The trial schema is shown below.
Patients were eligible for trial enrollment if they were candidates for radical cystectomy, fit for cisplatin therapy (including CrCl >=50), and had cT2-T3a, N<=1, M0 bladder cancer. TURBT samples were collected for molecular correlate studies. Cystectomy was mandated within 6-8 weeks of completing neoadjuvant therapy. The primary endpoint was pathological non-muscle invasive rate (<pT2), and the secondary endpoints were safety and progression-free survival at 2 years. Based on statistical considerations, 41 patients were required for enrollment, and the achievement of 55% of patients having downstaging to non-muscle invasive disease would be a positive study.
The median age of the 41 patients enrolled was 66, range 45-82. Two-thirds of patients were men, and 90% of the cohort had cT2N0 disease. Any patient that received at least one cycle of neoadjuvant therapy prior to cystectomy was considered evaluable. Therefore, all 41 patients were evaluable, and all patients received cystectomy within the specified time range.
The most common grade 3+ treatment-related adverse events were anemia and neutropenia. Fatigue and nausea were the overall most common side effect of therapy. Immune-related adverse events were rare.
Response rates were encouraging in this cohort, with 27/41 or 66% of patients achieving the primary endpoint of non-invasive disease at the time of surgery. Complete responses were seen in 20/41 or 49% of patients. No association was observed between PD-L1 status and response.
Dr. Gupta presented preliminary molecular studies from two patients for whom genomic subtype classifier analysis was performed. Most interestingly, a patient classified as claudin-low (which in prior studies has been a subtype with poorer outcome regardless of neoadjuvant therapy), experienced a complete response with the study neoadjuvant regimen. Further analysis from this cohort will be forthcoming.
In conclusion, the addition of neoadjuvant nivolumab to gemcitabine and cisplatin was able to achieve pathological downgrading in 66% of patients and resulted in pathological complete response rates in 49% of patients. The addition of nivolumab was also safe, with limited additional toxicity. A phase 3 trial, ENERGIZE (NCT03661320), is planned to further evaluate this combination therapy. The planned biomarker correlative studies will help prospectively identify patients who will benefit from this particular neoadjuvant regimen.
Presented by: Shilpa Gupta, MD, Medical Oncologist, Cleveland Clinic, Ohio
Written by: Alok Tewari, MD, Ph.D., Medical Oncology Fellow at the Dana-Farber Cancer Institute, at the 2020 Genitourinary Cancers Symposium, ASCO GU #GU20, February 13-15, 2020, San Francisco, California