Stereotactic radiosurgery and combined immune checkpoint therapy with ipilimumab and nivolumab in patients with melanoma brain metastases: A retrospective monocentric toxicity analysis

Raphael Bodensohn; Simone Werner; Jonas Reis; Montserrat Pazos Escudero; Anna-Lena Kaempfel; Indrawati Hadi; Robert Forbrig; Farkhad Manapov; Stefanie Corradini; Claus Belka; Sebastian Theurich; Lucie Heinzerling; Max Schlaak; Maximilian Niyazi

doi:10.1016/j.ctro.2022.100573

Stereotactic radiosurgery and combined immune checkpoint therapy with ipilimumab and nivolumab in patients with melanoma brain metastases: A retrospective monocentric toxicity analysis

Clin Transl Radiat Oncol. 2023 Jan 4:39:100573. doi: 10.1016/j.ctro.2022.100573. eCollection 2023 Mar.

Authors

Raphael Bodensohn¹, Simone Werner¹, Jonas Reis², Montserrat Pazos Escudero¹, Anna-Lena Kaempfel¹, Indrawati Hadi¹, Robert Forbrig², Farkhad Manapov¹, Stefanie Corradini¹, Claus Belka^{1

3}, Sebastian Theurich⁴, Lucie Heinzerling^{5

6}, Max Schlaak⁷, Maximilian Niyazi^{1

3}

Affiliations

¹ Department of Radiation Oncology, University Hospital, LMU Munich, Marchioninistraße 15, 81377 Munich, Germany.
² Institute of Neuroradiology, University Hospital, LMU Munich, Marchioninistraße 15, 81377 Munich, Germany.
³ German Cancer Consortium (DKTK), Partner Site, Munich, Germany.
⁴ Department of Medicine III, University Hospital, LMU Munich, Ziemssenstraße 1, 80336 Munich, Germany.
⁵ Department of Dermatology and Allergology, University Hospital, LMU Munich, Frauenlobstraße 9-11, 80337 Munich, Germany.
⁶ Department of Dermatology, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nürnberg, Ulmenweg 18, 91052 Erlangen, Germany.
⁷ Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Dermatology, Venereology and Allergology, Charitéplatz 1, 10117 Berlin, Germany.

Abstract

Purpose and objective: Adding stereotactic radiosurgery (SRS) to combined immune checkpoint therapy with ipilimumab and nivolumab (IPI + NIVO) has led to promising results for patients with melanoma brain metastases (MBM). This study retrospectively analyzes the toxicity profile depending on the timing of SRS with regard to IPI + NIVO.

Materials and methods: For this study, the clinical database was searched for all patients with MBM who were treated with SRS and IPI + NIVO. The patients were separated into three groups: group A completed IPI + NIVO (usually up to four cycles) >14 days before SRS, in group B IPI + NIVO was initiated>14 days after SRS, and group C received SRS concurrently to IPI + NIVO. Treatment related toxicity was obtained from clinical and neuroradiological records. Analyses were performed using the Fisher-Yates-test.

Results: 31 patients were assessed including six (19.4 %), seven (22.6 %) and 18 (58.1 %) patients, in groups A, B and C, respectively. Baseline prognostic markers between groups were balanced. In total, five (16.1 %) patients experienced neurological grade 3 toxicities related to SRS. All of these five patients were in group C, which was near-significantly correlated with a risk for grade 3 toxicities (p = 0.058). Post-hoc analyses showed that a maximum time period of seven days between SRS and IPI + NIVO was significantly correlated with grade 3 toxicity (p = 0.048).

Conclusion: Application of SRS to IPI + NIVO within a seven-day span was related to higher toxicity rates in this retrospective analysis. After previous studies focused on immune checkpoint monotherapies with SRS and declared it as safe, this study indicates that concomitant application of IPI + NIVO and SRS might increase side effects. Prospective validation is warranted to corroborate these findings.

Keywords: AE, Adverse events; CTCAE, Common Terminology Criteria for Adverse Events; Checkpoint inhibition; GPA, graded prognostic assessment; IPI, ipilimumab; Intracranial hemorrhage; Ipilimumab; LDH, lactate dehydrogenase; MBM, Melanoma brain metastases; MRI, magnet resonance imaging; NIVO, nivolumab; Nivolumab; OS, overall survival; PFS, progression-free survival; RN, radiation necrosis; Radiation necrosis; SRS, Stereotactic radiosurgery; SRT, Stereotactic radiotherapy; Side effects; Stereotactic radiosurgery.