Dynamics of eligibility criteria for central nervous system metastases in non-small cell lung cancer randomized clinical trials over time: A systematic review.

Although central nervous system (CNS) metastases frequently occur in patients with non-small cell lung cancer (NSCLC), historically these patients have been excluded from clinical trials. However, due to improving NSCLC prognosis, time to develop CNS metastases increases and information on CNS efficacy of systemic treatment is important. We performed a systematic PubMed review (2000-2020) to describe CNS related eligibility and screening criteria over time. Randomized phase III, and for tyrosine kinase inhibitors (TKIs) also randomized phase II trials enrolling advanced/metastatic NSCLC patients were included. 256/1195 trials were included. In 71 %, CNS metastases were eligible, but in only 3% regardless of symptoms/treatment. Only 37 % required baseline CNS screening (most often TKI and immunotherapy trials), without significant increase over time. A CNS endpoint was pre-specified in 4%. CONCLUSION: CNS screening and eligibility criteria are heterogenous across trials, and CNS related endpoints are rare. These criteria and endpoints should be improved and harmonized.

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?

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).