A Randomized Phase II Study of Coexpression Extrapolation (COXEN) with Neoadjuvant Chemotherapy for Bladder Cancer (SWOG S1314; NCT02177695)

Abstract

Purpose: Dose-dense Methotrexate-Vinblastine-Adriamycin-Cisplatin (ddMVAC) and Gemcitabine-Cisplatin (GC) are accepted neoadjuvant regimens for muscle-invasive bladder cancer (BC). The aim of this study was to validate the score from a Coexpression extrapolation (COXEN) algorithm-generated gene expression model (GEM) as a biomarker in patients undergoing radical cystectomy.Experimental Design: Eligibility included cT2-T4a N0 M0, urothelial BC, ≥ 5 mm of viable tumor, cisplatin eligible, with plan for cystectomy; 237 patients were randomized between ddMVAC, given every 14 days for 4 cycles, and GC, given every 21 days for 4 cycles. The primary objective assessed pre-specified dichotomous treatment specific COXEN score as predictive of pT0 rate or ≤ pT1 (downstaging) at surgery.Results: Among 167 evaluable patients, the odds ratio for pT0 with the GC GEM score in GCtreated patients was 2.63 (p=0.10; 95% CI [0.82,8.36]); for the ddMVAC COXEN GEM score with ddMVAC treatment, the OR was 1.12 (p=0.82, 95% CI [0.42, 2.95]). The GC GEM score was applied to pooled arms (GC and ddMVAC) for downstaging with an OR of 2. 33 (p=0.02; 95% CI [1.11, 4.89]). In an intention to treat analysis of eligible patients (n=227), pT0 rates for ddMVAC and GC were 28% and 30% (p = 0.75); downstaging was 47% and 40% (p = 0.27), respectively. Conclusion:Treatment-specific COXEN scores were not significantly predictive for response to individual chemotherapy treatment. The COXEN GEM GC score was significantly associated with downstaging in the pooled arms. Additional biomarker development is planned. *These patients are included in secondary analysis of intent-to-treat comparison of path response rates between arms Flaig et al.

Curative Effect and Survival Assessment Comparing Gemcitabine and Cisplatin Versus Methotrexate, Vinblastine, Doxorubicin and Cisplatin as Neoadjuvant Therapy for Bladder Cancer: A Systematic Review and Meta-Analysis

“…However, in 2021, Pfister C. et al. performed the latest VESPER randomized phase III trial with a large sample size and prospectively demonstrated the superiority of ddMVAC ( 25 ), which was taken as strong evidence in our meta-analysis. The results of this large-scale clinical trial showed that although GC was more manageable with slighter asthenia and gastrointestinal side effects than ddMVAC, the latter had a higher local control rate and showed prominent advantage in pathological response.…”

“…A total of 18 reports of 3116 patients receiving neoadjuvant chemotherapy were included, comprising 4 RCTs and 14 retrospective studies (8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25). All 18 articles provided comparative outcomes of PCR, in which seven studies had PPR outcomes and four studies conducted survival analyses.…”

Bladder cancer: shedding light on the most promising investigational drugs in clinical trials

“…** COXEN is an algorithm that predicts drug sensitivity of a previously analyzed panel of diverse cancer cell models. COXEN trial (NCT02177695) which was designed to assess the utility of a gene expression based biomarker to predict pathologic responses in patients receiving NAC showed similar results comparing ddMVAC and GC in a secondary analysis [27]. While VESPER will likely answer whether to use ddMVAC or GC, several different strategies are also being tested to improve outcomes from neoadjuvant therapy.…”

Bladder Cancer: Current Challenges and Future Directions

“…According to one such study, basal tumors were observed to provide the most significant improvement in OS with NAC compared to surgery alone, whereas luminal tumors were associated with the best outcome regardless of perioperative treatment [ 40 ]. However, in a randomized, phase II SWOG S1314 study, the score generated based on gene expression profile failed to predict the response to NAC in patients undergoing radical cystectomy [ 41 ]. This and other studies suggest that additional factors beyond genetic profiles must be taken under consideration to predict the response to NAC.…”