Abstract 3267
Background
Recently, the world of oncology has been revolutionized by immunotherapy which has shown considerable advantages in terms of overall survival in cancer patients. The association of Pembrolizumab and Trastuzumab was recently proposed in clinical trials for the treatment of Trastuzumab-resistant advanced HER2-positive breast cancer. Although immunotherapies are frequently associated with a wide spectrum of immune-related adverse events, the cardiactoxicity has not been properly studied.
Methods
In human fetal cardiomyocytes exposed to Trastuzumab and Pembrolizumab alone or in combination, we studied: the cell viability (through MTS assay), the quantification of intracellular calcium, Interleukin 1β, 6 and 8; the expression of NF-kB and Leukotrienes. Preclinical studies were also performed in C57BL6 mice dividing them in 4 groups (6/group: untreated mice (control) ; mice treated with Pembrolizumab at 10 mg/Kg for the first dose, followed by 5 mg/Kg dose every 5 days until the study end point, according to literature; mice treated with Trastuzumab at 10 mg/kg/day; mice treated with both drugs in combination. After the administration period, we analyzed the fibrosis and inflammation in heart tissues.
Results
The combination of Pembrolizumab and Trastuzumab increases the intracellular calcium overload (of 3 times compared to untreated cells) and reduces the cardiomyocytes viability (of 65 and 20-25%, compared to untreated and Pembrolizumab or Trastuzumab treated cells, respectively; p < 0.01 for both). Combination therapy increases the inflammation of cardiomyocytes by enhancing the expression of NF-kB and Interleukins. Moreover, in preclinical models, the association of Pembrolizumab and Trastuzumab increases the cardiac fibrosis and Interleukins expression of 40-50 % compared to the single treatments; the expression of NF-kB and Leukotriene B4 were also significantly increased, compared to the single treatments.
Conclusions
The association of Pembrolizumab and Trastuzumab exerts pro-inflammatory and pro fibrotic effects in the heart; these effects are mainly mediated by overexpression of NF-kB and Leukotriene B4 related pathways and pro-inflamamtory cytokines.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
This work was funded by the “Ricerca Corrente” grant from the Italian Ministry of Health.
Disclosure
All authors have declared no conflicts of interest.
Resources from the same session
4370 - Continental differences in pathologic response with neoadjuvant ipilimumab (IPI) plus nivolumab (NIVO) in patients with macroscopic stage III melanoma in the phase 2 OpACIN-neo trial.
Presenter: Irene Reijers
Session: Poster Display session 3
Resources:
Abstract
3230 - Comparable responses of melanoma at primary site and synchronous lymph node metastases upon neoadjuvant ipilimumab (IPI) and nivolumab (NIVO)
Presenter: Judith Versluis
Session: Poster Display session 3
Resources:
Abstract
3171 - Adjuvant Therapies for Stage III Melanoma: Benchmarks for Bringing Clinical Trials to Clinical Practice
Presenter: Tina HIEKEN
Session: Poster Display session 3
Resources:
Abstract
3493 - Mixture-cure modeling for resected stage III/IV melanoma in the phase 3 CheckMate 238 trial
Presenter: Jeffrey Weber
Session: Poster Display session 3
Resources:
Abstract
3036 - An open-label, non-randomized, phase IIIb study of trametinib in combination with dabrafenib for patients with unresectable advanced BRAFV600-mutant melanoma: a subgroup analysis of patients with brain metastasis
Presenter: Caroline Dutriaux
Session: Poster Display session 3
Resources:
Abstract
2233 - Adverse event (AE) kinetics in patients (pts) treated with dabrafenib + trametinib (D + T) in the metastatic and adjuvant setting
Presenter: Jean Jacques Grob
Session: Poster Display session 3
Resources:
Abstract
2435 - A Single Arm, Open Label, Phase II, Multicenter Study to Assess the Detection of the BRAF V600 Mutation on cfDNA from Plasma in Patients with Advanced Melanoma
Presenter: Piotr Rutkowski
Session: Poster Display session 3
Resources:
Abstract
1766 - Efficacy and Safety of Dabrafenib and Trametinib in Patients with Metastatic BRAFV600 Mutation-positive Melanoma in the Real-World Setting – Interim results of the non-interventional COMBI-r study
Presenter: Carola Berking
Session: Poster Display session 3
Resources:
Abstract
2131 - Trial update: A randomized Phase Ib/II study of the selective small molecule Axl inhibitor Bemcentinib (BGB324) in combination with either dabrafenib/trametinib (D/T) or pembrolizumab in patients with metastatic melanoma
Presenter: Oddbjørn Straume
Session: Poster Display session 3
Resources:
Abstract
4074 - Analysis of pyrexia in patients (pts) treated with dabrafenib (D) and/or trametinib (T) across clinical trials
Presenter: Caroline Robert
Session: Poster Display session 3
Resources:
Abstract