Immunotherapy for NSCLC With Brain Metastases: What Can We Learn From Real-World Data?
Authors: Shunichi Kouno, Shinji Atagi
Journal: Journal of Thoracic Oncology (2019)

Brain metastases (BMs) are common among patients with lung cancer, melanoma, and breast cancer. The treatment of metastatic brain tumor is crucial for better symptom control and for improving survival. Historically, local therapies, such as whole-brain radiation therapy, stereotactic radiosurgery, and surgical resection have been the cornerstone of these therapies. The addition of stereotactic radiosurgery to whole-brain radiation therapy has been compared with whole-brain radiation therapy alone or stereotactic radiosurgery alone.1Aoyama H. Shirato H. Tago M. et al.Stereotactic radiosurgery plus whole-brain radiation therapy vs stereotactic radiosurgery alone for treatment of brain metastases: a randomized controlled trial.JAMA. 2006; 295: 2483-2491Google Scholar However, neurotoxicity resulting from radiation therapy and/or surgery is a major problem.2Soffietti R. Kocher M. Abacioglu U.M. et al.A European Organisation for Research and Treatment of Cancer phase III trial of adjuvant whole-brain radiotherapy versus observation in patients with one to three brain metastases from solid tumors after surgical resection or radiosurgery: quality-of-life results.J Clin Oncol. 2013; 31: 65-72Google Scholar The use of cytotoxic chemotherapy for BM has shown limited activity in the nervous system, which has been attributed to the blood-brain barrier (BBB). Some types of NSCLC have oncogene addiction, such as EGFR mutation, anaplastic lymphoma kinase translocation, and ROS1 and ret proto-oncogene (RET) rearrangements. Molecular targeted drugs are effective when they inhibit abnormal gene products. In particular, the third-generation EGFR tyrosine kinase inhibitor osimertinib has shown better BBB penetration compared to first-generation EGFR tyrosine kinase inhibitors, with higher response rates and more durable control of central nervous system (CNS) lesions.3Ballard P. Yates J.W. Yang Z. et al.Preclinical comparison of osimertinib with other EGFR-TKIs in EGFR-mutant NSCLC brain metastases models, and early evidence of clinical brain metastases activity.Clin Cancer Res. 2016; 22: 5130-5140Google Scholar Thus, targeted therapies seem to be promising for patients with BM harboring treatable mutations. Immune checkpoint inhibitors (ICIs) have emerged as a game changer in cancer treatment. However, patients with untreated or active BM have been systematically excluded from clinical trials of ICIs owing to poor outcome and the risk of brain pseudoprogression. Patients who require systemic corticosteroids have also been excluded due to immunosuppressive effects. Therefore, the intracranial efficacy of ICIs has not yet been researched. In this issue of the Journal of Thoracic Oncology, Hendriks et al.4Hendriks L.E.L. Henon C. Auclin E. et al.Outcome of patients with non–small cell lung cancer and brain metastases treated with checkpoint inhibitors.J Thorac Oncol. 2019; 14: 1244-1254Google Scholar evaluated BM outcome in a less-selected NSCLC cohort. This report represents a significant contribution in terms of providing real-world data, considering the overall lack of evidence for such patients. Using multivariate analysis, they found BM to not be associated with poorer survival in ICI-treated NSCLC patients. Furthermore, in multivariate analysis for the BM subgroup, the use of corticosteroids at the start of ICI therapy was associated with poorer progression-free survival (PFS), whereas stable BM and a higher disease-specific Graded Prognostic Assessment (ds-GPA) score were associated with improved PFS. Meanwhile, intensive cancer treatment may not be recommended in patients with active BM, poor ds-GPA score, and corticosteroid requirement due to toxicity. As for cytotoxic chemotherapy and molecular targeted drugs, it is necessary for the drugs to reach cancer lesions in order to kill cancer cells. However, ICIs themselves cannot directly kill cancer cells, but they can remove the inhibitory signals of T-cell activation, which enables tumor-reactive T cells to exert an antitumor response. The brain is considered an immune-privileged site that may dampen the therapeutic efficacy of ICIs because of the presence of the BBB.5Bechmann I. Galea I. Perry V.H. What is the blood-brain barrier (not)?.Trends Immunol. 2007; 28: 5-11Google Scholar There are several unclarified aspects that should be considered for understanding the mechanism for the intracranial response to ICI. First, can ICIs penetrate the BBB? Brain tumors can disrupt the BBB, and some preclinical animal data have shown that ICIs can penetrate the BBB to access brain tumors.6Fecci P.E. Ochiai H. Mitchell D.A. et al.Systemic CTLA-4 blockade ameliorates glioma-induced changes to the CD4+ T cell compartment without affecting regulatory T-cell function.Clin Cancer Res. 2007; 13: 2158-2167Google Scholar Second, are activated T lymphocytes capable of infiltrating BM? The infiltration of immune cells into the CNS is very tightly restricted by the BBB.7Berghoff A.S. Fuchs E. Ricken G. et al.Density of tumor-infiltrating lymphocytes correlates with extent of brain edema and overall survival time in patients with brain metastases.Oncoimmunology. 2016; 5e1057388Google Scholar Zeng et al.8Zeng J. See A.P. Phallen J. et al.Anti–PD-1 blockade and stereotactic radiation produce long-term survival in mice with intracranial gliomas.Int J Radiat Oncol Biol Phys. 2013; 86: 343-349Google Scholar reported on intracranial implantation of a mouse glioma cell line treated with radiation, programmed death 1 (PD-1) antibody, and combination anti–PD-1 and radiation. Mice treated with either modality alone or combination showed increased cytotoxic T cells and decreased regulatory T cells in the mouse brain. Furthermore, combination treatment showed an increase in the number of cytotoxic T cells and decrease in regulatory T cells in the brain, improving survival compared with either modality alone. The third aspect is that there are some differences between programmed death ligand 1 (PD-L1) expression in BM and the primary lesion. PD-L1 expression is not a robust biomarker but is currently used as a biomarker in clinical practice. Furthermore, the heterogeneity and dynamics of PD-L1 expression may also limit its use as a tissue-based predictive biomarker. Mansfield et al.9Mansfield A.S. Aubry M.C. Moser J.C. et al.Temporal and spatial discordance of programmed cell death-ligand 1 expression and lymphocyte tumor infiltration between paired primary lesions and brain metastases in lung cancer.Ann Oncol. 2016; 27: 1953-1958Google Scholar reported that upon ICI treatment, many BM lost PD-L1 expression or tumor lymphocyte infiltration that was present in the primary lung cancer lesion. ICIs are expected to have a durable response and to achieve a cure, although their response rate is low. In a study by Kim et al.,10Kim R. Keam B. Kim S. et al.Differences in tumor microenvironments between primary lung tumors and brain metastases in lung cancer patients: therapeutic implications for immune checkpoint inhibitors.BMC Cancer. 2019; 19: 19Google Scholar the BM of lung cancer did not respond well to ICIs. Immunohistochemical analysis revealed a decreased infiltration of PD-1–positive cells in BM compared to primary lung cancer. An interim analysis of a phase II study of pembrolizumab for patients with melanoma or NSCLC and untreated BM has been reported.11Goldberg S.B. Gettinger S.N. Mahajan A. et al.Durability of brain metastasis response and overall survival in patients with non–small cell lung cancer (NSCLC) treated with pembrolizumab.J Clin Oncol. 2018; 36 (abstr 2009)Google Scholar For NSCLC patients, cohort 1 was for PD-L1–positive patients and cohort 2, for PD-L1–negative or unevaluable patients. The response rate in the CNS was 29.4% (95% confidence interval: 15.1–47.5) in cohort 1; no patient in cohort 2 had a BM response. This study showed that almost one-third of the patients lived for more than 2 years. The relatively superior response rate observed in this study might be due to the exclusion of patients with symptomatic BM and those requiring urgent local therapy or systemic corticosteroids. Therefore, the condition of the microenvironment in BM is important. Hendriks et al.4Hendriks L.E.L. Henon C. Auclin E. et al.Outcome of patients with non–small cell lung cancer and brain metastases treated with checkpoint inhibitors.J Thorac Oncol. 2019; 14: 1244-1254Google Scholar report in the same issue that ICIs resulted in an overall response rate (ORR) of 20.6% of the patients with BM and 22.7% of those without BM. There was no significant difference between them. They also reported that the intracranial ORR was 27.3%. For 23 active BM patients with brain imaging data available, the ORR was 35.7% in patients with 1% or greater PD-L1 expression level and 11.1% in PD-L1–negative patients. Recently, Crinò et al.12Crinò 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: 35-40Google Scholar reported the results of nivolumab treatment in patients with CNS metastases from an expanded access program in Italy. Four hundred nine (26%) patients who were asymptomatic and had controlled CNS metastases were treated with nivolumab. The ORR was 17% in CNS metastases patients and 18% in all patients. These results suggest that patients with CNS metastases could benefit from treatment with ICIs. Therefore, we can expect that real-world evidence can be useful to investigate the effectiveness for patients who are excluded from clinical trials. The combination of local therapy such as stereotactic radiosurgery and ICIs appears to be a promising treatment strategy without increasing toxicities. The abscopal effect — tumor regression at a site distant from the primary site of radiotherapy — is a possible outcome.13Postow M.A. Callahan M.K. Barker C.A. et al.Immunologic correlates of the abscopal effect in a patient with melanoma.N Engl J Med. 2012; 366: 925-931Google Scholar Radiotherapy itself reduces leukocytes and acts on immunosuppression. However, radiotherapy also has an immunostimulatory effect through the release of cancer cell antigens to the immune system and the generation of key molecular signals from radiation-induced cell death.14Demaria S. Golden E.B. Formenti S.C. Role of local radiation therapy in cancer immunotherapy.JAMA Oncol. 2015; 1: 1325-1332Google Scholar Shaverdian et al.15Shaverdian N. Lisberg A.E. Bornazyan K. et al.Previous radiotherapy and the clinical activity and toxicity of pembrolizumab in the treatment of non–small-cell lung cancer: a secondary analysis of the KEYNOTE-001 phase 1 trial.Lancet Oncol. 2017; 18: 895-903Google Scholar report a secondary analysis of the KEYNOTE-001 phase I trial at a single institution. They investigated whether previously received radiotherapy influences the efficacy and toxicity with pembrolizumab treatment compared with patients who had not undergone radiotherapy. The results suggested that the patients who had previous radiotherapy showed longer PFS and overall survival with pembrolizumab treatment compared to patients who had not undergone radiotherapy. A 4-year update of KEYNOTE-001 was presented in the American Society of Clinical Oncology meeting in 2018.16Felip e Hellmann M. Hui R. et al.4-year overall survival for patients with advanced NSCLC treated with pembrolizumab: results from KEYNOTE-001.J Clin Oncol. 2018; 36 (abstr 9030)Google Scholar However, as Hendriks et al.4Hendriks L.E.L. Henon C. Auclin E. et al.Outcome of patients with non–small cell lung cancer and brain metastases treated with checkpoint inhibitors.J Thorac Oncol. 2019; 14: 1244-1254Google Scholar describes in the Discussion in the same issue, an updated analysis including all patients (not at a single institution) in the KEYNOTE-001 trial did not show the benefits of previous radiotherapy. Hendriks et al.4Hendriks L.E.L. Henon C. Auclin E. et al.Outcome of patients with non–small cell lung cancer and brain metastases treated with checkpoint inhibitors.J Thorac Oncol. 2019; 14: 1244-1254Google Scholar note that, compared to active BM, cranial irradiation within 3 months of ICI was associated with a superior outcome, whereas no cranial irradiation within 3 months of the start of ICI showed no such association. Lung cancer patients often receive palliative radiotherapy for bone metastases, superior vena cava syndrome, or bronchial stenosis, as well as BM at some point. Radiation also increases PD-L1 expression, creating an opportunity for synergy with ICI therapy.17Dovedi S.J. Adlard A.L. Lipowska-Bhalla G. et al.Acquired resistance to fractionated radiotherapy can be overcome by concurrent PD-L1 blockade.Cancer Res. 2014; 74: 5458-5468Google Scholar The abscopal effect warrants attention in combined treatment with ICI. Therefore, radiotherapy might become a promising combination therapy candidate. The results of ongoing clinical trials that are investigating the efficacy of immunotherapy in combination with radiotherapy in the patients with BM are anticipated (NCT02696993, NCT02858869, NCT02710253). The five “too’s” are known as limitations in clinical trials: too few, too simple, too narrow, too median-aged, and too brief.18Rogers A.S. Adverse drug events: identification and attribution.Drug Intell Clin Pharm. 1987; 21: 915-920Google Scholar Randomized controlled trials have stringent inclusion and exclusion criteria, and highly selected patients and selected institutions can enroll in these clinical trials. Therefore, such evidence might overestimate benefits and underestimate harm. However, drugs after marketing approval can be used for patients who have poor prognosis, other malignancies, comorbidities, organ dysfunction, et cetera. It remains unclear whether such evidence can be applied for these patients. Therefore, making use of real-world data is important in the investigation of the effectiveness and safety of treatments in a wide range of patients. Outcome of Patients with Non–Small Cell Lung Cancer and Brain Metastases Treated with Checkpoint InhibitorsJournal of Thoracic OncologyVol. 14Issue 7PreviewAlthough frequent in NSCLC, patients with brain metastases (BMs) are often excluded from immune checkpoint inhibitor (ICI) trials. We evaluated BM outcome in a less-selected NSCLC cohort. Full-Text PDF Open Archive