Outcomes remain poor for patients with advanced squamous-cell non-small cell lung cancer (SCC). Chemotherapy remains the standard 1st line treatment, but benefits are often transient with rapid development of resistance. Heat shock protein 27 (Hsp27) plays a role in apoptosis evasion and is highly expressed in 70-98% of SCCs. Induction of Hsp27 by chemotherapy can be an early compensatory mechanism associated with resistance that can be exploited therapeutically to increase the efficacy of chemotherapy. Apatorsen (OGX-427) is a second generation antisense oligonucleotide that effectively down-regulates Hsp27 in vitro and in vivo. This study investigated whether the combination of Apatorsen and chemotherapy (GC+A) can improve the outcome of patients with advanced SCC compared to treatment with gemcitabine/carboplatin (GC) alone.
This is a multicentre investigator led, randomised (1:1), open-label phase 2 trial, stratified by stage and performance status. A total of 86 patients with newly diagnosed Stage IIIB/IV SCC received up to 6 cycles of gemcitabine (1250 mg/m2) and carboplatin (AUC5) with or without Apatorsen (600 or 400 mg IV/week) until disease progression. Tumour evaluation took place q6 weeks. The primary endpoint was progression-free survival (PFS). Secondary endpoints included safety, Objective response rate (ORR), disease control rate (DCR) and overall survival (OS).
With a median follow up of 20.8 months, there was no difference between both treatment arms in PFS (median PFS, GC 5.7 mths, GC+A 4.9 mths; HR 0.84; 95% CI 0.54, 1.31; p = 0.40) or OS (median OS, GC 11.4 mths, GC+A 8.5 mths; HR 0.68, 95% CI 0.41, 1.13; p = 0.11). ORR was 42% for GC and 33% for GC+A (p = 0.37). DCR was 56% for GC and 42% for GC+A (p = 0.2). There was no difference in chemotherapy dose intensity between both treatment groups. GC+A was associated with increased toxicity compared to GC alone with myelosuppression and infection being most comments adverse events.
This trial failed to demonstrate a benefit for adding apatorsen to standard chemotherapy in newly diagnosed SCC.
Clinical trial identification
EudraCT Number: 2014-000199-25, Clinicaltrials.gov Identifier: NCT02423590
Legal entity responsible for the study
Queen Mary University of London
OncoGenex Pharmaceuticals Inc.
All authors have declared no conflicts of interest.