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EGFR mutations are associated with response to depatux-m in combination with temozolomide and result in a receptor that is hypersensitive to ligand.

ABSTRACT: Background:The randomized phase II INTELLANCE-2/EORTC_1410 trial on EGFR-amplified recurrent glioblastomas showed a trend towards improved overall survival when patients were treated with depatux-m plus temozolomide compared with the control arm of alkylating chemotherapy only. We here performed translational research on material derived from this clinical trial to identify patients that benefit from this treatment. Methods:Targeted DNA-sequencing and whole transcriptome analysis was performed on clinical trial samples. High-throughput, high-content imaging analysis was done to understand the molecular mechanism underlying the survival benefit. Results:We first define the tumor genomic landscape in this well-annotated patient population. We find that tumors harboring EGFR single-nucleotide variations (SNVs) have improved outcome in the depatux-m + TMZ combination arm. Such SNVs are common to the extracellular domain of the receptor and functionally result in a receptor that is hypersensitive to low-affinity EGFR ligands. These hypersensitizing SNVs and the ligand-independent EGFRvIII variant are inversely correlated, indicating two distinct modes of evolution to increase EGFR signaling in glioblastomas. Ligand hypersensitivity can explain the therapeutic efficacy of depatux-m as increased ligand-induced activation will result in increased exposure of the epitope to the antibody-drug conjugate. We also identified tumors harboring mutations sensitive to "classical" EGFR tyrosine-kinase inhibitors, providing a potential alternative treatment strategy. Conclusions:These data can help guide treatment for recurrent glioblastoma patients and increase our understanding into the molecular mechanisms underlying EGFR signaling in these tumors.

SUBMITTER: Hoogstrate Y

PROVIDER: S-EPMC7212878 | biostudies-literature | 2020 Jan-Dec

REPOSITORIES: biostudies-literature

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EGFR mutations are associated with response to depatux-m in combination with temozolomide and result in a receptor that is hypersensitive to ligand.

Hoogstrate Youri Y Vallentgoed Wies W Kros Johan M JM de Heer Iris I de Wit Maurice M Eoli Marica M Sepulveda Juan Manuel JM Walenkamp Annemiek M E AME Frenel Jean-Sebastien JS Franceschi Enrico E Clement Paul M PM Weller Micheal M van Royen Martin E ME Ansell Peter P Looman Jim J Bain Earle E Morfouace Marie M Gorlia Thierry T Golfinopoulos Vassilis V van den Bent Martin M French Pim J PJ

Neuro-oncology advances 20191209 1

<h4>Background</h4>The randomized phase II INTELLANCE-2/EORTC_1410 trial on EGFR-amplified recurrent glioblastomas showed a trend towards improved overall survival when patients were treated with depatux-m plus temozolomide compared with the control arm of alkylating chemotherapy only. We here performed translational research on material derived from this clinical trial to identify patients that benefit from this treatment.<h4>Methods</h4>Targeted DNA-sequencing and whole transcriptome analysis ...[more]

PMID: 32642719

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Project description:Abstract Background Depatux-M is a n antibody-drug-conjugate consisting of an antibody (ABT-806) specific to the activated conformation of epidermal growth factor receptor (EGFR) bound to the toxin monomethylauristatin-F. In the primary analysis on EORTC 1410 we reported a trend (p = 0.06) towards improved overall survival (OS) in patients with EGFR-amplified recurrent glioblastoma treated with Depatux-M in combination with TMZ. We now present updated results. Material and Methods Eligible were patients with centrally confirmed EGFR-amplified glioblastoma at 1st recurrence after TMZ chemo-irradiation, occurring ≥3 months after radiotherapy. Patients were randomized to either a) Depatux-M 1.0 mg/kg every 2 weeks intravenously, or b) the same treatment combined with TMZ 150–200 mg/m2 day 1–5 every 4 weeks, or c) either LOM or TMZ (TMZ/LOM) depending on the time of relapse. Primary endpoint was OS. Pharmacokinetic (PK) sampling was done on day (d) 1 before and after dosing, d 4–7, d 1 course 2 before and after dosing, d 5–7 course 2, d 1 course 3, and then every 2 cycles. All available PK samples were used to calculate the Depatux-M average concentration during course 1 (CavgC1). The level of EGFR amplification was determined using both qPCR, next generation sequencing and FISH. Results In February 2018, an updated OS comparison with longer follow-up (median: 21 mo) performed after 220 observed deaths of Depatux-M in combination with TMZ versus TMZ/LOM using log-rank test and cox models stratified by stratification factors at randomization showed a HR of 0.68 (95%CI [0.48, 0.95]; p = 0.024) and 1-year OS rates of 40% versus 28%. In multivariate analysis including performance status, MGMT, surgery for recurrence, time from last TMZ to relapse and lesion diameter, CavgC1 was a significant predictor for OS (HR 0.96, 95% CI [0.93, 0.98], p = 0.0013). In Depatux-M treated patients, EGFR status (high vs low level amplification) did not correlate with OS. At the meeting further follow-up data will be presented obtained at database cleaning done > 24 months after the end of accrual allowing definitive analysis. Conclusion This updated OS analysis confirmed the OS improvement in EGFR-amplified recurrent glioblastoma after treatment with of Depatux-M in combination with TMZ. In Depatux-M treated patients, higher drug levels during course 1 were associated with improved OS but high levels of EGFR amplification at first diagnosis were not.

Project description:Abstract BACKGROUND Depatux-M is an antibody-drug-conjugate consisting of an antibody (ABT-806) specific to the activated conformation of EGFR bound to the toxin monomethylauristatin-F. In the primary analysis on EORTC 1410 we reported a trend (p = 0.06) towards improved overall survival (OS) in patients with EGFR-amplified (amp) recurrent glioblastoma treated with Depatux-M in combination with temozolomide. METHODS Eligible were patients with centrally confirmed EGFRamp glioblastoma at 1st recurrence after temozolomide chemo-irradiation. Patients were randomized to either a) Depatux-M 1.0 mg/kg every 2 weeks intravenously, or b) the same treatment combined with temozolomide 150–200 mg/m2 day 1–5 every 4 weeks, or c) either lomustine or temozolomide (TMZ/LOM) depending on the time of relapse. Primary endpoint was OS. Pharmacokinetic sampling was part of the study design, all samples were used to calculate the Depatux-M average concentration during course 1 (CavgC1). The level of EGFRamp was re-analysed using next generation sequencing. RESULTS In February 2018, an updated OS comparison performed after 220 observed deaths of Depatux-M in combination with TMZ versus TMZ/LOM using log-rank test and cox models stratified by stratification factors at randomization showed a HR of 0.68 (95%CI [0.48, 0.95]; p = 0.024) and 1-year OS rates of 40% versus 28%. In multivariate analysis CavgC1 was a significant predictor for OS (HR 0.96, 95% CI [0.93, 0.98], p = 0.0013). In Depatux-M treated patients, EGFR status (high vs low level amplification) did not correlate with OS. At the meeting the follow-up from Aug 2018 will be presented, obtained more than 24 months after the end of accrual. CONCLUSION: This updated OS analysis of Depatux-M in combination with temozolomide confirmed the OS improvement in EGFRamp recurrent glioblastoma. In Depatux-M treated patients, higher drug levels during course 1 were associated with improved OS, but high levels of EGFR amplification at first diagnosis were not.

Project description:Although mutations in the microtubules-associated protein Tau have long been connected with several neurodegenerative diseases, the underlying molecular mechanisms causing these tauopathies are still not fully understood. Studies in various models suggested that dominant gain-of-function effects underlie the pathogenicity of these mutants; however, there is also evidence that the loss of normal physiological functions of Tau plays a role in tauopathies. Previous studies on Tau in Drosophila involved expressing the human Tau protein in the background of the endogenous Tau gene in addition to inducing high expression levels. To study Tau pathology in more physiological conditions, we recently created Drosophila knock-in models that express either wildtype human Tau (hTauWT) or disease-associated mutant hTau (hTauV337M and hTauK369I) in place of the endogenous Drosophila Tau (dTau). Analyzing these flies as homozygotes, we could therefore detect recessive effects of the mutations while identifying dominant effects in heterozygotes. Using memory, locomotion and sleep assays, we found that homozygous mutant hTau flies showed deficits already when quite young whereas in heterozygous flies, disease phenotypes developed with aging. Homozygotes also revealed an increase in microtubule diameter, suggesting that changes in the cytoskeleton underlie the axonal degeneration we observed in these flies. In contrast, heterozygous mutant hTau flies showed abnormal axonal targeting and no detectable changes in microtubules. However, we previously showed that heterozygosity for hTauV337M interfered with synaptic homeostasis in central pacemaker neurons and we now show that heterozygous hTauK369I flies have decreased levels of proteins involved in the release of synaptic vesicles. Taken together, our results demonstrate that both mutations induce a combination of dominant and recessive disease-related phenotypes that provide behavioral and molecular insights into the etiology of Tauopathies.

Project description:For pediatric patients with high-grade gliomas, standard-of-care treatment includes surgery, chemotherapy, and radiation therapy; however, most patients ultimately succumb to their disease. With advances in genomic characterization of pediatric high-grade gliomas, the use of targeted therapies in combination with current treatment modalities offer the potential to improve survival in this patient population. In this report, we present the case of a 3-year-old girl with glioblastoma who continues to experience an exceptional and durable response (>2?years) to the poly (ADP-ribose) polymerase (PARP) inhibitor olaparib. Our patient presented with persistent and progressive seizure activity that upon workup was the result of a large heterogeneously enhancing, mixed cystic and solid mass in the left frontal-parietal-temporal region. Histopathologic analysis of resected tumor tissue confirmed the diagnosis of glioblastoma, and comprehensive genomic profiling demonstrated absence of any BRAF or H3F3A mutations. Genomic profiling, however, did reveal a probable germline heterozygous BRCA2 Lys3326Ter (K3226*) nonsense variant. After debulking surgery, the patient received standard-of-care treatment with radiation and temozolomide. Nine months later the PARP inhibitor olaparib was administered in combination with temozolomide for 16 cycles. This regimen was well tolerated by the patient and serial imaging showed reduction in tumor size. Since completion of the regimen, the patient remains neurologically intact with no evidence of tumor recurrence. To our knowledge, this represents the first case of a pediatric glioblastoma that maintains a durable response to a therapeutic strategy that included the PARP inhibitor olaparib and more generally highlights the potential clinical utility of incorporating these agents into the treatment of pediatric high-grade gliomas. KEY POINTS: Germline mutations detected in pediatric gliomas may represent a cancer predisposition syndrome. Integrating molecular testing into routine clinical care for pediatric patients with glioma is critical to identify therapeutic targets and patients with a cancer predisposition syndrome. Patients with glioma with defects in DNA repair pathway components (e.g., BRCA1/2) may show increased responsiveness to poly (ADP-ribose) polymerase (PARP) inhibitors. Combining PARP inhibitors with temozolomide (standard-of-care treatment) revealed no adverse events or toxicities over the course of 18 months.

Dataset Information

EGFR mutations are associated with response to depatux-m in combination with temozolomide and result in a receptor that is hypersensitive to ligand.

Publications

EGFR mutations are associated with response to depatux-m in combination with temozolomide and result in a receptor that is hypersensitive to ligand.

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