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.

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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Publications

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.

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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.

Background

Methods

Results

Conclusions

Publications

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

Similar Datasets

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