Activity and safety of brigatinib in ALK-rearranged non-small-cell lung cancer and other malignancies: a single-arm, open-label, phase 1/2 trial

Gettinger, Scott; Bazhenova, Lyudmila; Langer, Corey J.; Salgia, Ravi; Gold, Kathryn A.; Rosell, Rafael; Shaw, Alice T.; Weiss, Glen J.; Tugnait, Meera; Narasimhan, Narayana I.; Dorer, David J.; Kerstein, David; Rivera, Victor M.; Clackson, Timothy Piers; Haluska, Frank G.; Camidge, D. Ross

doi:10.1016/s1470-2045(16)30392-8

Cited by 310 publications

(335 citation statements)

References 24 publications

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“…Brigatinib recently received accelerated FDA approval for use in advanced ALK -rearranged NSCLC (78, 79). Like crizotinib and ceritinib, it also has anti-ROS1 activity based on preclinical studies, with an IC 50 of 7.5 nM (versus anti-ALK IC 50 of 9.8 nM) in CD74-ROS1 -expressing Ba/F3 cells (80).…”

Section: Ros1-targeted Therapies In Lung Cancermentioning

confidence: 99%

Recent Advances in Targeting ROS1 in Lung Cancer

Lin

Shaw

2017

Journal of Thoracic Oncology

211

208

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ROS1 is a validated therapeutic target in non-small cell lung cancer (NSCLC). In a phase I study, the multi-targeted MET/ALK/ROS1 inhibitor crizotinib demonstrated remarkable efficacy in ROS1-rearranged NSCLCs, and consequently gained approval by the United States Food and Drug Administration as well as the European Medicines Agency in 2016. However, similar to other oncogene-driven lung cancers, ROS1-rearranged lung cancers treated with crizotinib eventually acquire resistance, leading to disease relapse. Novel ROS1 inhibitors and therapeutic strategies are therefore needed. Insights into the mechanisms of resistance to ROS1-directed tyrosine kinase inhibitors (TKIs) are now beginning to emerge and are helping to guide the development of new ROS1 inhibitors. This review discusses the biology and diagnosis of ROS1-rearranged NSCLC, and current and emerging treatment options for this disease. Future challenges in the field are highlighted.

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Section: Ros1-targeted Therapies In Lung Cancermentioning

confidence: 99%

Recent Advances in Targeting ROS1 in Lung Cancer

Lin

Shaw

2017

Journal of Thoracic Oncology

211

208

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“…The phase I/II trial showed an ORR of 72% in previously crizotinib-treated ALK -rearranged NSCLC patients with an intracranial response rate of 53% [33]. Updated data presented at the 2016 World Conference on Lung Cancer (WCLC) showed a mPFS of 13.4 months in crizotinib-refractory patients, which is longer than for ceritinib and alectinib in this setting [34].…”

Section: Therapeutic Optionsmentioning

confidence: 99%

“…Updated data presented at the 2016 World Conference on Lung Cancer (WCLC) showed a mPFS of 13.4 months in crizotinib-refractory patients, which is longer than for ceritinib and alectinib in this setting [34]. An AE unique to brigatinib is early pulmonary events, including cough, dyspnea, pneumonia/pneumonitis, and hypoxia, which occurred in 6–8% of patients [33, 35] with onset typically within 7 days after initiation of brigatinib therapy. The phase II ALTA trial therefore looked at two different dosing schedules at either 90 mg daily (group A) or 90 mg daily with escalation to 180 mg daily after 7 days (group B).…”

Section: Therapeutic Optionsmentioning

confidence: 99%

The Current Landscape of Anaplastic Lymphoma Kinase (ALK) in Non-Small Cell Lung Cancer: Emerging Treatment Paradigms and Future Directions

Qin

Gadgeel

2017

Targ Oncol

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Tumorigenic rearrangements in anaplastic lymphoma kinase (ALK) account for 3–7% of all non-small cell lung cancers (NSCLC). Treatment with targeted tyrosine kinase inhibitors (TKIs) has shown impressive clinical responses. Crizotinib was the first agent approved for front-line therapy of ALK-rearranged NSCLC after it demonstrated superiority to chemotherapy in response rate, duration of response, and progression-free survival. However, eventually all patients progress on crizotinib therapy, with the central nervous system (CNS) being the most common site, which served as the impetus for the development of more potent next-generation ALK inhibitors. Currently, ceritinib, alectinib, and brigatinib are all approved for second-line therapy after progression on or intolerance to crizotinib. Investigations into whether the initiation of a second-generation ALK inhibitor as first-line therapy is the superior treatment paradigm has resulted in the approval of ceritinib as initial therapy. Alectinib has also shown impressive results as front-line therapy, as recently reported in two large randomized studies that compared it to crizotinib. There is a significant need to better understand the drivers of and mechanisms underlying resistance to ALK inhibitors. While specific mutations have been identified, there is currently only limited evidence that the identification of specific mutations should impact selection of the next ALK inhibitor. The best treatment option for patients who become TKI refractory is also unclear, though there is some evidence to suggests that these patients are not responsive to checkpoint inhibitors and may respond better to chemotherapy. Combination therapy with other classes of agents may help to overcome resistance mechanisms and should be investigated further.

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“…Further clinical trials will help address outstanding questions. As more data become available on additional ALK-inhibitors such as brigatinib and lorlatinib, the question will be of the optimal sequencing of therapies, especially since early reports demonstrate CNS activity with these agents as well (21). Also, the choice of SRS, alectinib, or both has yet to be delineated in prospective trials.…”

Section: Commentarymentioning

confidence: 99%

New treatment options and challenges for patients with anaplastic lymphoma kinase-positive non-small cell lung cancer with brain metastases

Owen

2017

J. Thorac. Dis.

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Activity and safety of brigatinib in ALK-rearranged non-small-cell lung cancer and other malignancies: a single-arm, open-label, phase 1/2 trial

Cited by 310 publications

References 24 publications

Recent Advances in Targeting ROS1 in Lung Cancer

Recent Advances in Targeting ROS1 in Lung Cancer

The Current Landscape of Anaplastic Lymphoma Kinase (ALK) in Non-Small Cell Lung Cancer: Emerging Treatment Paradigms and Future Directions

New treatment options and challenges for patients with anaplastic lymphoma kinase-positive non-small cell lung cancer with brain metastases

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