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Shirish M Gadgeel - One of the best experts on this subject based on the ideXlab platform.
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updated efficacy and safety data and impact of the eml4 alk fusion variant on the efficacy of Alectinib in untreated alk positive advanced non small cell lung cancer in the global phase iii alex study
Journal of Thoracic Oncology, 2019Co-Authors: Ross D Camidge, Rafal Dziadziuszko, Solange Peters, Tony Mok, Johannes Noe, Malgorzata Nowicka, Shirish M Gadgeel, P Cheema, Nick Pavlakis, Filippo De MarinisAbstract:Abstract Introduction At the prior data cutoff (February 9, 2017) the ALEX trial showed superior investigator-assessed progression-free survival (PFS) for Alectinib versus crizotinib in untreated, anaplastic lymphoma kinase (ALK)-positive, advanced NSCLC (hazard ratio = 0.47, 95% confidence interval: 0.34–0.65, p Methods Patients were randomized to receive twice-daily Alectinib, 600 mg, or crizotinib, 250 mg, until disease progression, toxicity, death, or withdrawal. PFS was determined by the investigators. Baseline plasma and tissue biomarker samples were analyzed by using hybrid-capture, next-generation sequencing to determine EML4-ALK variant. Results Baseline characteristics were balanced. Investigator-assessed PFS was prolonged with Alectinib (stratified hazard ratio = 0.43, 95% confidence interval: 0.32–0.58). The median PFS times were 34.8 months with Alectinib and 10.9 months with crizotinib. EML4-ALK fusions were detectable in 129 patient plasma samples and 124 tissue samples; variants 1, 2, and 3/ab did not affect PFS, objective response rate, or duration of response. Investigator-assessed PFS was longer for Alectinib than for crizotinib across EML4-ALK variants 1, 2, and 3a/b in plasma and tissue. Despite longer treatment duration (27.0 months in the case of Alectinib versus 10.8 months in the case of crizotinib), the safety of Alectinib compared favorably with that of crizotinib. Conclusion Alectinib continues to demonstrate superior investigator-assessed PFS versus crizotinib in untreated ALK-positive NSCLC, irrespective of EML4-ALK variant.
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Alectinib versus crizotinib in treatment naive anaplastic lymphoma kinase positive alk non small cell lung cancer cns efficacy results from the alex study
Annals of Oncology, 2018Co-Authors: Shirish M Gadgeel, Solange Peters, Tony Mok, M Perol, Silvia Novello, Alice T Shaw, Dongwan Kim, Anna Wrona, R Rosell, A ZeaiterAbstract:ABSTRACT Background The phase III ALEX study in patients with treatment-naive advanced anaplastic lymphoma kinase mutation-positive (ALK+) non-small-cell lung cancer (NSCLC) met its primary end point of improved progression-free survival (PFS) with Alectinib versus crizotinib. Here, we present detailed central nervous system (CNS) efficacy data from ALEX. Patients and methods Overall, 303 patients aged ≥18 years underwent 1:1 randomization to receive twice-daily doses of Alectinib 600 mg or crizotinib 250 mg. Brain imaging was conducted in all patients at baseline and every subsequent 8 weeks. End points (analyzed by subgroup: patients with/without baseline CNS metastases; patients with/without prior radiotherapy) included PFS, CNS objective response rate (ORR), and time to CNS progression. Results In total, 122 patients had Independent Review Committee-assessed baseline CNS metastases (Alectinib,n = 64; crizotinib,n = 58), 43 had measurable lesions (Alectinib,n = 21; crizotinib,n = 22), and 46 had received prior radiotherapy (Alectinib,n = 25; crizotinib,n = 21). Investigator-assessed PFS with Alectinib was consistent between patients with baseline CNS metastases [hazard ratio (HR) 0.40, 95% confidence interval (CI): 0.25–0.64] and those without (HR 0.51, 95% CI: 0.33–0.80,P interaction = 0.36). Similar results were seen in patients regardless of prior radiotherapy. Time to CNS progression was significantly longer with Alectinib versus crizotinib and comparable between patients with and without baseline CNS metastases (P Conclusion Alectinib demonstrated superior CNS activity and significantly delayed CNS progression versus crizotinib in patients with previously untreated, advancedALK+ NSCLC, irrespective of prior CNS disease or radiotherapy. Clinical trial registration ClinicalTrials.gov NCT02075840
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Safety and clinical activity results from a phase Ib study of Alectinib plus atezolizumab in ALK+ advanced NSCLC (aNSCLC).
Journal of Clinical Oncology, 2018Co-Authors: Dongwan Kim, Shirish M Gadgeel, Scott N. Gettinger, Gregory J. Riely, Geoffrey R. Oxnard, Tarek Mekhail, Peter Schmid, Afshin Dowlati, Rebecca S. Heist, Antoinette J. WozniakAbstract:9009Background: Alectinib has proven systemic and CNS efficacy in patients (pts) with ALK+ aNSCLC (ALEX study). Tumor cell death caused by Alectinib may release antigens broadening the potential an...
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the use of Alectinib in the first line treatment of anaplastic lymphoma kinase positive non small cell lung cancer
Future Oncology, 2018Co-Authors: Shirish M GadgeelAbstract:Anaplastic lymphoma kinase (ALK) gene rearrangements as driver genetic alterations occur in approximately 2-4% of non-small-cell lung cancer (NSCLC) patients. Alectinib, a next generation ALK inhibitor, recently demonstrated, in two separate Phase III trials, superior efficacy to crizotinib, the first ALK inhibitor to demonstrate clinical efficacy in ALK-positive NSCLC patients. Alectinib also demonstrated superior efficacy in the CNS. The data from these two Phase III studies suggest that the efficacy of starting with Alectinib is superior to the overall clinical efficacy of starting with crizotinib followed by switching to Alectinib at the time of disease progression. These results have changed the standard of care to Alectinib as front-line therapy for advanced ALK-positive NSCLC patients. Areas covered: this paper reviews the available data on Alectinib as front-line therapy in patients with ALK-positive NSCLC patients including its activity against brain metastases. In addition, the paper will review the data with other ALK inhibitors as front-line therapy.
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efficacy and safety of Alectinib in alk non small cell lung cancer nsclc pooled data from two pivotal phase ii studies np28673 and np28761
Journal of Clinical Oncology, 2016Co-Authors: James Chih-hsin Yang, Luigi De Petris, Shirish M Gadgeel, Dongwan Kim, Leena Gandhi, Fabrice Barlesi, Ramaswamy Govindan, Annemarie C Dingemans, Lucio Crino, H LenaAbstract:e20507Background: Alectinib is a highly selective inhibitor of ALK and RET tyrosine kinase, with proven systemic and CNS activity in ALK+ NSCLC. Results of two single-arm, open-label phase II studies (NP28673 [NCT01801111] and NP28761 [NCT01871805]) led to FDA approval of Alectinib for patients (pts) with ALK+ NSCLC who progressed on or are intolerant to crizotinib. This pooled analysis further explored the efficacy and safety of Alectinib in ALK+ NSCLC. Methods: Pts ( ≥ 18 yrs; locally advanced or metastatic ALK+ NSCLC [by FDA-approved FISH test]; progressed on or intolerant to crizotinib) received Alectinib 600mg p.o. BID until progression, death or withdrawal. Crizotinib was the only prior ALK inhibitor permitted. This pooled analysis assessed objective response rate (ORR; RECIST v1.1) by independent review committee (IRC; primary endpoint); ORR by investigator; disease control rate (DCR); duration of response (DOR); progression-free survival (PFS); overall survival (OS); and safety. Results: The poole...
Peter N. Morcos - One of the best experts on this subject based on the ideXlab platform.
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Effect of Hepatic Impairment on the Pharmacokinetics of Alectinib
Journal of clinical pharmacology, 2018Co-Authors: Peter N. Morcos, Elena Guerini, Yumi Cleary, Bogdana Balas, Carolina Sturm-pellanda, Markus Abt, Massimiliano Donzelli, Faye Vazvaei, Neil ParrottAbstract:Alectinib is approved and recommended as the preferred first-line treatment for patients with anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer. The effect of hepatic impairment on the pharmacokinetics (PK) of Alectinib was assessed with physiologically based PK modeling prospectively and in a clinical study. An open-label study (NCT02621047) investigated a single 300-mg dose of Alectinib in moderate (n = 8) and severe (n = 8) hepatic impairment (Child-Pugh B/C), and healthy subjects (n = 12) matched for age, sex, and body weight. Physiologically based PK modeling was conducted prospectively to inform the clinical study design and support the use of a lower dose and extended PK sampling in the study. PK parameters were calculated for Alectinib, its major similarly active metabolite, M4, and the combined exposure of Alectinib and M4. Unbound concentrations were assessed at 6 and 12 hours postdose. Administration of Alectinib to subjects with hepatic impairment increased the area under the plasma concentration-time curve from time 0 to infinity of the combined exposure of Alectinib and M4 to 136% (90% confidence interval [CI], 94.7-196) and 176% (90%CI 98.4-315), for moderate and severe hepatic impairment, respectively, relative to matched healthy subjects. Unbound concentrations for Alectinib and M4 did not appear substantially different between hepatic-impaired and healthy subjects. Moderate hepatic impairment had only a modest, not clinically significant effect on Alectinib exposure, while the higher exposure observed in severe hepatic impairment supports a dose adjustment in this population.
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Exposure–response analysis of Alectinib in crizotinib-resistant ALK-positive non-small cell lung cancer
Cancer chemotherapy and pharmacology, 2018Co-Authors: Peter N. Morcos, Elena Guerini, Walter Bordogna, Bogdana Balas, Eveline Nueesch, Felix Jaminion, Joy C. Hsu, Francois MercierAbstract:Purpose Alectinib is a selective and potent anaplastic lymphoma kinase (ALK) inhibitor that is active in the central nervous system (CNS). Alectinib demonstrated robust efficacy in a pooled analysis of two single-arm, open-label phase II studies (NP28673, NCT01801111; NP28761, NCT01871805) in crizotinib-resistant ALK-positive non-small-cell lung cancer (NSCLC): median overall survival (OS) 29.1 months (95% confidence interval [CI]: 21.3–39.0) for Alectinib 600 mg twice daily (BID). We investigated exposure–response relationships from final pooled phase II OS and safety data to assess Alectinib dose selection.
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exposure response analysis of Alectinib in crizotinib resistant alk positive non small cell lung cancer
Cancer Chemotherapy and Pharmacology, 2018Co-Authors: Peter N. Morcos, Elena Guerini, Walter Bordogna, Bogdana Balas, Eveline Nueesch, Felix Jaminion, Joy C. Hsu, Francois MercierAbstract:Purpose Alectinib is a selective and potent anaplastic lymphoma kinase (ALK) inhibitor that is active in the central nervous system (CNS). Alectinib demonstrated robust efficacy in a pooled analysis of two single-arm, open-label phase II studies (NP28673, NCT01801111; NP28761, NCT01871805) in crizotinib-resistant ALK-positive non-small-cell lung cancer (NSCLC): median overall survival (OS) 29.1 months (95% confidence interval [CI]: 21.3–39.0) for Alectinib 600 mg twice daily (BID). We investigated exposure–response relationships from final pooled phase II OS and safety data to assess Alectinib dose selection.
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clinical drug drug interactions through cytochrome p450 3a cyp3a for the selective alk inhibitor Alectinib
Clinical pharmacology in drug development, 2017Co-Authors: Peter N. Morcos, Elena Guerini, Georgina Dall, Luigi De Petris, Santiago Viteri, Katrijn Bogman, Walter Bordogna, Yumi Cleary, Li Yu, Meret MartinfacklamAbstract:The efficacy and safety of Alectinib, a central nervous system-active and selective anaplastic lymphoma kinase (ALK) inhibitor, has been demonstrated in patients with ALK-positive (ALK+) non-small-cell lung cancer (NSCLC) progressing on crizotinib. Alectinib is mainly metabolized by cytochrome P450 3A (CYP3A) to a major similarly active metabolite, M4. Alectinib and M4 show evidence of weak time-dependent inhibition and small induction of CYP3A in vitro. We present results from three fixed-sequence studies evaluating drug–drug interactions for Alectinib through CYP3A. Studies NP28990 and NP29042 enrolled 17 and 24 healthy subjects, respectively, and investigated potent CYP3A inhibition with posaconazole and potent CYP3A induction through rifampin, respectively, on the single oral dose pharmacokinetics (PK) of Alectinib. A substudy of the global phase 2 NP28673 study enrolled 15 patients with ALK+ NSCLC to determine the effect of multiple doses of Alectinib on the single oral dose PK of midazolam, a sensitive substrate of CYP3A. Potent CYP3A inhibition or induction resulted in only minor effects on the combined exposure of Alectinib and M4. Multiple doses of Alectinib did not influence midazolam exposure. These results suggest that dose adjustments may not be needed when Alectinib is co-administered with CYP3A inhibitors or inducers, or for co-administered CYP3A substrates. This article is protected by copyright. All rights reserved
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clinical drug drug interactions through cytochrome p450 3a cyp3a for the selective alk inhibitor Alectinib
Clinical pharmacology in drug development, 2017Co-Authors: Peter N. Morcos, Elena Guerini, Georgina Dall, Luigi De Petris, Santiago Viteri, Meret Martinfacklam, Katrijn Bogman, Walter Bordogna, Yumi Cleary, Alex PhippsAbstract:The efficacy and safety of Alectinib, a central nervous system-active and selective anaplastic lymphoma kinase (ALK) inhibitor, has been demonstrated in patients with ALK-positive (ALK+) non-small cell lung cancer (NSCLC) progressing on crizotinib. Alectinib is mainly metabolized by cytochrome P450 3A (CYP3A) to a major similarly active metabolite, M4. Alectinib and M4 show evidence of weak time-dependent inhibition and small induction of CYP3A in vitro. We present results from 3 fixed-sequence studies evaluating drug-drug interactions for Alectinib through CYP3A. Studies NP28990 and NP29042 enrolled 17 and 24 healthy subjects, respectively, and investigated potent CYP3A inhibition with posaconazole and potent CYP3A induction through rifampin, respectively, on the single oral dose pharmacokinetics (PK) of Alectinib. A substudy of the global phase 2 NP28673 study enrolled 15 patients with ALK+ NSCLC to determine the effect of multiple doses of Alectinib on the single oral dose PK of midazolam, a sensitive substrate of CYP3A. Potent CYP3A inhibition or induction resulted in only minor effects on the combined exposure of Alectinib and M4. Multiple doses of Alectinib did not influence midazolam exposure. These results suggest that dose adjustments may not be needed when Alectinib is coadministered with CYP3A inhibitors or inducers or for coadministered CYP3A substrates.
Walter Bordogna - One of the best experts on this subject based on the ideXlab platform.
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alk mutation status before and after Alectinib treatment in locally advanced or metastatic alk positive nsclc pooled analysis of two prospective trials
Journal of Thoracic Oncology, 2020Co-Authors: Johannes Noe, Walter Bordogna, Alex Lovejoy, Stephanie J Yaung, Daniel M Klass, Craig Cummings, Alice T ShawAbstract:Abstract Introduction The effectiveness of ALK receptor tyrosine kinase (ALK) inhibitors can be limited by the development of ALK resistance mutations. This exploratory analysis assessed the efficacy of Alectinib in patients with NSCLC and ALK point mutations using pooled data from two single-arm phase II studies. Methods Studies NP28673 and NP28761 enrolled adults with locally advanced/metastatic ALK-positive NSCLC who had progressed on crizotinib. ALK mutation analysis was conducted on cell-free DNA from 187 patients post-crizotinib/pre-Alectinib, and from 49 of these patients who subsequently progressed on Alectinib. Results Baseline characteristics were generally balanced across patient subgroups. At baseline, 34 distinct ALK mutations were identified in 48 of 187 patients (25.7%). Median investigator-assessed progression-free survival was longer in patients without ALK single-nucleotide variants (n = 138) versus those with (n = 48): 10.2 months (95% confidence interval [CI]: 8.1–14.3) versus 5.6 months (95% CI: 4.5–10.9), respectively. Sixteen of 32 patients (50%) with ALK resistance mutations to crizotinib achieved an investigator-assessed response to Alectinib (all partial responses); most of these ALK mutations were known to be sensitive to Alectinib. Analysis of plasma samples obtained post-progression on Alectinib revealed that 26 of 49 (53%) samples harbored 16 distinct ALK mutations, with known Alectinib-resistance mutations, I1171 T/N/S, G1202R, and V1180L, observed in 15 of 49 (31%) tumors. Conclusions Alectinib appears clinically active against ALK rearrangements and mutations, as well as several ALK variants that can cause resistance to crizotinib. The use of cell-free DNA in plasma samples may be an alternative noninvasive method for monitoring resistance mutations during therapy.
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Comparative effectiveness from a single-arm trial and real-world data: Alectinib versus ceritinib.
Journal of comparative effectiveness research, 2018Co-Authors: Jessica Davies, Walter Bordogna, Michael Martinec, Paul Delmar, Mathieu Coudert, Sophie Golding, R. Martina, G CraneAbstract:Aim To compare the overall survival of anaplastic lymphoma kinase-positive non-small-cell lung cancer patients who received Alectinib with those who received ceritinib. Materials & methods Two treatment arms (Alectinib [n = 183] and ceritinib [n = 67]) were extracted from clinical trials and an electronic health record database, respectively. Propensity scores were applied to balance baseline characteristics. Kaplan-Meier and multivariate Cox regression were conducted. Results After propensity score adjustment, baseline characteristics were balanced. Alectinib had a prolonged median overall survival (Alectinib = 24.3 months and ceritinib = 15.6 months) and lower risk of death (hazard ratio: 0.65; 95% CI: 0.48-0.88). Conclusion Alectinib was associated with prolonged overall survival versus ceritinib, which is consistent with efficacy evidence from clinical trials.
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Exposure–response analysis of Alectinib in crizotinib-resistant ALK-positive non-small cell lung cancer
Cancer chemotherapy and pharmacology, 2018Co-Authors: Peter N. Morcos, Elena Guerini, Walter Bordogna, Bogdana Balas, Eveline Nueesch, Felix Jaminion, Joy C. Hsu, Francois MercierAbstract:Purpose Alectinib is a selective and potent anaplastic lymphoma kinase (ALK) inhibitor that is active in the central nervous system (CNS). Alectinib demonstrated robust efficacy in a pooled analysis of two single-arm, open-label phase II studies (NP28673, NCT01801111; NP28761, NCT01871805) in crizotinib-resistant ALK-positive non-small-cell lung cancer (NSCLC): median overall survival (OS) 29.1 months (95% confidence interval [CI]: 21.3–39.0) for Alectinib 600 mg twice daily (BID). We investigated exposure–response relationships from final pooled phase II OS and safety data to assess Alectinib dose selection.
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exposure response analysis of Alectinib in crizotinib resistant alk positive non small cell lung cancer
Cancer Chemotherapy and Pharmacology, 2018Co-Authors: Peter N. Morcos, Elena Guerini, Walter Bordogna, Bogdana Balas, Eveline Nueesch, Felix Jaminion, Joy C. Hsu, Francois MercierAbstract:Purpose Alectinib is a selective and potent anaplastic lymphoma kinase (ALK) inhibitor that is active in the central nervous system (CNS). Alectinib demonstrated robust efficacy in a pooled analysis of two single-arm, open-label phase II studies (NP28673, NCT01801111; NP28761, NCT01871805) in crizotinib-resistant ALK-positive non-small-cell lung cancer (NSCLC): median overall survival (OS) 29.1 months (95% confidence interval [CI]: 21.3–39.0) for Alectinib 600 mg twice daily (BID). We investigated exposure–response relationships from final pooled phase II OS and safety data to assess Alectinib dose selection.
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clinical drug drug interactions through cytochrome p450 3a cyp3a for the selective alk inhibitor Alectinib
Clinical pharmacology in drug development, 2017Co-Authors: Peter N. Morcos, Elena Guerini, Georgina Dall, Luigi De Petris, Santiago Viteri, Katrijn Bogman, Walter Bordogna, Yumi Cleary, Li Yu, Meret MartinfacklamAbstract:The efficacy and safety of Alectinib, a central nervous system-active and selective anaplastic lymphoma kinase (ALK) inhibitor, has been demonstrated in patients with ALK-positive (ALK+) non-small-cell lung cancer (NSCLC) progressing on crizotinib. Alectinib is mainly metabolized by cytochrome P450 3A (CYP3A) to a major similarly active metabolite, M4. Alectinib and M4 show evidence of weak time-dependent inhibition and small induction of CYP3A in vitro. We present results from three fixed-sequence studies evaluating drug–drug interactions for Alectinib through CYP3A. Studies NP28990 and NP29042 enrolled 17 and 24 healthy subjects, respectively, and investigated potent CYP3A inhibition with posaconazole and potent CYP3A induction through rifampin, respectively, on the single oral dose pharmacokinetics (PK) of Alectinib. A substudy of the global phase 2 NP28673 study enrolled 15 patients with ALK+ NSCLC to determine the effect of multiple doses of Alectinib on the single oral dose PK of midazolam, a sensitive substrate of CYP3A. Potent CYP3A inhibition or induction resulted in only minor effects on the combined exposure of Alectinib and M4. Multiple doses of Alectinib did not influence midazolam exposure. These results suggest that dose adjustments may not be needed when Alectinib is co-administered with CYP3A inhibitors or inducers, or for co-administered CYP3A substrates. This article is protected by copyright. All rights reserved
Yuto Yasuda - One of the best experts on this subject based on the ideXlab platform.
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Acquired Resistance to Alectinib in ALK-Rearranged Lung Cancer due to ABCC11/MRP8 Overexpression in a Clinically Paired Resistance Model.
Molecular cancer therapeutics, 2020Co-Authors: Tomoko Funazo, Hiroaki Ozasa, Takahiro Tsuji, Takashi Nomizo, Yuto Yasuda, Hitomi Ajimizu, Koh Furugaki, Yasushi Yoshimura, Tetsuya Oguri, Yuichi SakamoriAbstract:Alectinib is used as a first-line treatment for anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer (NSCLC). Whereas other ALK inhibitors have been reported to be involved in resistance to ATP-binding cassette (ABC) transporters, no data are available regarding the association between resistance to Alectinib and ABC-transporters. To investigate whether ABC-transporters contribute to Alectinib resistance, ABC-transporter expression in Alectinib-resistant cell lines derived from a patient with ALK-rearranged NSCLC and from H2228 lung cancer cells was evaluated and compared with that in each parent cell type. ATP-binding cassette subfamily C member 11 (ABCC11) expression was significantly increased in Alectinib-resistant cell lines compared with that in Alectinib-sensitive lines. ABCC11 inhibition increased sensitivity to Alectinib in vitro ABCC11-overexpressing cells were established by transfection of an ABCC11 expression vector into H2228 cells, while control cells were established by transfecting H2228 cells with an empty vector. ABCC11-overexpressing cells exhibited decreased sensitivity to Alectinib compared with that of control cells in vitro Moreover, the tumor growth rate following Alectinib treatment was higher in ABCC11-overexpressing cells than that in control cells in vivo In addition, the intracellular Alectinib concentration following exposure to 100 nmol/L Alectinib was significantly lower in the ABCC11-overexpressing cell line compared with that in control cells. This is the first preclinical evidence showing that ABCC11 expression may be involved in acquired resistance to Alectinib.
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YAP1 mediates survival of ALK-rearranged lung cancer cells treated with Alectinib via pro-apoptotic protein regulation.
Nature communications, 2020Co-Authors: Takahiro Tsuji, Hiroaki Ozasa, Hitomi Ajimizu, Tomoko Funazo, Koh Furugaki, Yasushi Yoshimura, Wataru Aoki, Shunsuke Aburaya, Masatoshi Yamazoe, Yuto YasudaAbstract:Despite the promising clinical efficacy of the second-generation anaplastic lymphoma kinase (ALK) inhibitor Alectinib in patients with ALK-rearranged lung cancer, some tumor cells survive and eventually relapse, which may be an obstacle to achieving a cure. Limited information is currently available on the mechanisms underlying the initial survival of tumor cells against Alectinib. Using patient-derived cell line models, we herein demonstrate that cancer cells survive a treatment with Alectinib by activating Yes-associated protein 1 (YAP1), which mediates the expression of the anti-apoptosis factors Mcl-1 and Bcl-xL, and combinatorial inhibition against both YAP1 and ALK provides a longer tumor remission in ALK-rearranged xenografts when compared with Alectinib monotherapy. These results suggest that the inhibition of YAP1 is a candidate for combinatorial therapy with ALK inhibitors to achieve complete remission in patients with ALK-rearranged lung cancer. Relapse is a limitation for the efficacy of the anaplastic lymphoma kinase (ALK)-inhibitor Alectinib in ALK-rearranged lung cancer. Here, the authors show that YAP1 activation upon Alectinib treatment leads to therapy resistance and that inhibiting both YAP1 and ALK leads to longer tumor remission in mice.
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Efficacy of Ceritinib After Alectinib for ALK-positive Non-small Cell Lung Cancer.
In vivo (Athens Greece), 2018Co-Authors: Hironori Yoshida, Young Hak Kim, Hiroaki Ozasa, Yuichi Sakamori, Takahiro Tsuji, Takashi Nomizo, Yuto Yasuda, Tomoko Yamamoto, Hitomi Ajimizu, Toyohiro HiraiAbstract:BACKGROUND Alectinib is a new standard treatment for treatment-naive anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC); however, resistance ultimately develops in almost all patients, and data regarding the efficiency of ceritinib for such patients are insufficient. PATIENTS AND METHODS Patients with ALK-positive NSCLC treated at the Kyoto University Hospital from January 2012 to March 2017 were reviewed. Patients who were treated with ceritinib after Alectinib were identified, and the efficacy of ceritinib after Alectinib was retrospectively evaluated. RESULTS There were 35 patients with ALK-positive NSCLC, nine of whom received ceritinib after Alectinib. The overall response rate to ceritinib was 44%. It was 16% in patients who received ceritinib immediately after Alectinib, and 100% in patients who received chemotherapy before ceritinib. The median progression-free survival for patients treated with ceritinib was 4.4 months (95% confidence interval(CI)=1.1-6.5 months). CONCLUSION Ceritinib demonstrated a modest clinical benefit after failure of Alectinib. Ceritinib may be a reasonable treatment option in this setting.
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Alectinib Resistance in ALK-Rearranged Lung Cancer by Dual Salvage Signaling in a Clinically Paired Resistance Model
Molecular cancer research : MCR, 2018Co-Authors: Takahiro Tsuji, Hiroaki Ozasa, Hitomi Ajimizu, Tomoko Funazo, Koh Furugaki, Yasushi Yoshimura, Wataru Aoki, Shunsuke Aburaya, Ryoko Okutani, Yuto YasudaAbstract:The mechanisms responsible for the development of resistance to Alectinib, a second-generation anaplastic lymphoma kinase (ALK) inhibitor, are still unclear, and few cell lines are currently available for investigating ALK-rearranged lung cancer. To identify the mechanisms underlying acquired resistance to Alectinib, two patient-derived cell lines were established from an Alectinib-naive ALK-rearranged lung cancer and then after development of Alectinib resistance. The properties acquired during treatments were detected by comparisons of the two cell lines, and then functional analyses were performed. Coactivation of c-Src and MET was identified after the development of Alectinib resistance. Combinatorial therapy against Src and MET significantly restored Alectinib sensitivity in vitro (17.2-fold). Increased apoptosis, reduction of tumor volume, and inhibition of MAPK and PI3K/AKT signaling molecules for proliferation and survival were observed when the three kinases (Src, MET, and ALK) were inhibited. A patient-derived xenograft from the Alectinib-resistant cells indicated that combination therapy with a saracatinib and crizotinib significantly decreased tumor size in vivo. To confirm the generality, a conventional Alectinib-resistant cell line model (H2228-AR1S) was established from NCI-H2228 cells (EML4-ALK variant 3a/b). In H2228-AR1S, combination inhibition of Src and MET also restored Alectinib sensitivity. These data reveal that dual salvage signaling from MET and Src is a potential therapeutic target in Alectinib-resistant patients. IMPLICATIONS: This study demonstrates the feasibility to elucidate personalized drug-resistance mechanisms from individual patient samples.
Alice T Shaw - One of the best experts on this subject based on the ideXlab platform.
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alk mutation status before and after Alectinib treatment in locally advanced or metastatic alk positive nsclc pooled analysis of two prospective trials
Journal of Thoracic Oncology, 2020Co-Authors: Johannes Noe, Walter Bordogna, Alex Lovejoy, Stephanie J Yaung, Daniel M Klass, Craig Cummings, Alice T ShawAbstract:Abstract Introduction The effectiveness of ALK receptor tyrosine kinase (ALK) inhibitors can be limited by the development of ALK resistance mutations. This exploratory analysis assessed the efficacy of Alectinib in patients with NSCLC and ALK point mutations using pooled data from two single-arm phase II studies. Methods Studies NP28673 and NP28761 enrolled adults with locally advanced/metastatic ALK-positive NSCLC who had progressed on crizotinib. ALK mutation analysis was conducted on cell-free DNA from 187 patients post-crizotinib/pre-Alectinib, and from 49 of these patients who subsequently progressed on Alectinib. Results Baseline characteristics were generally balanced across patient subgroups. At baseline, 34 distinct ALK mutations were identified in 48 of 187 patients (25.7%). Median investigator-assessed progression-free survival was longer in patients without ALK single-nucleotide variants (n = 138) versus those with (n = 48): 10.2 months (95% confidence interval [CI]: 8.1–14.3) versus 5.6 months (95% CI: 4.5–10.9), respectively. Sixteen of 32 patients (50%) with ALK resistance mutations to crizotinib achieved an investigator-assessed response to Alectinib (all partial responses); most of these ALK mutations were known to be sensitive to Alectinib. Analysis of plasma samples obtained post-progression on Alectinib revealed that 26 of 49 (53%) samples harbored 16 distinct ALK mutations, with known Alectinib-resistance mutations, I1171 T/N/S, G1202R, and V1180L, observed in 15 of 49 (31%) tumors. Conclusions Alectinib appears clinically active against ALK rearrangements and mutations, as well as several ALK variants that can cause resistance to crizotinib. The use of cell-free DNA in plasma samples may be an alternative noninvasive method for monitoring resistance mutations during therapy.
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Alectinib versus crizotinib in treatment naive anaplastic lymphoma kinase positive alk non small cell lung cancer cns efficacy results from the alex study
Annals of Oncology, 2018Co-Authors: Shirish M Gadgeel, Solange Peters, Tony Mok, M Perol, Silvia Novello, Alice T Shaw, Dongwan Kim, Anna Wrona, R Rosell, A ZeaiterAbstract:ABSTRACT Background The phase III ALEX study in patients with treatment-naive advanced anaplastic lymphoma kinase mutation-positive (ALK+) non-small-cell lung cancer (NSCLC) met its primary end point of improved progression-free survival (PFS) with Alectinib versus crizotinib. Here, we present detailed central nervous system (CNS) efficacy data from ALEX. Patients and methods Overall, 303 patients aged ≥18 years underwent 1:1 randomization to receive twice-daily doses of Alectinib 600 mg or crizotinib 250 mg. Brain imaging was conducted in all patients at baseline and every subsequent 8 weeks. End points (analyzed by subgroup: patients with/without baseline CNS metastases; patients with/without prior radiotherapy) included PFS, CNS objective response rate (ORR), and time to CNS progression. Results In total, 122 patients had Independent Review Committee-assessed baseline CNS metastases (Alectinib,n = 64; crizotinib,n = 58), 43 had measurable lesions (Alectinib,n = 21; crizotinib,n = 22), and 46 had received prior radiotherapy (Alectinib,n = 25; crizotinib,n = 21). Investigator-assessed PFS with Alectinib was consistent between patients with baseline CNS metastases [hazard ratio (HR) 0.40, 95% confidence interval (CI): 0.25–0.64] and those without (HR 0.51, 95% CI: 0.33–0.80,P interaction = 0.36). Similar results were seen in patients regardless of prior radiotherapy. Time to CNS progression was significantly longer with Alectinib versus crizotinib and comparable between patients with and without baseline CNS metastases (P Conclusion Alectinib demonstrated superior CNS activity and significantly delayed CNS progression versus crizotinib in patients with previously untreated, advancedALK+ NSCLC, irrespective of prior CNS disease or radiotherapy. Clinical trial registration ClinicalTrials.gov NCT02075840
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Long-term efficacy and outcomes with sequential crizotinib followed by Alectinib in ALK+ NSCLC.
Journal of Clinical Oncology, 2018Co-Authors: Jessica J. Lin, Justin F. Gainor, Beow Y. Yeap, Lorin A. Ferris, Ibiayi Dagogo-jack, Satoshi Yoda, Jochen K. Lennerz, Alice T ShawAbstract:9093Background: Alectinib was recently approved for first-line treatment of advanced ALK+ NSCLC based on the ALEX trial, which demonstrated improved PFS with first-line Alectinib compared to crizot...
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Alectinib Salvages CNS Relapses in ALK-Positive Lung Cancer Patients Previously Treated with Crizotinib and Ceritinib
Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer, 2015Co-Authors: Justin F. Gainor, Carol A. Sherman, Kathryn Willoughby, Jennifer A. Logan, Elizabeth Kennedy, Priscilla K. Brastianos, Andrew S. Chi, Alice T ShawAbstract:Background Leptomeningeal metastases (LM) are an increasingly frequent and devastating complication of anaplastic lymphoma kinase (ALK)-rearranged non–small-cell lung cancer (NSCLC). Currently, the optimal management of LM in ALK-positive patients remains poorly understood as these patients have been routinely excluded from clinical trials. Methods We describe four ALK-positive patients with LM who were treated with the next-generation ALK inhibitor Alectinib through single-patient, compassionate use protocols at two institutions. All patients had previously been treated with both FDA-approved ALK inhibitors—crizotinib and ceritinib. Patients received Alectinib at a starting dose of 600 mg twice daily. Results Four ALK-positive NSCLC patients with symptomatic leptomeningeal disease were identified. Three of four patients experienced significant clinical and radiographic improvements in LM upon treatment with Alectinib. A fourth patient had stable intracranial disease for 4 months before eventual systemic disease progression. Overall, Alectinib was well tolerated. One patient required dose reduction due to grade 2 hyperbilirubinemia. Conclusions Alectinib is active in ALK-rearranged NSCLC patients with LM, including in patients previously treated with crizotinib and ceritinib. Additional prospective studies of Alectinib in ALK-positive patients with LM are warranted.
