The brain has long been considered an immunologically privileged site, and the role of immunotherapy in treating intracranial disease has only recently been revived—with preclinical evidence showing that the systemic immune system responds to immunotherapy for intracranial disease, and with clinical evidence demonstrating improved locoregional control and survival compared with historical outcomes when immune-directed therapies are combined with radiation. Pharmaceutical industry–supported multi-institutional drug efficacy studies routinely exclude patients with brain metastases, so current evidence for treatment of brain metastases using stereotactic radiosurgery combined with immunotherapy comes from single-institution studies. Many studies of combinations of immune checkpoint blockade (with anti–cytotoxic T-lymphocyte–associated antigen 4 and anti–programmed death 1 antibodies) with stereotactic radiosurgery have demonstrated promising improvements in intracranial control and survival. In addition to evaluating the optimal combination of these therapies, future studies will likely search for predictive biomarkers to better select patients whose disease is most appropriately managed with this combined-modality approach.
Multiple phase III trials have demonstrated an improvement in survival with immunotherapy vs standard cytotoxic chemotherapy in metastatic melanoma, renal cell carcinoma, transitional cell carcinoma of the bladder, and non–small-cell lung cancer (NSCLC); however, patients with active and/or untreated brain metastases were and are often excluded from such trials because of the historically poor prognosis associated with brain metastases and the questionable permeability of the blood-brain barrier to these drugs. Additionally, concerns about the potential toxicities encountered with a combination of radiation and immunotherapy remain, regardless of the site of irradiation. In Part 1 of this series, we discussed the role of stereotactic radiosurgery in managing brain metastases, the immunologic effects of radiation, and the rationale for treating intracranial disease with systemic immunotherapy. In Part 2, we review the clinical evidence in support of combining immunotherapy with stereotactic radiosurgery for the treatment of brain metastases; examine controversies regarding radiation dose and fractionation, as well as temporal sequencing of multimodality treatment; and discuss future directions in combined therapy.
Radiation Therapy and Immune Checkpoint Blockade: The Use of Ipilimumab in the Management of Melanoma Brain Metastases
Patients with melanoma are unfortunately predisposed to the development of brain metastases: approximately 50% will develop brain metastases during the course of their disease. Historically, the median survival for melanoma patients with brain metastases managed with surgery, whole-brain radiation therapy (WBRT), and stereotactic radiosurgery was 4 to 5 months, with 12-month local control rates after stereotactic radiosurgery alone of 63% to 84%, and 12-month distant intracranial control rates of approximately 33%.[2-4] While melanoma is minimally responsive to chemotherapy, checkpoint inhibitors have opened up another front from which to battle this disease. Cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4)—the first checkpoint tested in cancer immunotherapy—prevents costimulation of T cells and thus negatively regulates T cell–mediated antitumor responses. Antibodies against CTLA-4 can remove this inhibition and improve T-cell activation and response to tumor cells. Ipilimumab, an antibody against CTLA-4, was approved for treating metastatic melanoma after demonstrating improved survival compared with standard chemotherapy; however, patients with brain metastases were excluded from the initial phase III trials.
The earliest single-institution retrospective report, led by investigators from the Yale Cancer Center, compared combination therapy with stereotactic radiosurgery and ipilimumab (35 patients) vs stereotactic radiosurgery alone (42 patients) for the treatment of melanoma brain metastases. The authors documented equivalent median survival time regardless of whether ipilimumab preceded stereotactic radiosurgery (19.8 months) or followed it (21.3 months). However, median survival times achieved with combined-modality therapy were quadruple those observed with stereotactic radiosurgery alone (21.3 months vs 4.9 months, respectively; P = .04). Although distant brain control was not reported, at a median follow-up of 17.9 months in the ipilimumab group, 37% of patients had not required salvage WBRT, indicating a potential improvement in regional control. Three patients required surgical intervention for edema, which was attributed to a rising rate of symptomatic radionecrosis with the extended survival times observed.
Shortly thereafter, the effectiveness of ipilimumab alone against melanoma brain metastases was demonstrated in a phase II trial. Patients with asymptomatic metastases had a response rate of 24%, compared with 10% in patients with symptomatic disease requiring corticosteroids; median survival times in these groups were 7.0 months vs 3.7 months, respectively. While this difference was attributed to baseline prognostic factors, the effect of ipilimumab might have been blunted by the corticosteroid use in the symptomatic group. Concordant intracranial and extracranial responses to ipilimumab were demonstrated in both the symptomatic and asymptomatic cohorts. The drug was well tolerated, with only one severe toxicity (grade 4 hemorrhage attributed to metastatic melanoma). The overall low response rate of melanoma brain metastases to immunotherapy alone in this study emphasizes the continued need for definitive irradiation as part of brain metastasis management.
Several additional single-institution retrospective analyses of stereotactic radiosurgery treatment of melanoma brain metastases with or without ipilimumab were subsequently reported. A small study (58 patients) demonstrated comparable toxicity, 6-month local and intracranial control, and overall survival in patients treated with combined-modality treatment or stereotactic radiosurgery alone. In another study, 33 of 70 patients received combined-modality treatment with either WBRT (48%) or stereotactic radiosurgery (52%). There was a survival advantage for combined-modality treatment compared with irradiation alone (18.3 months vs 5.3 months). Median survival time for patients receiving ipilimumab with stereotactic radiosurgery was 19.9 months compared with 4.0 months for patients who received stereotactic radiosurgery alone (P = .009); these results are strikingly similar to the Yale data. Stereotactic radiosurgery use predicted for improved survival compared with WBRT (P = .008), and radiation therapy prior to treatment with ipilimumab was associated with improved survival (18.4 months vs 8.1 months). However, the retrospective nature of these studies cannot eradicate concerns that selection biases for a specific treatment may contribute to these observed differences.
A later retrospective analysis of 46 patients treated with ipilimumab and stereotactic radiosurgery further examined the temporal sequencing of these therapies. The use of stereotactic radiosurgery before or during ipilimumab therapy improved 1-year overall survival rates compared with stereotactic radiosurgery after treatment with ipilimumab (56% vs 65% vs 40%) and decreased regional recurrences (64% vs 69% vs 92%). The study results showed that 50% of patients receiving stereotactic radiosurgery before or during treatment with ipilimumab experienced a greater than 150% increase in tumor size, compared with 13% who received ipilimumab prior to undergoing stereotactic radiosurgery; 82% of these cases were radiographically consistent with tumor edema or hemorrhage, and 18% were believed to represent local recurrence. Of 11 suspected recurrences that were resected, 5 were found to consist of only necrotic cells. In patients who received ipilimumab after stereotactic radiosurgery, a tumor size increase was often detected only after the start of systemic treatment. This and other reports on combined stereotactic radiosurgery and immunotherapy for brain metastases emphasize the complexity of interpreting potentially adverse imaging findings, since they may represent evidence of response.
With the goal of evaluating abscopal effects in patients with melanoma who received radiation therapy for progression after treatment with ipilimumab, Grimaldi et al described 21 patients, 13 of whom underwent radiation for melanoma brain metastases (9 with WBRT and 4 with stereotactic radiosurgery). Seven of the 13 experienced a tumor response outside of the radiation field at a median of 1 month after radiation treatment. This abscopal effect was seen exclusively in patients with a local response to radiation. Despite similar baseline absolute lymphocyte counts, patients with an abscopal response had a larger increase in their absolute lymphocyte count during ipilimumab therapy; this finding suggests that lymphocyte counts after treatment with ipilimumab may predict for abscopal effects. Survival was significantly increased in patients with an abscopal response, with a median survival time of 22.4 months in this group, compared with 8.3 months among nonresponders. Although this was a very small series, the study results suggest that irradiation after the failure of ipilimumab may enhance abscopal responses and potentially prolong survival.
Radiation Therapy and the Role of Programmed Death 1 (PD-1)/Programmed Death Ligand 1 (PD-L1) Inhibitors
PD-1 is an inhibitory cell-surface receptor that is expressed on CD4+ T cells, CD8+ T cells, natural killer T cells, dendritic cells, monocytes, and B cells. When PD-1 interacts with its ligands, PD-L1 and PD-L2, tumor cells can evade the immune system more effectively through suppression of T-cell inflammatory activity. Nivolumab and pembrolizumab block the PD-1/PD-L1 interaction, thus preventing T-cell inactivation and permitting an antitumor inflammatory response to occur. These agents have demonstrated survival advantages in advanced NSCLC, renal cell carcinoma, melanoma, recurrent or metastatic head and neck cancer, urothelial carcinoma, and Hodgkin lymphoma compared with traditional chemotherapy, resulting in US Food and Drug Administration approvals for these indications.
1. Cohen JV, Kluger HM. Systemic immunotherapy for the treatment of brain metastases. Front Oncol. 2016;6:49.
2. Davies MA, Liu P, McIntyre S, et al. Prognostic factors for survival in melanoma patients with brain metastases. Cancer. 2011;117:1687-96.
3. Liew DN, Kano H, Kondziolka D, et al. Outcome predictors of Gamma Knife surgery for melanoma brain metastases. J Neurosurg. 2011;114:769-79.
4. Gaudy-Marqueste C, Regis JM, Muracciole X, et al. Gamma-Knife radiosurgery in the management of melanoma patients with brain metastases: a series of 106 patients without whole-brain radiotherapy. Int J Radiat Oncol Biol Phys. 2006;65:809-16.
5. Callahan MK, Wolchok JD. At the bedside: CTLA-4- and PD-1-blocking antibodies in cancer immunotherapy. J Leukoc Biol. 2013;94:41-53.
6. Knisely JP, Yu JB, Flanigan J, et al. Radiosurgery for melanoma brain metastases in the ipilimumab era and the possibility of longer survival. J Neurosurg. 2012;117:227-33.
7. Margolin K, Ernstoff MS, Hamid O, et al. Ipilimumab in patients with melanoma and brain metastases: an open-label, phase 2 trial. Lancet Oncol. 2012;13:459-65.
8. Mathew M, Tam M, Ott PA, et al. Ipilimumab in melanoma with limited brain metastases treated with stereotactic radiosurgery. Melanoma Res. 2013;23:191-5.
9. Silk AW, Bassetti MF, West BT, et al. Ipilimumab and radiation therapy for melanoma brain metastases. Cancer Med. 2013;2:899-906.
10. Kiess AP, Wolchok JD, Barker CA, 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. 2015;92:368-75.
11. Grimaldi AM, Simeone E, Giannarelli D, et al. Abscopal effects of radiotherapy on advanced melanoma patients who progressed after ipilimumab immunotherapy. Oncoimmunology. 2014;3:e28780.
12. 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 2 trial. Lancet Oncol. 2016;17:976-83.
13. Lukas R, Gandhi M, O’Hear C, et al. Atezolizumab in advanced NSCLC patients with baseline brain metastases: a pooled cohort safety analysis. J Thorac Oncol. 2017;12(suppl):S941-S942.
14. Gadgeel S, Ciardiello F, Rittmeyer A, et al. OAK, a randomized phase III study of atezolizumab vs docetaxel in patients with advanced NSCLC: results from subgroup analyses. J Thorac Oncol. 2017;12(suppl):S9-S10.
15. Ahmed KA, Abuodeh YA, Echevarria MI, et al. Clinical outcomes of melanoma brain metastases treated with stereotactic radiosurgery and anti-PD-1 therapy, anti-CTLA-4 therapy, BRAF/MEK inhibitors, BRAF inhibitor, or conventional chemotherapy. Ann Oncol. 2016;27:2288-94.
16. Choong ES, Lo S, Drummond M, et al. Survival of patients with melanoma brain metastasis treated with stereotactic radiosurgery and active systemic drug therapies. Eur J Cancer. 2017;75:169-78.
17. Davies MA, Saiag P, Robert C, et al. Dabrafenib plus trametinib in patients with BRAF V600-mutant melanoma brain metastases (COMBI-MB): a multicentre, multicohort, open-label, phase 2 trial. Lancet Oncol. 2017;18:863-73.
18. Qian JM, Yu JB, Kluger HM, Chiang VL. Timing and type of immune checkpoint therapy affect the early radiographic response of melanoma brain metastases to stereotactic radiosurgery. Cancer. 2016;122:3051-8.
19. Wolchok JD, Hoos A, O’Day S, et al. Guidelines for the evaluation of immune therapy activity in solid tumors: immune-related response criteria. Clin Cancer Res. 2009;15:7412-20.
20. 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. 2015;26:798-803.
21. Twyman-Saint Victor C, Rech AJ, Maity A, et al. Radiation and dual checkpoint blockade activate non-redundant immune mechanisms in cancer. Nature. 2015;520:373-7.
22. Fontanella AN, Boss MK, Hadsell M, et al. Effects of high-dose microbeam irradiation on tumor microvascular function and angiogenesis. Radiat Res. 2015;183:147-58.
23. Vanpouille-Box C, Alard A, Aryankalayil MJ, et al. DNA exonuclease Trex1 regulates radiotherapy-induced tumour immunogenicity. Nat Commun. 2017;8:15618.
24. Berman DM, Wolchok JD, Weber J, et al. Association of peripheral blood absolute lymphocyte count (ALC) and clinical activity in patients (pts) with advanced melanoma treated with ipilimumab. J Clin Oncol. 2009;27(suppl):abstr 3020.
25. Callahan MK, Wolchok JD, Allison JP. Anti-CTLA-4 antibody therapy: immune monitoring during clinical development of a novel immunotherapy. Semin Oncol. 2010;37:473-84.