Review of SWOG S1314: Lessons from a Randomized Phase II Study of Co-Expression Extrapolation (COXEN) with Neoadjuvant Chemotherapy for Localized, Muscle-Invasive Bladder Cancer

Abstract

SWOG1314 is a randomized phase II study of co-expression extrapolation (COXEN) with neoadjuvant chemotherapy for localized, muscle-invasive bladder cancer. COXEN is a biomarker approach in which predictive biomarkers are developed using in vitro data, which may then be applied directly into a clinical testing application. Two separate Gene Expression Models (GEMs), one for the Methotrexate, Vinblastine, Doxorubicin, Cisplatin (MVAC) regimen and another for gemcitabine plus cisplatin (GC) were tested in S1314. The lessons learned from the development and operationalization of the S1314 clinical trial are described in detail, which may help to inform the future trials of predictive biomarkers for urothelial carcinoma in the neoadjuvant setting. Specific areas addressed include: The need for broad support from the bladder cancer community, planning for non-evaluable subjects, defining adequate neoadjuvant treatment, defining adequate tissue collection, setting expectations in phase II clinical studies of predictive biomarkers, and maximizing the impact of the samples collected in these studies for broader biomarker development. With a large number of newly available treatments in advanced urothelial carcinoma in the last few years, more investigations of these agents in the neoadjuvant setting is anticipated. There will be a great need for the development of predictive biomarkers in conjunction with the use of these agents in the preoperative setting. Insights from S1314 may provide useful information and lessons learned in this development.

Patients with Muscle-Invasive Bladder Cancer with Nonluminal Subtype Derive Greatest Benefit from Platinum Based Neoadjuvant Chemotherapy

“…However, in the recent SWOG S1314 trial, the gene expression-based COXEN (co-expression extrapolation) scores for gemcitabine/cisplatin and dose-dense MVAC (methotrexate, vinblastine, doxorubicin, cisplatin) were not predictive of response to the corresponding therapy. 29 Other ongoing clinical trials (RETAIN: NCT02710734; A031701: NCT03609216; HCRN GU16-257: NCT03558087) are using DNA repair gene mutation status to stratify patients to bladder sparing therapy if the patient achieves a good response to treatment. The data presented in this study set the stage for biomarker selected randomized clinical trials, comparing NAC for all-comers to subtype-selected treatment.…”

Clinical Perspectives of ERCC1 in Bladder Cancer

“…Once identified, nonresponders could avoid pointless systematic toxicity and receive an alternative more suitable therapy. Unfortunately, approximately one third of MIBC patients exhibit a pathologic response to platinum treatment [ 88 , 89 ]. Considering this low response rate, there is an unmet need for the identification of molecular biomarkers that could contribute to treatment optimization in urothelial cancer.…”

Emerging perioperative therapeutic approaches in muscle invasive bladder cancer

“…The odds ratio (OR) for ypT0 with the GC GEM score in GC-treated patients was 2.63 [ p = 0.10; 95% confidence interval (CI) 0.82–8.36] and for the ddMVAC COXEN score, the OR was 1.12 ( p = 0.82, 95% CI 0.42–2.95). 11 …”

“…The odds ratio (OR) for ypT0 with the GC GEM score in GC-treated patients was 2.63 [p = 0.10; 95% confidence interval (CI) 0.82-8.36] and for the ddMVAC COXEN score, the OR was 1.12 (p = 0.82, 95% CI 0.42-2.95). 11 While a formal comparison of efficacy of GC and ddMVAC was not among the stated objectives, as the study was inadequately powered, it did provide an opportunity for a descriptive comparison of efficacy. Reported ypT0 rates between GC and ddMVAC were 32% versus 35%, respectively, and pathologic downstaging < ypT1 occurred in 15% versus 24%, respectively, resulting in CR + pathologic response (PR) rates of 50% for GC and 56% for ddMVAC.…”