Phase II study of the HSP90 inhibitor AUY922 in patients with previously treated, advanced non-small cell lung cancer (NSCLC).

Abstract

7543 Background: AUY922 is a highly potent, non-geldanamycin, HSP90 inhibitor. A Phase I study in advanced solid tumors provided a recommended Phase II dose of 70 mg/m 2 . HSP90 acts as a chaperone of client proteins, including those relevant in NSCLC pathogenesis. This Phase II study assessed AUY922 in pts with previously treated advanced NSCLC stratified by molecular status. Methods: Pts with advanced NSCLC who progressed following ≥2 prior lines of chemotherapy, received AUY922 70 mg/m 2 as a 1-hr infusion once-weekly. Pts were assigned to 4 strata: EGFR activating mutations (EGFR mut), KRAS mut, ALK rearranged (ALK+), or EGFR/KRAS/ALK wild type (wt). Phase II Bayesian hypothesis testing design allowed sharing of information between strata based on assessing similarity in observed response data. Primary endpoint was confirmed (RECIST) objective response rate (ORR) or stable disease (SD) at 18 wks. Secondary endpoints included OS, PFS, and safety/tolerability. Results: A total of 112 pts (median age 60 years; 45% male; 86% adenocarcinoma; 28 [25%] pts KRAS mut; 35 [31%] EGFR mut; 14 [12%] ALK+; 31 [28%] EGFR/KRAS/ALK wt) were treated at the December 16 th 2011 cutoff. Most pts were heavily pretreated: 61% had received ≥3 prior systemic regimens; 64% had WHO PS 1 or 2. Mean duration of exposure was 9.1 wks. The most frequent adverse events (AEs, any grade [Gr]) were diarrhea (73%), visual AEs (71%), and nausea (43%). Most AEs were Gr 1/2; Gr 3/4 AE’s were rare (all <10%). The study is ongoing, and 29 pts were still receiving treatment at the cutoff date. Preliminary clinical activity of AUY922 (RECIST; investigator assessed) was seen with partial responses in 13/101 (13%) pts: 2/8 (25%) ALK+ pts, 6/33 (18%) EGFR mut pts, 4/30 (13%) EGFR/KRAS/ALK wt pts, 0/26 (0%) KRAS mut pts, and 1/4 (25%) pts of unknown status. In ALK+ pts, responses were seen in crizotinib (CRZ)-naive pts, and SD was seen with tumor shrinkage in CRZ-resistant pts. PFS data will be presented. Conclusions: AUY922 had an acceptable safety profile and demonstrated preliminary activity in heavily pretreated pts with advanced NSCLC. This trial demonstrates clinical activity of AUY922 in EGFR mut and EGFR/KRAS/ALK wt NSCLC pts in addition to ALK+ pts.