HCRN 16-257 is a phase II study exploring a slightly different approach than our traditional treatment paradigms for muscle-invasive bladder cancer. The concept behind this study is that we know that with chemotherapy after TURBT when cystectomy is performed there’s a pathological complete response in the surgical specimen in 30-40% of patients. Now, paradoxically, we only know that after the bladder has been removed but it really raises the question: is there a subset of patients who don’t require cystectomy to achieve cure? I think everyone acknowledges that there probably are, the challenge has been identifying those patients. So we really need biomarkers to define those patients.
Most of the focus has been on molecular or genomic biomarkers, and there is certainly an important role for developing those tools, but we have to recognise that our clinical response assessments are biomarkers as well. So after giving systemic treatment and doing imaging and doing cystoscopies, that’s all a biomarker that needs to be harmonised, needs to be defined, and we need to assess the performance characteristics of those measures in informing treatment decisions, so that’s what we did in 16-257. Patients with muscle-invasive bladder cancer received four cycles of gemcitabine cisplatin plus nivolumab; they underwent clinical restaging which included an MRI of the bladder, cystoscopy, biopsies of the bladder and urine cytology. If all of those assessments were normal then they had the opportunity to not have their bladders removed and an additional eight cycles of nivolumab followed by surveillance. In patients who didn’t have a clinical complete response cystectomy was recommended.
So what we reported was that we enrolled 76 patients, 33 patients achieved a clinical complete response for a clinical CR rate of 43% and clinical CR predicted a benefit as we pre-specified in the study. Benefit was defined as being two years metastasis-free in patients whose bladders were left intact or having a pathological complete response if patients opted for immediate cystectomy. The positive predictive value for that endpoint benefit was 0.96. So clinical complete response is a biomarker and a tool that has prognostic impact that could potentially be used to inform a risk-adapted personalised treatment approach for muscle-invasive bladder cancer instead of treating everyone the same way.