Many studies over the past several years have clearly demonstrated the efficacy of PD-1 and PD-L1 inhibitors for NSCLC, and these agents are now part of the standard treatment of patients with advanced NSCLC. However, several outstanding questions remain regarding the optimal use of checkpoint inhibitors, including the specific patient populations most likely to benefit.
Approximately 25% of patients with advanced NSCLC have brain metastases at diagnosis, and typically radiation is used to treat central nervous system (CNS) disease prior to initiation of systemic therapy. There are potential down-sides to this strategy, including the risk of side effects from radiation (particularly with whole-brain radiation therapy) and the delay in starting systemic therapy. There have been several recent examples of systemic therapies that have excellent CNS penetration and can be used to treat both the brain and the body with similar effect, most notably many of the targeted therapies commonly used for lung cancer. Whether the same is true for immunotherapy was previously unknown.
A recent phase II trial1 of pembrolizumab in patients with brain metastases from NSCLC demonstrated that PD-1 inhibition can be effective in the CNS, with almost 30% of patients whose tumors expressed PD-L1 having a brain metastasis response. OS at 2 years was 34%, highlighting the improvement in prognosis that was previously considered dismal for those with CNS involvement from lung cancer. This strategy was also found to be safe. Typical toxicities from checkpoint inhibitors were observed, but there were no significant neurologic side effects. An important limitation of this study was that not all patients with brain metastases were included: brain lesions could be no larger than 2 cm, and patients were required to be neurologically asymptomatic and to not need corticosteroids to control peri-tumoral edema.
Based on this and other studies,2,3 we have learned that that immunotherapy can be effective in the brain in a subset of patients. There has not yet been a randomized trial that confirms that immunotherapy is sufficient for the management of brain metastases, and unfortunately, many patients will not have a response in the brain. However, upfront pembrolizumab with close surveillance of the brain may be an option for select patients who have asymptomatic CNS disease and a high likelihood of benefit from PD-1 inhibition.
References:
- Goldberg SB, Schalper KA, Gettinger SN, et al. Pembrolizumab for management of patients with NSCLC and brain metastases: long-term results and biomarker analysis from a non-randomised, open-label, phase 2 trial. Lancet Oncol. 2020;21(5)655-663.
- Gadgeel S, Rodríguez-Abreu D, Speranza G, et al. Updated Analysis From KEYNOTE-189: Pembrolizumab or Placebo Plus Pemetrexed and Platinum for Previously Untreated Metastatic Nonsquamous Non–Small-Cell Lung Cancer. J Clin Oncol. 2020;38(14):1505-1517.
- Crinò L, Bronte G, Bidoli P, et al. Nivolumab and brain metastases in patients with advanced non-squamous non-small cell lung cancer. Lung Cancer. 2019;129:35-40.
