Phase 2 Study of the HSP-90 Inhibitor AUY922 in Previously Treated and Molecularly Defined Patients with Advanced Non–Small Cell Lung Cancer

Enriqueta Felip, Fabrice Barlesi, Benjamin Besse, Quincy Chu, Leena Gandhi, Sang We Kim, Enric Carcereny, Lecia V. Sequist, Paal Brunsvig, Christos Chouaid, Egbert F. Smit, Harry J.M. Groen, Dong Wan Kim, Keunchil Park, Emin Avsar, Sebastian Szpakowski, Mikhail Akimov, Edward B. Garon

Research output: Contribution to journalArticle

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Abstract

Introduction: In this phase 2 study, we evaluated the activity of AUY922 in pretreated patients with stage IV NSCLC. Methods: Patients with advanced NSCLC were divided into molecularly defined strata based on mutations in the EGFR gene, the ALK receptor tyrosine kinase gene (ALK), the KRAS gene, or the wild type of all three. All patients must have received more than two prior lines of therapy, except for those in a fifth stratum for a less pretreated EGFR cohort (EGFR<2). In the EGFR-mutant and ALK-rearranged strata, prior platinum therapy was not required. Patients with EGFR mutation must have received an EGFR tyrosine kinase inhibitor unless they had de novo resistance (e.g., T790M or exon 20 insertions). Eligible patients received weekly intravenous AUY922, 70 mg/m 2 . The primary objective was to estimate efficacy (complete or partial response, or in the absence of complete or partial response, stable disease) at 18 weeks, by the Response Criteria in Solid Tumors. Results: A total of 153 patients from 21 global centers were enrolled from October 2010 to November 2014. The investigator-assessed overall response rate and stable disease rate at 18 weeks were 31.8% and 9.1% in the ALK-rearranged stratum, 17.1% and 8.6% in EGFR-mutant stratum, 9.7% and 22.6% in the EGFR<2 stratum, 0% and 7.1% in KRAS-mutant stratum, and 8.8% and 8.8% in wild-type stratum. Biomarker data showed activity of AUY922 in EGFR-mutant patients with exon 19 deletion, T790M mutation, and exon 20 insertion. The most common (≥40%) all-causality adverse events were diarrhea, nausea, and decreased appetite. Visual-related disorders were reported in 79.7% of patients (most were grade 1/2). Thirty-five patients (22.9%) reported night blindness. Conclusion: AUY922 is active in patients with NSCLC, particularly among patients with ALK rearrangements and EGFR mutations.

Original languageEnglish
Pages (from-to)576-584
Number of pages9
JournalJournal of Thoracic Oncology
Volume13
Issue number4
DOIs
StatePublished - Apr 2018

Fingerprint

Non-Small Cell Lung Carcinoma
Exons
Mutation
5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-morpholin-4-ylmethylphenyl)isoxazole-3-carboxylic acid ethylamide
Night Blindness
erbB-1 Genes
Sequence Deletion
Vision Disorders
Appetite
Platinum
Causality
Protein-Tyrosine Kinases
Nausea
Genes
Diarrhea
Biomarkers
Research Personnel

Keywords

  • ALK rearrangement
  • AUY922
  • EGFR mutation
  • HSP90 inhibitor
  • KRAS mutation
  • NSCLC

Cite this

Felip, Enriqueta ; Barlesi, Fabrice ; Besse, Benjamin ; Chu, Quincy ; Gandhi, Leena ; Kim, Sang We ; Carcereny, Enric ; Sequist, Lecia V. ; Brunsvig, Paal ; Chouaid, Christos ; Smit, Egbert F. ; Groen, Harry J.M. ; Kim, Dong Wan ; Park, Keunchil ; Avsar, Emin ; Szpakowski, Sebastian ; Akimov, Mikhail ; Garon, Edward B. / Phase 2 Study of the HSP-90 Inhibitor AUY922 in Previously Treated and Molecularly Defined Patients with Advanced Non–Small Cell Lung Cancer. In: Journal of Thoracic Oncology. 2018 ; Vol. 13, No. 4. pp. 576-584.
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abstract = "Introduction: In this phase 2 study, we evaluated the activity of AUY922 in pretreated patients with stage IV NSCLC. Methods: Patients with advanced NSCLC were divided into molecularly defined strata based on mutations in the EGFR gene, the ALK receptor tyrosine kinase gene (ALK), the KRAS gene, or the wild type of all three. All patients must have received more than two prior lines of therapy, except for those in a fifth stratum for a less pretreated EGFR cohort (EGFR<2). In the EGFR-mutant and ALK-rearranged strata, prior platinum therapy was not required. Patients with EGFR mutation must have received an EGFR tyrosine kinase inhibitor unless they had de novo resistance (e.g., T790M or exon 20 insertions). Eligible patients received weekly intravenous AUY922, 70 mg/m 2 . The primary objective was to estimate efficacy (complete or partial response, or in the absence of complete or partial response, stable disease) at 18 weeks, by the Response Criteria in Solid Tumors. Results: A total of 153 patients from 21 global centers were enrolled from October 2010 to November 2014. The investigator-assessed overall response rate and stable disease rate at 18 weeks were 31.8{\%} and 9.1{\%} in the ALK-rearranged stratum, 17.1{\%} and 8.6{\%} in EGFR-mutant stratum, 9.7{\%} and 22.6{\%} in the EGFR<2 stratum, 0{\%} and 7.1{\%} in KRAS-mutant stratum, and 8.8{\%} and 8.8{\%} in wild-type stratum. Biomarker data showed activity of AUY922 in EGFR-mutant patients with exon 19 deletion, T790M mutation, and exon 20 insertion. The most common (≥40{\%}) all-causality adverse events were diarrhea, nausea, and decreased appetite. Visual-related disorders were reported in 79.7{\%} of patients (most were grade 1/2). Thirty-five patients (22.9{\%}) reported night blindness. Conclusion: AUY922 is active in patients with NSCLC, particularly among patients with ALK rearrangements and EGFR mutations.",
keywords = "ALK rearrangement, AUY922, EGFR mutation, HSP90 inhibitor, KRAS mutation, NSCLC",
author = "Enriqueta Felip and Fabrice Barlesi and Benjamin Besse and Quincy Chu and Leena Gandhi and Kim, {Sang We} and Enric Carcereny and Sequist, {Lecia V.} and Paal Brunsvig and Christos Chouaid and Smit, {Egbert F.} and Groen, {Harry J.M.} and Kim, {Dong Wan} and Keunchil Park and Emin Avsar and Sebastian Szpakowski and Mikhail Akimov and Garon, {Edward B.}",
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Felip, E, Barlesi, F, Besse, B, Chu, Q, Gandhi, L, Kim, SW, Carcereny, E, Sequist, LV, Brunsvig, P, Chouaid, C, Smit, EF, Groen, HJM, Kim, DW, Park, K, Avsar, E, Szpakowski, S, Akimov, M & Garon, EB 2018, 'Phase 2 Study of the HSP-90 Inhibitor AUY922 in Previously Treated and Molecularly Defined Patients with Advanced Non–Small Cell Lung Cancer', Journal of Thoracic Oncology, vol. 13, no. 4, pp. 576-584. https://doi.org/10.1016/j.jtho.2017.11.131

Phase 2 Study of the HSP-90 Inhibitor AUY922 in Previously Treated and Molecularly Defined Patients with Advanced Non–Small Cell Lung Cancer. / Felip, Enriqueta; Barlesi, Fabrice; Besse, Benjamin; Chu, Quincy; Gandhi, Leena; Kim, Sang We; Carcereny, Enric; Sequist, Lecia V.; Brunsvig, Paal; Chouaid, Christos; Smit, Egbert F.; Groen, Harry J.M.; Kim, Dong Wan; Park, Keunchil; Avsar, Emin; Szpakowski, Sebastian; Akimov, Mikhail; Garon, Edward B.

In: Journal of Thoracic Oncology, Vol. 13, No. 4, 04.2018, p. 576-584.

Research output: Contribution to journalArticle

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T1 - Phase 2 Study of the HSP-90 Inhibitor AUY922 in Previously Treated and Molecularly Defined Patients with Advanced Non–Small Cell Lung Cancer

AU - Felip, Enriqueta

AU - Barlesi, Fabrice

AU - Besse, Benjamin

AU - Chu, Quincy

AU - Gandhi, Leena

AU - Kim, Sang We

AU - Carcereny, Enric

AU - Sequist, Lecia V.

AU - Brunsvig, Paal

AU - Chouaid, Christos

AU - Smit, Egbert F.

AU - Groen, Harry J.M.

AU - Kim, Dong Wan

AU - Park, Keunchil

AU - Avsar, Emin

AU - Szpakowski, Sebastian

AU - Akimov, Mikhail

AU - Garon, Edward B.

PY - 2018/4

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N2 - Introduction: In this phase 2 study, we evaluated the activity of AUY922 in pretreated patients with stage IV NSCLC. Methods: Patients with advanced NSCLC were divided into molecularly defined strata based on mutations in the EGFR gene, the ALK receptor tyrosine kinase gene (ALK), the KRAS gene, or the wild type of all three. All patients must have received more than two prior lines of therapy, except for those in a fifth stratum for a less pretreated EGFR cohort (EGFR<2). In the EGFR-mutant and ALK-rearranged strata, prior platinum therapy was not required. Patients with EGFR mutation must have received an EGFR tyrosine kinase inhibitor unless they had de novo resistance (e.g., T790M or exon 20 insertions). Eligible patients received weekly intravenous AUY922, 70 mg/m 2 . The primary objective was to estimate efficacy (complete or partial response, or in the absence of complete or partial response, stable disease) at 18 weeks, by the Response Criteria in Solid Tumors. Results: A total of 153 patients from 21 global centers were enrolled from October 2010 to November 2014. The investigator-assessed overall response rate and stable disease rate at 18 weeks were 31.8% and 9.1% in the ALK-rearranged stratum, 17.1% and 8.6% in EGFR-mutant stratum, 9.7% and 22.6% in the EGFR<2 stratum, 0% and 7.1% in KRAS-mutant stratum, and 8.8% and 8.8% in wild-type stratum. Biomarker data showed activity of AUY922 in EGFR-mutant patients with exon 19 deletion, T790M mutation, and exon 20 insertion. The most common (≥40%) all-causality adverse events were diarrhea, nausea, and decreased appetite. Visual-related disorders were reported in 79.7% of patients (most were grade 1/2). Thirty-five patients (22.9%) reported night blindness. Conclusion: AUY922 is active in patients with NSCLC, particularly among patients with ALK rearrangements and EGFR mutations.

AB - Introduction: In this phase 2 study, we evaluated the activity of AUY922 in pretreated patients with stage IV NSCLC. Methods: Patients with advanced NSCLC were divided into molecularly defined strata based on mutations in the EGFR gene, the ALK receptor tyrosine kinase gene (ALK), the KRAS gene, or the wild type of all three. All patients must have received more than two prior lines of therapy, except for those in a fifth stratum for a less pretreated EGFR cohort (EGFR<2). In the EGFR-mutant and ALK-rearranged strata, prior platinum therapy was not required. Patients with EGFR mutation must have received an EGFR tyrosine kinase inhibitor unless they had de novo resistance (e.g., T790M or exon 20 insertions). Eligible patients received weekly intravenous AUY922, 70 mg/m 2 . The primary objective was to estimate efficacy (complete or partial response, or in the absence of complete or partial response, stable disease) at 18 weeks, by the Response Criteria in Solid Tumors. Results: A total of 153 patients from 21 global centers were enrolled from October 2010 to November 2014. The investigator-assessed overall response rate and stable disease rate at 18 weeks were 31.8% and 9.1% in the ALK-rearranged stratum, 17.1% and 8.6% in EGFR-mutant stratum, 9.7% and 22.6% in the EGFR<2 stratum, 0% and 7.1% in KRAS-mutant stratum, and 8.8% and 8.8% in wild-type stratum. Biomarker data showed activity of AUY922 in EGFR-mutant patients with exon 19 deletion, T790M mutation, and exon 20 insertion. The most common (≥40%) all-causality adverse events were diarrhea, nausea, and decreased appetite. Visual-related disorders were reported in 79.7% of patients (most were grade 1/2). Thirty-five patients (22.9%) reported night blindness. Conclusion: AUY922 is active in patients with NSCLC, particularly among patients with ALK rearrangements and EGFR mutations.

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