Friday, October 24, 2014

Immunotherapy for the Treatment of Bladder Cancer

CASE PRESENTATION


A 57-year-old man presented with a 30-pack year smoking history and high grade non-invasive bladder cancer. He initially underwent resection followed by a course of BCG, but developed a low-grade recurrence. He required further resection and a subsequent course of BCG + Interferon. He was kept on surveillance, but is again found to have T1 high-grade bladder cancer. He is strongly opposed to radical cystectomy and seeks alternative "bladder-sparing" options. Molecular analysis of his tumor was performed and showed FGFR3 mutation.

DISCUSSION

One of the most challenging dilemmas in urologic oncology is the patient with BCG-refractory and recurrent high-grade, non-muscle invasive urothelial cancer of the bladder. These patients are at an extremely high risk of progression to muscle-invasive, dangerous or fatal disease; however, justifying a major extirpative surgery is difficult when no invasive disease is present. This blog will review immunotherapy as a cutting edge therapy for such patients.

At initial diagnosis of bladder cancer, 75% of disease is locally confined, while 25% has advanced to regional/metastatic disease.[1] Of localized disease, 70% is found to be non-muscle invasive.[2] Indeed, molecular analyses of numerous bladder tumors demonstrate that there are two alternative processes that occur in the development of bladder cancer (Figure 1). A hyperplastic process that is associated with mutations in HRAS and FGFR3 genes can occur, leading to a low-grade non-invasive papillary tumor phenotype. Alternatively, a dysplastic process that is associated with loss of tumor suppressors p53 and RB can also occur, leading to an invasive tumor phenotype.[3]

Figure 1. Diagram of alternative processes occurring in urothelial carcinoma. Xu WR. 2005.[3]
Studies looking specifically at FGFR3 mutation status in tumor tissue show that FGFR3 is commonly mutated in non-invasive bladder cancer and also associated with a high level of recurrence.[4] Indeed, mutation occurs more frequently in lower stage and lower grade tumors (Figure 2).

Figure 2. FGFR3 is mutated more frequently in lower stage and grade tumors. Knowles. 2007.[4]

FGFR3 belongs to the Fibroblast Growth Factor Receptor family and includes 18 different proteins (ligands) and 4 different FGF receptors that control functions such as cell differentiation, proliferation, angiogenesis, and invasion.[5] There is a wealth of pre-clinical and laboratory literature that suggests FGFR3 may be an effective therapeutic target in bladder cancer. For instance, a mouse model of bladder tumors demonstrated an 84% reduction in UM-UC1 (a tumor cell line that overexpresses FGFR3), shrinking tumor size and reduced cell proliferation on microscopic examination (Figure 3).[6]

Figure 3. R3Mab, a monoclonal antibody against FGFR3, resulted in smaller UM-UC1 (over-expresses wt FGFR3) tumor xenografts and decreased cell proliferation compared to control IgG in an orthotopic in vivo mouse model. The cell line was transfected with a luciferase plasmid for the bioluminescence scan. Gust et al. 2013.[6]

Dovitinib is an oral medication, classified as a multi-kinase inhibitor with activity against a number of target molecules including FGFR1-4, VEGFR, PDGFR, FLT3, and c-KIT.[7] Laboratory evidence presented by Milowsky et al. demonstrated that Dovitinib could reduce tumor markers and tumor size in a dose-dependent manner, and was superior to tyrosine kinase inhibitors, sorafenib and sunitinib, at inhibiting growth.[8]

There is also clinical data to support the use of Dovitinib. Andre et al. analyzed the effectiveness of Dovitinib in treating women with metastatic breast cancer with FGFR1 mutation. This trial was in a patient population with very advanced disease – 78% of women had liver metastases and had received prior treatment with up to 3 hormone and chemotherapeutic agents or up to 3 chemotherapeutic agents, depending on their hormone receptor status. Nevertheless, there were a greater proportion of the patients treated with Dovitinib that had a partial clinical response or stable disease at ≥ 24 weeks follow up. Furthermore, tumors with large amounts of FGFR1 (amplification greater than 6 copies) showed a 20.2% reduction in tumor burden from baseline compared to tumors with less than 6 copies that had a mean 8.3% increase from baseline. The authors also showed in a waterfall plot that patients with FGF pathway mutation trended toward reduction in tumor burden as compared to increase in tumor burden in those that did not have FGF amplification (Figure 4).[9] Because of its effects against multiple tyrosine kinases, toxicity is a concern for Dovitinib and safety data from the trial showed that nausea, vomiting, diarrhea, and asthenia were common complications. Less common, but more serious complications included: hypertriglyceridemia, pulmonary embolism, and myocardial infarction.

Figure 4. Dovitinib was more effective in reducing tumor burden in tumors with FGF pathway amplification.
From Andre et al 2013.[9]
A recent Dovitinib Trial has opened at Johns Hopkins for the treatment of non-muscle invasive, recurrent bladder cancer.  The trial was designed by Dr. Noah M. Hahn, MD, Associate Professor of Oncology and Urology at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, and is open to patients with histologically confirmed low stage disease (Ta, T1, or Tis), FGFR3 mutation, and documented BCG-refractory disease (evidence of disease after two courses of BCG). Patients are not allowed into the study if they have muscle-invasive disease, non-resectable locally advanced disease, or concurrent upper urinary tract non-invasive urothelial carcinoma. Patients enrolled in the trial will receive Dovitinib 500 mg orally for 5 days on and 2 days off. Cystoscopy with tumor and bladder biopsy, and urine cytology will occur every 3 months. The primary end point of the study is the 6-month complete response rate (no evidence of disease). Other outcomes of interest include the 1-year relapse free survival rate, the rate of progression to invasive bladder cancer, and the 3 and 6-month partial response rates (evidence of disease but lower stage than initially diagnosed). Further information can be found on clinicaltrials.gov: GU12-157.[10]

In conclusion, FGFR3 is a potential therapeutic target in non-invasive urothelial carcinoma and Dovitinib is a multi-kinase inhibitor that may be effective for treatment in this setting. The Dovitinib trial at Hopkins is currently enrolling patients and offers bladder sparing treatment for patients with non-invasive BCG-refractory disease and FGFR3 mutation.



This blog was written by Matthew Lee, a medical student at Columbia University, College of Physicians & Surgeons in New York, New York. Matthew recently finished a four-week sub-internship at the Brady Urological Institute and gave a presentation to the department on "A Phase II Clinical Trial of Dovitinib in BCG Refractory Bladder Cancer" from which this blog is inspired. Matthew is looking forward to a career in urology.








[1] Konety BR, Carroll PR. Urothelial Carcinoma: Cancers of the Bladder, Ureter, & Renal Pelvis. Smith’s Urology. Ch 21. 18 ed. 2013
[2] Pandith AA, Shah ZA, Siddiqui MA. Oncogenic role of fibroblast growth factor receptor 3 in tumorigenesis of urinary bladder cancer. Urologic Oncology: Seminars and Original Investigations. 2013; 31: 398-406. 
[3] Wu XR. Urothelial tumorigenesis: a tale of divergent pathways. Nature Reviews Cancer. 2005; 5:713-25.
[4] Knowles MA. Role of FGFR3 in urothelial carcinoma: biomarker and potential therapeutic target. World J Urology. 2007; 25: 581-593.
[5] Katoh M, Nakagama H. FGF Receptors: Cancer Biology and Therapeutics. Medicinal Research Reviews. 2014; 34(2):280-300.
[6] Gust KM, McConkey DK, Awrey S. et al. Fibroblast growth factor receptor 3 is a rational therapeutic target in bladder cancer. Mol Cancer Ther. 2013; 12: 1245-1254.
[7] Chase A, Grand FH, Cross NCP. Activity of TKI258 against primary cells and cell lines with FGFR1 fusion genes associated with the 8p11 myeloproliferative syndrome. Blood. 2007; 110: 3729-3734.
[8] Milowsky MI. Carlson GL, Shi MM, Urbanowitz G.  Zhang Y.  Sternbeerg CN. A multicenter, open-label phase II trial of dovitinib (TKI258) in advanced urothelial carcinoma patients with either mutated or wild-type FGFR3. Poster presented at ASCO Annual Meeting 2011. J clin ONcol 29: 2011 (suppl; abstr TPS186).
[9] Andre F, Bachelot T, Campone M, et al. Targeting FGFR with Dovitinib (TKI258): Preclinical and Clinical data in Breast Cancer. Clin Cancer Res. 2013; 19: 3693-3702.
[10] Hahn N. Dovitinib in BCG Refractory Urothelial Carcinoma with FGFR3 mutation or overexpression. Clinicaltrials.gov: NCT01732107.

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