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Journal ArticleDOI

Ipilimumab and Stereotactic Radiosurgery Versus Stereotactic Radiosurgery Alone for Newly Diagnosed Melanoma Brain Metastases.

01 Oct 2017-American Journal of Clinical Oncology (Am J Clin Oncol)-Vol. 40, Iss: 5, pp 444-450
TL;DR: Use of ipilimumab within 4 months of SRS seems to be safe, with no increase in radiation necrosis or hemorrhage; however, the retrospective institutional experience with this treatment regimen was not associated with improved outcomes.
Abstract: Background:We compared the safety and efficacy of ipilimumab and stereotactic radiosurgery (SRS) to SRS alone for newly diagnosed melanoma brain metastases (MBM).Materials and Methods:We reviewed records of newly diagnosed MBM patients treated with SRS from 2009 to 2013. The primary endpoint of over
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Journal ArticleDOI
TL;DR: Delivering SRS-SRT with concurrent ICI may be associated with a decreased incidence of new BMs and favorable survival outcomes without increased rates of adverse events.
Abstract: Purpose To characterize the effect of concurrent stereotactic radiosurgery–stereotactic radiation therapy (SRS-SRT) and immune checkpoint inhibitors on patient outcomes and safety in patients with brain metastases (BMs). Methods and Materials We retrospectively identified metastatic non-small cell lung cancer, melanoma, and renal cell carcinoma patients who had BMs treated with SRS-SRT from 2010 to 2016 without prior whole-brain radiation therapy. We included SRS-SRT patients who were treated with anti-cytotoxic T-lymphocyte-associated protein 4 (ipilimumab) and anti-programmed cell death protein 1 receptor (nivolumab, pembrolizumab). Patients who were given immune checkpoint inhibitors on active or unreported clinical trials were excluded, and concurrent immune checkpoint inhibition (ICI) was defined as ICI given within 2 weeks of SRS-SRT. Patients were managed with SRS-SRT, SRS-SRT with nonconcurrent ICI, or SRS-SRT with concurrent ICI. Progression-free survival and overall survival (OS) were estimated using Kaplan-Meier survival curves, and Cox proportional hazards models were used for multivariate analysis. Logistic regression was used to identify predictors of acute neurologic toxicity, immune-related adverse events, and new BMs. Results A total of 260 patients were treated with SRS-SRT to 623 BMs. Of these patients, 181 were treated with SRS-SRT alone, whereas 79 received SRS-SRT and ICI, 35% of whom were treated with concurrent SRS-SRT and ICI. Concurrent ICI was not associated with increased rates of immune-related adverse events or acute neurologic toxicity and predicted for a decreased likelihood of the development of ≥3 new BMs after SRS-SRT (P=.045; odds ratio, 0.337). Median OS for patients treated with SRS-SRT, SRS-SRT with nonconcurrent ICI, and SRS-SRT with concurrent ICI was 12.9 months, 14.5 months, and 24.7 months, respectively. SRS-SRT with concurrent ICI was associated with improved OS compared with SRS-SRT alone (P=.002; hazard ratio [HR], 2.69) and compared with nonconcurrent SRS-SRT and ICI (P=.006; HR, 2.40) on multivariate analysis. The OS benefit of concurrent SRS-SRT and ICI was significant in comparison with patients treated with SRS-SRT before ICI (P=.002; HR, 3.82) or after ICI (P=.021; HR, 2.64). Conclusions Delivering SRS-SRT with concurrent ICI may be associated with a decreased incidence of new BMs and favorable survival outcomes without increased rates of adverse events.

233 citations

Journal ArticleDOI
TL;DR: This Perspective provides a biological rationale supporting the abandonment of the abscopal approach, and advocates exploring comprehensive irradiation of multiple/all lesions in order to enhance the likelihood of obtaining meaningful clinical outcomes.
Abstract: Considerable interest is being directed toward combining immune-checkpoint inhibition (ICI) with radiotherapy to improve response rates to ICI, which have been disappointingly low at around 15-30% among patients with advanced-stage cancers other than melanoma. Since a case report published in 2012, in which authors described the resolution of metastatic disease after irradiation of a single lesion in a patient who had been receiving ICI, hundreds of clinical trials have been launched with the aim of testing the safety and/or efficacy of radiotherapy in combination with immunotherapy, nearly all of which use this single-site irradiation, or 'abscopal', approach. However, emerging preclinical and clinical evidence suggests that this approach likely produces suboptimal results. In this Perspective, we describe this evidence and provide a biological rationale supporting the abandonment of the single-site abscopal approach. We instead advocate exploring comprehensive irradiation of multiple/all lesions in order to enhance the likelihood of obtaining meaningful clinical outcomes - if such a clinical synergy between radiation and ICI does exist - before the failure of the current, single-site approach leads to the potential premature and inappropriate abandonment of radiotherapy in combination with ICI altogether.

204 citations

Journal ArticleDOI
TL;DR: RNA sequencing on 88 resected MBMs and 42 patient-matched extracranial metastases identified significant immunosuppression and enrichment of oxidative phosphorylation (OXPHOS) in MBMs.
Abstract: There is a critical need to improve our understanding of the pathogenesis of melanoma brain metastases (MBM). Thus, we performed RNA sequencing on 88 resected MBMs and 42 patient-matched extracranial metastases; tumors with sufficient tissue also underwent whole-exome sequencing, T-cell receptor sequencing, and IHC. MBMs demonstrated heterogeneity of immune infiltrates that correlated with prior radiation and post-craniotomy survival. Comparison with patient-matched extracranial metastases identified significant immunosuppression and enrichment of oxidative phosphorylation (OXPHOS) in MBMs. Gene-expression analysis of intracranial and subcutaneous xenografts, and a spontaneous MBM model, confirmed increased OXPHOS gene expression in MBMs, which was also detected by direct metabolite profiling and [U-13C]-glucose tracing in vivo. IACS-010759, an OXPHOS inhibitor currently in early-phase clinical trials, improved survival of mice bearing MAPK inhibitor-resistant intracranial melanoma xenografts and inhibited MBM formation in the spontaneous MBM model. The results provide new insights into the pathogenesis and therapeutic resistance of MBMs. SIGNIFICANCE: Improving our understanding of the pathogenesis of MBMs will facilitate the rational development and prioritization of new therapeutic strategies. This study reports the most comprehensive molecular profiling of patient-matched MBMs and extracranial metastases to date. The data provide new insights into MBM biology and therapeutic resistance.See related commentary by Egelston and Margolin, p. 581.This article is highlighted in the In This Issue feature, p. 565.

202 citations

Journal ArticleDOI
TL;DR: Data from numerous retrospective series and a handful of prospective studies provide burgeoning evidence that the combination of palliative radiotherapy and ICI is safe overall without a substantial site-specific increase in adverse events.
Abstract: Immune-checkpoint inhibitors targeting cytotoxic T- lymphocyte antigen 4 (CTLA-4), programmed cell death protein 1 (PD-1), or programmed cell death 1 ligand 1 (PD-L1) have transformed the care of patients with a wide range of advanced-stage malignancies. More than half of these patients will also have an indication for treatment with radiotherapy. The effects of both radiotherapy and immune-checkpoint inhibition (ICI) involve a complex interplay with the innate and adaptive immune systems, and accumulating evidence suggests that, under certain circumstances, the effects of radiotherapy synergize with those of ICI to augment the antitumour responses typically observed with either modality alone and thus improve clinical outcomes. However, the mechanisms by which radiotherapy and immune-checkpoint inhibitors synergistically modulate the immune response might also affect both the type and severity of treatment-related toxicities. Moreover, in patients receiving immune-checkpoint inhibitors, the development of immune-related adverse events has been linked with superior treatment responses and patient survival durations, suggesting a relationship between the antitumour and adverse autoimmune effects of these agents. In this Review, we discuss the emerging data on toxicity profiles related to immune-checkpoint inhibitors and radiotherapy, both separately and in combination, their potential mechanisms, and the approaches to managing these toxicities.

196 citations


Cites background from "Ipilimumab and Stereotactic Radiosu..."

  • ...Patel, 2017 (reF.(141)) Singleinstitution, retrospective study involving 54 patients with brain metastases from melanoma Intracranial SRT ± ipilimumab within 4 months (n = 20) TABN in 21% of patients receiving SRT versus 30% of patients receiving SRT + ipilimumab (P = 0....

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Journal ArticleDOI
01 Oct 2016-Cancer
TL;DR: The administration of immunotherapy within 4 weeks of SRS results in an improved lesional response of melanoma BrMets in comparison with treatment separated by longer than 4 weeks.
Abstract: BACKGROUND Growing evidence suggests that immunotherapy and radiation therapy can be synergistic in the treatment of cancer. This study was performed to determine the effect of the relative timing and type of immune checkpoint therapy on the response of melanoma brain metastases (BrMets) to treatment with stereotactic radiosurgery (SRS). METHODS Seventy-five melanoma patients with 566 BrMets were treated with both SRS and immune checkpoint therapy between 2007 and 2015 at a single institution. Immunotherapy and radiosurgery treatment of any single lesion were considered concurrent if SRS was administered within 4 weeks of immunotherapy. The impact of the timing and type of immunotherapy on the lesional response was determined with the Wilcoxon rank-sum test, which was used to compare the median percent lesion volume change 1.5, 3, and 6 months after SRS treatment, with significance determined by P = .0167 according to the Bonferroni correction for multiple comparisons. RESULTS Concurrent use of immunotherapy and SRS resulted in a significantly greater median percent reduction in the lesion volume at 1.5 (−63.1% vs −43.2%, P < .0001), 3 (−83.0% vs −52.8%, P < .0001), and 6 months (−94.9% vs −66.2%, P < .0001) in comparison with nonconcurrent therapy. The median percent reduction in the lesion volume was also significantly greater for anti–programmed cell death protein 1 (anti–PD-1) than anti–cytotoxic T-lymphocyte-associated protein 4 (anti–CTLA-4) at 1.5 (−71.1% vs −48.2%, P < .0001), 3 (−89.3% vs −66.2%, P < .0001), and 6 months (−95.1% vs −75.9%, P = .0004). CONCLUSIONS The administration of immunotherapy within 4 weeks of SRS results in an improved lesional response of melanoma BrMets in comparison with treatment separated by longer than 4 weeks. Anti–PD-1 therapy also results in a greater lesional response than anti–CTLA-4 after SRS. Cancer 2016;122:3051-3058. © 2016 American Cancer Society.

168 citations

References
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Journal ArticleDOI
TL;DR: Ipilimumab, with or without a gp100 peptide vaccine, as compared with gp100 alone, improved overall survival in patients with previously treated metastatic melanoma.
Abstract: Background An improvement in overall survival among patients with metastatic melanoma has been an elusive goal. In this phase 3 study, ipilimumab — which blocks cytotoxic T-lymphocyte–associated antigen 4 to potentiate an antitumor T-cell response — administered with or without a glycoprotein 100 (gp100) peptide vaccine was compared with gp100 alone in patients with previously treated metastatic melanoma. Methods A total of 676 HLA-A*0201–positive patients with unresectable stage III or IV melanoma, whose disease had progressed while they were receiving therapy for metastatic disease, were randomly assigned, in a 3:1:1 ratio, to receive ipilimumab plus gp100 (403 patients), ipilimumab alone (137), or gp100 alone (136). Ipilimumab, at a dose of 3 mg per kilogram of body weight, was administered with or without gp100 every 3 weeks for up to four treatments (induction). Eligible patients could receive reinduction therapy. The primary end point was overall survival. Results The median overall survival was 10.0 months among patients receiving ipilimumab plus gp100, as compared with 6.4 months among patients receiving gp100 alone (hazard ratio for death, 0.68; P<0.001). The median overall survival with ipilimumab alone was 10.1 months (hazard ratio for death in the comparison with gp100 alone, 0.66; P = 0.003). No difference in overall survival was detected between the ipilimumab groups (hazard ratio with ipilimumab plus gp100, 1.04; P = 0.76). Grade 3 or 4 immune-related adverse events occurred in 10 to 15% of patients treated with ipilimumab and in 3% treated with gp100 alone. There were 14 deaths related to the study drugs (2.1%), and 7 were associated with immune-related adverse events. Conclusions Ipilimumab, with or without a gp100 peptide vaccine, as compared with gp100 alone, improved overall survival in patients with previously treated metastatic melanoma. Adverse events can be severe, long-lasting, or both, but most are reversible with appropriate treatment. (Funded by Medarex and Bristol-Myers Squibb; ClinicalTrials.gov number, NCT00094653.)

13,081 citations


"Ipilimumab and Stereotactic Radiosu..." refers background in this paper

  • ...To investigate the efficacy of ipilimumab on intracranial disease, Margolin et al9 conducted a prospective nonrandomized phase II trial of ipilimumab alone for untreated MBM....

    [...]

  • ...2% and 0% of patients enrolled to the ipilimumab arms had stable MBM.(1,2) With up to 50% of melanoma patients developing brain metastasis (BM),(5,6) a poor prognostic indicator,(7) the efficacy of ipilimumab against MBM is a highly debated and clinically relevant question....

    [...]

  • ...Key Words: melanoma brain metastasis, stereotactic radiosurgery, ipilimumab (Am J Clin Oncol 2017;40:444–450) Antibodies targeting cytotoxic T-lymphocyte–associatedantigen 4, a T-cell inhibitory signaling molecule, have demonstrated improvements in overall survival (OS) at 3 years for metastatic melanoma patients in 2 randomized phase III.1,2 Distinct from chemotherapy or targeted agents, the survival rates stabilized after 2 years and remained durable at 5 years.3,4 These promising results led the FDA to approve anti-CTLA-4 antibody, ipilimumab, for metastatic melanoma....

    [...]

  • ...Antibodies targeting cytotoxic T-lymphocyte–associated antigen 4, a T-cell inhibitory signaling molecule, have demonstrated improvements in overall survival (OS) at 3 years for metastatic melanoma patients in 2 randomized phase III.(1,2) Distinct from chemotherapy or targeted agents, the survival rates stabilized after 2 years and remained durable at 5 years....

    [...]

  • ...In both of these phase III trials with ipilimumab, patients with melanoma brain metastasis (MBM) were poorly represented: only 12.2% and 0% of patients enrolled to the ipilimumab arms had stable MBM.1,2 With up to 50% of melanoma patients developing brain metastasis (BM),5,6 a poor prognostic indicator,7 the efficacy of ipilimumab against MBM is a highly debated and clinically relevant question....

    [...]

Journal ArticleDOI
TL;DR: Ipilimumab (at a dose of 10 mg per kilogram) in combination with dacarbazine, as compared with dACarbazine plus placebo, improved overall survival in patients with previously untreated metastatic melanoma.
Abstract: A B S T R AC T Background Ipilimumab monotherapy (at a dose of 3 mg per kilogram of body weight), as compared with glycoprotein 100, improved overall survival in a phase 3 study involving patients with previously treated metastatic melanoma. We conducted a phase 3 study of ipilimumab (10 mg per kilogram) plus dacarbazine in patients with previously untreated metastatic melanoma. Methods We randomly assigned 502 patients with previously untreated metastatic melanoma, in a 1:1 ratio, to ipilimumab (10 mg per kilogram) plus dacarbazine (850 mg per square meter of body-surface area) or dacarbazine (850 mg per square meter) plus placebo, given at weeks 1, 4, 7, and 10, followed by dacarbazine alone every 3 weeks through week 22. Patients with stable disease or an objective response and no doselimiting toxic effects received ipilimumab or placebo every 12 weeks thereafter as maintenance therapy. The primary end point was overall survival. Results Overall survival was significantly longer in the group receiving ipilimumab plus dacarbazine than in the group receiving dacarbazine plus placebo (11.2 months vs. 9.1 months, with higher survival rates in the ipilimumab–dacarbazine group at 1 year (47.3% vs. 36.3%), 2 years (28.5% vs. 17.9%), and 3 years (20.8% vs. 12.2%) (hazard ratio for death, 0.72; P<0.001). Grade 3 or 4 adverse events occurred in 56.3% of patients treated with ipilimumab plus dacarbazine, as compared with 27.5% treated with dacarbazine and placebo (P<0.001). No drug-related deaths or gastrointestinal perforations occurred in the ipilimumab–dacarbazine group. Conclusions Ipilimumab (at a dose of 10 mg per kilogram) in combination with dacarbazine, as compared with dacarbazine plus placebo, improved overall survival in patients with previously untreated metastatic melanoma. The types of adverse events were consistent with those seen in prior studies of ipilimumab; however, the rates of elevated liver-function values were higher and the rates of gastrointestinal events were lower than expected on the basis of prior studies. (Funded by Bristol-Myers Squibb; ClinicalTrials.gov number, NCT00324155.)

4,069 citations


"Ipilimumab and Stereotactic Radiosu..." refers background in this paper

  • ...To investigate the efficacy of ipilimumab on intracranial disease, Margolin et al9 conducted a prospective nonrandomized phase II trial of ipilimumab alone for untreated MBM....

    [...]

  • ...2% and 0% of patients enrolled to the ipilimumab arms had stable MBM.(1,2) With up to 50% of melanoma patients developing brain metastasis (BM),(5,6) a poor prognostic indicator,(7) the efficacy of ipilimumab against MBM is a highly debated and clinically relevant question....

    [...]

  • ...Key Words: melanoma brain metastasis, stereotactic radiosurgery, ipilimumab (Am J Clin Oncol 2017;40:444–450) Antibodies targeting cytotoxic T-lymphocyte–associatedantigen 4, a T-cell inhibitory signaling molecule, have demonstrated improvements in overall survival (OS) at 3 years for metastatic melanoma patients in 2 randomized phase III.1,2 Distinct from chemotherapy or targeted agents, the survival rates stabilized after 2 years and remained durable at 5 years.3,4 These promising results led the FDA to approve anti-CTLA-4 antibody, ipilimumab, for metastatic melanoma....

    [...]

  • ...Antibodies targeting cytotoxic T-lymphocyte–associated antigen 4, a T-cell inhibitory signaling molecule, have demonstrated improvements in overall survival (OS) at 3 years for metastatic melanoma patients in 2 randomized phase III.(1,2) Distinct from chemotherapy or targeted agents, the survival rates stabilized after 2 years and remained durable at 5 years....

    [...]

  • ...In both of these phase III trials with ipilimumab, patients with melanoma brain metastasis (MBM) were poorly represented: only 12.2% and 0% of patients enrolled to the ipilimumab arms had stable MBM.1,2 With up to 50% of melanoma patients developing brain metastasis (BM),5,6 a poor prognostic indicator,7 the efficacy of ipilimumab against MBM is a highly debated and clinically relevant question....

    [...]

Journal ArticleDOI
TL;DR: An analysis of tumor/patient characteristics and treatment variables in previous Radiation Therapy Oncology Group (RTOG) brain metastases studies was considered necessary to fully evaluate the benefit of these new interventions.
Abstract: Promising results from new approaches such as radiosurgery or stereotactic radiosurgery of brain metastases have recently been reported. Are these results due to the therapy alone or can the results be attributed in part to patient selection? An analysis of tumor/patient characteristics and treatment variables in previous RTOG brain metastases studies was considered necessary to fully evaluate the benefit of these new interventions.

2,330 citations


"Ipilimumab and Stereotactic Radiosu..." refers background or methods in this paper

  • ...7 months.(18) By activating immune cells, which can cross the BBB and target tumors, immunotherapy is a possible novel adjuvant approach against BM....

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  • ...Patient age, ECOG PS, and number of BM were classified into categories per previously published prognostic indices.(18) The number of BM was separated into categories of 1, 2 to 3, and Z4....

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Journal ArticleDOI
07 Jun 2006-JAMA
TL;DR: Compared with SRS alone, the use of W BRT plus SRS did not improve survival for patients with 1 to 4 brain metastases, but intracranial relapse occurred considerably more frequently in those who did not receive WBRT.
Abstract: ContextIn patients with brain metastases, it is unclear whether adding up-front whole-brain radiation therapy (WBRT) to stereotactic radiosurgery (SRS) has beneficial effects on mortality or neurologic function compared with SRS alone.ObjectiveTo determine if WBRT combined with SRS results in improvements in survival, brain tumor control, functional preservation rate, and frequency of neurologic death.Design, Setting, and PatientsRandomized controlled trial of 132 patients with 1 to 4 brain metastases, each less than 3 cm in diameter, enrolled at 11 hospitals in Japan between October 1999 and December 2003.InterventionsPatients were randomly assigned to receive WBRT plus SRS (65 patients) or SRS alone (67 patients).Main Outcome MeasuresThe primary end point was overall survival; secondary end points were brain tumor recurrence, salvage brain treatment, functional preservation, toxic effects of radiation, and cause of death.ResultsThe median survival time and the 1-year actuarial survival rate were 7.5 months and 38.5% (95% confidence interval, 26.7%-50.3%) in the WBRT + SRS group and 8.0 months and 28.4% (95% confidence interval, 17.6%-39.2%) for SRS alone (P = .42). The 12-month brain tumor recurrence rate was 46.8% in the WBRT + SRS group and 76.4% for SRS alone group (P<.001). Salvage brain treatment was less frequently required in the WBRT + SRS group (n = 10) than with SRS alone (n = 29) (P<.001). Death was attributed to neurologic causes in 22.8% of patients in the WBRT + SRS group and in 19.3% of those treated with SRS alone (P = .64). There were no significant differences in systemic and neurologic functional preservation and toxic effects of radiation.ConclusionsCompared with SRS alone, the use of WBRT plus SRS did not improve survival for patients with 1 to 4 brain metastases, but intracranial relapse occurred considerably more frequently in those who did not receive WBRT. Consequently, salvage treatment is frequently required when up-front WBRT is not used.Trial Registrationumin.ac.jp/ctr Identifier: C000000412

1,962 citations


"Ipilimumab and Stereotactic Radiosu..." refers background in this paper

  • ...Furthermore, intracranial local control (LC) rate of 29% with ipilimumab alone was lower than the 67% to 75% LC rate with stereotactic radiation therapy (SRS).(10,11) With ipilimumab alone constrained by lower LC and higher intracranial progression, adding radiation is a potential treatment approach to help address these limitations....

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Journal ArticleDOI
TL;DR: A case of the abscopal effect is reported in a patient with melanoma treated with ipilimumab and radiotherapy, with temporal associations of tumor shrinkage with antibody responses to the cancer-testis antigen NY-ESO-1, changes in peripheral-blood immune cells, and increases in antibodies to other antigens after radiotherapy.
Abstract: The abscopal effect is a phenomenon in which local radiotherapy is associated with the regression of metastatic cancer at a distance from the irradiated site. The abscopal effect may be mediated by activation of the immune system. Ipilimumab is a mono‑ clonal antibody that inhibits an immunologic checkpoint on T cells, cytotoxic T‑lymphocyte–associated antigen 4 (CTLA ‑ 4). We report a case of the abscopal effect in a patient with melanoma treated with ipilimumab and radiotherapy. Temporal associations were noted: tumor shrinkage with antibody responses to the cancer– testis antigen NY‑ ESO‑ 1, changes in peripheral‑ blood immune cells, and increases in antibody responses to other antigens after radiotherapy. (Funded by the National Institutes of Health and others.)

1,769 citations


"Ipilimumab and Stereotactic Radiosu..." refers background in this paper

  • ...Case reports combining high-dose, ablative radiation with concurrent ipilimumab have demonstrated durable systemic responses and higher than expected survival.(22,23) Because these case reports delivered concurrent ipilimumab and radiation, one possible explanation for the no improvement in survival is that timing of therapy may be critical to maximize the synergy between SRS and radiation....

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