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.
Introduction
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.[1] 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.[5] 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).[6] 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.[6]
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).[7] 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.[8] 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)[9]; 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%).[10] 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.[10] 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).[11] 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.
Immunotherapy alone has demonstrated modest activity in melanoma and NSCLC brain metastases. In a small phase II trial of pembrolizumab in patients with melanoma or NSCLC who were either untreated or were treated but had progressive brain metastases, 22% of patients with melanoma brain metastases and 33% of those with NSCLC brain metastases responded to the drug.[12] Seventeen percent of patients experienced grade 1/2 seizures, a rate that was considered acceptably safe. Of note, there was a concordance between systemic and intracranial responses in both histologies.
KEY POINTS
- Combined use of stereotactic radiosurgery and anti–cytotoxic T-lymphocyte–associated antigen 4 or anti–programmed death 1/programmed death ligand 1 antibodies appears safe and effective in the treatment of various brain metastases.
- Brain metastases treated with combined radiation therapy and immunotherapy may develop increased edema and hemorrhage, which can be difficult to distinguish from disease progression. Physicians will need to become familiar with the potentially dramatic posttreatment changes that may signify a response to treatment rather than treatment failure.
Atezolizumab, an antibody that targets PD-L1, has shown efficacy against advanced NSCLC and urothelial carcinoma, and it may have some efficacy against brain metastases. In a pooled analysis of four clinical trials that assessed the safety of atezolizumab in more than 800 patients, 27 of whom had brain metastases and 23 of whom had received prior irradiation, the drug was deemed safe in this small cohort; however, no data on efficacy were presented.[13] Another phase III study evaluating atezolizumab vs docetaxel for platinum-refractory advanced NSCLC found a near-doubling of survival time for patients with brain metastases who received atezolizumab (20.1 months vs 11.9 months for patients treated with docetaxel; P = .0279), without any increase in severe adverse events. Patients with active brain metastases could not be enrolled in the trial, indicating that all patients had undergone radiation therapy prior to study. Additionally, the development of new brain metastases was delayed in patients receiving atezolizumab.[14] Currently, no published detailed data are available from this study on brain metastasis management and outcomes; therefore, related clinical questions await further analysis.
Many series of patients managed with stereotactic radiosurgery and different immunotherapies include a number of patients who previously received treatment with BRAF and/or MEK inhibitors.[15,16] Combined BRAF/MEK inhibitor therapy for brain metastases has shown promising results, but intracranial control is still far below that achievable with stereotactic radiosurgery.[17] Given the variety of systemic treatments employed in these studies, it is difficult to elucidate the relative impact of immunotherapy and tyrosine kinase inhibition on local control, intracranial control, and survival. It appears from at least one of these studies that combined-modality treatment that includes stereotactic radiosurgery and anti–PD-1 therapy provides the best overall survival outcomes.[16] In patients with melanoma brain metastases managed with stereotactic radiosurgery, there may be a better lesional response and improved intracranial control with PD-1 inhibition than with CTLA-4 inhibition.[15,18]
Important Considerations and Future Directions
Anecdotally, radiation necrosis following stereotactic radiosurgery is more common in patients receiving immunotherapy and may develop when patients are started on immune therapies long after receiving stereotactic radiosurgery; this probably represents manifestation of an overexuberant immune response.[6,10] However, most studies confirm that combined-modality treatment with immunotherapy and stereotactic radiosurgery improves disease control and overall survival without an unacceptable increase in treatment-related toxicities. Since the use of these treatments continues to increase, physicians will need to familiarize themselves with postradiation imaging findings expected with immunotherapy. Several studies have reported a significant increase in the size of the irradiated lesion, often due to hemorrhage or edema, which can be difficult to distinguish from tumor progression.[1,6,10] Further, if radiation is delivered before immunotherapy, these dramatic postradiation changes may surprise oncologists who are not anticipating tumor enlargement as a sign of a positive treatment response. Just as Response Evaluation Criteria in Solid Tumors (RECIST) was developed for standardizing the interpretation of radiologic responses to anticancer therapies, immune-related response criteria have been promulgated for patients receiving immunotherapy.[19]
There are currently multiple ongoing studies addressing the efficacy and toxicity of combined immunotherapy and stereotactic radiosurgery, as well as use of radiation for salvage after progression on immunotherapy, which are listed in the Table. Other efforts to improve efficacy include examining the combination of systemic cytotoxic chemotherapy agents with additive or synergistic effects. In the NIBIT-M1 study by the Italian Network for Tumor Biotherapy, patients with metastatic melanoma-including 20 with asymptomatic melanoma brain metastases that could have been previously irradiated-were treated with ipilimumab and fotemustine. The rates of long-term survival in the combined-therapy group compared favorably with historical rates of survival in patients with metastatic melanoma treated with ipilimumab alone (with 2- and 3-year survival rates of 33.4% and 28.5%, respectively, reported for the overall study population). Surprisingly, survival outcomes were not inferior among patients with brain metastases (with 2- and 3-year survival rates of 38.9% and 27.8%, respectively).[20] The NIBIT-M2 study will test these findings in a larger cohort of patients with melanoma brain metastases. Another technique to improve the efficacy of combined radiation and anti–CTLA-4 may be the addition of an anti–PD-L1 agent, which overcomes a mechanism of resistance against the initial checkpoint inhibitor.[21] Other combinations of immunotherapy agents may prove beneficial in improving response rates and durability.
Another approach to improving efficacy and potentially decreasing toxicities is to decrease the stereotactic radiosurgery dose in combined-modality treatment. This offers the potential to improve preservation of immune cells and vasculature for trafficking immune cells to the tumor.[22] Importantly, fractionated treatments (with radiation delivered in 2 to 3 fractions instead of a single fraction) may yield promise and reduce the risk of edema and radionecrosis. Fractionated treatments may also decrease 3' repair exonuclease 1 (TREX1) signaling and help induction of the cyclic GMP-AMP synthase stimulator of interferon genes (STING) sensing pathway. TREX1 and STING are opposing regulators of the cytosolic DNA-sensing pathway and can affect immune responses after irradiation.[23]
With immunotherapy, an improvement in outcomes can be dramatic for some, but many patients will experience no benefit. In one study, patients with symptomatic brain metastases requiring corticosteroid therapy had a much lower response rate than those with asymptomatic disease.[7] Perhaps this was because smaller-volume disease may be more effectively treated with immunotherapy-but because large metastases may develop in noneloquent regions of the brain, the immunosuppressive role of steroids in managing the latter may be important. Since many patients with intracranial metastases are prescribed steroids for symptom palliation, their potential to benefit from immunosuppression with stereotactic radiosurgery and checkpoint inhibitors must be investigated further.
Predictive biomarkers may also help determine which patients will respond better to immunotherapy. In one study of ipilimumab, an absolute neutrophil count that was greater than 1,000/μL at baseline and which increased through the early treatment period was associated with improved outcomes.[24] In the NIBIT-M1 study, higher levels of circulating CD3+CD4+ICOS+CD45RO+ T cells at week 12 predicted for improved survival.[20] Additionally, lower neutrophil-to-lymphocyte ratios at baseline, week 4, and week 7 were associated with improved survival. Other studies have described increased levels of CD8+ T cells between weeks 1 and 7, higher sustained levels of inducible costimulator, and increased expression of histocompatibility leukocyte antigen D-related, as predictive of improved response to a variety of immunotherapeutic agents.[25] Finding pretreatment biomarkers predictive of tumor response can identify patients unlikely to respond, and help them to avoid the toxicity of a marginally beneficial treatment.
Conclusions
Multiple immunotherapy agents have demonstrated improved efficacy compared with standard chemotherapy in the management of intracranial metastases; however, the role of these agents in combination with radiation is less well defined. While there does not appear to be unacceptably increased treatment toxicity when combining stereotactic radiosurgery with CTLA-4 and PD-1/PD-L1 inhibitors, the available data are still limited by small patient numbers and a broad definition of “concurrent” therapy among studies published in the literature. The optimal timing of stereotactic radiosurgery and immunotherapy likely depends on the immunotherapy used, and we may be able to improve the efficacy of this approach not only by optimizing dose, fractionation, and timing, but also by integrating various immunotherapy and chemotherapy agents into treatment regimens for intracranial metastases, and evaluating patient responses in clinical trials. Predictive biomarkers assessed at baseline and early in treatment may help guide initiation and early discontinuation of therapy if poor responses are expected.
Financial Disclosure: Dr. Formenti receives grant/research support from Bristol Myers-Squibb, Eisai, Janssen, Merck, Regeneron, and Varian; and honoraria from AstraZeneca, Bristol Myers-Squibb, Dynavax, Eisai, Elekta, GlaxoSmithKline, Merck, Regeneron, and Varian. Dr. Zhang and Dr. Knisely have no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.
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