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ALK inhibitor

January 01, 1970

ALK inhibitors are anti-cancer drugs that act on tumours with variations of anaplastic lymphoma kinase (ALK) such as an EML4-ALK translocation.[1] They fall under the category of tyrosine kinase inhibitors, which work by inhibiting proteins involved in the abnormal growth of tumour cells. All the current approved ALK inhibitors function by binding to the ATP pocket of the abnormal ALK protein, blocking its access to energy and deactivating it. A majority of ALK-rearranged NSCLC harbour the EML4-ALK fusion,[2] although as of 2020, over 92 fusion partners have been discovered in ALK+ NSCLC.[3] For each fusion partner, there can be several fusion variants depending on the position the two genes were fused at, and this may have implications on the response of the tumour and prognosis of the patient.[4]

Micrograph showing an ALK positive adenocarcinoma of the lung. The ALK immunostain allows individuals with ALK rearrangements to be identified.

Approved inhibitors edit

First generation edit

Crizotinib (also a ROS1 and c-MET inhibitor) was approved in Aug 2011 by the US FDA for ALK-positive NSCLC.[5] At the time of the discovery of ALK translocations as a molecular driver in NSCLC, crizotinib was being investigated by Pfizer as a potential c-MET inhibitor. Its activity against ALK being known, Pfizer shifted its investigations to focus on this indication, and obtained a full approval 4 years later. Crizotinib's efficacy was proven in phase III trial, PROFILE 1007,[6] when it was compared to then-standard second-line pemetrexed or docetaxel chemotherapy.[7][8][9] It induced tumour stabilisation or shrinkage in 90% of patients. Its lack of penetrance in the brain and non-optimal specificity for ALK meant resistance mostly arose within a year, with the brain being a common site of progression. Blockade of ALKAL2 with crizotinib has been shown to produce analgesic effects in animal models.[10]

Second generation edit

Despite the excitement of crizotinib's therapeutic success, there was a need to conceive new drugs with better brain penetrance, higher specificity and targeting a broader set of resistance mutations. As such, Novartis' ceritinib was approved by the FDA in April 2014 for treatment of NSCLC.[2][11] It provided good brain penetrance and a significant progression-free survival benefit against chemotherapy in the first line as demonstrated in the ASCEND-4 trial.[12]

Roche's alectinib was FDA approved Dec 2015 (accelerated) for patients who had progressed on crizotinib, with full approval in 2017 as a first-line treatment for ALK-positive NSCLC. Like ceritinib, it provided excellent brain penetrance and high response rates. It demonstrated a clear benefit against both first-line chemotherapy and first-line crizotinib.[13] This was based on the phase 3 ALEX trial comparing it with crizotinib.[13]

Ariad's and Takeda's brigatinib (also an inhibitor of mutated EGFR) was the latest second-generation inhibitor and was approved in April 2017 by the US FDA for ALK-positive NSCLC.[14] It is very similar to alectinib in efficacy, while being active against some resistant mutations such as the common G1202R mutation that provides resistance to alectinib.

Third generation edit

Pfizer's lorlatinib was the first third-generation inhibitor and was approved in 2018 by the US FDA for ALK-positive NSCLC after progression on a first or second-generation inhibitor. Its macrocyclic structure was designed specifically to address some of the most recalcitrant resistance mutations. Still, most tumours eventually develop resistance through various mechanisms, namely compound-mutations (two or three mutations simultaneously) or activation of alternative pathways, such as the c-MET pathway.

Clinical trials edit

Additional ALK inhibitors currently (or soon to be) undergoing clinical trials include:

  • Ensartinib (Xcovery's X-396, undergoing the eXalt3 Phase III multicenter clinical trial against crizotinib in ALK-TKI naïve patients who received up to one prior chemotherapy)
  • Entrectinib (Nerviano's NMS-E628, licensed by Ignyta and renamed RXDX-101, in the U.S. orphan drug designation and rare pediatric disease designation for the treatment of neuroblastoma and orphan drug designation for treatment of TrkA-, TrkB-, TrkC-, ROS1- and ALK-positive NSCLC)
  • Repotrectinib (TPX-0005, Turning Point Therapeutics)
  • Belizatinib (TSR-011, Tesaro)
  • Alkotinib (ZG-0418, a dual ALK/ROS1 inhibitor, Suzhou Zelgen Biopharmaceuticals)
  • Foritinib (SAF-189, a dual ALK/ROS1 inhibitor undergoing a phase I/II trial as of 2020, Fochon Pharmaceuticals)
  • CEP-37440 (Teva)
  • TQ-B3139 (dual ALK/c-MET inhibitor by Chia Tai Tianqing Pharmaceuticals, undergoing a phase III clinical trial against crizotinib in TKI-naïve patients)
  • PLB1003 (Beijing Pearl Biotechnology)
  • Zotizalkib (TPX-0131, Turning Point Therapeutics)— a next generation ALK inhibitor, shown to work even against compound mutations resistant to lorlatinib
  • Conteltinib (Shouyao Holdings, Beijing) - multi-kinase inhibitor that specifically targets ALK, FAK and Pyk2

Discontinued

Investigational combinations edit

While the response to ALK inhibitors is often very encouraging in patients with ALK+ NSCLC and lasts for a relatively long time, most of them eventually develop resistance, either through mutations in the ATP binding pocket or activation of alternative oncogenic pathways. Much research is being carried out on understanding the ways the cancer adapts and on how to reverse or delay resistance.

MEK pathway edit

The MEK pathway (short for MAPK/ERK-Kinase) has been extensively shown to be critical for the survival of tumour cells subjected to ALK inhibition.[15] Inhibition of this pathway was shown to enhance response and delay the onset of resistance in preclinical models. As of 2020, three clinical trials are running to test the following combinations of ALK inhibitors with MEK inhibitors: brigatinib+binimetinib,[16] ceritinib+trametinib,[17] and alectinib+cobimetinib.[18] Results for the last two are expected around 2020-2021.

EGFR/HER2 pathway edit

The EGFR and HER2 pathways are commonly abnormally activated in a large proportion of cancers. This was shown to be the case in preclinical models of ALK+ NSCLC subjected to ALK inhibition, both in vitro and in vivo. Surprisingly, cells were only sensitive to EGFR/HER2 inhibition when in the process of adapting to ALK inhibitors: both naïve cells and fully-adapted cells showed no measurable response to EGFR/HER2 inhibition alone.[19] Currently, solid preclinical studies have been carried out with second-generation inhibitors combined with afatinib, erlotinib[20] and lapatinib. In all cases, the responses were enhanced by the combination with respect to monotherapy, but seemed more pronounced in afatinib and lapatinib (dual EGFR/HER2 inhibitors) than in erlotinib (which only inhibits EGFR).

Anti-VEGF therapies edit

Several trials are investigating the combination of anti-VEGF antibody bevacizumab with ALK inhibitors such as alectinib and brigatinib.[21][22][23] Bevacizumab is an antiangiogenic antibody, which normalizes the complex blood vessel structures around cancer and prevents new blood vessels from forming, thus starving the tumour and preventing its proliferation.

Local consolidation therapy edit

The use of either radiotherapy or surgery in addition to an ALK inhibitor is known as local consolidation therapy, and as of 2020, it is being investigated by three clinical trials. Their goal is to determine whether it delays resistance to the drugs compared with monotherapy.[24] Some make use of SBRT (stereotactic body radiation therapy), a very precise radiation technique able to provide high doses with minimal side effects. Most trials of LCT in NSCLC focus on oligometastatic disease (under 3-5 lesions, depending on the definitions), but preliminary results of the BRIGHTSTAR trial [24] indicate this method may be safe and well tolerated irrespective of the number of lesions.

NPM-ALK edit

NPM-ALK is a different variation/fusion of ALK that drives anaplastic large-cell lymphomas (ALCLs) and is the target of other ALK inhibitors such as TAE-684.[25] [26]

References edit

  1. ^ Nelsen R (15 January 2010). "ALK Inhibitors: Possible New Treatment for Lung Cancer". Medscape.
  2. ^ a b Farmer G (October 2010). "Non-Small-Cell Lung Cancer Standards of Care Challenged by a Cornucopia of New Drugs". Genetic Engineering & Biotechnology News. 30 (17).
  3. ^ Ou SI, Zhu VW, Nagasaka M (March 2020). "Catalog of 5' Fusion Partners in ALK-positive NSCLC Circa 2020". JTO Clinical and Research Reports. 1 (1): 100015. doi:10.1016/j.jtocrr.2020.100015. PMC 8474466. PMID 34589917.
  4. ^ Christopoulos P (2018). "EML4-ALK fusion variant V3 confers early treatment failure with first and second generation ALK TKI". Pneumologie. 72 (S 01): 402. doi:10.1055/s-0037-1619261. S2CID 79799403.
  5. ^ Chustecka Z (7 June 2010). "Crizotinib in ALK-NSCLC; Response Rate "Unprecedented"". MedScape.
  6. ^ "Crizotinib Clinical Trials – Currently Ongoing and/or Enrolling" (PDF). Fact Sheet. Pfizer.
  7. ^ Clinical trial number NCT00932451 for "An Investigational Drug, PF-02341066, Is Being Studied In Patients With Advanced Non-Small Cell Lung Cancer With A Specific Gene Profile Involving The Anaplastic Lymphoma Kinase (ALK) Gene" at ClinicalTrials.gov
  8. ^ (PDF) (Press release). Pfizer Oncology. 2010-05-20. Archived from the original (PDF) on 2010-06-12. Retrieved 2010-06-07.
  9. ^ Clinical trial number NCT00932893 for "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" at ClinicalTrials.gov
  10. ^ Defaye M, Iftinca MC, Gadotti VM, Basso L, Abdullah NS, Cumenal M, et al. (May 2022). "The neuronal tyrosine kinase receptor ligand ALKAL2 mediates persistent pain". The Journal of Clinical Investigation. 132 (12). doi:10.1172/JCI154317. PMC 9197515. PMID 35608912.
  11. ^ "FDA Approves Ceritinib for ALK-Positive Lung Cancer". Medscape. April 29, 2014.
  12. ^ Soria JC, Tan DS, Chiari R, Wu YL, Paz-Ares L, Wolf J, et al. (March 2017). "First-line ceritinib versus platinum-based chemotherapy in advanced ALK-rearranged non-small-cell lung cancer (ASCEND-4): a randomised, open-label, phase 3 study". Lancet. 389 (10072): 917–929. doi:10.1016/s0140-6736(17)30123-x. PMID 28126333. S2CID 4739527.
  13. ^ a b FDA approves Alecensa for ALK-positive metastatic non-small cell lung cancer Nov 2017
  14. ^ "Novel Drug Approvals for 2017". FDA. 25 January 2021.
  15. ^ Hrustanovic G, Bivona TG (2015). "RAS-MAPK in ALK targeted therapy resistance". Cell Cycle. 14 (23): 3661–3662. doi:10.1080/15384101.2015.1096103. PMC 4825705. PMID 26654768.
  16. ^ Clinical trial number NCT04005144 for "Brigatinib and Binimetinib in Treating Patients With Stage IIIB-IV ALK or ROS1-Rearranged Non-small Cell Lung Cancer" at ClinicalTrials.gov
  17. ^ Clinical trial number NCT03087448 for "Ceritinib + Trametinib in Patients With Advanced ALK-Positive Non-Small Cell Lung Cancer (NSCLC)" at ClinicalTrials.gov
  18. ^ Clinical trial number NCT03202940 for "A Phase IB/II Study of Alectinib Combined With Cobimetinib in Advanced ALK-Rearranged (ALK+) NSCLC" at ClinicalTrials.gov
  19. ^ Vander Velde R, Yoon N, Marusyk V, Durmaz A, Dhawan A, Miroshnychenko D, et al. (May 2020). "Resistance to targeted therapies as a multifactorial, gradual adaptation to inhibitor specific selective pressures". Nature Communications. 11 (1): 2393. Bibcode:2020NatCo..11.2393V. doi:10.1038/s41467-020-16212-w. PMC 7224215. PMID 32409712.
  20. ^ Dong X, Fernandez-Salas E, Li E, Wang S (March 2016). "Elucidation of Resistance Mechanisms to Second-Generation ALK Inhibitors Alectinib and Ceritinib in Non-Small Cell Lung Cancer Cells". Neoplasia. 18 (3): 162–171. doi:10.1016/j.neo.2016.02.001. PMC 4796802. PMID 26992917.
  21. ^ Clinical trial number NCT02521051 for "Phase I/II Trial of Alectinib and Bevacizumab in Patients With Advanced, Anaplastic Lymphoma Kinase (ALK)-Positive, Non-Small Cell Lung Cancer" at ClinicalTrials.gov
  22. ^ Clinical trial number NCT03779191 for "Alectinib in Combination With Bevacizumab in ALK Positive NSCLC" at ClinicalTrials.gov
  23. ^ Clinical trial number NCT04227028 for "Brigatinib and Bevacizumab for the Treatment of ALK-Rearranged Locally Advanced, Metastatic, or Recurrent Non-small Cell Lung Cancer" at ClinicalTrials.gov
  24. ^ a b Clinical trial number NCT03707938 for "Local Consolidative Therapy and Brigatinib in Treating Patients With Stage IV or Recurrent Non-small Cell Lung Cancer" at ClinicalTrials.gov
  25. ^ Galkin AV, Melnick JS, Kim S, Hood TL, Li N, Li L, et al. (January 2007). "Identification of NVP-TAE684, a potent, selective, and efficacious inhibitor of NPM-ALK". Proceedings of the National Academy of Sciences of the United States of America. 104 (1): 270–275. Bibcode:2007PNAS..104..270G. doi:10.1073/pnas.0609412103. PMC 1765448. PMID 17185414.
  26. ^ . axonmedchem.com. Archived from the original on 2010-12-23. Retrieved 2010-10-02.

External links edit

  • alkinhibitors.com
  • ALK inhibitor discussion forum

January 01, 1970
inhibitor, anti, cancer, drugs, that, tumours, with, variations, anaplastic, lymphoma, kinase, such, eml4, translocation, they, fall, under, category, tyrosine, kinase, inhibitors, which, work, inhibiting, proteins, involved, abnormal, growth, tumour, cells, c. ALK inhibitors are anti cancer drugs that act on tumours with variations of anaplastic lymphoma kinase ALK such as an EML4 ALK translocation 1 They fall under the category of tyrosine kinase inhibitors which work by inhibiting proteins involved in the abnormal growth of tumour cells All the current approved ALK inhibitors function by binding to the ATP pocket of the abnormal ALK protein blocking its access to energy and deactivating it A majority of ALK rearranged NSCLC harbour the EML4 ALK fusion 2 although as of 2020 over 92 fusion partners have been discovered in ALK NSCLC 3 For each fusion partner there can be several fusion variants depending on the position the two genes were fused at and this may have implications on the response of the tumour and prognosis of the patient 4 Micrograph showing an ALK positive adenocarcinoma of the lung The ALK immunostain allows individuals with ALK rearrangements to be identified Contents 1 Approved inhibitors 1 1 First generation 1 2 Second generation 1 3 Third generation 2 Clinical trials 3 Investigational combinations 3 1 MEK pathway 3 2 EGFR HER2 pathway 3 3 Anti VEGF therapies 3 4 Local consolidation therapy 4 NPM ALK 5 References 6 External linksApproved inhibitors editFirst generation edit Crizotinib also a ROS1 and c MET inhibitor was approved in Aug 2011 by the US FDA for ALK positive NSCLC 5 At the time of the discovery of ALK translocations as a molecular driver in NSCLC crizotinib was being investigated by Pfizer as a potential c MET inhibitor Its activity against ALK being known Pfizer shifted its investigations to focus on this indication and obtained a full approval 4 years later Crizotinib s efficacy was proven in phase III trial PROFILE 1007 6 when it was compared to then standard second line pemetrexed or docetaxel chemotherapy 7 8 9 It induced tumour stabilisation or shrinkage in 90 of patients Its lack of penetrance in the brain and non optimal specificity for ALK meant resistance mostly arose within a year with the brain being a common site of progression Blockade of ALKAL2 with crizotinib has been shown to produce analgesic effects in animal models 10 Second generation edit Despite the excitement of crizotinib s therapeutic success there was a need to conceive new drugs with better brain penetrance higher specificity and targeting a broader set of resistance mutations As such Novartis ceritinib was approved by the FDA in April 2014 for treatment of NSCLC 2 11 It provided good brain penetrance and a significant progression free survival benefit against chemotherapy in the first line as demonstrated in the ASCEND 4 trial 12 Roche s alectinib was FDA approved Dec 2015 accelerated for patients who had progressed on crizotinib with full approval in 2017 as a first line treatment for ALK positive NSCLC Like ceritinib it provided excellent brain penetrance and high response rates It demonstrated a clear benefit against both first line chemotherapy and first line crizotinib 13 This was based on the phase 3 ALEX trial comparing it with crizotinib 13 Ariad s and Takeda s brigatinib also an inhibitor of mutated EGFR was the latest second generation inhibitor and was approved in April 2017 by the US FDA for ALK positive NSCLC 14 It is very similar to alectinib in efficacy while being active against some resistant mutations such as the common G1202R mutation that provides resistance to alectinib Third generation edit Pfizer s lorlatinib was the first third generation inhibitor and was approved in 2018 by the US FDA for ALK positive NSCLC after progression on a first or second generation inhibitor Its macrocyclic structure was designed specifically to address some of the most recalcitrant resistance mutations Still most tumours eventually develop resistance through various mechanisms namely compound mutations two or three mutations simultaneously or activation of alternative pathways such as the c MET pathway Clinical trials editAdditional ALK inhibitors currently or soon to be undergoing clinical trials include Ensartinib Xcovery s X 396 undergoing the eXalt3 Phase III multicenter clinical trial against crizotinib in ALK TKI naive patients who received up to one prior chemotherapy Entrectinib Nerviano s NMS E628 licensed by Ignyta and renamed RXDX 101 in the U S orphan drug designation and rare pediatric disease designation for the treatment of neuroblastoma and orphan drug designation for treatment of TrkA TrkB TrkC ROS1 and ALK positive NSCLC Repotrectinib TPX 0005 Turning Point Therapeutics Belizatinib TSR 011 Tesaro Alkotinib ZG 0418 a dual ALK ROS1 inhibitor Suzhou Zelgen Biopharmaceuticals Foritinib SAF 189 a dual ALK ROS1 inhibitor undergoing a phase I II trial as of 2020 Fochon Pharmaceuticals CEP 37440 Teva TQ B3139 dual ALK c MET inhibitor by Chia Tai Tianqing Pharmaceuticals undergoing a phase III clinical trial against crizotinib in TKI naive patients PLB1003 Beijing Pearl Biotechnology Zotizalkib TPX 0131 Turning Point Therapeutics a next generation ALK inhibitor shown to work even against compound mutations resistant to lorlatinib Conteltinib Shouyao Holdings Beijing multi kinase inhibitor that specifically targets ALK FAK and Pyk2 Discontinued ASP 3026 Astellas Investigational combinations editWhile the response to ALK inhibitors is often very encouraging in patients with ALK NSCLC and lasts for a relatively long time most of them eventually develop resistance either through mutations in the ATP binding pocket or activation of alternative oncogenic pathways Much research is being carried out on understanding the ways the cancer adapts and on how to reverse or delay resistance MEK pathway edit The MEK pathway short for MAPK ERK Kinase has been extensively shown to be critical for the survival of tumour cells subjected to ALK inhibition 15 Inhibition of this pathway was shown to enhance response and delay the onset of resistance in preclinical models As of 2020 three clinical trials are running to test the following combinations of ALK inhibitors with MEK inhibitors brigatinib binimetinib 16 ceritinib trametinib 17 and alectinib cobimetinib 18 Results for the last two are expected around 2020 2021 EGFR HER2 pathway edit The EGFR and HER2 pathways are commonly abnormally activated in a large proportion of cancers This was shown to be the case in preclinical models of ALK NSCLC subjected to ALK inhibition both in vitro and in vivo Surprisingly cells were only sensitive to EGFR HER2 inhibition when in the process of adapting to ALK inhibitors both naive cells and fully adapted cells showed no measurable response to EGFR HER2 inhibition alone 19 Currently solid preclinical studies have been carried out with second generation inhibitors combined with afatinib erlotinib 20 and lapatinib In all cases the responses were enhanced by the combination with respect to monotherapy but seemed more pronounced in afatinib and lapatinib dual EGFR HER2 inhibitors than in erlotinib which only inhibits EGFR Anti VEGF therapies edit Several trials are investigating the combination of anti VEGF antibody bevacizumab with ALK inhibitors such as alectinib and brigatinib 21 22 23 Bevacizumab is an antiangiogenic antibody which normalizes the complex blood vessel structures around cancer and prevents new blood vessels from forming thus starving the tumour and preventing its proliferation Local consolidation therapy edit The use of either radiotherapy or surgery in addition to an ALK inhibitor is known as local consolidation therapy and as of 2020 it is being investigated by three clinical trials Their goal is to determine whether it delays resistance to the drugs compared with monotherapy 24 Some make use of SBRT stereotactic body radiation therapy a very precise radiation technique able to provide high doses with minimal side effects Most trials of LCT in NSCLC focus on oligometastatic disease under 3 5 lesions depending on the definitions but preliminary results of the BRIGHTSTAR trial 24 indicate this method may be safe and well tolerated irrespective of the number of lesions NPM ALK editNPM ALK is a different variation fusion of ALK that drives anaplastic large cell lymphomas ALCLs and is the target of other ALK inhibitors such as TAE 684 25 26 References edit Nelsen R 15 January 2010 ALK Inhibitors Possible New Treatment for Lung Cancer Medscape a b Farmer G October 2010 Non Small Cell Lung Cancer Standards of Care Challenged by a Cornucopia of New Drugs Genetic Engineering amp Biotechnology News 30 17 Ou SI Zhu VW Nagasaka M March 2020 Catalog of 5 Fusion Partners in ALK positive NSCLC Circa 2020 JTO Clinical and Research Reports 1 1 100015 doi 10 1016 j jtocrr 2020 100015 PMC 8474466 PMID 34589917 Christopoulos P 2018 EML4 ALK fusion variant V3 confers early treatment failure with first and second generation ALK TKI Pneumologie 72 S 01 402 doi 10 1055 s 0037 1619261 S2CID 79799403 Chustecka Z 7 June 2010 Crizotinib in ALK NSCLC Response Rate Unprecedented MedScape Crizotinib Clinical Trials Currently Ongoing and or Enrolling PDF Fact Sheet Pfizer Clinical trial number NCT00932451 for An Investigational Drug PF 02341066 Is Being Studied In Patients With Advanced Non Small Cell Lung Cancer With A Specific Gene Profile Involving The Anaplastic Lymphoma Kinase ALK Gene at ClinicalTrials gov Pfizer Oncology To Present New Clinical Data From Ten Molecules Across Multiple Tumor Types PDF Press release Pfizer Oncology 2010 05 20 Archived from the original PDF on 2010 06 12 Retrieved 2010 06 07 Clinical trial number NCT00932893 for 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 at ClinicalTrials gov Defaye M Iftinca MC Gadotti VM Basso L Abdullah NS Cumenal M et al May 2022 The neuronal tyrosine kinase receptor ligand ALKAL2 mediates persistent pain The Journal of Clinical Investigation 132 12 doi 10 1172 JCI154317 PMC 9197515 PMID 35608912 FDA Approves Ceritinib for ALK Positive Lung Cancer Medscape April 29 2014 Soria JC Tan DS Chiari R Wu YL Paz Ares L Wolf J et al March 2017 First line ceritinib versus platinum based chemotherapy in advanced ALK rearranged non small cell lung cancer ASCEND 4 a randomised open label phase 3 study Lancet 389 10072 917 929 doi 10 1016 s0140 6736 17 30123 x PMID 28126333 S2CID 4739527 a b FDA approves Alecensa for ALK positive metastatic non small cell lung cancer Nov 2017 Novel Drug Approvals for 2017 FDA 25 January 2021 Hrustanovic G Bivona TG 2015 RAS MAPK in ALK targeted therapy resistance Cell Cycle 14 23 3661 3662 doi 10 1080 15384101 2015 1096103 PMC 4825705 PMID 26654768 Clinical trial number NCT04005144 for Brigatinib and Binimetinib in Treating Patients With Stage IIIB IV ALK or ROS1 Rearranged Non small Cell Lung Cancer at ClinicalTrials gov Clinical trial number NCT03087448 for Ceritinib Trametinib in Patients With Advanced ALK Positive Non Small Cell Lung Cancer NSCLC at ClinicalTrials gov Clinical trial number NCT03202940 for A Phase IB II Study of Alectinib Combined With Cobimetinib in Advanced ALK Rearranged ALK NSCLC at ClinicalTrials gov Vander Velde R Yoon N Marusyk V Durmaz A Dhawan A Miroshnychenko D et al May 2020 Resistance to targeted therapies as a multifactorial gradual adaptation to inhibitor specific selective pressures Nature Communications 11 1 2393 Bibcode 2020NatCo 11 2393V doi 10 1038 s41467 020 16212 w PMC 7224215 PMID 32409712 Dong X Fernandez Salas E Li E Wang S March 2016 Elucidation of Resistance Mechanisms to Second Generation ALK Inhibitors Alectinib and Ceritinib in Non Small Cell Lung Cancer Cells Neoplasia 18 3 162 171 doi 10 1016 j neo 2016 02 001 PMC 4796802 PMID 26992917 Clinical trial number NCT02521051 for Phase I II Trial of Alectinib and Bevacizumab in Patients With Advanced Anaplastic Lymphoma Kinase ALK Positive Non Small Cell Lung Cancer at ClinicalTrials gov Clinical trial number NCT03779191 for Alectinib in Combination With Bevacizumab in ALK Positive NSCLC at ClinicalTrials gov Clinical trial number NCT04227028 for Brigatinib and Bevacizumab for the Treatment of ALK Rearranged Locally Advanced Metastatic or Recurrent Non small Cell Lung Cancer at ClinicalTrials gov a b Clinical trial number NCT03707938 for Local Consolidative Therapy and Brigatinib in Treating Patients With Stage IV or Recurrent Non small Cell Lung Cancer at ClinicalTrials gov Galkin AV Melnick JS Kim S Hood TL Li N Li L et al January 2007 Identification of NVP TAE684 a potent selective and efficacious inhibitor of NPM ALK Proceedings of the National Academy of Sciences of the United States of America 104 1 270 275 Bibcode 2007PNAS 104 270G doi 10 1073 pnas 0609412103 PMC 1765448 PMID 17185414 NVP TAE684 TAE 684 axonmedchem com Archived from the original on 2010 12 23 Retrieved 2010 10 02 External links editalkinhibitors com ALK inhibitor discussion forum Retrieved from https en wikipedia org w index php title ALK inhibitor amp oldid 1198911411, wikipedia, wiki, book, books, library,

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