Central nervous system metastases and oligoprogression during treatment with tyrosine kinase inhibitors in oncogene-addicted non-small cell lung cancer: how to treat and when?

Abstract

Up to 70% of non-small cell lung cancer (NSCLC) patients develop central nervous system (CNS) metastases during the course of their disease, especially those with oncogenic drivers treated with a first-generation tyrosine kinase inhibitor (TKI), because of the relatively poor CNS penetration. CNS metastases are associated with a negative impact on quality of life and survival. As, with the introduction of newer generation TKIs, the survival rates are increasing in this particular population, treatment and/ or prevention of CNS metastases becomes even more relevant and the TKI with the best CNS efficacy should be selected. Unfortunately, CNS efficacy data in clinical trials are not fully comparable. Furthermore, oligoprogression to the brain without extracranial progression regularly occurs in the oncogenic driver population and both local therapy and switch of systemic therapy are possible treatment options. However, the best order of systemic and local therapy is still not precisely known. In this narrative review, we will summarize incidence and treatment of CNS metastases in oncogene driven NSCLC, including the optimal treatment of CNS oligometastatic disease (synchronous as well as oligoprogressive).

Resistance to TKIs in EGFR-Mutated Non-Small Cell Lung Cancer: From Mechanisms to New Therapeutic Strategies

“…While examining the therapeutic challenges and options for each type of NSCLC metastasis exceeds the scope of the present review, the authors focus on NSCLC-related CNS disease. This type of metastasis affects up to 70% of patients with NSCLC harboring an oncogenic driver mutation during the course of the disease and is particularly resistant to treatment due to the anatomical intricacies of cerebral circulation [ 126 ]. Discussing therapeutic developments in this field encompasses a significant proportion of clinical studies related to the precise and personalized management of advanced NSCLC.…”

CNS Efficacy of Osimertinib With or Without Chemotherapy in Epidermal Growth Factor Receptor–Mutated Advanced Non–Small-Cell Lung Cancer

“…Approximately 30%-50% of these patients develop CNS metastases within 5 years of diagnosis, 3-5 and the incidence is rising owing to improved survival and enhanced detection. 2,6 Treatment is challenging as many drugs cannot cross the blood-brain barrier or are effluxed, making the CNS a sanctuary site for metastases and limiting the ability of systemic treatments to affect intracranial disease. 2…”

“…Approximately 30%-50% of these patients develop CNS metastases within 5 years of diagnosis, [3][4][5] and the incidence is rising owing to improved survival and enhanced detection. 2,6 Treatment is challenging as many drugs cannot cross the blood-brain barrier or are effluxed, making the CNS a sanctuary site for metastases and limiting the ability of systemic treatments to affect intracranial disease. 2 EGFR-tyrosine kinase inhibitors (EGFR-TKIs) are the recommended first-line treatment for certain patients with EGFR-mutated advanced NSCLC and brain metastases; some guidelines specifically recommend osimertinib.…”

Mechanistic modeling of brain metastases in NSCLC provides computational markers for personalized prediction of outcome

“…Oligoprogression is defined as the progression of a limited number of metastases, ranging from 3 to 5, and possibly treated by local therapies [10][11][12] . Existing data on intracranial oligoprogression are mostly related to palliative situations, and to patients receiving tyrosine kinase inhibitors 13 . There are no real guidelines for the management of single intracranial oligoprogression in patients with early-stage NSCLC at diagnosis, initially treated with curative intent.…”