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. 2023 Nov 30:13:1256800.
doi: 10.3389/fonc.2023.1256800. eCollection 2023.

Outcome and treatment-related adverse events of combined immune checkpoint inhibition with flipped dosing in a real-world cohort of 79 patients with metastasized melanoma

Charlotte Nübel  1 , Teresa Amaral  1 , Ulrike Leiter  1 , Lukas Flatz  1 , Andrea Forschner  1
Affiliations

Outcome and treatment-related adverse events of combined immune checkpoint inhibition with flipped dosing in a real-world cohort of 79 patients with metastasized melanoma

Charlotte Nübel et al. Front Oncol. .

Abstract

Introduction: Combined immune checkpoint inhibition (ICI) with ipilimumab and nivolumab is a widely used treatment regimen for metastatic melanoma with non-resectable metastases. Nevertheless, the standard dose of ipilimumab 3 mg/kg bw and nivolumab 1 mg/kg bw is associated with a high rate of treatment-related adverse events (trAEs) (59% grade 3-4). In the CheckMate 511 study, it could be shown that flipped dosing with ipilimumab 1 mg/kg bw and nivolumab 3 mg/kg bw resulted in a significant reduction of trAE.

Methods: We have also used this regimen in the clinical setting and report the trAE, progression-free survival, and overall survival for 79 patients with metastatic melanoma who started combined ICI in the flipped dosing between March 2019 and April 2020.

Results: in total, 40 patients started first-line, 50% of whom had an elevated lactate dehydrogenase level at baseline. The disease control rate of these patients was 50%. The 2-year overall survival rate 67%. Moreover, 33% of the patients suffered grade 3 or 4 treatment related adverse events.

Discussion: The results of our study correspond very well to the results of the CheckMate 511 study (2-year OS: 65%, grade 3-4 immune-related side effects: 35%). Combined ICI with ipilimumab 1 mg/kg bw and nivolumab 3 mg/kg bw seems to be an equally effective but better-tolerated therapy regimen for metastasized melanoma patients, also in a real-world cohort.

Keywords: advanced melanoma; combined immune checkpoint inhibitors; immune related adverse events; immunotherapies; ipilimumab; nivolumab.

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Conflict of interest statement

TA reports institutional funding from SkylineDx B.V. in relation to the submitted work. TA reports personal honoraria from BMS, CeCaVa, Novartis and Pierre-Fabre; Institutional financial support from iFIT, Neracare, Novartis and Sanofi and institutional research Grant from Novartis, outside the submitted work. UL reports research support from MSD, consulting fees and honoraria from Sun Pharma, Sanofi personal and institutional, MSD personal and institutional, Novartis, Roche, Almirall Hermal, support for attending meeting from Sun Pharma and participation on a Data Safety Monitoring Board or Advisory Board from Sun Pharma, Sanofi, MSD, Novartis, Roche, Almirall Hermal, outside the submitted work. LF reports Grants or contracts from Hookipa Pharma, SAKK/Immunophotonics, DFG Grant Deutsche Forschungsgemeinschaft, Philogen and Mundipharma; consulting fees from Philogen, Sanofi, Novartis, BMS; participation on Data Safety Board University of Basel and stocks or stock options from Hookipa Pharma, outside the submitted work. AF reports honoraria for presentations for BMS, MSD, Novartis, Pierre-Fabre; Travel support and congress participation support from BMS, Pierre-Fabre, Novartis; Advisory Boards from MSD, BMS, Novartis, Pierre-Fabre, Immunocore and institutional funding from BMS Stiftung Immunonkologie, outside the submitted work. The remaining author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Impact of patient characteristics (total cohort) on overall survival. (A) BRAF mutant vs. wild-type tumors (p < 0.001). (B) LDH at start normal vs. elevated (p < 0.001). (C) Protein S100 at start normal vs. elevated (p = 0.02). (D) M-stage at start M0-M1d (p = 0.002).
Figure 2
Figure 2
Impact of patient characteristics (total cohort) on progression-free survival. (A) BRAF mutant vs. wild-type tumors (p < 0.001). (B) LDH at start normal vs. elevated (p < 0.001). (C) Protein S100 at start normal vs. elevated (p = 0.047). (D) M-stage at start (p < 0.001).
Figure 3
Figure 3
Impact of patient characteristics (first-line cohort) on overall survival. (A) BRAF mutant vs. wild-type tumors (p = 0.038). (B) LDH at start normal vs. elevated (p < 0.001). (C) Protein S100 at start normal vs. elevated (p = 0.154). (D) M-stage at start M0-M1b vs. M1c vs. M1d (p < 0.001).
Figure 4
Figure 4
Impact of patient characteristics (first-line cohort) on progression-free survival. (A) BRAF mutant vs. wild-type tumors (p = 0.069). (B) LDH at start normal vs. elevated (p < 0.001). (C) Protein S100 at start normal vs. elevated (p = 0.165). (D) M-stage at start M0-M1b vs. M1c vs. M1d (p < 0.001).
See this image and copyright information in PMC

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