- The PD-1 inhibitor pembrolizumab has been approved for patients that have progressed during or after previous platinum-based chemotherapy based on the results of a phase III trial [1].
- The PD-1 inhibitor nivolumab has been approved for patients that have progressed during or after previous platinum-based chemotherapy based on results of a phase II trial [2].
- The PD-1 inhibitor pembrolizumab has been approved for patients with advanced or metastatic urothelial cancer ineligible for cisplatin-based first-line chemotherapy based on the results of a phase II trial [3].
- The PD-L1 inhibitor atezolizumab has been approved in patients with advanced or metastatic urothelial cancer ineligible for cisplatin-based first-line chemotherapy based on the results of a phase II trial [4].
Tumor heterogeneity is a challenge for precision oncology. Dr. Todenhofer gives an example of a man in 2014 that underwent a cystectomy for pT2N0M0 urothelial carcinoma that underwent 6 cycles of gem/cis adjuvant chemotherapy, which was followed in mid-2016 by lung and lymph node metastasis for which he received vinflunine. Subsequently, in late 2016 he had a partial response, but progressed with brain and lymph node metastases, followed by a biopsy of the lymph node and brain metastases in 2017. Indeed, genetic heat mapping studies of the lung, brain and lymph node biopsies demonstrated significant tumor heterogeneity.
Plasma ctDNA for the molecular assessment of bladder cancer has also emerged, with early studies reporting comparable tumor genetic make-up when comparing ctDNA samples to metastatic biopsies. The potential applications of ctDNA for bladder cancer patients are numerous, however Dr. Todenhofer feels that the greatest benefit could be in monitoring patients for disease recurrence.
Dr. Todenhofer feels that treatment based on molecular characterization is feasible. The recently published MOSCOTO 01 Trial [5] performed NGS/CGH on biopsies from 843 patients with advanced “hard to treat” cancers (of which 158 were urological malignancies); the median number of prior treatment regimens was 4. Based on these results, an actionable target was found in 411 (48.8%) of patients, and 199 received therapy matched to their molecular alteration. The median time from biopsy to decision in the molecular board was 21 days, and 127 patients received targeted monotherapy and 72 combination targeted treatment. The most common targets in this trial were PIK3CA, ERBB2, and FGFR. Specific targets in patients with partial/complete response included HER2 inhibitors (n=8), FGFR inhibitors (n=4), EGFR inhibitors (n=3), ALK inhibitors (n=3), and PIDK/AKT/mTOR inhibitors (n=2).
It appears that FGFR is the best candidate for future targeted therapy for bladder cancer patients. A phase II study presented at GU ASCO 2018 included 170 patients treated with 3 different regimens of the FGFR inhibitor erdafitinib (10 mg intermittent, 6 mg continuous, 8 mg continuous) [6]. Despite most patients having 1-2 prior treatment regimens, the objective response rate was 35%, which included 42% for patients receiving 8mg of continuous erdafitinib. Based off of these results, the FDA provided approval for erdafitinib in this setting.
Dr. Todenhofer concluded with several take-home points:
- A major change of MIBC guidelines is expected in the field of molecular characterization and systemic treatment of bladder cancer
- In 2025, histopathology will be mostly likely be supplemented by DNA/RNA profiling in the majority of cases
- The identification of specific clusters and their translation into clinical trials will be a key to successful implementation of precision oncology
- The number of treatment options for patients with heavily pretreated bladder cancer will significantly increase as we move towards 2025 (ie. FGFR inhibitors)
- The analysis of ctDNA has a high potential to serve as a tool for both surveillance and personalized therapy
1. Bellmunt J, de Wit R, Vaughn DJ, et al. Pembrolizumab as Second-Line Therapy for Advanced Urothelial Carcinoma. N Engl J Med 2017;376(11):1015-1026.
2. Sharma P, Callahan MK, Bono P, et al. Nivolumab monotherapy in recurrent metastatic urothelial carcinoma (CheckMate 032): A multicentre, open-label, two-stage, multi-arm, phase I/II trial. Lancet Oncol 2016;17(11):1590-1598.
3. Balar AV, Costellano D, O’Donnell PH, et al. First-line pembrolizumab in cisplatin-ineligible patients with locally advanced and unresectable or metastatic urothelial cancer (KEYNOTE-052): A multicentre, single arm, phase 2 study. Lancet Oncol 2017;18(11):1483-1492.
4. Balar AV, Galsky MD, Rosenberg JE, et al. Atezolizumab as first-line treatment in cisplatin-ineligible patients with locally advanced and metastatic urothelial carcinoma: A single-arm, multicentre, phase 2 trial. Lancet 2017;389(10064):67-76.
5. Massard C, Michiels S, Gerte C, et al. High-Throughput Genomics and Clinical Outcome in Hard-to-Treat Advanced Cancers: Results of the MOSCATO 01 Trial. Cancer Discov 2017;7(6):586-595.
6. Loriot Y, Necchi A, Park SH, et al. Erdafitinib (ERDA;JNJ-42756493), a pan-fibroblast growth factor receptor (FGFR) inhibitor, in patients with metastatic or unresectable urothelial (mUC) and FGFR alterations (FGFRa): Phase 2 continuous versus intermittent dosing. J Clin Oncol 36, 2018 (suppl 6S; abstr 411).
Presented by: Tilman W. Todenhofer, University Hospital, Tubingen, Germany
Written by: Zachary Klaassen, MD, Urologic Oncology Fellow, University of Toronto, Princess Margaret Cancer Centre, twitter: @zklaassen_md at the 2018 European Association of Urology Meeting EAU18, 16-20 March, 2018 Copenhagen, Denmark