In gratitude of the loyal support of our members, the CNS is offering complimentary 2021 Annual Meeting registration to all members! Learn more.

  • Stereotactic Radiosurgery with and without Checkpoint Inhibition for Patients with Metastatic Non-Small Cell Lung Cancer to the Brain: A Matched Cohort Study

    Final Number:
    218

    Authors:
    Matthew Shepard MD; Zhiyuan Xu; Joseph Donahue MD; Thomas Eluvathingal Muttikkal; Diogo Codeiro MD; Leslie Hansen; Nasser Mohammed; Ryan D Gentzler MD; James Larner; Camilo Fadul; Jason P. Sheehan MD PhD FACS

    Study Design:
    Clinical Research

    Subject Category:
    Tumor: Intra-Axial

    Meeting: Congress of Neurological Surgeons 2019 Annual Meeting

    Introduction: Immune checkpoint inhibitors (ICIs) improve survival in patients with advanced non-small cell lung cancer (NSCLC). Clinical trials examining the efficacy of ICI in patients with NSCLC excluded patients with untreated brain metastases (BM). As stereotactic radiosurgery (SRS) is commonly employed for NSCLC-BMs, we sought to define the safety, radiologic/clinical outcomes for patients with NSCLC-BM treated with concurrent ICI/SRS.

    Methods: A retrospective, matched cohort study was performed on patients who underwent SRS to one or more NSCLC-derived BM. Two matched cohorts were identified: one who received ICI within 3-months of SRS (concurrent-ICI) and one who did not (ICI-naive). Locoregional tumor control, peritumoral edema, and central nervous system adverse events were compared.

    Results: Seventeen patients (45-BMs) and 34 patients (92-BMs) comprised the concurrent-ICI and ICI-naive cohorts, respectively. Per RANO criteria, there was no difference in overall-survival (HR 0.99, 95%-CI: 0.39-2.52) or CNS progression-free-survival (HR 2.18, 95%-CI 0.72-6.62) between both groups. Similarly, the 12-month local tumor control rate was 84.9% and 76.3% for tumors in the concurrent-ICI and ICI-naive cohorts, respectively (p=0.94). Nevertheless, patients receiving concurrent-ICI had increased rates of complete response for BMs treated with SRS (50% versus 15.6%; p=.012) per RANO criteria. There was a shorter median time to BM regression in the concurrent-ICI cohort (2.5-months versus 3.1-months, p<.001). There was no increased rate of radiation necrosis or intratumoral hemorrhage in patients receiving concurrent-ICI (concurrent-ICI: 5.9%; ICI-naive: 2.9%, p=0.99). There was no difference in the rate of peritumoral edema progression across both groups (concurrent-ICI: 11.1%, ICI-naive: 21.7%; p=0.162).

    Conclusions: The use of ICI/SRS to treat NSCLC-BM was well tolerated while providing more rapid BM regression. Concurrent-ICI did not increase rates of peritumoral edema, radiation necrosis or intratumoral hemorrhage. Further studies are needed to evaluate whether concurrent ICI/SRS improves PFS/OS for patients with metastatic NSCLC.

    Patient Care: The use of checkpoint inhibitors has recently been shown to increase survival for patients with advanced non-small cell lung cancer (NSCLC). Patients with untreated brain metastases, however, were excluded from the initial clinical trials that examined the efficacy of nivolumab, pembrolizumab and atezolizumab. As many patients with NSCLC will develop brain metastases and ultimately undergo stereotactic radiosurgery, understanding the safety and efficacy of concurrent stereotactic radiosurgery and immune checkpoint inhibitors is imperative. In this study, we retrospectively analyzed the clinical and radiographic outcomes of patients with NSCLC with brain metastases who were treated with stereotactic radiosurgery with or without concurrent checkpoint inhibitors. While our results do not show improved OS or PFS when combining ICI/SRS, patients treated with ICI/SRS were more likely to have complete response per RANO criteria. Similarily, more rapid BM regression was noted in the ICI/SRS cohort. Furthermore, the combination of ICI/SRS did not increase rates of radiation necrosis, intratumoral hemorrhage or peritumoral edema. While further prospective studies are needed to verify these results, we feel that this data will be hypothesis generating and aids in the management of patients with NSCLC brain metastases undergoing SRS and concurrent immunotherapy.

    Learning Objectives: (1) Describe the role of immune checkpoint inhibitors (ICIs) in the management of non-small cell lung cancer (NSCLC) brain metastases (2) Discuss whether or not combining ICIs and stereotactic radiosurgery improve progression free survival in patients with NSCLC. (3) Explain the abscopal effect and the rational behind combining radiation and immune checkpoint inhibitors

    References: 1. Ahmed KA, Stallworth DG, Kim Y, Johnstone PAS, Harrison LB, Caudell JJ, et al: Clinical outcomes of melanoma brain metastases treated with stereotactic radiation and anti-PD-1 therapy. Ann Oncol 27:434–441, 2016 2. Ahmed KA, Kim S, Arrington J, Naghavi AO, Dilling TJ, Creelan BC, et al: Outcomes targeting the PD-1/PD-L1 axis in conjunction with stereotactic radiation for patients with non-small cell lung cancer brain metastases. J Neurooncol 133:331–338, 2017 3. An Y, Jiang W, Kim BYS, Qian JM, Tang C, Fang P, et al: Stereotactic radiosurgery of early melanoma brain metastases after initiation of anti-CTLA-4 treatment is associated with improved intracranial control. Radiother Oncol 125:80–88, 2017 4. Borghaei H, Paz-Ares L, Horn L, Spigel DR, Steins M, Ready NE, et al: Nivolumab versus Docetaxel in Advanced Nonsquamous Non–Small-Cell Lung Cancer. N Engl J Med 373:1627–1639, 2015 5. Brahmer J, Reckamp KL, Baas P, Crinò L, Eberhardt WEE, Poddubskaya E, et al: Nivolumab versus Docetaxel in Advanced Squamous-Cell Non–Small-Cell Lung Cancer. N Engl J Med 373:123–135, 2015 6. Brown PD, Jaeckle K, Ballman K V., Farace E, Cerhan JH, Anderson SK, et al: Effect of Radiosurgery Alone vs Radiosurgery With Whole Brain Radiation Therapy on Cognitive Function in Patients With 1 to 3 Brain Metastases: A Randomized Clinical Trial. Jama 316:401–409, 2016 7. Büttner R, Gosney JR, Skov BG, Adam J, Motoi N, Bloom KJ, et al: Programmed Death-Ligand 1 Immunohistochemistry Testing: A Review of Analytical Assays and Clinical Implementation in Non–Small-Cell Lung Cancer. J Clin Oncol 35:3867–3876, 2017 8. Chen L, Douglass J, Kleinberg L, Ye X, Marciscano AE, Forde PM, et al: Concurrent Immune Checkpoint Inhibitors and Stereotactic Radiosurgery for Brain Metastases in Non-Small Cell Lung Cancer, Melanoma, and Renal Cell Carcinoma. Int J Radiat Oncol 100:916–925, 2018 9. Cohen-Inbar O, Shih H-H, Xu Z, Schlesinger D, Sheehan JP: The effect of timing of stereotactic radiosurgery treatment of melanoma brain metastases treated with ipilimumab. J Neurosurg 127:1007–1014, 2017 10. Gaspar L, Scott C, Rotman M, Asbell S, Phillips T, Wasserman T, et al: Recursive partitioning analysis (RPA) of prognostic factors in three Radiation Therapy Oncology Group (RTOG) brain metastases trials. Int J Radiat Oncol Biol Phys 37:745–51, 1997 11. Goldberg SB, Gettinger SN, Mahajan A, Chiang AC, Herbst RS, Sznol M, et al: Pembrolizumab for patients with melanoma or non-small-cell lung cancer and untreated brain metastases: early analysis of a non-randomised, open-label, phase 2 trial. Lancet Oncol 17:976–983, 2016 12. Gray RJ: A Class of K-Sample Tests for Comparing the Cumulative Incidence of a Competing Risk. Ann Stat 16:1141–1154, 1988 13. Hubbeling HG, Schapira EF, Horick NK, Goodwin KEH, Lin JJ, Oh KS, et al: Safety of Combined PD-1 Pathway Inhibition and Intracranial Radiation Therapy in Non-Small Cell Lung Cancer. J Thorac Oncol 13:550–558, 2018 14. Kiess AP, Wolchok JD, Barker CA, Postow MA, Tabar V, Huse JT, et al: Stereotactic radiosurgery for melanoma brain metastases in patients receiving ipilimumab: safety profile and efficacy of combined treatment. Int J Radiat Oncol Biol Phys 92:368–75, 2015 15. Knisely JPS, Yu JB, Flanigan J, Sznol M, Kluger HM, Chiang VLS: Radiosurgery for melanoma brain metastases in the ipilimumab era and the possibility of longer survival. J Neurosurg 117:227–233, 2012 16. Kotecha R, Kim JM, Miller JA, Juloori A, Chao ST, Murphy ES, et al: The Impact of Sequencing PD-1/PD-L1 Inhibitors and Stereotactic Radiosurgery for Patients with Brain Metastasis. Neuro Oncol: epub ahead of print 2019 17. Lehrer EJ, Peterson J, Brown PD, Sheehan JP, Quiñones-Hinojosa A, Zaorsky NG, et al: Treatment of brain metastases with stereotactic radiosurgery and immune checkpoint inhibitors: An international meta-analysis of individual patient data. Radiother Oncol 130:104–112, 2018 18. Lin NU, Lee EQ, Aoyama H, Barani IJ, Barboriak DP, Baumert BG, et al: Response assessment criteria for brain metastases: Proposal from the RANO group. Lancet Oncol 16:270–278, 2015 19. Lynch TJ, Bondarenko I, Luft A, Serwatowski P, Barlesi F, Chacko R, et al: Ipilimumab in Combination With Paclitaxel and Carboplatin As First-Line Treatment in Stage IIIB/IV Non–Small-Cell Lung Cancer: Results From a Randomized, Double-Blind, Multicenter Phase II Study. J Clin Oncol 30:2046–2054, 2012 20. Martin A, Cagney D, Catalano P, Alexander B, Redig A, Schoenfeld J, et al: Immunotherapy and Symptomatic Radiation Necrosis in Patients With Brain Metastases Treated With Stereotactic Radiation. JAMA Oncol 4:1123–1124, 2018 21. Mathew M, Tam M, Ott PA, Pavlick AC, Rush SC, Donahue BR, et al: Ipilimumab in melanoma with limited brain metastases treated with stereotactic radiosurgery. Melanoma Res 23:191–5, 2013 22. Miller JA, Bennett EE, Xiao R, Kotecha R, Chao ST, Vogelbaum MA, et al: Association Between Radiation Necrosis and Tumor Biology After Stereotactic Radiosurgery for Brain Metastasis. Int J Radiat Oncol 96:1060–1069, 2016 23. Patel KR, Shoukat S, Oliver DE, Chowdhary M, Rizzo M, Lawson DH, et al: Ipilimumab and Stereotactic Radiosurgery Versus Stereotactic Radiosurgery Alone for Newly Diagnosed Melanoma Brain Metastases. Am J Clin Oncol 40:444–450, 2017 24. Reck M, Rodríguez-Abreu D, Robinson AG, Hui R, Csoszi T, Fülöp A, et al: Pembrolizumab versus Chemotherapy for PD-L1–Positive Non–Small-Cell Lung Cancer. N Engl J Med 375:1823–1833, 2016 25. Reck M, Rodríguez-Abreu D, Robinson AG, Hui R, Csoszi T, Fülöp A, et al: Pembrolizumab versus Chemotherapy for PD-L1-Positive Non-Small-Cell Lung Cancer. N Engl J Med 375:1823–1833, 2016 26. Rittmeyer A, Barlesi F, Waterkamp D, Park K, Ciardiello F, von Pawel J, et al: Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): a phase 3, open-label, multicentre randomised controlled trial. Lancet 389:255–265, 2017 27. Salvetti DJ, Nagaraja TG, McNeill IT, Xu Z, Sheehan J: Gamma Knife surgery for the treatment of 5 to 15 metastases to the brain: clinical article. J Neurosurg 116:1250–1257, 2013 28. Sharabi AB, Lim M, DeWeese TL, Drake CG: Radiation and checkpoint blockade immunotherapy: radiosensitisation and potential mechanisms of synergy. Lancet Oncol 16:e498–e509, 2015 29. Shaverdian N, Lisberg AE, Bornazyan K, Veruttipong D, Goldman JW, Formenti SC, 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 18:895–903, 2017 30. Silk AW, Bassetti MF, West BT, Tsien CI, Lao CD: Ipilimumab and radiation therapy for melanoma brain metastases. Cancer Med 2:899–906, 2013 31. Singh C, Qian JM, Yu JB, Chiang VL: Local tumor response and survival outcomes after combined stereotactic radiosurgery and immunotherapy in non-small cell lung cancer with brain metastases. J Neurosurg 15:1–6, 2019 32. Singh R, Zhou Z, Tisnado J, Haque S, Peck KK, Young RJ, et al: A novel magnetic resonance imaging segmentation technique for determining diffuse intrinsic pontine glioma tumor volume. J Neurosurg Pediatr 18:565–572, 2016 33. Soria J-C, Marabelle A, Brahmer JR, Gettinger S: Immune Checkpoint Modulation for Non-Small Cell Lung Cancer. Clin Cancer Res 21:2256–2262, 2015

We use cookies to improve the performance of our site, to analyze the traffic to our site, and to personalize your experience of the site. You can control cookies through your browser settings. Please find more information on the cookies used on our site. Privacy Policy