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Article ; Online: Evaluation of the drug-drug interaction potential of brigatinib using a physiologically-based pharmacokinetic modeling approach.

Hanley, Michael J / Yeo, Karen Rowland / Tugnait, Meera / Iwasaki, Shinji / Narasimhan, Narayana / Zhang, Pingkuan / Venkatakrishnan, Karthik / Gupta, Neeraj

CPT: pharmacometrics & systems pharmacology

2024 Volume 13, Issue 4, Page(s) 624–637

Abstract: Brigatinib is an oral anaplastic lymphoma kinase (ALK) inhibitor approved for the treatment of ALK-positive metastatic non-small cell lung cancer. In vitro studies indicated that brigatinib is primarily metabolized by CYP2C8 and CYP3A4 and inhibits P-gp, ...

Abstract	Brigatinib is an oral anaplastic lymphoma kinase (ALK) inhibitor approved for the treatment of ALK-positive metastatic non-small cell lung cancer. In vitro studies indicated that brigatinib is primarily metabolized by CYP2C8 and CYP3A4 and inhibits P-gp, BCRP, OCT1, MATE1, and MATE2K. Clinical drug-drug interaction (DDI) studies with the strong CYP3A inhibitor itraconazole or the strong CYP3A inducer rifampin demonstrated that CYP3A-mediated metabolism was the primary contributor to overall brigatinib clearance in humans. A physiologically-based pharmacokinetic (PBPK) model for brigatinib was developed to predict potential DDIs, including the effect of moderate CYP3A inhibitors or inducers on brigatinib pharmacokinetics (PK) and the effect of brigatinib on the PK of transporter substrates. The developed model was able to predict clinical DDIs with itraconazole (area under the plasma concentration-time curve from time 0 to infinity [AUC
MeSH term(s)	Humans ; Rifampin/pharmacokinetics ; Cytochrome P-450 CYP3A Inhibitors/pharmacology ; Itraconazole/pharmacology ; Cytochrome P-450 CYP3A/metabolism ; Carcinoma, Non-Small-Cell Lung ; ATP Binding Cassette Transporter, Subfamily G, Member 2 ; Lung Neoplasms ; Neoplasm Proteins/metabolism ; Cytochrome P-450 CYP3A Inducers/pharmacokinetics ; Drug Interactions ; Membrane Transport Proteins ; Receptor Protein-Tyrosine Kinases/metabolism ; Models, Biological ; Organophosphorus Compounds ; Pyrimidines
Chemical Substances	Rifampin (VJT6J7R4TR) ; Cytochrome P-450 CYP3A Inhibitors ; brigatinib (HYW8DB273J) ; Itraconazole (304NUG5GF4) ; Cytochrome P-450 CYP3A (EC 1.14.14.1) ; ATP Binding Cassette Transporter, Subfamily G, Member 2 ; Neoplasm Proteins ; Cytochrome P-450 CYP3A Inducers ; Membrane Transport Proteins ; Receptor Protein-Tyrosine Kinases (EC 2.7.10.1) ; Organophosphorus Compounds ; Pyrimidines
Language	English
Publishing date	2024-01-30
Publishing country	United States
Document type	Journal Article
ZDB-ID	2697010-7
ISSN	2163-8306 ; 2163-8306
ISSN (online)	2163-8306
ISSN	2163-8306
DOI	10.1002/psp4.13106
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Clinical Pharmacology of Brigatinib: A Next-Generation Anaplastic Lymphoma Kinase Inhibitor.

Gupta, Neeraj / Hanley, Michael J / Griffin, Robert J / Zhang, Pingkuan / Venkatakrishnan, Karthik / Sinha, Vikram

Clinical pharmacokinetics

2023 Volume 62, Issue 8, Page(s) 1063–1079

Abstract: Brigatinib, a next-generation anaplastic lymphoma kinase (ALK) inhibitor designed to overcome mechanisms of resistance associated with crizotinib, is approved for the treatment of ALK-positive advanced or metastatic non-small cell lung cancer. After oral ...

Abstract	Brigatinib, a next-generation anaplastic lymphoma kinase (ALK) inhibitor designed to overcome mechanisms of resistance associated with crizotinib, is approved for the treatment of ALK-positive advanced or metastatic non-small cell lung cancer. After oral administration of single doses of brigatinib 30-240 mg, the median time to reach maximum plasma concentration ranged from 1 to 4 h. In patients with advanced malignancies, brigatinib showed dose linearity over the dose range of 60-240 mg once daily. A high-fat meal had no clinically meaningful effect on systemic exposures of brigatinib (area under the plasma concentration-time curve); thus, brigatinib can be administered with or without food. In a population pharmacokinetic analysis, a three-compartment pharmacokinetic model with transit absorption compartments was found to adequately describe brigatinib pharmacokinetics. In addition, the population pharmacokinetic analyses showed that no dose adjustment is required based on body weight, age, race, sex, total bilirubin (< 1.5× upper limit of normal), and mild-to-moderate renal impairment. Data from dedicated phase I trials have indicated that no dose adjustment is required for patients with mild or moderate hepatic impairment, while a dose reduction of approximately 40% (e.g., from 180 to 120 mg) is recommended for patients with severe hepatic impairment, and a reduction of approximately 50% (e.g., from 180 to 90 mg) is recommended when administering brigatinib to patients with severe renal impairment. Brigatinib is primarily metabolized by cytochrome P450 (CYP) 3A, and results of clinical drug-drug interaction studies and physiologically based pharmacokinetic analyses have demonstrated that coadministration of strong or moderate CYP3A inhibitors or inducers with brigatinib should be avoided. If coadministration with a strong or moderate CYP3A inhibitor cannot be avoided, the dose of brigatinib should be reduced by approximately 50% (strong CYP3A inhibitor) or approximately 40% (moderate CYP3A inhibitor), respectively. Brigatinib is a weak inducer of CYP3A in vivo; data from a phase I drug-drug interaction study showed that coadministration of brigatinib 180 mg once daily reduced the oral midazolam area under the plasma concentration-time curve from time zero to infinity by approximately 26%. Brigatinib did not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP2D6 at clinically relevant concentrations in vitro. Exposure-response analyses based on data from the ALTA (ALK in Lung Cancer Trial of AP26113) and ALTA-1L pivotal trials of brigatinib confirm the favorable benefit versus risk profile of the approved titration dosing regimen of 180 mg once daily (after a 7-day lead-in at 90 mg once daily).
MeSH term(s)	Humans ; Carcinoma, Non-Small-Cell Lung/drug therapy ; Lung Neoplasms/drug therapy ; Anaplastic Lymphoma Kinase ; Cytochrome P-450 CYP3A Inhibitors/therapeutic use ; Protein Kinase Inhibitors/pharmacology ; Protein Kinase Inhibitors/therapeutic use
Chemical Substances	brigatinib (HYW8DB273J) ; Anaplastic Lymphoma Kinase (EC 2.7.10.1) ; Cytochrome P-450 CYP3A Inhibitors ; Protein Kinase Inhibitors
Language	English
Publishing date	2023-07-26
Publishing country	Switzerland
Document type	Journal Article ; Review ; Research Support, Non-U.S. Gov't
ZDB-ID	197627-8
ISSN	1179-1926 ; 0312-5963
ISSN (online)	1179-1926
ISSN	0312-5963
DOI	10.1007/s40262-023-01284-w
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Article ; Online: Brigatinib in Japanese patients with ALK-positive non-small-cell lung cancer: Final results of the phase 2 J-ALTA trial.

Yoshida, Tatsuya / Kumagai, Toru / Toyozawa, Ryo / Katayama, Ryohei / Nishio, Makoto / Seto, Takashi / Goto, Koichi / Yamamoto, Nobuyuki / Ohe, Yuichiro / Kudou, Kentarou / Asato, Takayuki / Zhang, Pingkuan / Nakagawa, Kazuhiko

Cancer science

2023 Volume 114, Issue 9, Page(s) 3698–3707

Abstract: The phase 2, single-arm, multicenter, open-label J-ALTA study evaluated the efficacy and safety of brigatinib in Japanese patients with advanced ALK+ non-small-cell lung cancer (NSCLC). One expansion cohort of J-ALTA enrolled patients previously treated ... ...

Abstract	The phase 2, single-arm, multicenter, open-label J-ALTA study evaluated the efficacy and safety of brigatinib in Japanese patients with advanced ALK+ non-small-cell lung cancer (NSCLC). One expansion cohort of J-ALTA enrolled patients previously treated with ALK tyrosine kinase inhibitors (TKIs); the main cohort included patients with prior alectinib ± crizotinib. The second expansion cohort enrolled patients with TKI-naive ALK+ NSCLC. All patients received brigatinib 180 mg once daily (7-day lead-in at 90 mg daily). Among 47 patients in the main cohort, 5 (11%) remained on brigatinib at the study end (median follow-up: 23 months). In this cohort, the independent review committee (IRC)-assessed objective response rate (ORR) was 34% (95% CI, 21%-49%); median duration of response was 14.8 months (95% CI, 5.5-19.4); median IRC-assessed progression-free survival (PFS) was 7.3 months (95% CI, 3.7-12.9). Among 32 patients in the TKI-naive cohort, 25 (78%) remained on brigatinib (median follow-up: 22 months); 2-year IRC-assessed PFS was 73% (90% CI, 55%-85%); IRC-assessed ORR was 97% (95% CI, 84%-100%); the median duration of response was not reached (95% CI, 19.4-not reached); 2-year duration of response was 70%. Grade ≥3 adverse events occurred in 68% and 91% of TKI-pretreated and TKI-naive patients, respectively. Exploratory analyses of baseline circulating tumor DNA in ALK TKI-pretreated NSCLC showed associations between poor PFS and EML4-ALK fusion variant 3 and TP53. Brigatinib is an important treatment option for Japanese patients with ALK+ NSCLC, including patients previously treated with alectinib.
MeSH term(s)	Humans ; Carcinoma, Non-Small-Cell Lung/drug therapy ; Carcinoma, Non-Small-Cell Lung/genetics ; Carcinoma, Non-Small-Cell Lung/chemically induced ; Lung Neoplasms/drug therapy ; Lung Neoplasms/genetics ; Lung Neoplasms/chemically induced ; East Asian People ; Anaplastic Lymphoma Kinase/genetics ; Protein Kinase Inhibitors/adverse effects
Chemical Substances	brigatinib (HYW8DB273J) ; Anaplastic Lymphoma Kinase (EC 2.7.10.1) ; Protein Kinase Inhibitors
Language	English
Publishing date	2023-07-11
Publishing country	England
Document type	Multicenter Study ; Clinical Trial, Phase II ; Journal Article
ZDB-ID	2115647-5
ISSN	1349-7006 ; 1349-7006
ISSN (online)	1349-7006
ISSN	1349-7006
DOI	10.1111/cas.15888
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Article ; Online: Indirect comparison of mobocertinib and real-world therapies for pre-treated non-small cell lung cancer with EGFR exon 20 insertion mutations.

Christopoulos, Petros / Prawitz, Thibaud / Hong, Jin-Liern / Lin, Huamao M / Hernandez, Luis / Jin, Shu / Tan, Min / Proskorovsky, Irina / Lin, Jianchang / Zhang, Pingkuan / Patel, Jyoti D / Ou, Sai-Hong I / Thomas, Michael / Stenzinger, Albrecht

Lung cancer (Amsterdam, Netherlands)

2023 Volume 179, Page(s) 107191

Abstract: Objectives: Mobocertinib, a novel oral epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, is available for the treatment of non-small cell lung cancer (NSCLC) with EGFR exon 20 insertion (ex20ins) mutations after platinum chemotherapy. ... ...

Abstract	Objectives: Mobocertinib, a novel oral epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, is available for the treatment of non-small cell lung cancer (NSCLC) with EGFR exon 20 insertion (ex20ins) mutations after platinum chemotherapy. We performed an indirect comparison of clinical trial data and real-world data (RWD) to determine the relative efficacy of mobocertinib vs. other treatments for these patients. Materials and methods: Data on the efficacy of mobocertinib from a phase I/II trial (NCT02716116) were compared to RWD from a retrospective study in 12 German centers using inverse probability of treatment weighting to adjust for age, sex, Eastern Cooperative Oncology Group score, smoking status, presence of brain metastasis, time from advanced diagnosis, and histology. Tumor response assessment was based on RECIST v1.1. Results: The analysis included 114 patients in the mobocertinib group and 43 in the RWD group. The confirmed overall response rate (cORR) according to investigator assessment was 0% for standard treatments and 35.1% (95% confidence interval [CI], 26.4-44.6) for mobocertinib (p < 0.0001). Compared to standard regimens in the weighted population, mobocertinib prolonged overall survival (OS, median [95% CI] = 9.8 [4.3-13.7] vs. 20.2 [14.9-25.3] months; hazard ratio [HR] = 0.42 [0.25-0.69], p = 0.0035), progression-free survival (PFS, median [95% CI] = 2.6 [1.5-5.7] vs. 7.3 [5.6-8.8] months; HR = 0.28 [0.18-0.44], p < 0.0001), and time to treatment discontinuation (median [95% CI] = 2.1 [1.2-3.1] vs. 7.4 [6.4-8.5] months; HR = 0.34 [0.18-0.65], p = 0.0004). Conclusion: Mobocertinib was associated with an improved cORR and prolonged PFS and OS compared to standard treatments for patients with EGFR ex20ins-positive NSCLC previously treated with platinum-based chemotherapy.
MeSH term(s)	Humans ; Carcinoma, Non-Small-Cell Lung/drug therapy ; Lung Neoplasms/drug therapy ; Retrospective Studies ; Mutagenesis, Insertional ; Prognosis ; Protein Kinase Inhibitors/therapeutic use ; Mutation ; ErbB Receptors/genetics ; Exons
Chemical Substances	mobocertinib ; Protein Kinase Inhibitors ; ErbB Receptors (EC 2.7.10.1) ; EGFR protein, human (EC 2.7.10.1)
Language	English
Publishing date	2023-04-08
Publishing country	Ireland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	632771-0
ISSN	1872-8332 ; 0169-5002
ISSN (online)	1872-8332
ISSN	0169-5002
DOI	10.1016/j.lungcan.2023.107191
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Zs.A 2135: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
Zs.MO 423: Show issues

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Article ; Online: Correction to: Brigatinib in Japanese patients with tyrosine kinase inhibitor-naive ALK-positive non-small cell lung cancer: first results from the phase 2 J-ALTA study.

Sugawara, Shunichi / Kondo, Masashi / Yokoyama, Toshihide / Kumagai, Toru / Nishio, Makoto / Goto, Koichi / Nakagawa, Kazuhiko / Seto, Takashi / Yamamoto, Nobuyuki / Kudou, Kentarou / Asato, Takayuki / Zhang, Pingkuan / Ohe, Yuichiro

International journal of clinical oncology

2023 Volume 28, Issue 5, Page(s) 724–725

Language	English
Publishing date	2023-01-12
Publishing country	Japan
Document type	Published Erratum
ZDB-ID	1400227-9
ISSN	1437-7772 ; 1341-9625
ISSN (online)	1437-7772
ISSN	1341-9625
DOI	10.1007/s10147-022-02286-7
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Zs.A 4828: Show issues

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Article ; Online: Comparative effectiveness of mobocertinib and standard of care in patients with NSCLC with EGFR exon 20 insertion mutations: An indirect comparison.

Ou, Sai-Hong I / Lin, Huamao M / Hong, Jin-Liern / Yin, Yu / Jin, Shu / Lin, Jianchang / Mehta, Minal / Zhang, Pingkuan / Nguyen, Danny / Neal, Joel W

Lung cancer (Amsterdam, Netherlands)

2023 Volume 179, Page(s) 107186

Abstract: Introduction: Mobocertinib is a novel, first-in-class, irreversible, oral epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) designed to selectively target in-frame EGFR exon 20 insertions (ex20ins). Comparative effectiveness data ... ...

Abstract	Introduction: Mobocertinib is a novel, first-in-class, irreversible, oral epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) designed to selectively target in-frame EGFR exon 20 insertions (ex20ins). Comparative effectiveness data for mobocertinib versus real-world treatments are lacking in this rare population. This study compared data for mobocertinib reported in a Phase I/II single-arm clinical trial with an external control group consisting of patients who received available treatment in the real-world setting in the United States (US). Materials and methods: The mobocertinib group included platinum-pretreated patients with advanced EGFR ex20ins non-small cell lung cancer (NSCLC) receiving mobocertinib 160 mg QD in an ongoing, single-arm, phase 1/2 clinical trial (NCT02716116; n = 114). The real-world data (RWD) group included platinum-pretreated patients with advanced EGFR ex20ins-mutant NSCLC from the Flatiron Health database (n = 50). Inverse probability treatment weighting based on the propensity score method controlled for potential confounding between groups. Confirmed overall response rate (cORR), progression-free survival (PFS), and overall survival (OS) were compared between groups. Results: After weighting, baseline characteristics were balanced. Patients in the RWD group received EGFR TKI (20 %), immuno-oncology therapy (40 %), or any regimens containing chemotherapy (40 %) in the second- or later-line setting. In the mobocertinib and RWD groups, respectively, cORR was 35.1 % and 11.9 % (odds ratio: 3.75 [95 % confidence interval (CI): 2.05, 6.89]); median PFS was 7.3 and 3.3 months (hazard ratio [HR]: 0.57 [95 % CI: 0.36, 0.90]); and median OS was 24.0 and 12.4 months (HR: 0.53 [95 % CI: 0.33, 0.83]) after weighting. Discussion: Mobocertinib showed substantially improved outcomes versus an external control group using available therapies in platinum-pretreated patients with EGFR ex20ins-mutant NSCLC. In the absence of comparative evidence from randomized trials, these findings help elucidate potential benefits of mobocertinib in this rare population.
MeSH term(s)	Humans ; Carcinoma, Non-Small-Cell Lung/drug therapy ; Lung Neoplasms/drug therapy ; Platinum/therapeutic use ; Mutagenesis, Insertional ; Standard of Care ; Protein Kinase Inhibitors/therapeutic use ; ErbB Receptors/genetics ; Exons ; Mutation
Chemical Substances	mobocertinib ; Platinum (49DFR088MY) ; Protein Kinase Inhibitors ; ErbB Receptors (EC 2.7.10.1) ; EGFR protein, human (EC 2.7.10.1)
Language	English
Publishing date	2023-04-01
Publishing country	Ireland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	632771-0
ISSN	1872-8332 ; 0169-5002
ISSN (online)	1872-8332
ISSN	0169-5002
DOI	10.1016/j.lungcan.2023.107186
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Zs.A 2135: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: Efficacy of Mobocertinib and Amivantamab in Patients With Advanced Non-Small Cell Lung Cancer With EGFR Exon 20 Insertions Previously Treated With Platinum-Based Chemotherapy: An Indirect Treatment Comparison.

Ou, Sai-Hong Ignatius / Prawitz, Thibaud / Lin, Huamao M / Hong, Jin-Liern / Tan, Min / Proskorovsky, Irina / Hernandez, Luis / Jin, Shu / Zhang, Pingkuan / Lin, Jianchang / Patel, Jyoti / Nguyen, Danny / Neal, Joel W

Clinical lung cancer

2023

Abstract: Introduction: Exon 20 insertions (ex20ins) mutations of the EGFR gene account for 1% to 2% of all non-small-cell lung cancers (NSCLCs). Targeted therapies have been developed to treat this cancer type but have not been studied in head-to-head trials. ... ...

Abstract	Introduction: Exon 20 insertions (ex20ins) mutations of the EGFR gene account for 1% to 2% of all non-small-cell lung cancers (NSCLCs). Targeted therapies have been developed to treat this cancer type but have not been studied in head-to-head trials. Our objective was to use a matching-adjusted indirect comparison (MAIC) to assess the efficacy of mobocertinib and amivantamab in patients with NSCLC EGFR ex20ins mutations who were previously treated with platinum-based chemotherapy. Materials and methods: An unanchored MAIC was conducted to estimate the treatment effects of mobocertinib and amivantamab using individual-level data from the mobocertinib phase I/II single-arm trial (NCT02716116) and published data from the amivantamab single-arm CHRYSALIS trial (NCT02609776). Confirmed overall response rate (cORR), progression-free survival (PFS), overall survival (OS), and duration of response (DoR) were assessed. Results: Both trials were comparable in terms of study population, study design, and outcome definitions and included 114 patients who received mobocertinib and 114 patients who received amivantamab. After MAIC weighting, all reported baseline characteristics were balanced between mobocertinib and amivantamab. The weighted odds ratio (OR) [95% confidence interval (CI)] comparing mobocertinib to amivantamab was 0.56 (0.30-1.04) for independent review committee (IRC)-assessed cORR and 0.98 (0.53-1.82) for investigator (INV)-assessed cORR. The weighted hazard ratio (HR) comparing mobocertinib to amivantamab was 0.74 (0.51-1.07) for IRC-assessed PFS, 0.92 (0.57-1.48) for OS, and 0.59 (0.30-1.18) for INV-assessed DoR. Conclusion: MAIC analysis showed that mobocertinib and amivantamab had similar efficacy in patients with NSCLC harboring EGFR ex20ins mutations whose disease progressed during or after platinum-based chemotherapy. These findings may benefit patients by supporting future treatment options.
Language	English
Publishing date	2023-12-04
Publishing country	United States
Document type	Journal Article
ZDB-ID	2145146-1
ISSN	1938-0690 ; 1525-7304
ISSN (online)	1938-0690
ISSN	1525-7304
DOI	10.1016/j.cllc.2023.11.011
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Zs.A 5893: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
Zs.MO 440: Show issues

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Article ; Online: ALTA-2: Phase II study of brigatinib in patients with ALK-positive, advanced non-small-cell lung cancer who progressed on alectinib or ceritinib.

Kim, Edward S / Barlesi, Fabrice / Mok, Tony / Ahn, Myung-Ju / Shen, Junwu / Zhang, Pingkuan / Ou, Sai-Hong Ignatius

Future oncology (London, England)

2021 Volume 17, Issue 14, Page(s) 1709–1719

Abstract: Anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) have improved outcomes ... ...

Abstract	Anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) have improved outcomes in
MeSH term(s)	Adult ; Anaplastic Lymphoma Kinase/antagonists & inhibitors ; Carbazoles/administration & dosage ; Carbazoles/adverse effects ; Carcinoma, Non-Small-Cell Lung/diagnosis ; Carcinoma, Non-Small-Cell Lung/drug therapy ; Carcinoma, Non-Small-Cell Lung/mortality ; Carcinoma, Non-Small-Cell Lung/pathology ; Clinical Trials, Phase II as Topic ; Disease Progression ; Drug Administration Schedule ; Drug Resistance, Neoplasm ; Female ; Humans ; Lung Neoplasms/diagnosis ; Lung Neoplasms/drug therapy ; Lung Neoplasms/mortality ; Lung Neoplasms/pathology ; Male ; Middle Aged ; Organophosphorus Compounds/administration & dosage ; Organophosphorus Compounds/adverse effects ; Piperidines/administration & dosage ; Piperidines/adverse effects ; Progression-Free Survival ; Protein Kinase Inhibitors/administration & dosage ; Protein Kinase Inhibitors/adverse effects ; Pyrimidines/administration & dosage ; Pyrimidines/adverse effects ; Quality of Life ; Response Evaluation Criteria in Solid Tumors ; Sulfones/administration & dosage ; Sulfones/adverse effects
Chemical Substances	Carbazoles ; Organophosphorus Compounds ; Piperidines ; Protein Kinase Inhibitors ; Pyrimidines ; Sulfones ; ALK protein, human (EC 2.7.10.1) ; Anaplastic Lymphoma Kinase (EC 2.7.10.1) ; brigatinib (HYW8DB273J) ; ceritinib (K418KG2GET) ; alectinib (LIJ4CT1Z3Y)
Language	English
Publishing date	2021-02-11
Publishing country	England
Document type	Clinical Trial Protocol ; Journal Article
ZDB-ID	2274956-1
ISSN	1744-8301 ; 1479-6694
ISSN (online)	1744-8301
ISSN	1479-6694
DOI	10.2217/fon-2020-1119
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Zs.A 6478: Show issues

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Article ; Online: Health-related quality of life in the randomized phase III trial of brigatinib vs crizotinib in advanced ALK inhibitor-naive ALK + non-small cell lung cancer (ALTA-1L).

Garcia Campelo, Maria Rosario / Lin, Huamao M / Zhu, Yanyan / Pérol, Maurice / Jahanzeb, Mohammad / Popat, Sanjay / Zhang, Pingkuan / Camidge, D Ross

Lung cancer (Amsterdam, Netherlands)

2021 Volume 155, Page(s) 68–77

Abstract: Objective: In ALTA-1 L, first-line brigatinib versus crizotinib significantly prolonged progression-free survival in advanced ALK-positive (ALK+) non-small cell lung cancer (NSCLC). We report health-related quality of life (HRQOL) outcomes from ALTA-1 L. ...

Abstract	Objective: In ALTA-1 L, first-line brigatinib versus crizotinib significantly prolonged progression-free survival in advanced ALK-positive (ALK+) non-small cell lung cancer (NSCLC). We report health-related quality of life (HRQOL) outcomes from ALTA-1 L. Materials and methods: HRQOL was assessed using European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) and lung cancer-specific module (QLQ-LC13). HRQOL time to worsening, change from baseline, and duration of improvement were analyzed. Results: EORTC QLQ-C30 and QLQ-LC13 compliance was >90 % for both groups (n = 131 each). Brigatinib versus crizotinib significantly delayed time to worsening in the EORTC QLQ-C30 global health status (GHS)/QOL (median: 26.74 vs 8.31 months; hazard ratio [HR]: 0.70; 95 % CI: 0.49, 1.00; log-rank P = 0.0485); emotional functioning, social functioning, fatigue, nausea and vomiting, appetite loss, and constipation scales (log-rank P < 0.05); delays in time to worsening for the physical, role, and cognitive functioning scales were not statistically significant. Mean change from baseline showed greater improvement in GHS/QOL and most EORTC QLQ-C30 functional and symptom scales with brigatinib versus crizotinib. Among patients with GHS/QOL improvement, brigatinib had longer duration of improvement versus crizotinib (median: not reached vs 11.99 months); similar results were seen in the physical, role, emotional, and social functioning; fatigue; nausea and vomiting; and appetite loss scales. Median time to worsening in dyspnea (QLQ-LC13) was 23.98 versus 8.25 months (brigatinib vs crizotinib; HR: 0.64; 95 % CI: 0.39, 1.05). Conclusion: Brigatinib significantly delayed time to worsening and prolonged duration of improvement in GHS/QOL versus crizotinib, supported by improvement in functional and symptom scores. These preliminary analyses suggest brigatinib is the first ALK inhibitor with better HRQOL versus another ALK inhibitor in ALK inhibitor-naive advanced ALK + NSCLC.
MeSH term(s)	Anaplastic Lymphoma Kinase/genetics ; Carcinoma, Non-Small-Cell Lung/drug therapy ; Crizotinib/therapeutic use ; Humans ; Lung Neoplasms/drug therapy ; Organophosphorus Compounds ; Pyrimidines ; Quality of Life
Chemical Substances	Organophosphorus Compounds ; Pyrimidines ; Crizotinib (53AH36668S) ; Anaplastic Lymphoma Kinase (EC 2.7.10.1) ; brigatinib (HYW8DB273J)
Language	English
Publishing date	2021-03-09
Publishing country	Ireland
Document type	Clinical Trial, Phase III ; Journal Article ; Randomized Controlled Trial ; Research Support, Non-U.S. Gov't
ZDB-ID	632771-0
ISSN	1872-8332 ; 0169-5002
ISSN (online)	1872-8332
ISSN	0169-5002
DOI	10.1016/j.lungcan.2021.03.005
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Article ; Online: Real-World Efficacy and Tolerability of Brigatinib in Patients with Non-Small Cell Lung Cancer with Prior ALK-TKIs in the United States.

Jahanzeb, Mohammad / Lin, Huamao M / Wu, Yanyu / Zhang, Pingkuan / Gorritz, Magdaliz / McGuiness, Catherine B / Huang, Wei-Ti / Sun, Kainan / Chen, Chi-Chang / Camidge, D Ross

The oncologist

2022 Volume 27, Issue 9, Page(s) 790–798

Abstract: Background: Real-world evidence for brigatinib, a next-generation anaplastic lymphoma kinase-tyrosine kinase inhibitor (ALK-TKI) used in ALK-rearranged non-small cell lung cancer, is scarce. This retrospective study evaluated real-world brigatinib ... ...

Abstract	Background: Real-world evidence for brigatinib, a next-generation anaplastic lymphoma kinase-tyrosine kinase inhibitor (ALK-TKI) used in ALK-rearranged non-small cell lung cancer, is scarce. This retrospective study evaluated real-world brigatinib utilization in the US post other ALK-TKIs. Materials and methods: Adults with ≥1 brigatinib claim (index date) between 1 April 2017 and 30 September 2020 in the IQVIA longitudinal pharmacy claims database were followed until dose reduction, discontinuation, or end of follow-up. Patients had ≥12 months pre- and ≥1-month post-index observations. Results: A total of 413 patients treated with brigatinib were analyzed. Over 80% received ≥1 prior ALK-TKI; alectinib and crizotinib were the most common (58.8% and 51.3% patients, respectively). The median follow-up was 8.4 months. The median time to treatment discontinuation (TTD) for brigatinib was 10.3 months (95% CI, 8.2-15.0), with 45% remaining on therapy at 12 months. The TTD was shortest (~8 months) in patients receiving both crizotinib and alectinib and longest in patients who received alectinib only prior to brigatinib (11.8 months). Adherence was high, with 92.7% of patients having a medication possession ratio of >80%. The mean dose compliance score was 1.0. Most patients reached the brigatinib dose of 180 mg/day (77%); 13.2% of patients had a dose reduction, with 89.3% and 84.6% continuing 180 mg/day therapy at 3 and 6 months, respectively. Conclusions: Brigatinib appears to be effective and well-tolerated in the real-world ALK+ NSCLC population in the US, showing benefit in patients after a next-generation ALK-TKI. Notably, dose reduction rates appeared markedly less than those seen in trials when most trial-related dose reductions were for asymptomatic laboratory abnormalities.
MeSH term(s)	Adult ; Anaplastic Lymphoma Kinase ; Carcinoma, Non-Small-Cell Lung/drug therapy ; Carcinoma, Non-Small-Cell Lung/pathology ; Crizotinib/therapeutic use ; Humans ; Lung Neoplasms/drug therapy ; Lung Neoplasms/pathology ; Organophosphorus Compounds ; Protein Kinase Inhibitors/adverse effects ; Pyrimidines ; Retrospective Studies ; United States
Chemical Substances	Organophosphorus Compounds ; Protein Kinase Inhibitors ; Pyrimidines ; Crizotinib (53AH36668S) ; Anaplastic Lymphoma Kinase (EC 2.7.10.1) ; brigatinib (HYW8DB273J)
Language	English
Publishing date	2022-07-02
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1409038-7
ISSN	1549-490X ; 1083-7159
ISSN (online)	1549-490X
ISSN	1083-7159
DOI	10.1093/oncolo/oyac116
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