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The combination of stereotactic radiosurgery with immune checkpoint inhibition or targeted therapy in melanoma patients with brain metastases: a retrospective study

Abstract

Background

Evidence pointing to a synergistic effect of stereotactic radiosurgery (SRS) with concurrent immunotherapy or targeted therapy in patients with melanoma brain metastases (BM) is increasing. We aimed to analyze the effect on overall survival (OS) of immune checkpoint inhibitors (ICI) or BRAF/MEK inhibitors initiated during the 9 weeks before or after SRS. We also evaluated the prognostic value of patients’ and disease characteristics as predictors of OS in patients treated with SRS.

Methods

We identified patients with BM from cutaneous or unknown primary origin melanoma treated with SRS between 2011 and 2018.

Results

We included 84 patients. The median OS was 12 months (95% CI 9–20 months). The median follow-up was 30 months (95% CI 28–49). Twenty-eight patients with newly diagnosed BM initiated anti-PD-1 +/−CTLA-4 therapy (n = 18), ipilimumab monotherapy (n = 10) or BRAF+/- MEK inhibitors (n = 11), during the 9 weeks before or after SRS. Patients who received anti-PD-1 +/−CTLA-4 mAb showed an improved survival in comparison to ipilimumab monotherapy (OS 24 vs. 7.5 months; HR 0.32, 95% 0.12–0.83, p = 0.02) and BRAF +/−MEK inhibitors (OS 24 vs. 7 months, respectively; HR 0.11, 95% 0.04–0.34, p = 0.0001). This benefit remained significant when compared to the subgroup of patients treated with dual BRAF/MEK inhibition (BMi) (n = 5). In a multivariate Cox regression analysis an age > 65, synchronous BM, > 2 metastatic sites, > 4 BM, and an ECOG > 1 were correlated with poorer prognosis. A treatment with anti-PD-1+/−CTLA-4 mAbs within 9 weeks of SRS was associated with better outcomes. The presence of serum lactate dehydrogenase (LDH) levels ≥ 2xULN at BM diagnosis was associated with lower OS (HR 1.60, 95% CI 1.03–2.50; p = 0.04).

Conclusions

The concurrent administration of anti-PD-1+/−CTLA-4 mAbs with SRS was associated with improved survival in melanoma patients with newly diagnosed BM. In addition to CNS tumor burden, the extension of systemic disease retains its prognostic value in patients treated with SRS. Elevated serum LDH levels are predictors of poor outcome in these patients.

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Abbreviations

BM:

Brain metastasis

BMi:

BRAF/MEK inhibition

BRA:

i BRAF inhibition

MBM:

Metastatic brain melanoma

MEKi:

MEK inhibition

MM:

Metastatic melanoma

CNS:

Central nervous system

CTLA-4:

Cytotoxic T lymphocyte-associated antigen 4

DCI:

Double checkpoint inhibition

ICI:

Immune-checkpoint inhibitor

IRR:

Intracranial response rate

mAb:

Monoclonal antibody

OS:

Overall survival

PD-1:

Programmed death 1 receptor

PD-L1:

Programmed death-ligand 1

RT:

Radiation therapy

SRS:

Stereotactic radiation surgery

ULN:

Upper limit of the normal range

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Acknowledgements

We thank the Oncology teams of the Hospitals of Valais and Fribourg for their help in treatment and survival data collection. FM thanks the Personalized Health and Related Technologies (PHRT) strategic focus area of the Swiss Federal Institutes of Technology (ETH) Domain and the Swiss Personalized Health Network (SPHN) initiative of the Swiss Academy of Medical Sciences for its support (Project No. #2017-407). CT gratefully acknowledges the receipt of the grant “Jeune Chercheur en Recherche Clinique” from the University of Lausanne, Faculty of Biology and Medicine”.

Funding

None declared.

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Authors and Affiliations

Authors

Contributions

FM, LS and OM designed and conceptualized this study. FM did the literature research and wrote the manuscript. FM, LS, MC analyzed and interpreted the patient data regarding the survival analysis and treatment comparisons groups. All authors read, edited and approved the final manuscript.

Corresponding authors

Correspondence to Filipe Martins, Jean Bourhis or Olivier Michielin.

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Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

This study is a retrospective analysis of patients from Lausanne University Hospital, Switzerland and was conducted in accordance with the Declaration of Helsinki, the Swiss legal requirements and the principles of Good Clinical Practice. The protocol was approved by the Research Ethics Committee-Vaud Canton, Switzerland (Protocol No. 2019-00448). According to Swiss law on Human Research using non-genomic related data, all except one living patient (which was consequently excluded from analysis) gave their consent to use their health-related data for this study.

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Martins, F., Schiappacasse, L., Levivier, M. et al. The combination of stereotactic radiosurgery with immune checkpoint inhibition or targeted therapy in melanoma patients with brain metastases: a retrospective study. J Neurooncol 146, 181–193 (2020). https://doi.org/10.1007/s11060-019-03363-0

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  • DOI: https://doi.org/10.1007/s11060-019-03363-0

Keywords

  • BRAF
  • CTLA-4
  • CyberKnife
  • Gamma knife
  • Immune-checkpoint inhibitors
  • MEK
  • Immunotherapy
  • PD-1
  • PD-L1
  • Stereotactic radiation surgery