438O - Phase II activity of the HSP90 inhibitor AUY922 in patients with ALK-rearranged (ALK+) or AGFR-mutated advanced non-small cell lung cancer (NSCLC)

Date 29 September 2012
Event ESMO Congress 2012
Session Developmental therapeutics
Topics Drug Development
Non-Small-Cell Lung Cancer, Metastatic
Presenter Enriqueta Felip
Authors E. Felip1, E. Carcereny2, F. Barlesi3, L. Gandhi4, L.V. Sequist5, S. Kim6, H.J.M. Groen7, B. Besse8, D. Kim9, E.F. Smit10, M. Akimov11, E. Avsar12, S. Bailey13, W. Ofosu-Appiah14, E.B. Garon15
  • 1Medical Oncology, Vall d'Hebron University Hospital, Barcelona/ES
  • 2Medical Oncology Service, Catalan Institute of Oncology, Hospital Germans Trias i Pujol, 08916 - Badalona/ES
  • 3Multidisciplinary Oncology & Therapeutic Innovatio, Aix Marseille Univ, 13915 - Marseille/FR
  • 4Oncology, Dana-Faber Cancer Institute, Boston/US
  • 5Center For Thoracic Cancers, Massachusetts General Hospital, MA 02114 - Boston/US
  • 6Oncology, Asan Medical Center, Seoul/KR
  • 7Pulmonary Diseases, University Hospital Groningen (UMCG), NL-9700 RB - Groningen/NL
  • 8Dept. Of Medicine, Institute Gustave Roussy, 94805 - Villejuif/FR
  • 9Department Of Internal Medicine, Seoul National University Hospital (SNUH), 110-744 - Seoul/KR
  • 10Dept. Of Pulmonary Diseases, Vrije University Medical Centre (VUMC), NL-1081 HV - Amsterdam/NL
  • 11Otm Oncology Translational Medicine, Novartis Pharma AG, CH-4057 - Basel/CH
  • 12Oncology Translational Medicine, Novartis Pharmaceuticals, East Hanover/US
  • 13Biometreics And Data Management, Novartis Pharma AG, Basel/CH
  • 14Oncology, Novartis Oncology, Florham Park/US
  • 15Translational Oncology Research, David Geffen School of Medicine at UCLA, Los Angeles/US

 

Abstract

Background

AUY922 is a highly potent, non-geldanamycin, HSP90 inhibitor. HSP90 is a chaperone of client proteins relevant in NSCLC pathogenesis, including ALK and EGFR. Oncogenic fusion genes giving constitutive ALK activity (ALK+) occur in up to 6% of NSCLCs, and EGFR mutation (mut) occurs in 10–20% of cases. We report data from a Phase II study of AUY922 in patients (pts) with previously treated, advanced NSCLC, stratified by molecular status.

Methods

Pts with advanced NSCLC who progressed following ≥1 prior line of chemotherapy, received AUY922 (70 mg/m2) as a once-weekly, 1-hr infusion. Pts were assigned to 1 of 4 strata: ALK + , EGFR-mut, KRAS-mut, or EGFR/KRAS/ALK wild-type. A Bayesian partially exchangeable multinomial model was used in the statistical analysis of the study. Primary endpoint was confirmed objective response rate or stable disease at 18 wks. Secondary endpoints included OS, PFS, and safety/tolerability.

Results

On 6 April 2012 cutoff, 121 pts had been treated (ALK+ [n = 22; both crizotinib (CRZ) treated and naïve], EGFR-mut [n = 35], KRAS-mut [n = 28], EGFR/KRAS/ALK wild-type [n = 33], undetermined [n = 3]); pts were heavily pretreated (61% had received ≥3 prior regimens). Clinical activity of AUY922 was seen in pts with ALK+ and EGFR-mut NSCLC, with partial responses in 6/21 (29%) pts and 7/35 (20%) pts, respectively. 4/6 ALK+ responders were CRZ-naïve and 2/6 were pretreated. Estimated median PFS rates (FAS) were 42% and 34% at 18 wks in ALK+ and EGFR mut pts, respectively. In EGFR-mut pts who had progressed just after EGFR tyrosine kinase inhibitor (TKI) therapy, median PFS rate at 18 wks was 45% vs 21% in pts who had not received a TKI as their immediate pre-AUY922 therapy. The most frequent adverse events (AEs) were eye disorders (77%), diarrhea (74%), and nausea (46%). Most AEs were grade (Gr) 1/2; Gr 3/4 AEs were rare (all <10%).

Conclusions

AUY922 had an acceptable safety profile. Activity was demonstrated in both ALK+ and EGFR-mut pts. Response and PFS rates suggest further studies are warranted in these patient populations, particularly in EGFR-mut pts who progressed following treatment with TKIs.

Disclosure

L.V. Sequist: I have a paid consulting role for Clovis, Celgene and GSK, and unpaid consulting for Daiichi-sankyo and Merrimack.

H.J.M. Groen: Roche and Eli Lilly sponsored investigator initiated studies - paid to institution UMCG.

M. Akimov: I am an employee of Novartis Pharma AG and have stock ownership in Novartis.

E. Avsar: Empoyee of Novartis.

S. Bailey: Employee of Novartis.

W. Ofosu-Appiah: Employee of Novartis.

E. Garon: I have received reaserch funding from Novartis.

All other authors have declared no conflicts of interest.