A Randomized, Double-Blinded, Phase II Trial of Carboplatin and Pemetrexed with or without Apatorsen (OGX-427) in Patients with Previously Untreated Stage IV Non-Squamous-Non-Small-Cell Lung Cancer: The SPRUCE Trial

Abstract

Background. This randomized, double-blinded, phase II trial evaluated the efficacy of carboplatin and pemetrexed plus either apatorsen, an antisense oligonucleotide targeting heat shock protein (Hsp) 27 mRNA, or placebo in patients with previously untreated metastatic nonsquamous non-small cell lung cancer (NSCLC). Methods. Patients were randomized 1:1 to Arm A (carboplatin/ pemetrexed plus apatorsen) or Arm B (carboplatin/pemetrexed plus placebo). Treatment was administered in 21-day cycles, with restaging every two cycles, until progression or intolerable toxicity. Serum Hsp27 levels were analyzed at baseline and during treatment. The primary endpoint was progression-free survival (PFS); secondary endpoints included overall survival (OS), objective response rate, and toxicity. Results. The trial enrolled 155 patients (median age 66 years; 44% Eastern Cooperative Oncology Group performance status 0). Toxicities were similar in the 2 treatment arms; cytopenias, nausea, vomiting, and fatigue were the most frequent treatment-related adverse events. Median PFS and OS were 6.0 and 10.8 months, respectively, for Arm A, and 4.9 and 11.8 months for Arm B (differences not statistically significant). Overall response rates were 27% for Arm A and 32% for Arm B. Sixteen patients (12%) had high serum levels of Hsp27 at baseline. In this small group, patients who received apatorsen had median PFS of 10.8 months, and those who received placebo had median PFS 4.8 months.Conclusion. The addition of apatorsen to carboplatin and pemetrexed was well tolerated but did not improve outcomes in patients with metastatic nonsquamous NSCLC cancer in the first-line setting. The Oncologist 2019;24: e1409-e1416 Implications for Practice: This randomized, double-blinded, phase II trial evaluated the efficacy of carboplatin and pemetrexed plus either apatorsen, an antisense oligonucleotide targeting heat shock protein 27 mRNA, or placebo in patients with previously untreated metastatic nonsquamous non-small cell lung cancer (NSCLC). The addition of apatorsen to carboplatin and pemetrexed was well tolerated but did not improve outcomes in patients with metastatic nonsquamous NSCLC cancer in the first-line setting.

Recent Advances in Oligonucleotide Therapeutics in Oncology

“…Preclinical experiments indicate that apatorsen combined with erlotinib inhibits growth of A549 xenografts significantly, leading to high apoptosis rates compared to controls [ 135 ]. However, three phase 2 trials (NCT01844817 for pancreatic cancer, NCT01829113 for non-squamous-non-small-cell lung cancer, NCT01120470 for prostate cancer) investigating apatorsen combined with chemotherapy did not significantly improve either PFS and OS (NCT01120470 and NCT01844817), or disease response (NCT01829113) in cancer patients without HSP27 level screening ( p > 0.05) [ 136 , 137 , 138 ].…”

Small Heat Shock Proteins in Cancers: Functions and Therapeutic Potential for Cancer Therapy

“…In a Phase II trial for castrate-resistant prostate cancer (CRPC), 71% of patients treated with OGX-427 and prednisone were progression-free at 12 weeks, compared to 40% of patients treated with prednisone alone [ 167 ]. However, in another Phase II trial for metastatic non-small-cell lung cancer (NSCLC), the addition of OGX-427 to the carboplatin–pemetrexed regimen did not improve outcomes and the efficacy of first-line chemotherapy for patients [ 168 ]. More clinical studies are needed to evaluate the efficacy and side effects of OGX-427 as a combinational clinical therapy in the treatment of different cancer patients.…”

Progress in the Use of Antisense Oligonucleotides for Vaccine Improvement

“…Nusinersen was approved for spinal muscular atrophy treatment [50]. Apatorsen is a HSP27 targeting ASO that is being studied in phase II clinical trials in patients with metastatic castration resistant prostate cancer [51] and Untreated Stage IV Non-Squamous-Non-Small-Cell Lung Cancer [52].…”