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J.P. Marcoux
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P3.01 - Poster Session/ Treatment of Advanced Diseases – NSCLC (ID 208)
- Event: WCLC 2015
- Type: Poster
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 9/09/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P3.01-023 - A Phase II Trial of AUY922, a Heat Shock Protein 90 (HSP90) Inhibitor, in ALK-Positive Lung Cancer Patients Previously Treated with ALK Inhibitors (ID 1739)
09:30 - 09:30 | Author(s): J.P. Marcoux
- Abstract
Background:
Anaplastic lymphoma kinase (ALK) fusions are key oncogenic drivers in non-small cell lung cancer (NSCLC) that confer sensitivity to treatment with ALK tyrosine kinase inhibitors (TKIs), such as crizotinib. Despite this activity, ALK-positive patients ultimately develop resistance to ALK TKIs. In preclinical models, ALK fusion proteins are HSP90 clients and remain sensitive to HSP90 inhibition despite acquired resistance to ALK TKIs. We therefore designed a phase II trial of the HSP90 inhibitor AUY922 in patients with previously treated, ALK-positive NSCLC.
Methods:
In this single-arm, multicenter, open-label study, we enrolled patients with advanced, ALK-positive NSCLC who had failed at least one prior ALK inhibitor. Key eligibility criteria included ECOG PS 0-2, measurable disease based upon RECIST version 1.1, and presence of an ALK rearrangement by FISH. Participants were treated with AUY922 at a dose of 70 mg/m[2 ]IV once weekly until disease progression, unacceptable toxicity, or death. The primary endpoint was objective response rate (ORR) according to RECIST version 1.1. Key secondary endpoints included safety, progression-free survival (PFS), and disease control rate (DCR). The planned sample size was 20 patients.
Results:
Between December 2012 and December 2014, 6 patients were enrolled. Median age was 52.5 years (range 42-54 years). A majority of patients (83%) were female. The median number of prior lines of therapy was 3 (range 2-4). All patients had previously received at least 1 ALK TKI (crizotinib n=5, alectinib n=1), and 2 patients had received a second ALK inhibitor (ceritinib n=2). Most patients (n=4) had received an ALK inhibitor as the last line of therapy prior to enrollment. Among the 6 patients enrolled, no objective responses were observed (ORR 0%). Three patients (50%) had a best response of stable disease (SD), but none remained on therapy beyond 3 months from the time of enrollment (Table). The median PFS was 1.43 months (95% CI 1.3-2.8 months). Common adverse events (AEs) included grade 1-2 diarrhea (83%), vision disorders (50%), fatigue (50%), and constipation (33%). The only treatment-related grade 3 AE was alkaline phosphatase elevation in 1 patient. The study was closed due to poor accrual in December 2012. Table 1Patient Best Response RECIST v1.1. Progression-Free Survival (months) 1 -4.9% 2.80 2 36.5 0.73 3 5.1 1.03* 4 121.9 1.43 5 11 2.60 6 69.5 1.30 * Censored (Discontinued due to toxicity)
Conclusion:
Although limited by a small sample size and premature closure, this study suggests that AUY922 is associated with minimal anti-tumor activity in ALK-positive patients previously treated with ALK inhibitors. Combinations of ALK TKIs and HSP90 inhibitors may represent an alternative strategy, and several such studies are now ongoing.
