Enriqueta Felip1, Fabrice Barlesi2, Benjamin Besse3, Quincy Chu4, Leena Gandhi5, Sang-We Kim6, Enric Carcereny7, Lecia V Sequist8, Paal Brunsvig9, Christos Chouaid10, Egbert F Smit11, Harry J M Groen12, Dong-Wan Kim13, Keunchil Park14, Emin Avsar15, Sebastian Szpakowski16, Mikhail Akimov17, Edward B Garon18. 1. Vall d'Hebron University Hospital and Vall d'Hebron Institute of Oncology, Barcelona, Spain. Electronic address: efelip@vhio.net. 2. Multidisciplinary Oncology and Therapeutic Innovations Department, Aix-Marseille University, Assistance Publique Hôpitaux de Marseille, Marseille, France. 3. Gustave Roussy Cancer Campus, Villejuif, France, and Paris-Sud University, Le Kremlin-Bicêtre, France. 4. Cross Cancer Institute, Edmonton, Canada. 5. New York University Perlmutter Cancer Center, New York, New York. 6. Oncology, Asan Medical Center, Seoul, Republic of Korea. 7. Catalan Institute of Oncology, Hospital Germans Trias i Pujol, Badalona, Spain. 8. Massachusetts General Hospital Cancer Center, Boston, Massachusetts. 9. Department of Oncology, Oslo University Hospital, Oslo, Norway. 10. Department of Pulmonology, Centre Hospitalier Intercommunal de Créteil, Créteil, France. 11. Department of Pulmonary Diseases, VU University Medical Center, Amsterdam, The Netherlands. 12. Department of Pulmonary Diseases, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands. 13. Seoul National University Hospital, Seoul, Republic of Korea. 14. Innovative Cancer Medicine Institute, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea. 15. Novartis Pharma, East Hanover, New Jersey. 16. Novartis Institutes for Biomedical Research, Cambridge, Massachusetts. 17. Novartis Pharma AG, Basel, Switzerland. 18. David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, California.
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/m2. 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.
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/m2. 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.
Authors: Susan E Jorge; Antonio R Lucena-Araujo; Hiroyuki Yasuda; Zofia Piotrowska; Geoffrey R Oxnard; Deepa Rangachari; Mark S Huberman; Lecia V Sequist; Susumu S Kobayashi; Daniel B Costa Journal: Clin Cancer Res Date: 2018-08-28 Impact factor: 12.531
Authors: Pavel Solopov; Ruben M L Colunga Biancatelli; Margarita Marinova; Christiana Dimitropoulou; John D Catravas Journal: Int J Mol Sci Date: 2020-07-03 Impact factor: 5.923