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      Clinicogenomic factors and treatment patterns among patients with advanced non–small cell lung cancer with or without brain metastases in the United States

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          Abstract

          Background

          This retrospective, real-world study evaluated the prevalence of brain metastases, clinicodemographic characteristics, systemic treatments, and factors associated with overall survival among patients with advanced non–small cell lung cancer (aNSCLC) in the US. We also described the genomic characterization of 180 brain metastatic specimens and frequency of clinically actionable genes.

          Materials and Methods

          De-identified electronic health records-derived data of adult patients diagnosed with aNSCLC between 2011 and 2017 were analyzed from a US-nationwide clinicogenomic database.

          Results

          Of 3257 adult patients with aNSCLC included in the study, approximately 31% ( n = 1018) had brain metastases. Of these 1018 patients, 71% ( n = 726) were diagnosed with brain metastases at initial NSCLC diagnosis; 57% ( n = 583) of patients with brain metastases received systemic treatment. Platinum-based chemotherapy combinations were the most common first-line therapy; single-agent chemotherapies, epidermal growth factor receptor tyrosine kinase inhibitors, and platinum-based chemotherapy combinations were used in second line. Patients with brain metastases had a 1.56 times greater risk of death versus those with no brain metastases. In the brain metastatic specimens ( n = 180), a high frequency of genomic alterations in the p53, MAPK, PI3K, mTOR, and cell-cycle associated pathways was observed.

          Conclusion

          The frequency of brain metastases at initial clinical presentation and associated poor prognosis for patients in this cohort underscores the importance of early screening for brain metastasis in NSCLC. Genomic alterations frequently identified in this study emphasize the continued need for genomic research and investigation of targeted therapies in patients with brain metastases.

          Abstract

          This article evaluates the prevalence of brain metastases, clinicodemographic characteristics, systemic treatments, and factors associated with overall survival among patients with advanced non–small cell lung cancer in the US.

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          Most cited references57

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          Cancer statistics, 2023

          Each year, the American Cancer Society estimates the numbers of new cancer cases and deaths in the United States and compiles the most recent data on population-based cancer occurrence and outcomes using incidence data collected by central cancer registries and mortality data collected by the National Center for Health Statistics. In 2023, 1,958,310 new cancer cases and 609,820 cancer deaths are projected to occur in the United States. Cancer incidence increased for prostate cancer by 3% annually from 2014 through 2019 after two decades of decline, translating to an additional 99,000 new cases; otherwise, however, incidence trends were more favorable in men compared to women. For example, lung cancer in women decreased at one half the pace of men (1.1% vs. 2.6% annually) from 2015 through 2019, and breast and uterine corpus cancers continued to increase, as did liver cancer and melanoma, both of which stabilized in men aged 50 years and older and declined in younger men. However, a 65% drop in cervical cancer incidence during 2012 through 2019 among women in their early 20s, the first cohort to receive the human papillomavirus vaccine, foreshadows steep reductions in the burden of human papillomavirus-associated cancers, the majority of which occur in women. Despite the pandemic, and in contrast with other leading causes of death, the cancer death rate continued to decline from 2019 to 2020 (by 1.5%), contributing to a 33% overall reduction since 1991 and an estimated 3.8 million deaths averted. This progress increasingly reflects advances in treatment, which are particularly evident in the rapid declines in mortality (approximately 2% annually during 2016 through 2020) for leukemia, melanoma, and kidney cancer, despite stable/increasing incidence, and accelerated declines for lung cancer. In summary, although cancer mortality rates continue to decline, future progress may be attenuated by rising incidence for breast, prostate, and uterine corpus cancers, which also happen to have the largest racial disparities in mortality.
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            KRASG12C Inhibition with Sotorasib in Advanced Solid Tumors

            No therapies for targeting KRAS mutations in cancer have been approved. The KRAS p.G12C mutation occurs in 13% of non–small-cell lung cancers (NSCLCs) and in 1 to 3% of colorectal cancers and other cancers. Sotorasib is a small molecule that selectively and irreversibly targets KRAS G12C . We conducted a phase 1 trial of sotorasib in patients with advanced solid tumors harboring the KRAS p.G12C mutation. Patients received sotorasib orally once daily. The primary end point was safety. Key secondary end points were pharmacokinetics and objective response, as assessed according to Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1. A total of 129 patients (59 with NSCLC, 42 with colorectal cancer, and 28 with other tumors) were included in dose escalation and expansion cohorts. Patients had received a median of 3 (range, 0 to 11) previous lines of anticancer therapies for metastatic disease. No dose-limiting toxic effects or treatment-related deaths were observed. A total of 73 patients (56.6%) had treatment-related adverse events; 15 patients (11.6%) had grade 3 or 4 events. In the subgroup with NSCLC, 32.2% (19 patients) had a confirmed objective response (complete or partial response) and 88.1% (52 patients) had disease control (objective response or stable disease); the median progression-free survival was 6.3 months (range, 0.0+ to 14.9 [with + indicating that the value includes patient data that were censored at data cutoff]). In the subgroup with colorectal cancer, 7.1% (3 patients) had a confirmed response, and 73.8% (31 patients) had disease control; the median progression-free survival was 4.0 months (range, 0.0+ to 11.1+). Responses were also observed in patients with pancreatic, endometrial, and appendiceal cancers and melanoma. Sotorasib showed encouraging anticancer activity in patients with heavily pretreated advanced solid tumors harboring the KRAS p.G12C mutation. Grade 3 or 4 treatment-related toxic effects occurred in 11.6% of the patients. (Funded by Amgen and others; CodeBreaK100 ClinicalTrials.gov number, NCT03600883 .)
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              Systemic Therapy for Locally Advanced and Metastatic Non–Small Cell Lung Cancer

              Non-small cell lung cancer remains the leading cause of cancer death in the United States. Until the last decade, the 5-year overall survival rate for patients with metastatic non-small cell lung cancer was less than 5%. Improved understanding of the biology of lung cancer has resulted in the development of new biomarker-targeted therapies and led to improvements in overall survival for patients with advanced or metastatic disease.
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                Author and article information

                Contributors
                Journal
                Oncologist
                Oncologist
                oncolo
                The Oncologist
                Oxford University Press (US )
                1083-7159
                1549-490X
                November 2023
                26 June 2023
                26 June 2023
                : 28
                : 11
                : e1075-e1091
                Affiliations
                Eli Lilly and Company , Value Evidence Outcomes - Research, Indianapolis, IN 46225, USA
                Eli Lilly and Company , Value Evidence Outcomes - Research, Indianapolis, IN 46225, USA
                Eli Lilly and Company , Value Evidence Outcomes - Research, Indianapolis, IN 46225, USA
                Eli Lilly and Company , Lilly Global Clinical Development, Indianapolis, IN 46225, USA
                Eli Lilly and Company , Value Evidence Outcomes - Research, Indianapolis, IN 46225, USA
                Eli Lilly and Company , Value Evidence Outcomes - Research, Indianapolis, IN 46225, USA
                Eli Lilly and Company , Value Evidence Outcomes - Research, Indianapolis, IN 46225, USA
                Eli Lilly and Company , Statistics RWE, Indianapolis, IN 46225, USA
                Divisions of Hematology/Oncology and Neuro-Oncology , Massachusetts General Hospital, Boston, MA 02114, USA
                Author notes
                Corresponding author: Emily Nash Smyth, PharmD, Eli Lilly and Company, 893 S. Delaware St., Indianapolis, IN 46225, USA. Email: nash_smyth_emily@ 123456lilly.com

                R.V.T. and L.B. were employees of Eli Lilly and Company when this study was conducted.

                Article
                oyad170
                10.1093/oncolo/oyad170
                10628559
                37358877
                97b90bf5-2ed3-4a9e-9829-8f1137f4cd6d
                © The Author(s) 2023. Published by Oxford University Press.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License ( https://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com.

                History
                : 15 February 2023
                : 19 May 2023
                Page count
                Pages: 17
                Funding
                Funded by: Eli Lilly and Company, DOI 10.13039/100004312;
                Categories
                Neuro-Oncology
                AcademicSubjects/MED00010

                Oncology & Radiotherapy
                brain metastasis,advanced nsclc,treatment patterns,survival,genomics
                Oncology & Radiotherapy
                brain metastasis, advanced nsclc, treatment patterns, survival, genomics

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