Expanding the application of targeted therapies and immune checkpoint inhibitors in advanced melanoma and recurrent glioblastoma

Abstract

The prognosis of patients with advanced melanoma that progresses after treatment with immune checkpoint inhibitors and BRAF-/MEK-inhibitors, and of patients with glioblastoma that recurs after radiation therapy and temozolomide chemotherapy is grim. In this research, we have explored new applications of molecular-targeted therapies and immune checkpoint inhibitors in these disease settings.
The phase 2 TraMel-WT trial investigated the efficacy and safety of the MEK-inhibitor trametinib in patients with advanced BRAFV600 wild-type, NRASQ61R/K/L mutant or BRAFV600 wild-type, NRASQ61R/K/L wild-type melanoma who were previously treated with immune checkpoint inhibitors. In order to prevent trametinib-related skin toxicity, a low dose of the BRAF-inhibitor dabrafenib was added to trametinib. We show that adding low-dose dabrafenib to trametinib effectively mitigates trametinib-related skin toxicity. Promising antitumor activity was observed with trametinib plus low-dose dabrafenib in patients with advanced NRASQ61R/K/L wild-type melanoma, especially when mutations known to activate the mitogen-activated protein kinase pathway were present. In NRASQ61R/K/L mutant melanoma however, this combination is insufficiently active.
The phase 1/2 COMBI-R 2 trial investigated the efficacy and safety of dabrafenib, trametinib and the autophagy inhibitor hydroxychloroquine in patients with advanced pretreated (with immune checkpoint inhibitors and BRAF-/MEK-inhibitors) BRAFV600 mutant melanoma. We did not observe a benefit of adding hydroxychloroquine to dabrafenib and trametinib in this setting.
The phase 2 GliAvAx trial investigated the efficacy and safety of the vascular endothelial growth factor receptor 1-3 inhibitor axitinib and the programmed cell death ligand 1 immune checkpoint inhibitor avelumab in patients with recurrent glioblastoma. Although this combination was sufficiently safe, the trial did not meet its primary endpoint of improving the progression-free survival rate at 6 months to more than 50%.
Finally, in a population of 183 advanced melanoma patients who were treated with the programmed cell death 1 immune checkpoint inhibitor pembrolizumab, we performed a multivariable analysis to determine which baseline characteristics and biomarkers are independently associated with progression-free and overall survival.

Date of Award	18 Jun 2021
Original language	English
Awarding Institution	Vrije Universiteit Brussel
Supervisor	Bart Neyns (Promotor), Keith Flaherty (Jury), Véronique Del Marmol (Jury), Frederik Jan Hes (Jury), Benedikt Engels (Jury), Amy de Haar-Holleman (Jury) & Henri Schots (Jury)