Neuro-Oncology Advance Access published May 25, 2015

Neuro-Oncology

Neuro-Oncology 2015; 0, 1 – 10, doi:10.1093/neuonc/nov093

Two heads better than one? Ipilimumab immunotherapy and radiation therapy for melanoma brain metastases Kirtesh R. Patel, David H. Lawson, Ragini R. Kudchadkar, Bradley C. Carthon, Daniel E. Oliver, Derick Okwan-Duodu, Rafi Ahmed, and Mohammad K. Khan Department of Radiation Oncology, Winship Cancer Institute, Emory University, Atlanta, Georgia (K.R.P., D.O.-D., M.K.K.); Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, Georgia (D.H.L., R.R.K., B.C.C.); School of Medicine, Emory University, Atlanta, Georgia (D.E.O.); Emory Vaccine Center and Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, Georgia (R.A.) Corresponding Author: Mohammad K. Khan, MD, PhD, Emory University, Department of Radiation Oncology, 1365 Clifton Rd NE, AT-1312, Atlanta, GA 30322 ([email protected]).

Melanoma is an aggressive malignancy with a deplorable penchant for spreading to the brain. While focal therapies such as surgery and stereotactic radiosurgery can help provide local control, the majority of patients still develop intracranial progression. Novel therapeutic combinations to improve outcomes for melanoma brain metastases (MBM) are clearly needed. Ipilimumab, the anticytotoxic T-lymphocyte-associated antigen 4 monoclonal antibody, has been shown to improve survival in patients with metastatic melanoma, but many of these trials either excluded or had very few patients with MBM. This article will review the efficacy and limitations of ipilimumab therapy for MBM, describe the current evidence for combining ipilimumab with radiation therapy, illustrate potential mechanisms for synergy, and discuss emerging clinical trials specifically investigating this combination in MBM. Keywords: Brain metastases, ipilimumab, melanoma, radiation.

In 2013, 10% –30% of all adult cancer patients developed brain metastases, r\which represents 170 000 newly diagnosed secondary brain malignancies in the United States.1 While the highest number of brain metastases arise from lung malignancies, stage IV melanoma has the highest relative proclivity (50%–75%) for developing brain metastases.2,3 Among melanoma patients with documented brain metastases, these intracranial lesions contribute to death in up to 95% of cases.4 Survival rates for brain metastases patients vary according to each cancer subtype but have been dismal overall.5 Using 5 prospective RTOG studies with 1960 brain metastases patients, Sperduto et al developed a point-scoring system to predict patient outcomes.6 By applying this graded partitioning analysis (GPA) to a multi-institution retrospective database with 4259 brain metastases patients, they developed prognostic criteria for each of the main pathologic primary sites of metastasis.7 For newly diagnosed melanoma brain metastases (MBM) patients, 2 factors predicted survival: Karnofsky performance status and the number of intracranial metastases. The median survival (MS) for MBM patients is 6.7 months; the lowest risk group has a 13.2 month MS, while the highest risk group has a 3.4 month MS.7 Table 1 summarizes validated prognostic factors, risk groups, and outcomes for MBM

patients.7 While lactate dehydrogenase (LDH) is prognostic in metastatic melanoma patients, only small retrospective series (including our own) have demonstrated LDH to be prognostic in MBM.8,9 Further prospective studies evaluating the significance of incorporating LDH in to the GPA index are warranted.

Radiation Therapy Options for Melanoma Brain Metastasis Historically, most traditional cytotoxic chemotherapies have a limited role in brain metastasis, in part due to the blood-brain barrier (BBB) limiting penetration.10 As a result, the standard of care for brain metastasis includes surgery and/or radiation therapy. Although surgical resection is very effective for symptomatic control, Kocher et al demonstrated that resection alone commonly results in high local failure of 59% at 2 years.11 To improve local control (LC) and intracranial control, adjuvant whole brain radiation therapy (WBRT) has been utilized. More conformal radiation treatments have been developed due to concerns about late neurocognitive toxicities from irradiation of the whole brain.12 Stereotactic radiation therapy (SRS) is a technique that focuses high doses of radiation therapy

Received 9 March 2015; accepted 3 May 2015 # The Author(s) 2015. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: [email protected].

1 of 10

Review

Table 1. Prognostic factors, risk groups, and outcomes for melanoma brain metastases patients

Table 2. Efficacy of stereotactic radiosurgery alone for melanoma brain metastases

MBM Prognostic Markers

Authors

Risk Groups

Point Scores

90%–100% 70%–80% ,60%

2 1 0

1 2 –3 ≥4

2 1 0

No. of Median Patients KPS

Karnofsky performance status

Number of cranial metastases

Total Point Score

Median Survival

3.5–4 3.0 1.5–2.5 0 –1.0

13.2 8.8 4.7 3.4

Abbreviations: MBM, melanoma brain metastases; GPA, graded prognostic analysis. The 2 prognostic factors predictive of survival for MBM patients are Karnofsky Performance status and number of brain metastases. Based on these factors, point scores are awarded and summed. The total point score then correlates with expected medial survival.

to the tumor while minimizing radiation exposure to the rest of the brain. Although SRS has lower rates of distant intracranial control for nontargeted subclinical disease, a prospective study has illustrated that SRS alone has survival rates similar to WBRT alone.13 Furthermore, the addition of WBRT to SRS for patients with 1 – 3 brain metastases did not improve overall survival (OS).11 Retrospective analyses in the postoperative setting have also demonstrated that SRS has similar LC and OS to WBRT after controlling for the number of brain metastases.14 While these studies illustrate the efficacy of the different radiation regimens for brain metastases, MBMs were not highly represented. With in vitro clonogenic assays showing resistance at low doses of radiation,15 concern arose that standard dose fractionation with WBRT alone may not provide effective LC. Retrospective series in nonbrain metastases patients have demonstrated larger doses per fraction, correlating with improved LC.16,17 However, the evidence is not as clear intracranially. Some studies have found dose escalation to be associated with improved LC, while others have not.18 Despite the controversy, many institutions have adopted high-dose SRS for MBM to avoid neurocognitive toxicity. Table 2 demonstrates the baseline characteristics and LC rates for MBM patients treated with SRS.19 – 22 SRS, however, is not without toxicities. Radiation necrosis is a form of radiation-induced damage to white matter tissue causing demyelination, surrounding edema, and normal tissue necrosis and death.23 Prospective clinical trials have demonstrated grade III toxicity rates of 10% – 15% with SRS.24 The greatest predictors for developing radiation necrosis include the number of fractions, dose, and target volume.25 For relatively larger brain metastases (.3 cm), our institution and others have demonstrated more acceptable grade III toxicities

2 of 10

Liew et al.20 333 Selek et al.21 103 Powell et al.22 50 Lwu et al.23 33

90% 90% 80% 90%

Median n of Brain Metastases

Median Tumor Volume (cc3)

% Local Control at 12 Months

3 1 3 2

1.4 1.9 1.9 0.4

63% 49%a 63% 75%

The 4 largest retrospective single institution studies on the efficacy of SRS for melanoma brain metastases are reported. Baseline characteristics and local control rates of melanoma brain metastases treated with SRS are reported. a After stratifying for lesion size, brain metastases ≤2.0 cm had a 12-month local control of 75%, while lesions . 2.0 cm had a local control of 42%.

rates (0%–5%) with hypofractionated (2 –5 fractions) SRS without a difference in LC.25,26 Further prospective studies comparing fractionation may help define the optimal doses and fractions for MBM.

The Immune System in Cancer In 2000, Hanahan and Weinberg published their seminal review describing the 6 biological hallmarks acquired during the progression from benign to malignant to metastatic tumors.27 Eleven years later, they demonstrated 2 additional important processes that have since been recognized, including “evading the immune system.”28 The immune system consists of 2 main components: the innate and adaptive systems. In brief, the innate system is a nonspecific response to differences between innate and foreign pathogens, while the adaptive system is a more tailored response that induces memory. As part of this adaptive response, macrophages and dendritic cells present foreign antigens to the T cell receptors. Further T cell activation is regulated by multiple factors, including both positive (costimulatory) and negative (coinhibitory) surface receptors. Tumors can subvert the related immune recognition in part through increase of coinhibitory molecule expression, including cytotoxic T-lymphocyte antigen-4 (CTLA-4). CTLA-4 (also called CD152) is a cell surface receptor that is expressed on T helper cells29 and competes with the T cell receptor CD28 for the B7 ligands on mature APC cells. While the CD28 receptor sends a stimulatory signal, CTLA-4, which has a much stronger affinity for B7, sends an inhibitory signal. Upon interaction with B7 ligands, CTLA-4’s inhibitory signal decreases cytotoxic T cell activity via decreasing cell proliferation, cell cycle progression, and cytokines release. Researchers subsequently hypothesized that transient increase in the immune system could possibly be used to target cancer. Seminal studies in mouse models of melanoma, colon cancer, and prostate cancer demonstrated that CTLA-4 blocking antibody mediated cancer-targeting immune responses.30,31

Neuro-Oncology

Review

A group led by Dr. James Allison, who discovered CTLA-4, developed a fully human anti – CTLA-4 antibody, which was later named ipilimumab.

Ipilimumab Therapy in Melanoma Patients Building upon the promise identified in smaller clinical trials, 3 larger phase 2 trials were conducted to further investigate ipilimumab’s safety and efficacy in melanoma patients. Two used ipilimumab 10 mg/kg,32,33 while the third used 3 doses (0.3 mg/kg, 3 mg/kg, or 10 mg/kg).34 Several immune-mediated toxicities were observed including enterocolitis, hypophysitis, uveitis, hepatitis, and nephritis. Adverse events were higher with the 10 mg/kg dose, but the majority of these side effects resolved within 2 weeks of prompt treatment with steroids. Response rates for the 10 mg/kg dose ranged from 5.8% – 15.2%, while the 3 mg/kg response rate was 4.8%. Ipilimumab also demonstrated a much different profile when compared with traditional chemotherapy. Responses were seen as late as 6 –12 months after treatment and even after initial increases in tumor burden. Thus, new criteria were created to capture ipilimumab’s unique pharmacodynamics Termed “immunerelated response criteria,” this new paradigm compared total volume of tumor burden. Patients with progression per standard radiographic RECIST criteria, due to either increasing volume of select metastases or developing new areas of disease, may in fact be responders if their overall tumor burden is less after treatment.35 With patients having a delayed response or progression followed by a response, OS was considered a better marker of efficacy for ipilimumab than progression-free survival.36 To investigate OS, Hodi et al conducted a phase 3 study in which participants were randomized to ipilimumab alone, ipilimumab with an experimental vaccine (gp100), or gp100 alone as the control arm. Ipilimumab 3 mg/kg was utilized out of concern for higher toxicity with 10 mg/kg, despite possible higher responses rates with the latter dose. The 2 ipilimumab arms demonstrated a MS of 10.1 months compared with 6.4 months in the control arm. Most excitingly, this response was durable: 3-year and 5-year OS remained unchanged at 20%.36 This significant benefit resulted in Food and Drug Administration approval of ipilimumab for metastatic melanoma patients.

Ipilimumab Therapy in Brain Metastasis Patients The BBB comprises 3 main cells: endothelial cells, astrocytes, and pericytes.37 Under normal physiological conditions, together these cells tightly limit the movement of circulating molecules, including immune cells and antibodies, from entering the brain parenchyma. MBMs are able to subvert the BBB and invade the brain parenchyma through a variety of mechanisms. In response, endothelial cells of the BBB initiate an inflammatory reaction that activates the immune cells, including the macrophages (termed “microglial cells”) already residing within the BBB’s layers.38 Furthermore, this inflammatory cascade can recruit circulating CD4+ and CD8+ T cells to extravasate past the BBB.38 Brain parenchyma infiltration by immune cells is also facilitated by metastases disrupting the cells forming the

Neuro-Oncology

BBB and forming a path of least resistance.39 For MBM, this immune cell penetration of the BBB has been found to be a favorable prognostic marker.40 Large monoclonal antibodies such as ipilimumab are often limited in ability to penetrate the BBB in patients without brain metastases.37 However, with the BBB disrupted by MBM, it is possible that ipilimumab may cross into the perivascular space and activate peripherally recruited T cells. Alternatively, ipilimumab-activated T cells in the peripheral circulation may enter at porous sites and target MBM. The first evidence to support these hypotheses was demonstrated in a case study by Hodi et al.41 A MBM patient was treated with ipilimumab 3 mg/kg after progressing with intracranial surgery, SRS, and temozolomide. Seven months post ipilimumab, the patient developed seizures and edema requiring neurosurgical excision. The pathology sample demonstrated abundant CD8+ and occasional CD4+ lymphocytes that were infiltrating the tumor. While this suggested that ipilimumab’s activity is likely related to effector T cells infiltrating MBM, the number of T cells was not compared with the patient’s untreated, initial resected MBM. Further studies investigating ipilimumab’s ability to penetrate the BBB by measuring concentration in the cerebrospinal fluid may help determine how ipilimumab exerts its efficacy on MBM. With melanoma having a high incidence of developing brain metastases and being relatively resistant to radiation therapy, validating Hodi et al’s report that ipilimumab may have efficacy against MBM is a high priority. To explore this further, Lebbe et al43 investigated the subset of patients with stable, previously treated brain metastasis enrolled on the phase 3 trial. Eighty-two patients with prior brain metastasis were enrolled; 61 received ipilimumab, and 21 received gp100 control.42 Compared with the patients receiving the control arm, ipilimumab with or without gp100 demonstrated a nonstatistically significant trend towards improved survival (HR, 0.70; 95% CI, 0.41 – 1.20 and HR, 0.76; 95% CI, 0.38– 1.54), respectively.43,44 Based on these data, Margolin et al initiated a phase 2 trial of ipilimumab for patients with untreated MBM. The supporting evidence41,43 suggested that ipilimumab had intracranial efficacy at a dose of 3 mg/kg. Due to intracranial swelling, however, MBM may require dexamethasone, which can possibly mitigate the efficacy of ipilimumab. With the 10 mg/kg dose having a response rate as high as a 15.2%, this dose may have been chosen to account for the need for steroids. Inclusion criteria were ECOG performance status of 0 – 1 and at least one untreated lesion. Although size and a minimum number of lesions were also part of the stratification criteria, the number of intracranial lesions and LDH-known prognostic factors for MBM were not (Table 1).7 – 9 Seventy-two MBM patients were enrolled; 51 were asymptomatic, and 21 were symptomatic and required corticosteroids treatment. Response rates (12.5%) were similar to those previously reported in multiple studies of ipilimumab 10 mg/kg in extracranial sites.42,45 However, only 23.8% –28.8% of patients were able to complete the 12 weeks of induction therapy. The majority of patients discontinued treatment due to progression of disease or death. Furthermore, MS for asymptomatic patients (7.0 mo) was similar to the MS of MBM reported by Sperduto et al (6.7 mo), suggesting that ipilimumab alone may not significantly improve survival for patients with untreated MBM. However, because RTOG GPA prognostic criteria or LDH were not used, it is unclear

3 of 10

Review

how these survival rates compared directly with appropriate historical controls. Three subsequent studies (Table 3) have confirmed the efficacy and low side-effect profile found by Margolin et al. The first 2 groups reported outcomes of ipilimumab 10 mg/kg for untreated MBM patients enrolled into 2 distinct prospective clinical trials. In 20 asymptomatic patients, Di Giacomo et al demonstrated that 5 patients (25%) had a complete response, and 6 other patients had either a partial response or stable disease (30%).46 In Weber’s cohort of 12 patients with asymptomatic MBM,47 the response rate (16%) and control rate (41.6%) more closely approximated the results of Di Giacomo’s cohort. A fourth study, from the extended access program in Italy48 retrospectively demonstrated that the efficacy of ipilimumab 3 mg/kg was similar to that reported for 10 mg/kg by Margolin et al. Taken together (Table 3), these studies reveal that ipilimumab has similar intracranial and extracranial response rates, suggesting that ipilimumab may not be limited by the BBB. The higher response rates seen in Di Giacomo and Weber may reflect the smaller cohort sizes. However, the LC rates with ipilimumab appear significantly lower in comparison with the standard of care regimens, such SRS alone, in which 1-year LC rates in prospective studies are 67% – 75%.12,13

Moreover, ipilimumab 10 mg/kg for MBM patients demonstrated markedly lower (28.8%) completion rates compared with completion rates of 50.7% – 61.4% with ipilimumab 10 mg/kg for non-CNS metastases. Furthermore, Margolin et al reported that 50 – 55% did not complete treatment due to progressive disease.44 This higher rate may reflect that in the brain, where relatively small amounts of progression can increase neurologic morbidity and mortality, ipilimumab’s delayed immunologic response may not provide a quick enough.

Ipilimumab with Radiation Therapy for Brain Metastases To potentially improve the results of ipilimumab alone, researchers have treated patients with ipilimumab and intracranial radiation therapy (Table 4).49 Knisely et al first reported on 77 MBM patients who received SRS, with 27 patients also receiving ipilimumab; 37.1% received ipilimumab treatment before SRS, and 62.9% received treatment after SRS. Patients receiving ipilimumab were younger and trended towards higher rates of targeted therapy but were otherwise similar at baseline. MS was dramatically higher for patients receiving ipilimumab for 21.3 months versus 4.9 months. Ipilimumab treatment,

Table 3. Efficacy of ipilimumab for melanoma brain metastases patients Authors

Study Design

No. of Patients

Ipilimumab Treatment Regimen

CNS Control Rate

Median Survival (Months)

Neurological Grades 3 –4 Toxicity

Lebbe et al43

Secondary analysis of prospective phase 3 study Prospective, phase 2 Prospective, phase 2

71

NR

NRa

NR

19.4% 55.0%

3.7– 7.0b 13.4

5.6% 2%

Secondary analysis of prospective phase 2 study

12

3 mg/kg q3wks×4 cycles+gp100 control 10 mg/kg q3wks×4 cycles 10 mg/kg q3wks×4 cycles + fotemustine 10 mg/kg, q3wks+budesonide

41.6%

14.0

16.6%c

Margolin et al44 Di Giacomo et al46 Weber et al47

72 20

Abbreviation: NR, not reported. The 4 studies on the efficacy of ipilimumab alone for untreated melanoma brain metastases. a Study is reported in abstract form alone, with only the hazard ratios on survival detailed. b Range of median survival reflects symptomatic patients who are on corticosteroids [median survival (MS), 3.7 mo] and asymptomatic patients (MS, 7.0 mo). c Both patients who had grades III–IV CNS toxicity received both ipilimumab and budesonide.

Table 4. Efficacy of combining ipilimumab with radiation therapy in melanoma brain metastases Authors

No. of Patients

Radiation Regimen

Ipilimumab

Median Survival, SRS only (mo)

Median Survival, SRS + IPI (mo)

Symptomatic Radiation Necrosis with SRS + IPI

Knisely et al49 Silk et al51 Mathew et al50

77 70 58

SRS SRS or WBRT SRS

Before or after SRS only Before or after SRS only Before, during, and after SRS

4.9 5.3 NRa

21.3 19.9 NRa

NR 0% 0%

Abbreviations: IPI, ipilimumab; NR, not reported; SRS, stereotactic radiosurgery; WBRT, whole brain radiation therapy. The 3 studies on the efficacy of ipilimumab and SRS for melanoma brain metastases. a Mathew et al did not describe the median survival for the 2 cohorts separately; rather, they found the median survival for the entire group to be 5.9 months, with no statistical difference in the hazard ratio for survival for patients receiving ipilimumab and SRS.

4 of 10

Neuro-Oncology

Review

however, was not statistically associated with a decrease in HR (0.61; 95% CI, 0.33 – 1.10; P ¼ .102) on multivariate analysis. Furthermore, LDH was not analyzed in these patients. Although ipilimumab demonstrated an impressive trend toward improved survival, it is unclear how selection biases may have contributed to this benefit. Mathew et al subsequently compared the outcomes of 25 MBM patients receiving ipilimumab with 33 patients who did not receive immunotherapy (Table 2).50 All patients received SRS. No significant benefit in 6-month OS was seen between the groups. Because prognostic indicators RTOG RPA and GPA classes were not included in this analysis, it is possible that selection bias may have also affected their conclusions. More recently, Silk et al reported their single institution outcomes, demonstrating that ipilimumab with SRS was associated with an improvement in MS compared with SRS alone.51 The ipilimumab cohort, however, had higher performance status and higher rates of BRAF therapy and were also likely to be neurologically asymptomatic. They also investigated the effect of fractionation, illustrating that lower dose per fraction with WBRT did not correlate with an increase in survival when combined with ipilimumab. With patients who received SRS having fewer intracranial lesions and improved OS (HR, 0.45; P ¼ .008), it is more likely that the lack of benefit for patients treated with WBRT was due to inherent difference in the cohorts. Consistent with this, Gerber et al demonstrated that OS was only 4 months in 13 MBM patients treated with ipilimumab 3 mg/kg and WBRT, which was not significantly increased from historical controls.52 A potential confounding factor may be the number of lesions since the median number of MBM lesions ranged from 1 – 3 with SRS49 – 51 and 7 with WBRT.52 One potential hypothesis is that the number and volume of intracranial foci may be an important factor when deciding to deliver ipilimumab with radiation for MBM. Treatment sequence may also be a critical parameter. Kiess et al demonstrated that patients treated with SRS during or before ipilimumab had higher rates of initial progression compared with those treated with SRS afterwards (50% vs 13%).53 When looking at these studies together, their findings suggest that patient characteristics and treatment specifics may affect outcomes when treating MBM with ipilimumab and radiation and that clinical trials investigating the optimal conditions are needed.

Toxicity of Intracranial Radiation and Ipilimumab Case series of patients treated with ipilimumab and SRS have reported the development of symptomatic radiation necrosis at irradiated sites. Du Four et al. reported on 3 patients who, after progressing on SRS and chemotherapy, were also treated with ipilimumab 3 mg/kg.54 These patients developed radiation necrosis 15 –18 months after initial radiation therapy. All were treated with steroids, but 1 patient required salvage surgery. The same group also reported on another 4 patients who were treated with SRS and ipilimumab and developed radiation necrosis.55 However, from these case reports, the rates of radiation necrosis compared with SRS alone or ipilimumab alone are not clear. Silk and Mathew et al reported 0% symptomatic radiation necrosis with SRS and ipilimumab (Table 4), while our

Neuro-Oncology

series found no difference between SRS and ipilimumab and the SRS cohorts (15.0% vs 14.7%, P . .99).56 Our rates were also similar to the prospective study of SRS alone for brain lesions.24 Nonetheless, with radiation necrosis incidence peaking at 12 –18 months, prospective trials are needed to determine if the improved survival of patients responding to ipilimumab places them at a high risk of radiation necrosis when treated with SRS. Another concerning side effect for MBM treated with radiation therapy and ipilimumab may be seizures. While prospective studies delivering ipilimumab alone in the setting of extracranial32 – 34,42 and brain metastases44 reported no seizures, the initial case report by Hodi et al demonstrated that a patient treated with SRS and then ipilimumab developed seizures.41 EEG analysis demonstrated that the seizure activity originated from a previously irradiated area that had developed radiation necrosis. Subsequently, Kiess et al demonstrated that patients treated with concurrent ipilimumab and SRS had a higher rate of grade 3 seizures compared with sequential treatment (13% vs. 0%).53 Interestingly, 50% of patients treated with SRS during or before ipilimumab developed swelling post treatment, while only 13% developed similar changes when treated with SRS after ipilimumab. It is possible that the increase in size correlates with infiltration of the tumor by T cells; however, this swelling may also lead to seizures. While giving SRS after ipilimumab may be associated with lower rates of seizure and swelling, radiation may kill the infiltrating, radiosensitive T cells, thereby limiting the efficacy of ipilimumab. Further studies are needed to investigate the ideal sequence of ipilimumab and SRS to minimize side effects while maximizing efficacy. Steroids have traditionally been utilized for symptoms from swelling caused directly by MBM or related treatment. Highdose steroids, however, can disrupt T cell function and lower the amount of circulating lymphocytes in the blood stream.57 Because ipilimumab works by activating T cells, steroids have been used cautiously. To support this approach, Margolin et al demonstrated that ipilimumab therapy was associated with lower OS in symptomatic patients requiring steroids compared with asymptomatic, steroid-free patients.44 Although brain metastasis size may be a possible confounding factor for these results, it has not been demonstrated to be prognostic for OS in MBM. At our institution, we have attempted to minimize the dose and length of steroid treatment for patients demonstrating nonprogressive disease by immune RECIST criteria who have been treated within 3 months of ipilimumab and radiation for MBM.

Evidence for Utilizing Radiation With Ipilimumab to Improve Systemic Responses At the molecular level, radiation induces an immune response through multiple different factors: upregulation of multiple inflammatory cytokines including IFN-g, TNFa, and CXCL16 that promote tumor lymphocyte infiltration,58 modulation of ligands in the B28 family that stimulate CD8T cell activation and tumor detection,59 and enhancement of APC cells to detect tumor specific antigens.60 Demaria et al have also demonstrated that irradiation of implanted mammary carcinoma

5 of 10

Review

67NR led to tumor shrinkage at the nonirradiated flank.61 This systemic effect of radiation therapy (termed the “abscopal effect”) was abrogated, however, when a different tumor (A20 lymphoma) was implanted at a distant site or if the host animal was T-cell deficient. A leading hypothesis is that tumor-specific epitopes were generated and presented to T cells that migrated to kill 67NR tumor cells but not others. Two studies have investigated the role of fractionation in activating the immune system against B16 in mouse melanoma models. Both Lugade et al and Lee et al demonstrated that while high dose therapy (15 – 20 Gy × 1-3fractions) and low dose radiation (3 –5 Gy×4 –5fractions) activated and increased T-cell infiltration, only the high-dose regimens resulted in significantly higher tumor growth delay. Building upon this, Dewan et al explored the effect of single versus multifractionated highdose radiation therapy (20 Gy ×1fraction, 8 Gy × 3fractions, and 6 Gy× 5fractions). They used 2 nonmelanoma, poorly immunogenic tumors. When combined with ipilimumab, only the fractionated regimens demonstrated the abscopal effect. The abscopal effect was also greater with 8 Gy× 3 when compared with 6 Gy× 5. To investigate the effect of fractionation at the molecular level, Tsai et al compared gene expression patterns after single

(10 Gy × 1fraction) or fractionated doses (2 Gy × 5fractions) of radiation therapy.62 In all 3 human tumor models (breast, prostate, and gliosarcoma), radiation-induced gene expression varied substantially between fractionated and single-fraction treatment, with the interferon-related genes being upregulated in both in vitro and in vivo fractionated radiation treatments. With IFN-g able to promote increased antigen exposure to T cells,63 the findings by Tsai et al provide a potential hypothesis explaining why the addition of fractionated radiation to ipilimumab is more likely to induce an abscopal effect (Figure 1). Further preclinical work using mouse models with intact immune systems and melanoma cells, rather than xenografts with nonmelanoma used by Tsai et al,62 may provide stronger preclinical evidence about the effect of radiation fractionation on the immunological response for melanoma. At the clinical level, evidence is emerging that demonstrates the abscopal effect of radiation therapy combined with immunotherapy. A case report by Postow et al demonstrated that the addition of extracranial, fractionated SRS markedly limited tumor growth not only at the irradiated site, but also to other lesions outside the radiation target field, in a patient being treated with ipilimumab maintenance therapy.64 Remarkably, the addition of radiation-enhanced melanoma-specific

Fig. 1. Potential mechanism of enhanced ipilimumab activity with radiotherapy. (A) Unirradiated tumor cells present limited antigen to macrophages and dendritic cells, thereby contributing to less activation of T cells by ipilimumab and immune escape by the tumor. (B) Tumor cells treated with fractionated radiation undergo cell death and present increased and novel antigens to antigen-present cells, inducing a more robust response to ipilimumab.

6 of 10

Neuro-Oncology

Review

antibody responses reduced circulating immunosuppressive T cells and exposed novel melanoma antigens to T cells. Our group has also recently compared response rates of patients receiving radiation and ipilimumab with ipilimumab alone.65 We identified 61 patients, 35 of whom received radiation within 4 months of ipilimumab and 26 with ipilimumab only. Systemic response rates were similar between the ipilimumab-alone and ipilimumab-radiation cohorts. However, comparing the radiation schema of 2 – 5 fractions to ipilimumab alone demonstrated a trend towards higher response rate (42.9% vs 11.5%; P ¼ .074). With the retrospective design and small number of patients in our analysis, prospective studies investigating the ideal radiation fractionation to improve ipilimumab response rates are warranted.

Conclusion Over the past 10 years, the arrival of novel therapies, including BRAF inhibitors and checkpoint blockade immunotherapy, has dramatically improved the prognosis for metastatic melanoma patients.66,67 Despite these therapies, in the 20% –50% of patients who ultimately develop brain metastasis, the mainstay for treating intracranial disease continues to be radiation, with surgery in those who are symptomatic. Recent studies of ipilimumab in MBM patients have demonstrated similar intracranial and extracranial response rates.44,68 However, ipilimumab’s unique response kinetics and low response rates limit its efficacy as a monotherapy for MBM. Retrospective series

suggest that combining ipilimumab with SRS may be associated with improved MS (Table 4), while preclinical and retrospective evidence suggest that fractionated, ablative radiation therapy may be the most immunogenic for ipilimumab. Because all of the clinical studies are limited by their retrospective design and likely bias of patient selection, the dramatic improvement in survival and response warrants prospective investigation. Studies investigating the ideal ipilimumab dose and the optimal radiation doses, fractionation, sites of treatment, and the sequence (either before, concurrent, or after ipilimumab) will help better illustrate the efficacy of combining the 2 agents. Moreover, analyses on the ability of ipilimumab to decrease the rates of developing CNS metastasis may help to better characterize and prevent MBM. Currently, there are 6 actively enrolling clinical trials combining radiation therapy with ipilimumab for MBM patients (Table 5). Three trials are phase 1 studies combining ipilimumab with different radiation regimens. The study at Stanford University is investigating palliative, nonablative doses of radiation therapy. The group at Johns Hopkins University is dose-escalating SRS alone for brain and spinal metastases, while the trial at Thomas Jefferson University is stratifying patients with ,4 MBM to SRS and those with more MBM to WBRT. In addition to determining the safety, these 3 studies taken together will help to better identify the ideal radiation dose with concurrent ipilimumab for MBM. In addition to the phase 1 studies, there are 3 phase 2 trials examining the efficacy of combination therapy. The New York University protocol is randomizing metastatic melanoma

Table 5. Currently enrolling prospective clinical trials combining radiation therapy with ipilimumab for melanoma brain metastases NCTN Number

Institution

Trial Type

Trial Arm(s)

Treatment Sequence

Planned Enrollment

NCT01449279

Stanford University

Phase 1

IPI + palliative radiation

Radiation within 2 days of IPI

NCT01703507

Thomas Jefferson University

Phase 1

SRS during the first cycle

NCT1950195

John Hopkins University

Phase 1, dose escalation

SRS during the first cycle

30 melanoma patients with brain and spinal metastases

NCT01689974

New York University

Phase 2, nonrandomized

SBRT during the second cycle

NCT02107755

Ohio State University

Phase 2, single arm

(a) IPI + SRS (, 4 lesions) (b) IPI + WBRT (. 4 lesions) (a) IPI + SRS (brain) (b) IPI + SRS (spine) (a) IPI alone (b) IPI + SBRT (6 Gy×5) IPI + SRS/SBRT

20 melanoma patients, including asymptomatic brain metastases 24 melanoma brain metastases patients

100 melanoma patients, brain metastases not mandatory but included 32 melanoma patients, including brain metastases

NCT02115139

Grupo Espan˜ol Multidisciplinar de Melanoma

Phase 2, single arm

IPI + WBRT

SRS/SBRT in between second and third cycles WBRT between cycles 1 and 2

66 melanoma brain metastases patients

Abbreviations: IPI, ipilimumab; NCTN, National Clinical Trials Network; SBRT, stereotactic body radiation therapy; SRS, stereotactic radiosurgery (single fraction); WBRT, whole brain radiation therapy. All 6 trials are using ipilimumab 3 mg/kg every 3 weeks for a total of 4 cycles.

Neuro-Oncology

7 of 10

Review

patients to standard FDA-approved dosing of ipilimumab alone or with fractionated radiation therapy (6 Gy×5) delivered during the first day of the second ipilimumab dose. Patients with brain metastasis will be included. By only including patients with one or more lesions outside of the irradiated field, this study may uniquely determine the efficacy of radiation therapy to induce the abscopal effect. The other 2 studies, Ohio State University and Grupo Espan˜ol Multidisciplinar de Melanoma, will deliver SRS and/or WBRT in between ipilimumab cycles. Together, these 3 studies will help characterize the optimal timing of ipilimumab and radiation for MBM.

Funding None declared.

12. Chang EL, Wefel JS, Hess KR, et al. Neurocognition in patients with brain metastases treated with radiosurgery or radiosurgery plus whole-brain irradiation: a randomised controlled trial. Lancet Oncol. 2009;10(11):1037–1044. 13. Aoyama 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(21):2483– 2491. 14.

15. Marshall ES, Matthews JH, Shaw JH, et al. Radiosensitivity of new and established human melanoma cell lines: comparison of [3H]thymidine incorporation and soft agar clonogenic assays. Eur J Cancer. 1994;30A(9):1370– 1376. 16.

Agrawal S, Kane JM 3rd, Guadagnolo BA, et al. The benefits of adjuvant radiation therapy after therapeutic lymphadenectomy for clinically advanced, high-risk, lymph node-metastatic melanoma. Cancer. 2009;115(24):5836 –5844.

17.

Chang DT, Amdur RJ, Morris CG, et al. Adjuvant radiotherapy for cutaneous melanoma: comparing hypofractionation to conventional fractionation. Int J Radiat Oncol Biol Phys. 2006;66(4): 1051– 1055.

Conflict of interest statement. Dr. David Lawson has served on advisory boards for Bristol-Myers Squibb (BMS). BMS has supported clinical trials at our institution.

References 1.

Nayak L, Lee EQ, Wen PY. Epidemiology of brain metastases. Curr Oncol Rep. 2012;14(1):48 –54.

2.

Barnholtz-Sloan JS, Sloan AE, Davis FG, et al. Incidence proportions of brain metastases in patients diagnosed (1973 to 2001) in the Metropolitan Detroit Cancer Surveillance System. J Clin Oncol. 2004;22(14):2865 –2872.

3.

Amer MH, Al-Sarraf M, Baker LH, et al. Malignant melanoma and central nervous system metastases: incidence, diagnosis, treatment and survival. Cancer. 1978;42(2):660 –668.

4.

Sampson JH, Carter JH Jr., Friedman AH, et al. Demographics, prognosis, and therapy in 702 patients with brain metastases from malignant melanoma. J Neurosurg. 1998;88(1):11– 20.

Patel KR, Prabhu RS, Kandula S, et al. Intracranial control and radiographic changes with adjuvant radiation therapy for resected brain metastases: whole brain radiotherapy versus stereotactic radiosurgery alone. J Neurooncol. 2014;120(3): 657– 63.

18. Khan N, Khan MK, Almasan A, et al. The evolving role of radiation therapy in the management of malignant melanoma. Int J Radiat Oncol Biol Phys. 2011;80(3):645– 654. 19.

Liew DN, Kano H, Kondziolka D, et al. Outcome predictors of Gamma Knife surgery for melanoma brain metastases. Clinical article. J Neurosurg. 2011;114(3):769–779.

20.

Selek U, Chang EL, Hassenbusch SJ 3rd, et al. Stereotactic radiosurgical treatment in 103 patients for 153 cerebral melanoma metastases. Int J Radiat Oncol Biol Phys. 2004;59(4): 1097 –1106.

21. Powell JW, Chung CT, Shah HR, et al. Gamma Knife surgery in the management of radioresistant brain metastases in high-risk patients with melanoma, renal cell carcinoma, and sarcoma. J Neurosurg. 2008;109(Suppl):122–128.

5.

Coia LR. The role of radiation therapy in the treatment of brain metastases. Int J Radiat Oncol Biol Phys. 1992;23(1):229– 238.

6.

Sperduto PW, Berkey B, Gaspar LE, et al. A new prognostic index and comparison to three other indices for patients with brain metastases: an analysis of 1,960 patients in the RTOG database. Int J Radiat Oncol Biol Phys. 2008;70(2):510 –514.

7.

Sperduto PW, Chao ST, Sneed PK, et al. Diagnosis-specific prognostic factors, indexes, and treatment outcomes for patients with newly diagnosed brain metastases: a multi-institutional analysis of 4,259 patients. Int J Radiat Oncol Biol Phys. 2010;77(3):655–661.

8.

Marcus DM, Lowe M, Khan MK, et al. Prognostic factors for overall survival after radiosurgery for brain metastases from melanoma. Am J Clin Oncol 2014;37(6):580 –4.

9.

Eigentler TK, Figl A, Krex D, et al. Number of metastases, serum lactate dehydrogenase level, and type of treatment are prognostic factors in patients with brain metastases of malignant melanoma. Cancer. 2011;117(8):1697– 1703.

10.

Steeg PS, Camphausen KA, Smith QR. Brain metastases as preventive and therapeutic targets. Nat Rev Cancer. 2011;11(5): 352– 363.

26.

Eaton BR, Gebhardt B, Prabhu R, et al. Hypofractionated radiosurgery for intact or resected brain metastases: defining the optimal dose and fractionation. Radiat Oncol. 2013;8:135.

11.

Kocher M, Soffietti R, Abacioglu U, et al. Adjuvant whole-brain radiotherapy versus observation after radiosurgery or surgical resection of one to three cerebral metastases: results of the EORTC 22952–26001 study. J Clin Oncol. 2011;29(2):134– 141.

27.

Hanahan D, Weinberg RA. The hallmarks of cancer. Cell. 2000; 100(1):57–70.

28.

Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144(5):646– 674.

8 of 10

22. Lwu S, Goetz P, Monsalves E, et al. Stereotactic radiosurgery for the treatment of melanoma and renal cell carcinoma brain metastases. Oncol Rep. 2013;29(2):407 –412. 23.

Chao ST, Ahluwalia MS, Barnett GH, et al. Challenges with the diagnosis and treatment of cerebral radiation necrosis. Int J Radiat Oncol Biol Phys. 2013;87(3):449–457.

24. Shaw E, Scott C, Souhami L, et al. Radiosurgery for the treatment of previously irradiated recurrent primary brain tumors and brain metastases: initial report of radiation therapy oncology group protocol (90 – 05). Int J Radiat Oncol Biol Phys. 1996;34(3): 647–654. 25. Minniti G, Clarke E, Lanzetta G, et al. Stereotactic radiosurgery for brain metastases: analysis of outcome and risk of brain radionecrosis. Radiat Oncol. 2011;6:48.

Neuro-Oncology

Review

29. Fong L, Small EJ. Anti-cytotoxic T-lymphocyte antigen-4 antibody: the first in an emerging class of immunomodulatory antibodies for cancer treatment. J Clin Oncol. 2008;26(32):5275 –5283. 30.

Leach DR, Krummel MF, Allison JP. Enhancement of antitumor immunity by CTLA-4 blockade. Science. 1996;271(5256):1734–1736.

31.

Kwon ED, Foster BA, Hurwitz AA, et al. Elimination of residual metastatic prostate cancer after surgery and adjunctive cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) blockade immunotherapy. Proc Natl Acad Sci USA. 1999;96(26): 15074– 15079.

32.

33.

O’Day SJ, Maio M, Chiarion-Sileni V, et al. Efficacy and safety of ipilimumab monotherapy in patients with pretreated advanced melanoma: a multicenter single-arm phase II study. Ann Oncol. 2010;21(8):1712– 1717. Weber J, Thompson JA, Hamid O, et al. A randomized, double-blind, placebo-controlled, phase II study comparing the tolerability and efficacy of ipilimumab administered with or without prophylactic budesonide in patients with unresectable stage III or IV melanoma. Clin Cancer Res. 2009;15(17): 5591 –5598.

34. Wolchok JD, Neyns B, Linette G, et al. Ipilimumab monotherapy in patients with pretreated advanced melanoma: a randomised, double-blind, multicentre, phase 2, dose-ranging study. Lancet Oncol. 2010;11(2):155–164. 35. 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(23):7412–7420. 36. Wolchok JD, Hodi FS, Weber JS, et al. Development of ipilimumab: a novel immunotherapeutic approach for the treatment of advanced melanoma. Ann N Y Acad Sci. 2013;1291:1 –13. 37.

Carson MJ, Doose JM, Melchior B, et al. CNS immune privilege: hiding in plain sight. Immunol Rev. 2006;213:48 –65.

38.

Hamilton A, Sibson NR. Role of the systemic immune system in brain metastasis. Mol Cell Neurosci. 2013;53:42 – 51.

an open-label, single-arm phase 2 trial. Lancet Oncol. 2012; 13(9):879–886. 47.

Weber JS, Amin A, Minor D, et al. Safety and clinical activity of ipilimumab in melanoma patients with brain metastases: retrospective analysis of data from a phase 2 trial. Melanoma Res. 2011;21(6):530– 534.

48.

Queirolo P, Spagnolo F, Ascierto PA, et al. Efficacy and safety of ipilimumab in patients with advanced melanoma and brain metastases. J Neurooncol. 2014;118(1):109– 16.

49.

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(2):227–233.

50.

Mathew M, Tam M, Ott PA, et al. Ipilimumab in melanoma with limited brain metastases treated with stereotactic radiosurgery. Melanoma Res. 2013;23(3):191–195.

51.

Silk AW, Bassetti MF, West BT, et al. Ipilimumab and radiation therapy for melanoma brain metastases. Cancer Med. 2013; 2(6):899– 906.

52. Gerber NK, Young RJ, Barker CA, et al. Ipilimumab and whole brain radiation therapy for melanoma brain metastases. J Neurooncol. 2015;121(1):159–165. 53. 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(2):368– 75. 54. Du Four S, Wilgenhof S, Duerinck J, et al. Radiation necrosis of the brain in melanoma patients successfully treated with ipilimumab, three case studies. Eur J Cancer 2012;48(16):3045 –3051. 55.

Du Four S, Hong A, Chan M, et al. Symptomatic Histologically Proven Necrosis of Brain following Stereotactic Radiation and Ipilimumab in Six Lesions in Four Melanoma Patients. Case Rep Oncol Med. 2014;2014:417913.

56.

Patel KR, Oliver DE, Rizzo M, et al. Ipilimumab and Stereotactic Radiosurgery vs. Stereotactic Radiosurgery alone for Newly Diagnosed Melanoma Brain Metastases. Am J Clin Oncol. 2015; In Press.

57.

Sackstein R, Borenstein M. The effects of corticosteroids on lymphocyte recirculation in humans: analysis of the mechanism of impaired lymphocyte migration to lymph node following methylprednisolone administration. J Investig Med. 1995;43(1): 68 –77.

39. Puhalla S, Elmquist W, Freyer D, et al. Unsanctifying the sanctuary: challenges and opportunities with brain metastases. Neuro Oncol. 2015;17(5):639– 651. 40.

Hamilton R, Krauze M, Romkes M, et al. Pathologic and gene expression features of metastatic melanomas to the brain. Cancer. 2013;119(15):2737– 2746.

41.

Hodi FS, Oble DA, Drappatz J, et al. CTLA-4 blockade with ipilimumab induces significant clinical benefit in a female with melanoma metastases to the CNS. Nat Clin Pract Oncol. 2008; 5(9):557–561.

58.

Hodi FS, O’Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363(8):711 –723.

Frey B, Rubner Y, Kulzer L, et al. Antitumor immune responses induced by ionizing irradiation and further immune stimulation. Cancer Immunol, Immunother: 2014;63(1):29– 36.

59.

Lee Y, Auh SL, Wang Y, et al. Therapeutic effects of ablative radiation on local tumor require CD8+ T cells: changing strategies for cancer treatment. Blood. 2009;114(3):589–595.

60.

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(5):459–465.

Reits EA, Hodge JW, Herberts CA, et al. Radiation modulates the peptide repertoire, enhances MHC class I expression, and induces successful antitumor immunotherapy. J Exp Med. 2006; 203(5):1259– 1271.

61.

Robert C, Thomas L, Bondarenko I, et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med. 2011;364(26):2517– 2526.

Demaria S, Ng B, Devitt ML, et al. Ionizing radiation inhibition of distant untreated tumors (abscopal effect) is immune mediated. Int J Radiat Oncol Biol Phys. 2004;58(3):862–870.

62.

Tsai MH, Cook JA, Chandramouli GV, et al. Gene expression profiling of breast, prostate, and glioma cells following single versus fractionated doses of radiation. Cancer Res. 2007;67(8): 3845 – 3852.

42.

43.

44.

45.

46.

Lebbe C, McDermott DF, Robert C, et al. Ipilimumab improves survival in previously treated, advanced melanoma patients with poor prognostic factors: subgroup analyses from a phase III trial [abstract]. Ann Oncol. 2010;21(suppl 8):401.

Di Giacomo AM, Ascierto PA, Pilla L, et al. Ipilimumab and fotemustine in patients with advanced melanoma (NIBIT-M1):

Neuro-Oncology

9 of 10

Review

63.

Schroder K, Hertzog PJ, Ravasi T, et al. Interferon-gamma: an overview of signals, mechanisms and functions. J Leukoc Biol. 2004;75(2):163–189.

66.

Banaszynski M, Kolesar JM. Vemurafenib and ipilimumab: new agents for metastatic melanoma. Am J Health Syst Pharm. 2013;70(14):1205– 1210.

64. Postow MA, Callahan MK, Barker CA, et al. Immunologic correlates of the abscopal effect in a patient with melanoma. N Engl J Med. 2012;366(10):925– 931.

67. Burgeiro A, Mollinedo F, Oliveira PJ. Ipilimumab and vemurafenib: two different routes for targeting melanoma. Curr Cancer Drug Targets. 2013;13(8):879– 94.

65.

68.

Patel KR, Liu YL, Shoukat S. Comparing radiation therapy and ipilimumab to Iipilimumab alone in metastatic melanoma patients [abstract 247]. In: American Association of Cancer Research Annual Meeting; April 19, 2015; Philadelphia.

10 of 10

Di Giacomo AM, Calabro L, Danielli R, et al. Long-term survival and immunological parameters in metastatic melanoma patients who responded to ipilimumab 10 mg/kg within an expanded access programme. Cancer Immunol Immunother. 2013;62(6):1021–1028.

Neuro-Oncology