Osimertinib in UntreatedEGFR-Mutated Advanced Non–Small-Cell Lung Cancer

New England Journal of Medicine, Journal Year: 2017, Volume and Issue: 378(2), P. 113 - 125

Published: Nov. 18, 2017

Osimertinib is an oral, third-generation, irreversible epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) that selectively inhibits both EGFR-TKI–sensitizing and EGFR T790M resistance mutations. We compared osimertinib with standard EGFR-TKIs in patients previously untreated, mutation–positive advanced non–small-cell lung cancer (NSCLC).

Language: Английский

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Resistance mechanisms to osimertinib in EGFR-mutated non-small cell lung cancer

British Journal of Cancer, Journal Year: 2019, Volume and Issue: 121(9), P. 725 - 737

Published: Sept. 29, 2019

Abstract Osimertinib is an irreversible, third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor that highly selective for EGFR- activating mutations as well the EGFR T790M mutation in patients with advanced non-small cell lung cancer (NSCLC) oncogene addiction. Despite documented efficacy of osimertinib first- and second-line settings, inevitably develop resistance, no further clear-cut therapeutic options to date other than chemotherapy locally ablative therapy selected individuals. On account high degree tumour heterogeneity adaptive cellular signalling pathways NSCLC, acquired resistance heterogeneous, encompassing - dependent EGFR-independent mechanisms. Furthermore, data from repeat plasma genotyping analyses have highlighted differences frequency preponderance mechanisms when administered a front-line versus setting, underlying discrepancies selection pressure clonal evolution. This review summarises molecular mutated including MET/HER2 amplification, activation RAS–mitogen-activated protein (MAPK) or RAS–phosphatidylinositol 3-kinase (PI3K) pathways, novel fusion events histological/phenotypic transformation, discussing current evidence regarding potential new approaches counteract resistance.

Language: Английский

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Systemic Therapy for Stage IV Non–Small-Cell Lung Cancer: American Society of Clinical Oncology Clinical Practice Guideline Update

Journal of Clinical Oncology, Journal Year: 2015, Volume and Issue: 33(30), P. 3488 - 3515

Published: Sept. 1, 2015

Purpose To provide evidence-based recommendations to update the American Society of Clinical Oncology guideline on systemic therapy for stage IV non–small-cell lung cancer (NSCLC). Methods An Update Committee NSCLC Expert Panel based a systematic review randomized controlled trials from January 2007 February 2014. Results This reflects changes in evidence since previous guideline. Recommendations There is no cure patients with NSCLC. For performance status (PS) 0 1 (and appropriate patient cases PS 2) and without an EGFR-sensitizing mutation or ALK gene rearrangement, combination cytotoxic chemotherapy recommended, guided by histology, early concurrent palliative care. first-line setting include platinum-doublet those (bevacizumab may be added carboplatin plus paclitaxel if contraindications); single-agent care alone 2; afatinib, erlotinib, gefitinib sensitizing EGFR mutations; crizotinib ROS1 rearrangement; following using platinum etoposide large-cell neuroendocrine carcinoma. Maintenance includes pemetrexed continuation stable disease response pemetrexed-containing regimens, alternative chemotherapy, break. In second-line setting, docetaxel, gefitinib, nonsquamous cell carcinoma; squamous ceritinib rearrangement who experience progression after crizotinib. third-line have not received erlotinib treatment recommended. are insufficient data recommend routine therapy. Decisions regarding should made age alone. Additional information can found at http://www.asco.org/guidelines/nsclc http://www.asco.org/guidelineswiki .

Language: Английский

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Systemic Therapy for Stage IV Non–Small-Cell Lung Cancer: American Society of Clinical Oncology Clinical Practice Guideline Update

Journal of Clinical Oncology, Journal Year: 2017, Volume and Issue: 35(30), P. 3484 - 3515

Published: Aug. 14, 2017

Purpose Provide evidence-based recommendations updating the 2015 ASCO guideline on systemic therapy for patients with stage IV non-small-cell lung cancer (NSCLC). Methods The NSCLC Expert Panel made based a systematic review of randomized controlled trials from February 2014 to December 2016 plus Cancer Care Ontario Program in Evidence-Based Care's update previous search. Results This reflects changes evidence since update. Fourteen provide base; earlier phase also informed recommendation development. Recommendations New or revised include following. Regarding first-line treatment non-squamous cell carcinoma squamous (without positive markers, eg, EGFR/ALK /ROS1), if patient has high programmed death ligand 1 (PD-L1) expression, pembrolizumab should be used alone; low PD-L1 clinicians offer standard chemotherapy. All other clinical scenarios follow recommendations. second-line who received chemotherapy, without prior immune checkpoint therapy, tumor is use single-agent nivolumab, pembrolizumab, atezolizumab; negative unknown nivolumab atezolizumab. recommended alone absence contraindications. For inhibitor, cannot receive inhibitor after docetaxel recommended; nonsquamous NSCLC, pemetrexed recommended. In sensitizing EGFR mutation, disease progression epidermal growth factor receptor tyrosine kinase and T790M osimertinib lacks then chemotherapy Patients ROS1 gene rearrangement crizotinib may offered crizotinib, they previously

Language: Английский

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The emerging treatment landscape of targeted therapy in non-small-cell lung cancer

Signal Transduction and Targeted Therapy, Journal Year: 2019, Volume and Issue: 4(1)

Published: Dec. 17, 2019

Abstract Lung cancer is one of the most common in world. In 2018, there were over 2 million new cases lung and 1.7 deaths attributed to cancer. Targeted therapy has emerged as an important mean disease management for patients with non-small-cell (NSCLC). Herein, we review analyze recent literature, discuss targeting pathways ongoing clinical trials Chemotherapy no longer best available treatment all patients. Therapeutic decisions should be guided by understanding molecular features patient’s tumor tissues. The future gains will likely emerge from finding optimal ways combining targeted therapy, immunotherapy, chemotherapy.

Language: Английский

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Liquid Biopsy for Advanced Non-Small Cell Lung Cancer (NSCLC): A Statement Paper from the IASLC

Journal of Thoracic Oncology, Journal Year: 2018, Volume and Issue: 13(9), P. 1248 - 1268

Published: June 6, 2018

Language: Английский

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Osimertinib As First-Line Treatment of EGFR Mutation–Positive Advanced Non–Small-Cell Lung Cancer

Journal of Clinical Oncology, Journal Year: 2017, Volume and Issue: 36(9), P. 841 - 849

Published: Aug. 25, 2017

Purpose The AURA study ( ClinicalTrials.gov identifier: NCT01802632) included two cohorts of treatment-naïve patients to examine clinical activity and safety osimertinib (an epidermal growth factor receptor [EGFR] –tyrosine kinase inhibitor selective for EGFR–tyrosine sensitizing [ EGFRm] EGFR T790M resistance mutations) as first-line treatment EGFR-mutated advanced non–small-cell lung cancer (NSCLC). Patients Methods Sixty with locally or metastatic EGFRm NSCLC received 80 160 mg once daily (30 per cohort). End points investigator-assessed objective response rate (ORR), progression-free survival (PFS), evaluation. Plasma samples were collected at after experienced disease progression, defined by Response Evaluation Criteria in Solid Tumors (RECIST), investigate mechanisms. Results At data cutoff (November 1, 2016), median follow-up was 19.1 months. Overall ORR 67% (95% CI, 47% 83%) the 80-mg group, 87% 69% 96%) 160-mg 77% 64% 87%) across doses. Median PFS time 22.1 months 13.7 30.2 months) 19.3 26.0 20.5 15.0 26.1 Of 38 postprogression plasma samples, 50% had no detectable circulating tumor DNA. Nine 19 putative mechanisms, including amplification MET (n = 1); KRAS MEK1, KRAS, PIK3CA mutation 1 each); C797S 2); JAK2 HER2 exon 20 insertion 1). Acquired not detected. Conclusion Osimertinib demonstrated a robust prolonged NSCLC. There evidence acquired samples.

Language: Английский

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Emerging insights of tumor heterogeneity and drug resistance mechanisms in lung cancer targeted therapy

Journal of Hematology & Oncology, Journal Year: 2019, Volume and Issue: 12(1)

Published: Dec. 1, 2019

The biggest hurdle to targeted cancer therapy is the inevitable emergence of drug resistance. Tumor cells employ different mechanisms resist targeting agent. Most commonly in EGFR-mutant non-small cell lung cancer, secondary resistance mutations on target kinase domain emerge diminish binding affinity first- and second-generation inhibitors. Other alternative include activating complementary bypass pathways phenotypic transformation. Sequential monotherapies promise temporarily address problem acquired resistance, but evidently are limited by tumor cells' ability adapt evolve new persist environment. Recent studies have nominated a model progression under as result small subpopulation being able endure (minimal residual disease cells) eventually develop further that allow them regrow become dominant population therapy-resistant tumor. This appears developed through subclonal event, resulting driver from mutation tumor-initiating most common ancestor. As such, an understanding intratumoral heterogeneity-the driving force behind minimal disease-is vital for identification drivers results branching evolution. Currently available methods more comprehensive holistic analysis heterogeneity issues associated with spatial temporal can now be properly addressed. review provides some background regarding how it leads incomplete molecular response therapies, proposes use single-cell methods, sequential liquid biopsy, multiregion sequencing discover link between early adaptive In summary, earliest form Emerging technologies such biopsy studying targetable contribute preemptive combinatorial both its cells.

Language: Английский

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CNS Efficacy of Osimertinib in Patients With T790M-Positive Advanced Non–Small-Cell Lung Cancer: Data From a Randomized Phase III Trial (AURA3)

Journal of Clinical Oncology, Journal Year: 2018, Volume and Issue: 36(26), P. 2702 - 2709

Published: July 30, 2018

Purpose In patients with epidermal growth factor receptor ( EGFR) mutation-positive advanced non-small-cell lung cancer (NSCLC), there is an unmet need for EGFR-tyrosine kinase inhibitors improved CNS penetration and activity against metastases, either at initial diagnosis or time of progression. We report the first comparative evidence osimertinib efficacy versus platinum-pemetrexed from a phase III study (AURA3; ClinicalTrials.gov identifier: NCT02151981) in EGFR T790M-positive NSCLC who experience disease progression prior inhibitor treatment. Methods Patients asymptomatic, stable metastases were eligible enrollment randomly assigned 2:1 to 80 mg once daily platinum-pemetrexed. A preplanned subgroup analysis was conducted measurable and/or nonmeasurable lesions on baseline brain scan by blinded independent central neuroradiological review. The evaluable response set included only one more lesions. primary objective this rate (ORR). Results Of 419 treatment, 116 had lesions, including 46 At data cutoff (April 15, 2016), ORR 70% (21 30; 95% CI, 51% 85%) 31% (5 16; 11% 59%) (odds ratio, 5.13; 1.44 20.64; P = .015); 40% (30 75; 29% 52%) 17% (7 41; 7% 32%), respectively, 3.24; 1.33 8.81; .014). Median duration 8.9 months (95% 4.3 not calculable) 5.7 4.4 months) platinum-pemetrexed; median progression-free survival 11.7 5.6 months, respectively (hazard 0.32; 0.15 0.69; .004). Conclusion Osimertinib demonstrated superior NSCLC.

Language: Английский

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Central Nervous System Cancers, Version 3.2020, NCCN Clinical Practice Guidelines in Oncology

Journal of the National Comprehensive Cancer Network, Journal Year: 2020, Volume and Issue: 18(11), P. 1537 - 1570

Published: Nov. 1, 2020

The NCCN Guidelines for Central Nervous System (CNS) Cancers focus on management of adult CNS cancers ranging from noninvasive and surgically curable pilocytic astrocytomas to metastatic brain disease. involvement an interdisciplinary team, including neurosurgeons, radiation therapists, oncologists, neurologists, neuroradiologists, is a key factor in the appropriate cancers. Integrated histopathologic molecular characterization tumors such as gliomas should be standard practice. This article describes recommendations WHO grade I, II, III, IV gliomas. Treatment metastases, most common intracranial adults, also described.

Language: Английский

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