SUO 2019: The S1314 COXEN Trial – Results and Next Steps in Personalized Systemic Therapy

Washington, DC (  At the SUO 2019 meeting in Washington, DC, during the Bladder Cancer Session II Session, Drs. Flaig and Meeks presented on SWOG S1314: A Randomized Phase II Study of Co-Expression Extrapolation with Neoadjuvant Chemotherapy for Localized, Muscle-Invasive Bladder Cancer. Their talk was focused on lessons learned from this trial and the next steps in personalized systemic therapy.

Dr. Flaig started the presentation with the background of this trial. Both dose-dense Methotrexate-Vinblastine-Adriamycin/doxorubicin-Cisplatin (ddMVAC) and Gemcitabine-Cisplatin (GC) are accepted neoadjuvant regimens for muscle-invasive bladder cancer (MIBC). The use of this therapy, despite level one randomized data support, remains suboptimal. To date, there are no predictive biomarkers in use for cytotoxic chemotherapy in this setting. The NCI-60 consists of 60 cell lines from nine common cancer types and provides a rich dataset for evaluating gene expression profiling of drug sensitivity. COXEN represents a “correlation of correlations,” allowing for the application of in vitro NCI-60 results to individual patients. The first step in this process is the identification of the gene expression associated with individual drug sensitivity in the NCI-60. These genes are then compared with the application set to identify concordant genes. By comparing the NCI-60 results with the gene expression of the target findings, a correlation coefficient (COXEN coefficient) is derived.

The trial schema and results have been previously presented at ASCO 2019 annual meeting. Briefly, eligible patients were randomized to either GC or ddMVAC and then underwent radical cystectomy with pelvic lymph node dissection. Eligible patients were T2-T4a N0M0 urothelial carcinoma patients. None of the patients received prior chemotherapy for urothelial carcinoma. The performance status was 0 or 1, the creatinine clearance was ≥60 ml/min, and patients could not have any hearing impairment. The primary objective was to characterize the relationship of dd MVAC- and GC- specific COXEN scores in terms of pathological stage T0 rate at cystectomy in patients treated with neoadjuvant chemotherapy (NAC). This was performed by assessing whether the COXEN score was prognostic of pathological T0 rate or ≤ pathological stage T1. The authors also assessed, in a preliminary fashion, whether the COXEN score is a predictive factor distinguishing between these two chemotherapy regimens. The results demonstrated that COXEN was not predictive of response by treatment arm. As a phase two study, there was low statistical power to detect this. It was shown that GC was predictive of pathologic response to chemotherapy in a pooled analysis of patients from both arms.

Dr. Flaig then highlighted the next steps for personalized systemic therapy. A randomized biomarker-driven trial in bladder cancer is achievable, and future studies will also require the broad support of the bladder cancer community. Non-evaluable subjects were a limitation of the COXEN trial. Accrual goal was increased from 212 to 237, but the trial still did not have 184 evaluable patients. The main reason for this was inadequate chemotherapy and no cystectomy within 100 days. There is also a need to define adequate therapy. The trial included a specific direction for four cycles of ddMVAC or GC chemotherapy, but in future trials, adequate versus ideal treatment can be differentiated. Possibly, three or even two cycles can be considered adequate. Another limitation was adequate tissue collection. This is essential to a biomarker trial, and therefore making tissue submission should be part of the eligibility. There is also a need to define tissue block versus slides submission as many institutions will only be able to send slides. Dr. Flaig also stressed on setting expectations in phase I and II biomarkers studies by identifying the signals needed from a phase II study to proceed to phase III studies, such as p-value, positive predictive value, negative predictive value, or specificity. Survival data is critical and maybe a better endpoint than pT0 status. There is also a need to maximize the utility of the tissue collected. S1314 has multiple translational aims within the trial to additionally include broad genomic, SNP, miRNA assessments. Broad research access is essential to maximize the positive impact and support.

Dr. Flaig concluded his outstanding summary by stressing that S1314 is an example of a successfully completed biomarker-driven study in MIBC. GC and ddMVAC COXEN scores were not significantly predictive for response in their individual arms. However, the COXEN GC score was shown to be a significant predictor for downstaging when combining subjects in the GC and ddMVAC arms. Future planned analysis with genomic, SNP, CTC, miRNA evaluations are underway. Lessons learned from this trial should be used to inform future studies in this area. Broad support from patients, clinicians, and researchers is essential, along with adequate tissue with precise requirements for therapy. Lastly, the number of non-evaluable patients will likely be higher than 25% and should be adjusted during power and accrual number calculations.

Dr. Meeks then gave a commentary on the COXEN trial and the controversy associated with NAC, such as cost, overtreatment, toxicity, delay in care, and poor acceptance rate. The goal of the COXEN trial was to address these problems. The COXEN trial showed a fantastic progression in a life-cycle of biomarker development from cell lines to retrospective validation, and finally to prospective validation. The strength of the trial was its numbers, with 119 sites enrolling 237 patients with MIBC in less than 3.5 years. The COXEN trial also established that NAC is safe and effective. Also, the pathologic response was between 50 to 60%, which is much higher than the current immunotherapy trials. The GC scores and MVAC scores were different between batches, resulting in a change from the responder to non-responder depending on the batch. The negative predictive value of COXEN was 50%, which was below imaging and exam under anesthesia. The real challenge could be intratumoral heterogeneity and needs to be further evaluated in the context of the COXEN trial. The validity of COXEN could also be established with better statistical methods such as silhouette scores. He then mentioned that other biomarkers such as DNA damage repair alteration genes has shown significant promise, and prospective trials such as RETAIN from Fox Chase Cancer will report exciting data. Dr. Meeks also highlighted several ongoing projects that will benefit from the COXEN trial.

Dr. Meeks concluded his commentary with a summary that GC score is prognostic for cisplatin NAC, but further validation is needed, and there is a significant need in MIBC for biomarker development to predict NAC response.

Clinical Trial Information:  NCT02177695

Presented by:  Thomas W. Flaig, MD, Professor, Medicine-Medical Oncology, Associate Dean for Clinical Research, School of Medicine, the University of Colorado School of Medicine and Joshua J. Meeks, MD, PhD, Assistant Professor of Urology at the Northwestern University Feinberg School of Medicine, Section Chief of Robotic Surgery at the Jesse Brown VA Medical Center

Written by: Abhishek Srivastava, MD, Society of Urologic Oncology Fellow, Fox Chase Cancer Center, Fox Chase Cancer Center, Philadelphia, PA at the 20th Annual Meeting of the Society of Urologic Oncology 2019.Twitter: @shekabhishek at the 20th Annual Meeting of the Society of Urologic Oncology (SUO), December 4 - 6, 2019, Washington, DC

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