Management of patients with brain metastases from NSCLC without a genetic driver alteration: upfront radiotherapy or immunotherapy?

Abstract

Lung cancer is the second most common cancer and the most common cause of cancer-related death in the United States. Brain metastases (BM) are detected in 21% of patients with lung cancer at the time of diagnosis and are the sole metastatic site in 35% of patients with stage IV disease. The best upfront therapy for non-small-cell lung cancer depends on both tumor programmed death 1 ligand-1 (PD-L1) expression and the presence or absence of a targetable genetic alteration in genes such as epidermal growth factor receptor and anaplastic lymphoma kinase. In the absence of a targetable genetic alteration, options include chemotherapy, immune checkpoint inhibitors (ICIs), and ICI combined with chemotherapy. Upfront local therapy followed by systemic therapy is the current standard of care for the management of BM, and may include whole brain radiotherapy, stereotactic radiosurgery (SRS), or craniotomy for surgical resection followed by consolidative SRS. This paradigm is effective in achieving local control, but it remains unclear if this approach is necessary for every patient. Prospective and retrospective data suggest that ICIs with or without chemotherapy can have activity against BM; however, appropriately selecting patients who are able to safely forgo local therapy and start an ICI-based treatment remains a challenge. To be considered for upfront ICI-based therapy, a patient should be free of neurologic symptoms, lesions should be small and not located in a critical region of the central nervous system, if corticosteroids are indicated the requirement should be low (prednisone 10 mg/d or less), and PD-L1 expression should be high. The decision to proceed with upfront ICI without local therapy to BM should be made in a multidisciplinary fashion and patients should undergo frequent surveillance imaging so that salvage local therapy can be administered when necessary. Prospective clinical trials are needed to validate this approach before it can be widely adopted.

Immunotherapy for metastatic non–small cell lung cancer: Is it really a no‐brainer?

“…Interestingly, patients without baseline brain metastasis were found to have a median OS of 15.6 months in the nivolumab with ipilimumab and chemotherapy group versus 12.1 months in the chemotherapy‐alone group 10 . There has been post hoc analysis of a large array of studies to review the impact of immunotherapy in treating brain metastasis; however, nearly every trial required that patients receive local therapy before initiating systemic therapy, which made interpreting the efficacy of immunotherapy challenging 11 . A prospective phase 2 study evaluated 42 patients with advanced NSCLC with previously untreated brain metastasis or brain metastasis progressing after radiation to assess the activity of PD‐1 blockade with pembrolizumab in the CNS 12 .…”

“…10 There has been post hoc analysis of a large array of studies to review the impact of immunotherapy in treating brain metastasis; however, nearly every trial required that patients receive local therapy before initiating systemic therapy, which made interpreting the efficacy of immunotherapy challenging. 11 A prospective phase 2 study evaluated 42 patients with advanced NSCLC with previously untreated brain metastasis or brain metastasis progressing after radiation to assess the activity of PD-1 blockade with pembrolizumab in the CNS. 12 In patients with PD-L1 expression greater than or equal to 1%, 11 of 37 patients (approximately 30%) had a response in their brain metastasis, with a duration of response of 5.7 months.…”

Biological Insights and Radiation–Immuno–Oncology Developments in Primary and Secondary Brain Tumors

“…Some of the specific pathways or receptors with mutations leading to solid tumors include epidermal growth factor receptor EGFR , ALK , KRAS , ROS1 , BRAF , and HER2 , which can be treated by drugs targeting those specific mutations. Many of the targeted drugs are small molecules which can cross the blood–brain barrier and thus are relatively effective in the upfront treatment of BM harboring these mutations [ 5 , 6 , 7 ]. However, in the absence of genetic targetable drivers, RT is typically used, sometimes in conjunction with surgery as the primary treatment.…”