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Combination treatments with immunotherapy in brain metastases patients

    Clemence Henon

    Department of Medical Oncology, Gustave Roussy Cancer Campus, Institut d'Oncologie Thoracique (IOT), Gustave Roussy, Villejuif, France

    ,
    Jordi Remon

    Department of Medical Oncology, Centro Integral Oncológico Clara Campal (HM CIOCC), Hospital HM Delfos, HM Hospitales, Barcelona, Spain

    &
    Lizza EL Hendriks

    *Author for correspondence: Tel.: 0031 043 387 1318; Fax: 0031 043 387 5051;

    E-mail Address: lizza.hendriks@mumc.nl

    Department of Pulmonary Diseases, GROW - School for Oncology & Developmental Biology, Maastricht University Medical Center+, Maastricht, The Netherlands

    Published Online:https://doi.org/10.2217/fon-2020-0156

    Immune checkpoint inhibitors (ICI) have revolutionized the treatment of many advanced cancers. However, in most pivotal trials, patients with brain metastases (BM) were either excluded, or only selected patients were allowed. Therefore, there are still some concerns about the safety/efficacy ratio of ICI in patients with BM. In this special report we will provide an overview on the biological rationale for using ICI in the treatment of BM, the reported BM-related outcomes of clinical trials with a focus on ICI plus chemotherapy and ICI plus ICI combinations. Last, we will provide future challenges with this strategy, as well as directions for future research.

    Papers of special note have been highlighted as: • of interest; •• of considerable interest

    References

    • 1. Bedikian AY, Wei C, Detry M et al. Predictive factors for the development of brain metastasis in advanced unresectable metastatic melanoma. Am. J. Clin. Oncol. 34(6), 603–610 (2011).
    • 2. Ajithkumar T, Parkinson C, Fife K, Corrie P, Jefferies S. Evolving treatment options for melanoma brain metastases. Lancet Oncol. 16(13), e486–497 (2015).
    • 3. Nayak L, Lee EQ, Wen PY. Epidemiology of brain metastases. Curr. Oncol. Rep. 14(1), 48–54 (2012).
    • 4. DeAngelis LM, Posner JB. Neurologic Complications of Cancer. 2nd Edition. Oxford University Press, Oxford, NY, USA
    • 5. Leone JP, Leone BA. Breast cancer brain metastases: the last frontier. Exp. Hematol. Oncol. 4, 33 (2015).
    • 6. Leone JP, Leone J, Zwenger AO, Iturbe J, Leone BA, Vallejo CT. Prognostic factors and survival according to tumour subtype in women presenting with breast cancer brain metastases at initial diagnosis. Eur. J. Cancer Oxf. Engl. 1990. 74, 17–25 (2017).
    • 7. Lin NU, Amiri-Kordestani L, Palmieri D, Liewehr DJ, Steeg PS. CNS metastases in breast cancer: old challenge, new frontiers. Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res. 19(23), 6404–6418 (2013).
    • 8. Berghoff AS, Schur S, Füreder LM et al. Descriptive statistical analysis of a real life cohort of 2419 patients with brain metastases of solid cancers. ESMO Open. 1(2), e000024 (2016).
    • 9. Achrol AS, Rennert RC, Anders C et al. Brain metastases. Nat. Rev. Dis. Primer. 5(1), 5 (2019).
    • 10. Sun M, De Velasco G, Brastianos PK et al. The development of brain metastases in patients with renal cell carcinoma: epidemiologic trends, survival, and clinical risk factors using a population-based cohort. Eur. Urol. Focus 5(3), 474–481 (2019).
    • 11. Peters S, Bexelius C, Munk V, Leighl N. The impact of brain metastasis on quality of life, resource utilization and survival in patients with non-small-cell lung cancer. Cancer Treat. Rev. 45, 139–162 (2016).
    • 12. Planchard D, Popat S, Kerr K et al. Metastatic non-small-cell lung cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann. Oncol. Off. J. Eur. Soc. Med. Oncol. 29(Suppl. 4), iv192–iv237 (2018).
    • 13. Paz-Ares L, Dvorkin M, Chen Y et al. Durvalumab plus platinum-etoposide versus platinum-etoposide in first-line treatment of extensive-stage small-cell lung cancer (CASPIAN): a randomised, controlled, open-label, phase 3 trial. Lancet Lond. Engl. 394(10212), 1929–1939 (2019).
    • 14. Horn L, Mansfield AS, Szczęsna A et al. First-line atezolizumab plus chemotherapy in extensive-stage small-cell lung cancer. N. Engl. J. Med. 379(23), 2220–2229 (2018).
    • 15. Michielin O, van Akkooi ACJ, Ascierto PA, Dummer R, Keilholz U. ESMO Guidelines Committee. Cutaneous melanoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann. Oncol. Off. J. Eur. Soc. Med. Oncol. 30(12), 1884–1901 (2019).
    • 16. Escudier B, Porta C, Schmidinger M et al. Renal cell carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann. Oncol. Off. J. Eur. Soc. Med. Oncol. 30(5), 706–720 (2019).
    • 17. Powell SF, Rodriguez-Abreu D, Langer C et al. Pembrolizumab plus platinum based chemotherapy in NSCLC with brain metastases: pooled analysis of KEYNOTE 021, 189, and 407. Ann. Oncol. 30, v602–v660 (2019). • This is the first trial data reporting on ICI-chemotherapy efficacy in NSCLC patients with brain metastases.
    • 18. Mansfield A, Herbst R, Castro G et al. Outcomes with pembrolizumab monotherapy in patients with PD L1 positive NSCLC with brain metastases: pooled analysis of KEYNOTE 001, 010, 024, and 042. Ann. Oncol. 30, v602–v660 (2019).
    • 19. El Rassy E, Botticella A, Kattan J, Le Péchoux C, Besse B, Hendriks L. non-small-cell lung cancer brain metastases and the immune system: from brain metastases development to treatment. Cancer Treat. Rev. 68, 69–79 (2018).
    • 20. Robert C, Schachter J, Long GV et al. Pembrolizumab versus ipilimumab in advanced melanoma. N. Engl. J. Med. 372(26), 2521–2532 (2015).
    • 21. Long GV, Atkinson V, Cebon JS et al. Standard-dose pembrolizumab in combination with reduced-dose ipilimumab for patients with advanced melanoma (KEYNOTE-029): an open-label, phase 1b trial. Lancet Oncol. 18(9), 1202–1210 (2017).
    • 22. Larkin J, Chiarion-Sileni V, Gonzalez R et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N. Engl. J. Med. 373(1), 23–34 (2015).
    • 23. Wolchok JD, Kluger H, Callahan MK et al. Nivolumab plus ipilimumab in advanced melanoma. N. Engl. J. Med. 369(2), 122–133 (2013).
    • 24. Wolchok JD, Chiarion-Sileni V, Gonzalez R et al. Overall survival with combined nivolumab and ipilimumab in advanced melanoma. N. Engl. J. Med. 377(14), 1345–1356 (2017).
    • 25. Larkin J, Chiarion-Selini V, Gonzalez R et al. Five-year survival with combined nivolumab and ipilimumab in advanced melanoma. N. Engl. J. Med 381(16), 1535–1546 (2019).
    • 26. Tykodi SS, Donskov F, Lee JL et al. First-line pembrolizumab (pembro) monotherapy in advanced clear cell renal cell carcinoma (ccRCC): updated results for KEYNOTE-427 cohort A. J. Clin. Oncol. 37(Suppl. 15), 4570–4570 (2019).
    • 27. McDermott DF, Lee JL, Ziobro M et al. First-line pembrolizumab (pembro) monotherapy for advanced non-clear cell renal cell carcinoma (nccRCC): Results from KEYNOTE-427 cohort B. J. Clin. Oncol. 37(Suppl. 7), 546–546 (2019).
    • 28. Ransohoff RM, Engelhardt B. The anatomical and cellular basis of immune surveillance in the central nervous system. Nat. Rev. Immunol. 12(9), 623–635 (2012).
    • 29. Owens T, Renno T, Taupin V, Krakowski M. Inflammatory cytokines in the brain: does the CNS shape immune responses? Immunol. Today 15(12), 566–571 (1994).
    • 30. Mansfield AS, Aubry MC, Moser JC 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. Off. J. Eur. Soc. Med. Oncol. 27(10), 1953–1958 (2016). • This is the first report evaluating PD-L1 expression differences between paired primary tumor and brain metastases in lung cancer.
    • 31. Stein MK, Pandey M, Xiu J et al. Tumor mutational burden is site specific in non–small-cell lung cancer and is highest in lung adenocarcinoma brain metastases. JCO Precis. Oncol. (3), 1–13 (2019).
    • 32. Steindl A, Bergen ES, Alpar D et al. 403PD – Tumour mutational burden and immune infiltrates in primary renal cell carcinoma and matched brain metastases. Ann. Oncol. 30, v148 (2019).
    • 33. Mansfield AS, Ren H, Sutor S et al. Contraction of T cell richness in lung cancer brain metastases. Sci. Rep. 8(1), 1–9 (2018). •• This is one of the first reports evaluating the immune enviroment of brain metastases.
    • 34. Kudo Y, Haymaker C, Zhang J et al. Suppressed immune microenvironment and repertoire in brain metastases from patients with resected non-small-cell lung cancer. Ann. Oncol. Off. J. Eur. Soc. Med. Oncol. 30(9), 1521–1530 (2019).
    • 35. Quail DF, Joyce JA. The microenvironmental landscape of brain tumors. Cancer Cell. 31(3), 326–341 (2017).
    • 36. Leibold AT, Monaco GN, Dey M. The role of the immune system in brain metastasis. Curr. Neurobiol. 10(2), 33–48 (2019).
    • 37. Cimino-Mathews A, Ye X, Meeker A, Argani P, Emens LA. Metastatic triple-negative breast cancers at first relapse have fewer tumor-infiltrating lymphocytes than their matched primary breast tumors: a pilot study. Hum. Pathol. 44(10), 2055–2063 (2013).
    • 38. Ogiya R, Niikura N, Kumaki N et al. Comparison of immune microenvironments between primary tumors and brain metastases in patients with breast cancer. Oncotarget 8(61), 103671–103681 (2017). • This is one of the first reports evaluating the immune environment in breast cancer brain metastases.
    • 39. Sobottka B, Pestalozzi B, Fink D, Moch H, Varga Z. Similar lymphocytic infiltration pattern in primary breast cancer and their corresponding distant metastases. Oncoimmunology 5(6), e1153208 (2016).
    • 40. Kluger HM, Zito CR, Barr ML et al. Characterization of PD-L1 expression and associated T-cell infiltrates in metastatic melanoma samples from variable anatomic sites. Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res. 21(13), 3052–3060 (2015).
    • 41. Zhou J, Gong Z, Jia Q, Wu Y, Yang Z-Z, Zhu B. Programmed death ligand 1 expression and CD8+ tumor-infiltrating lymphocyte density differences between paired primary and brain metastatic lesions in non-small-cell lung cancer. Biochem. Biophys. Res. Commun. 498(4), 751–757 (2018).
    • 42. Di Giacomo AM, Ascierto PA, Pilla L et al. Ipilimumab and fotemustine in patients with advanced melanoma (NIBIT-M1): an open-label, single-arm phase 2 trial. Lancet Oncol. 13(9), 879–886 (2012).
    • 43. Di Giacomo AM, Ascierto PA, Queirolo P et al. Three-year follow-up of advanced melanoma patients who received ipilimumab plus fotemustine in the Italian Network for Tumor Biotherapy (NIBIT)-M1 Phase II study. Ann. Oncol. Off. J. Eur. Soc. Med. Oncol. 26(4), 798–803 (2015).
    • 44. Tawbi HA, Forsyth PA, Algazi A et al. Combined nivolumab and ipilimumab in melanoma metastatic to the brain. N. Engl. J. Med. 379(8), 722–730 (2018).
    • 45. Tawbi H, Forsyth P, Hodi F et al. Efficacy and safety of the combination of nivolumab (NIVO) plus ipilimumab (IPI) in patients with symptomatic melanoma brain metastases (CheckMate 204). J. Clin. Oncol. (2019) https://ascopubs.org/doi/abs/10.1200/JCO.2019.37.15_suppl.9501 •• The first trial evaluating ICI in patients with symptomatic brain metastases.
    • 46. Emamekhoo H, Olsen M, Carthon BC et al. Safety and efficacy of nivolumab plus ipilimumab (NIVO+IPI) in patients with advanced renal cell carcinoma (aRCC) with brain metastases: Interim analysis of CheckMate 920. J. Clin. Oncol. 37(Suppl. 15), 4517–4517 (2019). •• The first trial evaluating ICI-ICI in RCC brain metastases.
    • 47. Goldberg SB, Schalpei 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 II trial. Lancet Oncol. 21(5), 655–663 (2020) epub ahead of print. doi:10.1016/S1470-2045(20)30111-X
    • 48. Hendriks LEL, Henon C, Auclin E et al. Outcome of non-small-cell lung cancer patients with brain metastases treated with checkpoint inhibitors. J. Thorac. Oncol. Off. Publ. Int. Assoc. Study Lung Cancer 14(7), 1244–1254 (2019).
    • 49. Tazi K, Hathaway A, Chiuzan C, Shirai K. Survival of melanoma patients with brain metastases treated with ipilimumab and stereotactic radiosurgery. Cancer Med. 4(1), 1–6 (2015).
    • 50. Margolin K, Ernstoff MS, Hamid O et al. Ipilimumab in patients with melanoma and brain metastases: an open-label, phase 2 trial. Lancet Oncol. 13(5), 459–465 (2012). •• This is the first report of ipilimumab efficacy in brain metastses from melanoma.
    • 51. Goldberg SB, Gettinger SN, Mahajan A 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 II trial. Lancet Oncol. 17(7), 976–983 (2016). •• This is the first Phase II trial evaluating pembrolizumab in NSCLC and melanoma brain metastases patients.
    • 52. Kluger HM, Chiang V, Mahajan A et al. Long-term survival of patients with melanoma with active brain metastases treated with pembrolizumab on a Phase II trial. J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol. 37(1), 52–60 (2019).
    • 53. Flippot R, Dalban C, Laguerre B et al. Safety and efficacy of nivolumab in brain metastases from renal cell carcinoma: results of the GETUG-AFU 26 NIVOREN multicenter Phase II study. J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol. 37(23), 2008–2016 (2019).
    • 54. Motzer RJ, Escudier B, McDermott DF et al. Nivolumab versus everolimus in advanced renal-cell carcinoma. N. Engl. J. Med. 373(19), 1803–1813 (2015).
    • 55. Albiges L, Negrier S, Dalban C et al. Safety and efficacy of nivolumab in metastatic renal cell carcinoma (mRCC): final analysis from the NIVOREN GETUG AFU 26 study. J.Clin. Oncol. 37(Suppl. 7), 452 (2019).
    • 56. Spranger S, Koblish HK, Horton B, Scherle PA, Newton R, Gajewski TF. Mechanism of tumor rejection with doublets of CTLA-4, PD-1/PD-L1, or IDO blockade involves restored IL-2 production and proliferation of CD8(+) T cells directly within the tumor microenvironment. J. Immunother. Cancer. 2, 3 (2014).
    • 57. Hellmann MD, Ciuleanu T-E, Pluzanski A et al. Nivolumab plus ipilimumab in lung cancer with a high tumor mutational burden. N. Engl. J. Med. 378(22), 2093–2104 (2018).
    • 58. Barlesi F, Audigier-Valette C, Felip E et al. OA04.02 CheckMate 817: first-line nivolumab + ipilimumab in patients with ECOG PS 2 and other special populations with advanced NSCLC. J. Thorac. Oncol. 14(10), S214–S215 (2019).
    • 59. Long GV, Atkinson V, Lo S et al. Combination nivolumab and ipilimumab or nivolumab alone in melanoma brain metastases: a multicentre randomised phase 2 study. Lancet Oncol. 19(5), 672–681 (2018). •• The first trial evaluating an ICI-ICI strategy in melanoma brain metastases.
    • 60. Qian JM, Yu JB, Mahajan A, Goldberg SB, Kluger HM, Chiang VLS. Frequent use of local therapy underscores need for multidisciplinary care in the management of patients with melanoma brain metastases treated with PD-1 inhibitors. Int. J. Radiat. Oncol. Biol. Phys. 105(5), 1113–1118 (2019).
    • 61. Motzer RJ, Rini BI, McDermott DF et al. Nivolumab plus ipilimumab versus sunitinib in first-line treatment for advanced renal cell carcinoma: extended follow-up of efficacy and safety results from a randomised, controlled, phase 3 trial. Lancet Oncol. 20(10), 1370–1385 (2019).
    • 62. Emens LA, Middleton G. The interplay of immunotherapy and chemotherapy: harnessing potential synergies. Cancer Immunol. Res. 3(5), 436–443 (2015).
    • 63. Mok TSK, Reck M, Horn L et al. IMpower133: primary efficacy and safety + CNS-related adverse events in a phase I/III study of first-line (1L) atezolizumab + carboplatin + etoposide in extensive-stage SCLC (ES-SCLC). Ann. Oncol. 29, ix173 (2018).
    • 64. Yu C, Liu X, Yang J et al. Combination of immunotherapy with targeted therapy: theory and practice in metastatic melanoma. Front. Immunol. 10, 990 (2019).
    • 65. Callahan MK, Masters G, Pratilas CA et al. Paradoxical activation of T cells via augmented ERK signaling mediated by a RAF inhibitor. Cancer Immunol. Res. 2(1), (2014).
    • 66. Callahan M, Masters G, Katz J et al. The immunological impact of the RAF inhibitor BMS908662: preclinical and early clinical experience in combination with CTLA-4 blockade. J.Clin. Oncol. 30( Suppl. 15), 2521 (2012).
    • 67. Amin A, Lawson DH, Salama AK et al. A single-arm, open-label, Phase II study to evaluate the safety of vemurafenib (VEM) followed by ipilimumab (IPI) in BRAF V600-mutated metastatic melanoma (MM). J. Clin. Oncol. 33(Suppl. 15), 9032–9032 (2015).
    • 68. Spaas M, Lievens Y. Is the combination of immunotherapy and radiotherapy in non-small-cell lung cancer a feasible and effective approach? Front. Med. 6, 244 (2019).
    • 69. Ishihara D, Pop L, Takeshima T, Iyengar P, Hannan R. Rationale and evidence to combine radiation therapy and immunotherapy for cancer treatment. Cancer Immunol. Immunother. CII. 66(3), 281–298 (2017).
    • 70. Lehrer EJ, Peterson J, Brown PD et al. Treatment of brain metastases with stereotactic radiosurgery and immune checkpoint inhibitors: an international meta-analysis of individual patient data. Radiother. Oncol. J. Eur. Soc. Ther. Radiol. Oncol. 130, 104–112 (2019).
    • 71. Wang Y, Deng W, Li N et al. Combining immunotherapy and radiotherapy for cancer treatment: current challenges and future directions. Front. Pharmacol. 9, (2018).
    • 72. Socinski MA, Jotte RM, Cappuzzo F et al. Atezolizumab for first-line treatment of metastatic nonsquamous NSCLC. N. Engl. J. Med. 378(24), 2288–2301 (2018).
    • 73. Loganadane G, Dhermain F, Louvel G et al. Brain radiation necrosis: current management with a focus on non-small-cell lung cancer patients. Front. Oncol. 8, 336 (2018).
    • 74. Besse B, Le Moulec S, Mazières J et al. Bevacizumab in patients with nonsquamous non-small-cell lung cancer and asymptomatic, untreated brain metastases (BRAIN): a nonrandomized, Phase II study. Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res. 21(8), 1896–1903 (2015).
    • 75. Rini BI, Plimack ER, Stus V et al. Pembrolizumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N. Engl. J. Med. [Internet]. 380(12), 1116–1127 (2019).
    • 76. Rini BI, Powles T, Atkins MB et al. Atezolizumab plus bevacizumab versus sunitinib in patients with previously untreated metastatic renal cell carcinoma (IMmotion151): a multicentre, open-label, Phase III, randomised controlled trial. Lancet Lond. Engl. 393(10189), 2404–2415 (2019).
    • 77. Motzer RJ, Penkov K, Haanen J et al. Avelumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N. Engl. J. Med. 380(12), 1103–1115 (2019).
    • 78. Khair DO, Bax HJ, Mele S et al. Combining immune checkpoint inhibitors: established and emerging targets and strategies to improve outcomes in melanoma. Front. Immunol. 10, (2019).
    • 79. Hu-Lieskovan S, Moon J, Campos D et al. Reversing resistance to PD-1 blockade by combination of talimogene laherparepvec (T-VEC) with pembrolizumab (pembro) in advanced melanoma patients following progression on a prior PD-1 inhibitor: SWOG S1607 (NCT#02965716). J.Clin. Oncol. 36(Suppl. 15), TPS9603 ( 2018).
    • 80. Blake Z, Marks DK, Gartrell RD et al. Complete intracranial response to talimogene laherparepvec (T-Vec), pembrolizumab and whole brain radiotherapy in a patient with melanoma brain metastases refractory to dual checkpoint-inhibition. J. Immunother. Cancer. 6(1), 25 (2018).
    • 81. Camidge DR, Lee EQ, Lin NU et al. Clinical trial design for systemic agents in patients with brain metastases from solid tumours: a guideline by the Response Assessment in Neuro-Oncology Brain Metastases working group. Lancet Oncol. 19(1), e20–e32 (2018).
    • 82. Doherty MK, Jao K, Shepherd FA, Hazrati L-N, Leighl NB. Central nervous system pseudoprogression in a patient treated with PD-1 checkpoint inhibitor. J. Thorac. Oncol. Off. Publ. Int. Assoc. Study Lung Cancer. 10(10), e100–101 (2015).
    • 83. Okada H, Weller M, Huang R et al. Immunotherapy response assessment in neuro-oncology: a report of the RANO working group. Lancet Oncol. 16(15), e534–e542 (2015). •• Proposal for response assessment in the brain in ICI-treated patients.
    • 84. Galldiks N, Lohmann P, Werner J-M, Ceccon G, Fink GR, Langen K-J. Molecular imaging and advanced MRI findings following immunotherapy in patients with brain tumors. Expert Rev. Anticancer Ther. 20(1), 9–15 (2020).
    • 85. Spain L, Walls G, Julve M et al. Neurotoxicity from immune-checkpoint inhibition in the treatment of melanoma: a single centre experience and review of the literature. Ann. Oncol. Off. J. Eur. Soc. Med. Oncol. 28(2), 377–385 (2017).