Other IDs
- TSTS
- Status last verified
- Jun 2025
- First submitted
- 12 Jun 2025
- Last updated
- 1 Jul 2025
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
Yoda S, Lin JJ, Lawrence MS, Burke BJ, Friboulet L, Langenbucher A, Dardaei L, Prutisto-Chang K, Dagogo-Jack I, Timofeevski S, Hubbeling H, Gainor JF, Ferris LA, Riley AK, Kattermann KE, Timonina D, Heist RS, Iafrate AJ, Benes CH, Lennerz JK, Mino-Kenudson M, Engelman JA, Johnson TW, Hata AN, Shaw AT. Sequential ALK Inhibitors Can Select for Lorlatinib-Resistant Compound ALK Mutations in ALK-Positive Lung Cancer. Cancer Discov. 2018 Jun;8(6):714-729. doi: 10.1158/2159-8290.CD-17-1256. Epub 2018 Apr 12.
PubMed 29650534Shaw AT, Kim DW, Mehra R, Tan DS, Felip E, Chow LQ, Camidge DR, Vansteenkiste J, Sharma S, De Pas T, Riely GJ, Solomon BJ, Wolf J, Thomas M, Schuler M, Liu G, Santoro A, Lau YY, Goldwasser M, Boral AL, Engelman JA. Ceritinib in ALK-rearranged non-small-cell lung cancer. N Engl J Med. 2014 Mar 27;370(13):1189-97. doi: 10.1056/NEJMoa1311107.
PubMed 24670165Hinshaw DC, Shevde LA. The Tumor Microenvironment Innately Modulates Cancer Progression. Cancer Res. 2019 Sep 15;79(18):4557-4566. doi: 10.1158/0008-5472.CAN-18-3962. Epub 2019 Jul 26.
PubMed 31350295Jamal-Hanjani M, Wilson GA, McGranahan N, Birkbak NJ, Watkins TBK, Veeriah S, Shafi S, Johnson DH, Mitter R, Rosenthal R, Salm M, Horswell S, Escudero M, Matthews N, Rowan A, Chambers T, Moore DA, Turajlic S, Xu H, Lee SM, Forster MD, Ahmad T, Hiley CT, Abbosh C, Falzon M, Borg E, Marafioti T, Lawrence D, Hayward M, Kolvekar S, Panagiotopoulos N, Janes SM, Thakrar R, Ahmed A, Blackhall F, Summers Y, Shah R, Joseph L, Quinn AM, Crosbie PA, Naidu B, Middleton G, Langman G, Trotter S, Nicolson M, Remmen H, Kerr K, Chetty M, Gomersall L, Fennell DA, Nakas A, Rathinam S, Anand G, Khan S, Russell P, Ezhil V, Ismail B, Irvin-Sellers M, Prakash V, Lester JF, Kornaszewska M, Attanoos R, Adams H, Davies H, Dentro S, Taniere P, O'Sullivan B, Lowe HL, Hartley JA, Iles N, Bell H, Ngai Y, Shaw JA, Herrero J, Szallasi Z, Schwarz RF, Stewart A, Quezada SA, Le Quesne J, Van Loo P, Dive C, Hackshaw A, Swanton C; TRACERx Consortium. Tracking the Evolution of Non-Small-Cell Lung Cancer. N Engl J Med. 2017 Jun 1;376(22):2109-2121. doi: 10.1056/NEJMoa1616288. Epub 2017 Apr 26.
PubMed 28445112Gainor JF, Dardaei L, Yoda S, Friboulet L, Leshchiner I, Katayama R, Dagogo-Jack I, Gadgeel S, Schultz K, Singh M, Chin E, Parks M, Lee D, DiCecca RH, Lockerman E, Huynh T, Logan J, Ritterhouse LL, Le LP, Muniappan A, Digumarthy S, Channick C, Keyes C, Getz G, Dias-Santagata D, Heist RS, Lennerz J, Sequist LV, Benes CH, Iafrate AJ, Mino-Kenudson M, Engelman JA, Shaw AT. Molecular Mechanisms of Resistance to First- and Second-Generation ALK Inhibitors in ALK-Rearranged Lung Cancer. Cancer Discov. 2016 Oct;6(10):1118-1133. doi: 10.1158/2159-8290.CD-16-0596. Epub 2016 Jul 18.
PubMed 27432227Katayama R, Shaw AT, Khan TM, Mino-Kenudson M, Solomon BJ, Halmos B, Jessop NA, Wain JC, Yeo AT, Benes C, Drew L, Saeh JC, Crosby K, Sequist LV, Iafrate AJ, Engelman JA. Mechanisms of acquired crizotinib resistance in ALK-rearranged lung Cancers. Sci Transl Med. 2012 Feb 8;4(120):120ra17. doi: 10.1126/scitranslmed.3003316. Epub 2012 Jan 25.
PubMed 22277784Camidge DR, Bang YJ, Kwak EL, Iafrate AJ, Varella-Garcia M, Fox SB, Riely GJ, Solomon B, Ou SH, Kim DW, Salgia R, Fidias P, Engelman JA, Gandhi L, Janne PA, Costa DB, Shapiro GI, Lorusso P, Ruffner K, Stephenson P, Tang Y, Wilner K, Clark JW, Shaw AT. Activity and safety of crizotinib in patients with ALK-positive non-small-cell lung cancer: updated results from a phase 1 study. Lancet Oncol. 2012 Oct;13(10):1011-9. doi: 10.1016/S1470-2045(12)70344-3. Epub 2012 Sep 4.
PubMed 22954507Shaw AT, Yeap BY, Mino-Kenudson M, Digumarthy SR, Costa DB, Heist RS, Solomon B, Stubbs H, Admane S, McDermott U, Settleman J, Kobayashi S, Mark EJ, Rodig SJ, Chirieac LR, Kwak EL, Lynch TJ, Iafrate AJ. Clinical features and outcome of patients with non-small-cell lung cancer who harbor EML4-ALK. J Clin Oncol. 2009 Sep 10;27(26):4247-53. doi: 10.1200/JCO.2009.22.6993. Epub 2009 Aug 10.
PubMed 19667264Lynch TJ, Bell DW, Sordella R, Gurubhagavatula S, Okimoto RA, Brannigan BW, Harris PL, Haserlat SM, Supko JG, Haluska FG, Louis DN, Christiani DC, Settleman J, Haber DA. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med. 2004 May 20;350(21):2129-39. doi: 10.1056/NEJMoa040938. Epub 2004 Apr 29.
PubMed 15118073Siegel RL, Kratzer TB, Giaquinto AN, Sung H, Jemal A. Cancer statistics, 2025. CA Cancer J Clin. 2025 Jan-Feb;75(1):10-45. doi: 10.3322/caac.21871. Epub 2025 Jan 16.
PubMed 39817679
Study at a glance
From the registry record, last updated by the sponsor on 1 Jul 2025. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Explore the Primary Resistance Mechanisms of Anaplastic Lymphoma Kinase Inhibitors
- ClinicalTrials.gov ID
- NCT07045610
- Acronym / sponsor ID
- 202504068RINB
- Keywords
- lung cancer, Anaplastic lymphoma kinase (ALK) gene rearrangement, gene mutation, Primary resistance, Next-generation sequencing, Target therapy
- Study type
- Observational
- Recruitment status
- Not yet recruiting
- Enrolment
- 20 participants (estimated)
- Lead sponsor
- National Taiwan University HospitalUniversity, hospital or other
- Study start
- 1 Jul 2025 (estimated)
- Primary completion
- 1 Jul 2027 (estimated)
- Study completion
- 1 Jul 2028 (estimated)
- First posted
- 1 Jul 2025 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Anaplastic lymphoma kinase (ALK) gene rearrangement is a known oncogenic driver in non-small cell lung cancer (NSCLC). ALK tyrosine kinase inhibitors (TKIs) have been clearly shown to produce excellent therapeutic effects and prolong survival in patients with this gene mutation. According to current treatment guidelines, ALK inhibitors are the first-line treatment of choice for ALK-positive advanced NSCLC patients. However, although ALK TKIs are very effective, there is still a small group of patients who do not achieve good treatment outcomes, developing resistance and tumor progression within 3 to 6 months of initial ALK TKI use. This is called primary resistance. Intrinsic resistance to ALK inhibition occurs when the best clinical response after first-generation and second/third-generation TKI treatment is disease progression. Approximately 5-7% of cases after crizotinib treatment, 9% after ceritinib treatment, and 25% after lorlatinib treatment show no response to treatment, and no specific ALK mutation has been found to explain the occurrence of primary resistance. Currently, many different resistance mechanisms are known, some of which are still ALK-related, while others are ALK-independent alternative survival pathways. However, most research focuses on acquired resistance, with very few studies on primary resistance, only a few case reports. Therefore, this study aims to explore the primary ALK TKI resistance mechanisms.
The investigators plan to explore the incidence and mechanisms of primary ALK TKI resistance in ALK-positive advanced NSCLC patients who develop primary resistance or rapid progression (within 3-6 months) during ALK inhibitor treatment by re-obtaining tumor samples for genetic analysis.
Detailed description
Lung cancer is the most common cause of cancer death in Taiwan and worldwide [1]. The traditional chemotherapy, platinum-doublet chemotherapy, provided limited survival benefit. In the recent decades, the major evolution in lung cancer is the molecular subtyping of NSCLC, especially lung adenocarcinoma, which has resulted in a paradigm shift in the management of patients in advanced disease. The target therapy provided better treatment response and longer overall survival. For example, patients with NSCLC harboring Epidermal growth factor receptor (EGFR) mutations can get remarkable benefit and longer survival from EGFR tyrosine kinase inhibitors (TKIs) treatment comparing with the traditional platinum-base chemotherapy [2].
Anaplastic lymphoma kinase (ALK) gene rearrangements define a distinct molecular subset of NSCLC, typically occurring in younger, non-smoking individuals with adenocarcinoma histology [3]. The discovery of ALK fusions, particularly EML4-ALK, revolutionized the treatment of these patients with the development of ALK TKIs. First-generation ALK inhibitors, such as crizotinib, demonstrated remarkable initial responses, significantly improving progression-free survival (PFS) compared to standard chemotherapy [4]. However, the emergence of resistance, both primary and acquired, remains a major clinical challenge.
Primary resistance, defined as the lack of initial response or early progression within the first few months of ALK TKI therapy, occurs in a subset of patients and represents a significant obstacle to optimal treatment outcomes [5]. Primary resistance to ALK inhibition occurs, even with advanced TKI therapies, when the best clinical outcome is disease progression. Notably, approximately 5-7% of patients following crizotinib, 9% following ceritinib, and 25% following lorlatinib demonstrated a lack of response, and in these cases, no identifiable ALK mutations were detected [6]. Unlike acquired resistance, which typically arises from secondary mutations within the ALK kinase domain or activation of bypass signaling pathways, the mechanisms underlying primary resistance are less well understood.
Several potential factors contribute to primary resistance. One key aspect involves inherent tumor heterogeneity. NSCLC tumors are complex ecosystems with diverse subclones, some of which may harbor pre-existing genetic alterations that confer resistance to ALK inhibition [7]. These alterations might include co-occurring mutations in genes involved in cell signaling pathways, such as KRAS, EGFR, or TP53, which can bypass ALK dependence [6]. Furthermore, variations in ALK fusion isoforms or copy number alterations may also influence initial drug sensitivity. For example, some less common ALK fusion variants might possess distinct structural properties that reduce their affinity for ALK TKIs.
Another potential mechanism involves the tumor microenvironment (TME). The TME, composed of stromal cells, immune cells, and extracellular matrix, plays a critical role in tumor growth and drug response [8]. Components of the TME, such as cancer-associated fibroblasts (CAFs) and immunosuppressive cells, can secrete growth factors and cytokines that activate alternative signaling pathways, thereby promoting resistance to ALK inhibition. Additionally, the TME can create a physical barrier that limits drug penetration and efficacy.
Furthermore, the complexity of ALK signaling networks and the potential for activation of bypass pathways contribute to primary resistance. For example, activation of the EGFR or MET signaling pathways can provide alternative growth signals, bypassing the need for ALK activation [9]. Understanding these bypass pathways is crucial for developing combination therapies that can overcome primary resistance.
Investigating primary resistance requires a comprehensive approach that integrates genomic, transcriptomic, and proteomic analyses. Next-generation sequencing (NGS) can identify pre-existing genetic alterations that confer resistance. Single-cell RNA sequencing can dissect tumor heterogeneity and identify resistant subclones. Proteomic profiling can reveal activation of bypass signaling pathways. Clinical studies analyzing pre-treatment tumor samples and correlating genomic and clinical data are essential for identifying predictive biomarkers of primary resistance.
In summary, primary resistance to ALK TKIs in NSCLC is a complex phenomenon driven by multiple factors, including tumor heterogeneity, TME interactions, pharmacokinetic variations, and activation of bypass signaling pathways. Further research is needed to elucidate the precise mechanisms underlying primary resistance and to develop strategies to overcome this clinical challenge, ultimately improving outcomes for patients with ALK-positive NSCLC.
Study design
- Observational model
- Case only
- Time perspective
- Prospective
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Patients who develop primary resistance or rapid progression after using ALK TKI. | – | Diagnostic Test: re-biopsy tumor with primary ALK tKI resistance for NGSLung cancer patients who initially use ALK TKI as first-line treatment will be invited to enroll and sign the consent form. Only those who meet the criteria for primary resistance or rapid progression will proceed with tumor sample collection for genetic analysis. Alternatively, patients who develop primary resistance or rapid progression after using ALK TKI and are about to undergo tumor re-biopsy can also sign the subject consent form to be included in this study. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
- Study population
- ALK-positive advanced NSCLC patients who develop primary resistance or rapid progression (within 3-6 months) during ALK inhibitor treatment.
Key inclusion criteria (5 listed)
- Age ≥ 18 years old.
- Histologically or cytologically diagnosed NSCLC
- ALK gene fusion detected at initial diagnosis of NSCLC
- Patients exhibiting primary resistance to ALK-TKI therapy, defined as the absence of initial response or progression within 3 to 6 months of treatment initiation, were included.
- Able and willing to provide written informed consent prior to performing any study related procedures and to comply with the study protocol.
Key exclusion criteria (3 listed)
- Unable to provide written inform consent
- The patients had received other systemic treatments except ALK TKI.
- Unable to undergo tumor biopsy or venipuncture
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| re-biopsy tumor with primary ALK tKI resistance for NGSLung cancer patients who initially use ALK TKI as first-line treatment will be invited to enroll and sign the consent form. Only those who meet the criteria for primary resistance or rapid progression will proceed with tumor sample collection for genetic analysis. Alternatively, patients who develop primary resistance or rapid progression after using ALK TKI and are about to undergo tumor re-biopsy can also sign the subject consent form to be included in this study. | Diagnostic test | Patients who develop primary resistance or rapid progression after using ALK TKI. |
Primary outcome
resistance mechanism
Time frame: From ALK TKI treatment to primary resistance or rapid progression for less than 6 months.
Lung cancer patients who initially use ALK TKI as first-line treatment will be invited to enroll and sign the consent form. Only those who meet the criteria for primary resistance or rapid progression will proceed with tumor sample collection for NGS analysis. Alternatively, patients who develop primary resistance or rapid progression after using ALK TKI and are about to undergo tumor re-biopsy can also sign the subject consent form to be included in this study.
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 1 Jul 2025.
- Background: PubMed 29650534Yoda S, Lin JJ, Lawrence MS, Burke BJ, Friboulet L, Langenbucher A, Dardaei L, Prutisto-Chang K, Dagogo-Jack I, Timofeevski S, Hubbeling H, Gainor JF, Ferris LA, Riley AK, Kattermann KE, Timonina D, Heist RS, Iafrate AJ, Benes CH, Lennerz JK, Mino-Kenudson M, Engelman JA, Johnson TW, Hata AN, Shaw AT. Sequential ALK Inhibitors Can Select for Lorlatinib-Resistant Compound ALK Mutations in ALK-Positive Lung Cancer. Cancer Discov. 2018 Jun;8(6):714-729. doi: 10.1158/2159-8290.CD-17-1256. Epub 2018 Apr 12.
- Background: PubMed 24670165Shaw AT, Kim DW, Mehra R, Tan DS, Felip E, Chow LQ, Camidge DR, Vansteenkiste J, Sharma S, De Pas T, Riely GJ, Solomon BJ, Wolf J, Thomas M, Schuler M, Liu G, Santoro A, Lau YY, Goldwasser M, Boral AL, Engelman JA. Ceritinib in ALK-rearranged non-small-cell lung cancer. N Engl J Med. 2014 Mar 27;370(13):1189-97. doi: 10.1056/NEJMoa1311107.
- Background: PubMed 31350295Hinshaw DC, Shevde LA. The Tumor Microenvironment Innately Modulates Cancer Progression. Cancer Res. 2019 Sep 15;79(18):4557-4566. doi: 10.1158/0008-5472.CAN-18-3962. Epub 2019 Jul 26.
- Background: PubMed 28445112Jamal-Hanjani M, Wilson GA, McGranahan N, Birkbak NJ, Watkins TBK, Veeriah S, Shafi S, Johnson DH, Mitter R, Rosenthal R, Salm M, Horswell S, Escudero M, Matthews N, Rowan A, Chambers T, Moore DA, Turajlic S, Xu H, Lee SM, Forster MD, Ahmad T, Hiley CT, Abbosh C, Falzon M, Borg E, Marafioti T, Lawrence D, Hayward M, Kolvekar S, Panagiotopoulos N, Janes SM, Thakrar R, Ahmed A, Blackhall F, Summers Y, Shah R, Joseph L, Quinn AM, Crosbie PA, Naidu B, Middleton G, Langman G, Trotter S, Nicolson M, Remmen H, Kerr K, Chetty M, Gomersall L, Fennell DA, Nakas A, Rathinam S, Anand G, Khan S, Russell P, Ezhil V, Ismail B, Irvin-Sellers M, Prakash V, Lester JF, Kornaszewska M, Attanoos R, Adams H, Davies H, Dentro S, Taniere P, O'Sullivan B, Lowe HL, Hartley JA, Iles N, Bell H, Ngai Y, Shaw JA, Herrero J, Szallasi Z, Schwarz RF, Stewart A, Quezada SA, Le Quesne J, Van Loo P, Dive C, Hackshaw A, Swanton C; TRACERx Consortium. Tracking the Evolution of Non-Small-Cell Lung Cancer. N Engl J Med. 2017 Jun 1;376(22):2109-2121. doi: 10.1056/NEJMoa1616288. Epub 2017 Apr 26.
- Background: PubMed 27432227Gainor JF, Dardaei L, Yoda S, Friboulet L, Leshchiner I, Katayama R, Dagogo-Jack I, Gadgeel S, Schultz K, Singh M, Chin E, Parks M, Lee D, DiCecca RH, Lockerman E, Huynh T, Logan J, Ritterhouse LL, Le LP, Muniappan A, Digumarthy S, Channick C, Keyes C, Getz G, Dias-Santagata D, Heist RS, Lennerz J, Sequist LV, Benes CH, Iafrate AJ, Mino-Kenudson M, Engelman JA, Shaw AT. Molecular Mechanisms of Resistance to First- and Second-Generation ALK Inhibitors in ALK-Rearranged Lung Cancer. Cancer Discov. 2016 Oct;6(10):1118-1133. doi: 10.1158/2159-8290.CD-16-0596. Epub 2016 Jul 18.
- Background: PubMed 22277784Katayama R, Shaw AT, Khan TM, Mino-Kenudson M, Solomon BJ, Halmos B, Jessop NA, Wain JC, Yeo AT, Benes C, Drew L, Saeh JC, Crosby K, Sequist LV, Iafrate AJ, Engelman JA. Mechanisms of acquired crizotinib resistance in ALK-rearranged lung Cancers. Sci Transl Med. 2012 Feb 8;4(120):120ra17. doi: 10.1126/scitranslmed.3003316. Epub 2012 Jan 25.
- Background: PubMed 22954507Camidge DR, Bang YJ, Kwak EL, Iafrate AJ, Varella-Garcia M, Fox SB, Riely GJ, Solomon B, Ou SH, Kim DW, Salgia R, Fidias P, Engelman JA, Gandhi L, Janne PA, Costa DB, Shapiro GI, Lorusso P, Ruffner K, Stephenson P, Tang Y, Wilner K, Clark JW, Shaw AT. Activity and safety of crizotinib in patients with ALK-positive non-small-cell lung cancer: updated results from a phase 1 study. Lancet Oncol. 2012 Oct;13(10):1011-9. doi: 10.1016/S1470-2045(12)70344-3. Epub 2012 Sep 4.
- Background: PubMed 19667264Shaw AT, Yeap BY, Mino-Kenudson M, Digumarthy SR, Costa DB, Heist RS, Solomon B, Stubbs H, Admane S, McDermott U, Settleman J, Kobayashi S, Mark EJ, Rodig SJ, Chirieac LR, Kwak EL, Lynch TJ, Iafrate AJ. Clinical features and outcome of patients with non-small-cell lung cancer who harbor EML4-ALK. J Clin Oncol. 2009 Sep 10;27(26):4247-53. doi: 10.1200/JCO.2009.22.6993. Epub 2009 Aug 10.
- Background: PubMed 15118073Lynch TJ, Bell DW, Sordella R, Gurubhagavatula S, Okimoto RA, Brannigan BW, Harris PL, Haserlat SM, Supko JG, Haluska FG, Louis DN, Christiani DC, Settleman J, Haber DA. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med. 2004 May 20;350(21):2129-39. doi: 10.1056/NEJMoa040938. Epub 2004 Apr 29.
- Background: PubMed 39817679Siegel RL, Kratzer TB, Giaquinto AN, Sung H, Jemal A. Cancer statistics, 2025. CA Cancer J Clin. 2025 Jan-Feb;75(1):10-45. doi: 10.3322/caac.21871. Epub 2025 Jan 16.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part.
Chin-Shing Chen, Professor principal investigator
Taiwan Society of Thoracic Surgeons
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of ALK-positive Advanced NSCLC Patients and Primary Resistance, run by National Taiwan University Hospital at 1 site in Taiwan.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 5 inclusion and 3 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: opening soon, as of the sponsor's last update on 1 Jul 2025. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Taiwan. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Contact Shang-Gin Wu, Attending Physician (+886223562905, b8501091@gmail.com), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
resistance mechanism (time frame: From ALK TKI treatment to primary resistance or rapid progression for less than 6 months.). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT07045610, which also lists 10 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 1 Jul 2025.