The Incidence of Brain Metastases in Stage IV ROS1-Rearranged Non-Small Cell Lung Cancer and Rate of Central Nervous System Progression on Crizotinib.

Since its approval in April 2018, osimertinib has been widely adopted as first-line therapy for patients with advanced EGFR-mutant non -small cell lung cancer (NSCLC). Understanding osimertinib resistance mechanisms and currently available treatment options are essential to selecting optimal second line therapy for patients whose disease progresses during front-line osimertinib. Using data compiled from 6 osimertinib-resistance series, we describe here the heterogeneous profile of EGFR-dependent and independent mechanisms of osimertinib treatment failure. We identified MET alterations (7%-24%), EGFR C797X (0%-29%), SCLC transformation (2%-15%), and oncogene fusions (1%-10%) as the most common mechanisms of resistance. This review provides an evidence-based, algorithmic approach to the evaluation and management of post-osimertinib progression as well as a compendium of active, enrolling clinical trials for this population.

Emerging Treatment Paradigms for EGFR-Mutant Lung Cancers Progressing on Osimertinib: A Review

Brain metastases (BM) are common in non-small cell lung cancer patients including in molecularly selected populations, such as EGFR-mutant and ALK-rearranged tumors. They are associated with a reduced quality of life, and are commonly the first site of progression for patients receiving tyrosine kinase inhibitors (TKIs). In this review, we summarize incidence of BM and intracranial efficacy with TKI agents according to oncogene driver mutations, focusing on important clinical issues, notably optimal first-line treatment in oncogene-addicted lung tumors with upfront BM (local therapies followed by TKI vs. TKI monotherapy). We also discuss the potential role of newly emerging late-generation TKIs as new standard treatment in oncogene-addicted lung cancer tumors compared with sequential strategies.

/pdf/brain-metastases-in-oncogene-addicted-non-small-cell-lung-4o4ep8j62y.pdf

Brain Metastases in Oncogene-Addicted Non-Small Cell Lung Cancer Patients: Incidence and Treatment.

Brain metastases and/or leptomeningeal disease (LMD) with associated central nervous system (CNS) metastases are known complications of advanced epidermal growth factor receptor (EGFR) mutation-positive non-small cell lung cancer (NSCLC). It is important, therefore, to assess the activity of EGFR tyrosine kinase inhibitors (TKIs) versus such CNS complications. This review explores the literature reporting the intracranial activity of EGFR TKIs, and finds that there is evidence for varying efficacy of the approved agents, erlotinib, gefitinib, afatinib, and osimertinib in patients with CNS metastases. Other EGFR TKIs in development, such as AZD3759, may have a future role as therapeutic options in this setting. Emerging evidence indicates that the second- and third-generation EGFR TKIs, afatinib and osimertinib, effectively penetrate the blood-brain barrier, and therefore represent viable treatment options for CNS lesions, and can reduce the risk of CNS progression. These agents should therefore be considered as first-line treatment options in patients with EGFR mutation-positive NSCLC who have brain metastases and/or LMD. While there are currently no prospective data comparing the intracranial efficacy of second- and third-generation EGFR TKIs in this setting, CNS activity and protection offered by different EGFR TKIs should be an additional consideration when making decisions about the optimal sequence of treatment with EGFR TKIs in order to maximize survival benefit in individual patients.

/pdf/medical-treatment-options-for-patients-with-epidermal-growth-gmozowhsmm.pdf

Medical Treatment Options for Patients with Epidermal Growth Factor Receptor Mutation-Positive Non-Small Cell Lung Cancer Suffering from Brain Metastases and/or Leptomeningeal Disease.

Background Non-small-cell lung cancer (NSCLC) is a global public health problem, and brain is a common metastatic site in advanced NSCLC. Currently, whole-brain radiotherapy (WBRT) remains a major treatment for brain metastases, while EGFR-tyrosine kinase inhibitor (TKI) is the standard treatment for advanced NSCLC harboring EGFR mutations, which is also effective for brain metastases. However, whether EGFR-TKIs plus radiotherapy is superior to EGFR-TKIs alone for the treatment of advanced EGFR-mutant NSCLS with brain metastases remains controversial. This study aimed to compare the efficacy of concurrent EGFR-TKIs and WBRT vs EGFR-TKI alone in a retrospective cohort of advanced EGFR-mutant NSCLS with brain metastases. Patients and methods The medical records of 104 treatment-naive, advanced EGFR-mutant NSCLC patients with brain metastases were retrospectively reviewed, and there were 56 patients undergoing concurrent EGFR-TKI and WBRT, and 48 patients given EGFR-TKI alone, including 20 cases with salvage WBRT upon brain metastasis progression. The survival prognosis was compared between the two cohorts. Results The baseline clinicopathologic factors were balanced between the two cohorts. After a median follow-up of 23 months, 35.6% of the study subjects survived. Concurrent EGFR-TKI and WBRT significantly improved the median intracranial PFS (iPFS) compared with EGFR-TKI alone (17.7 vs 11.0 months, P=0.015); however, no significant difference was seen in median overall survival between the two cohorts (28.1 vs 24.0 months, P=0.756). In addition, the median iPFS was found to significantly vary in the number of brain metastases (≤3 vs>3 metastases: 18.0 vs 12.5 months, P=0.044). Subgroup analysis showed that concurrent EGFR-TKI and WBRT improved median iPFS compared with EGFR-TKI alone in patients with more than three brain metastases (P=0.001); however, no significant difference was observed between the two regimens in patients with three or less brain metastases (P=0.526). Conclusion Our data demonstrate that concurrent EGFR-TKI and WBRT achieves longer iPFS than EGFR-TKI alone in advanced EGFR-mutant NSCLC with brain metastases. In advanced EGFR-mutant NSCLC with three or less brain metastases, EGFR-TKI alone may be an option as a first-line therapy.

/pdf/comparing-the-efficacy-of-concurrent-egfr-tki-and-whole-4b4ag1a8m1.pdf

Comparing the efficacy of concurrent EGFR-TKI and whole-brain radiotherapy vs EGFR-TKI alone as a first-line therapy for advanced EGFR-mutated non-small-cell lung cancer with brain metastases: a retrospective cohort study

CNS response to osimertinib vs standard of care (SoC) EGFR-TKI as first-line therapy in patients (pts) with EGFR-TKI sensitising mutation (EGFRm)-positive advanced non-small cell lung cancer (NSCLC): Data from the FLAURA study

Erratum: CNS response to osimertinib vs standard of care (SoC) EGFR-TKI as first-line therapy in patients (pts) with EGFR-TKI sensitising mutation (EGFRm)-positive advanced non-small cell lung cancer (NSCLC): Data from the FLAURA study (Annals of Oncology (2017) 28(S10) (x183), (S0923753419565462), (10.1093/annonc/mdx729))

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CNS response to osimertinib vs standard of care (SoC) EGFR-TKI as first-line therapy in patients (pts) with EGFR-TKI sensitising mutation (EGFRm)-positive advanced non-small cell lung cancer (NSCLC): Data from the FLAURA study