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      Weekly osimertinib dosing prevents EGFR mutant tumor cells destined to home mouse lungs

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          Highlights

          • Human lung cancer cells injected through mouse-tail vein colonize mouse lungs within 24 h and form lung tumors in about 30 days.

          • Pretreatment of mice with weekly or daily dosing of erlotinib reduces but does not abolish tail vein injected lung cancer cells to form lung tumors.

          • Pretreatment of mice with weekly or daily dosing of osimertinib abolish lung cancer cells injected through a tail vein to form lung tumors.

          • The low-dose once-a-week adjuvant osimertinib could have lower toxicity, higher affordability, and potentially affect acquired resistance.

          Abstract

          The recently conducted ADAURA trial concludes daily dosing of adjuvant osimertinib, a third-generation EGFR tyrosine kinase inhibitor (TKI), improves disease-free survival with stage IB/II/IIIA EGFR -mutated non-small cell lung cancer patients in comparison to placebo. We have developed a preclinical orthotopic mouse model, using luciferase tagged lung adenocarcinoma cells harboring EGFR TKI sensitive exon 19 deletion to model and extend trial implications comparing a weekly vs daily dosing outcome of osimertinib to a first-generation TKI- erlotinib. We find that 100% of mice in both the groups receiving osimertinib daily or weekly before injection of cells show a complete absence of homing of cells in mice's lungs from day three until day 18 post-injection of cells. On the other hand, 25% and 75% of mice receiving erlotinib daily and weekly before injecting cells show homing of cells to the lungs. The tumors observed in the lungs, when dissected at day 30, confirmed the colonization of the injected cells homing to the organ. Thus, our study establishes the efficacy of pretreatment with osimertinib in reducing tumor cells' homing to mouse lungs in an in vivo mouse model.

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          Most cited references 18

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          Preclinical Comparison of Osimertinib with Other EGFR-TKIs in EGFR-Mutant NSCLC Brain Metastases Models, and Early Evidence of Clinical Brain Metastases Activity.

          Approximately one-third of patients with non-small cell lung cancer (NSCLC) harboring tumors with EGFR-tyrosine kinase inhibitor (TKI)-sensitizing mutations (EGFRm) experience disease progression during treatment due to brain metastases. Despite anecdotal reports of EGFR-TKIs providing benefit in some patients with EGFRm NSCLC brain metastases, there is a clinical need for novel EGFR-TKIs with improved efficacy against brain lesions.
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            "Pulsatile" high-dose weekly erlotinib for CNS metastases from EGFR mutant non-small cell lung cancer.

            Erlotinib is effective for epidermal growth factor receptor (EGFR) mutant lung cancer, but CNS penetration at standard daily dosing is limited. We previously reported that intermittent "pulsatile" administration of high-dose (1500 mg) erlotinib once weekly was tolerable and achieved concentrations in cerebrospinal fluid exceeding the half maximal inhibitory concentration for EGFR mutant lung cancer cells in a patient with leptomeningeal metastases; we now expand this paradigm to a series of 9 patients. We retrospectively identified patients with EGFR mutant lung cancer treated with pulsatile erlotinib for CNS metastases (brain and/or leptomeningeal) that occurred despite conventional daily erlotinib or other EGFR tyrosine kinase inhibitors. Mutations in available lung and CNS tissue were correlated with efficacy. Erlotinib was administered as monotherapy at a median dose of 1500 mg weekly. Best CNS radiographic response was partial in 67% (6/9, including 2 with isolated leptomeningeal metastases), stable disease in 11% (1/9), and progressive disease in 22% (2/9). Median time to CNS progression was 2.7 months (range, 0.8-14.5 months) and median overall survival was 12 months (range, 2.5 months-not reached). Treatment was well tolerated. No acquired resistance mutations in EGFR were identified in the CNS metastases of 4 patients, including 1 harboring T790M outside the CNS. Pulsatile erlotinib can control CNS metastases from EGFR mutant lung cancer after failure of standard daily dosing. CNS disease may not harbor acquired resistance mutations that develop systemically. A prospective trial is planned.
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              Osimertinib in Resected EGFR-Mutated Non–Small-Cell Lung Cancer

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                Author and article information

                Contributors
                Journal
                Transl Oncol
                Transl Oncol
                Translational Oncology
                Neoplasia Press
                1936-5233
                13 May 2021
                August 2021
                13 May 2021
                : 14
                : 8
                Affiliations
                [a ]Integrated Cancer Genomics Laboratory, Advanced Centre for Treatment Research Education In Cancer (ACTREC), Tata Memorial Centre, Navi Mumbai, Maharashtra, India 410210
                [b ]Department of Medical Oncology, Tata Memorial Centre, Ernest Borges Marg, Parel, Mumbai, India 400012
                [c ]Homi Bhabha National Institute, Training School Complex, Anushakti Nagar, Mumbai, India 400094
                Author notes
                [* ]Correspondence should be addressed to: Integrated Cancer Genomics Laboratory, Advanced Center for Treatment, Research and Education in Cancer, Tata Memorial Center, Navi Mumbai 410210, India. adutt@ 123456actrec.gov.in
                [#]

                Equal contribution

                Article
                S1936-5233(21)00103-0 101111
                10.1016/j.tranon.2021.101111
                8236545
                33993094
                © 2021 The Authors

                This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

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