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Small-Molecule Targeted Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Brigatinib (AlunbrigTM), an inhibitor of both ALK and the mutated Epidermal Growth Factor Receptor (EGFR), was developed by ARIAD Pharmaceuticals which was acquired by Takeda in 2017 through a merger with Kiku Co., already owned by Takeda. Ariad filed an IND with the FDA in 2016, which led to orphan drug status for the agent the same year for the treatment of NSCLC. In 2017, the FDA granted an accelerated approval for metastatic NSCLC as a second-line therapy for ALK-positive NSCLC. In the UK, brigatinib is recommended by NICE for the treatment of ALK-positive advanced non-small-cell lung cancer when crizotinib has failed.
EML4-ALK Fusion Gene and Therapy with ALK-Targeted Agents in Non-Small Cell Lung Cancer
Published in Sherry X. Yang, Janet E. Dancey, Handbook of Therapeutic Biomarkers in Cancer, 2021
Francisco E. Vera-Badillo, Janet E. Dancey
Severe, life-threatening, or fatal treatment-related pneumonitis has been reported with ALK-TKIs. It may be more frequent with brigatinib with an incidence up to 4%. Earlier onset respiratory toxicity is also usually seen in patients treated with brigatinib, in about 3% of patients; in the early phase 1/2 trial, up to 7% of patients developed severe side effects [65].
First-line treatment of advanced non-small cell lung cancer with ALK rearrangement: state of the art and future development
Published in Expert Review of Respiratory Medicine, 2022
Danilo Rocco, Luigi Della Gravara, Ciro Battiloro, Cesare Gridelli
One of the most recent ones, evaluating 17 trials from 2011 to 2016, for a total of 1826 ALK+ NSCLC affected patients (1000 receiving crizotinib, 601 receiving ceritinib and 225 receiving alectinib) found that the frequency of grade ≥ 3 TRAEs was significantly greater in ceritinib-treated patients (49.7% of the treated patients), when compared to alectinib-treated (32,4% of the treated patients) and crizotinib-treated ones (22.9% of the treated patients), while the frequencies of treatment-related deaths and treatment-related withdrawal from therapy did not significantly differ between the three ALK-TKI [30]; an even more recent meta-analysis, evaluating 15 studies for a total of 2005 treated patients with ALK-rearranged NSCLC, came to analogous conclusions [31]. Patients treated with brigatinib were excluded from both analyses.
Brigatinib for treatment of anaplastic lymphoma kinase-rearranged metastatic non-small cell lung cancer
Published in Expert Opinion on Orphan Drugs, 2018
Brigatinib showed an acceptable safety profile in previous studies. In a phase I/II study (NCT01449461), dose-limiting toxicities were reported during the dose-escalation phase, which included grade 3 increased alanine aminotransferase at 240 mg once daily and grade 4 dyspnea at 300 mg once daily. Nausea (53%), fatigue (43%), and diarrhea (41%) were the most common adverse events (AEs) and were mostly grades 1 and 2. Serious pulmonary AEs were also noted, such as dyspnea (7%), pneumonia (7%), and hypoxia (5%). Grade 3–4 pulmonary AEs typically occur within 24–48 h at a dose of 180 mg once daily in dose escalation and an initial phase II expansion. To reduce early pulmonary events, a 7 day lead-in at 90 mg regimen was explored, and no pulmonary toxicities were reported [24,27]. Updated results of the ALTA study demonstrate that pulmonary adverse events with early onset (median day 2, range 1–9), including dyspnea, hypoxia, cough, and pneumonia, occurred in 14 (6%) of 219 treated patients with 7 (3%) grade 28,29].
Converting EORTC QLQ-C30 scores to utility scores in the brigatinib ALTA study
Published in Journal of Medical Economics, 2019
Ariane K. Kawata, William R. Lenderking, Olabimpe R. Eseyin, David Kerstein, Joice Huang, Hui Huang, Pingkuan Zhang, Huamao M. Lin
Brigatinib is a novel, synthetic, orally active tyrosine kinase inhibitor (TKI) targeting ALK that was approved by the US Food and Drug Administration (FDA) in 2017 and by the European Medicines Agency (EMA) in 2018. Brigatinib has exhibited substantial anti-cancer activity in patients with crizotinib-resistant ALK + NSCLC. The ALTA study (NCT02094573), an open-label, phase 2, multicenter, international clinical trial, studied the efficacy and safety of two randomized dosing regimens of brigatinib (Arm A: 90 mg once daily [QD] and Arm B: 180 mg QD with a 7-day lead-in of 90-mg QD) in patients with locally advanced or metastatic ALK + NSCLC that has progressed on therapy with crizotinib6. Initial reports from the ALTA study showed that patients in Arm B had a higher investigator-assessed confirmed objective response rate (ORR) than Arm A (54% vs 45%) and Arm A had a longer median duration of response than Arm B (13.8 months vs 11.1 months) with manageable toxicity6. This study supported the 180 mg regimen (with lead-in at 90 mg) to be the recommended dose for approval. After this initial reporting, the study remained open to collect longer-term follow-up. With longer follow-up, investigator-assessed confirmed ORR was 46% (97.5% confidence interval [CI] = 35–57%), with a median (range) follow-up time of 19.6 months (0.1–35.2) in Arm A, and 56% (45–67%), with a median follow-up time of 24.3 months (0.1–39.2) in Arm B7. The median independent review committee (IRC)-assessed progression-free survival (PFS) was 9.2 months (95% CI = 7.4–12.8) and 16.7 months (11.6–21.4) in Arms A and B, respectively7.