Targeting FGF in Bladder cancer after Neoadjuvant Immunotherapy and Surgery

Bladder cancer (BC) is the fifth most common cancer in the US and survival for Stage II (muscle-invasive BC, MIBC) cancer approaches 50% at 5 years. The most effective treatment for MIBC include systemic therapy prior to radical cystectomy, yet half of patients are unable to receive cisplatin-based chemotherapy due to advanced age, decreased performance status or poor renal function with the overall use of only 20%. Neoadjuvant immune checkpoint blockade (ICB) for MIBC is not FDA, but was recently reported by my collaborator, Andrea Necchi in which patients received 3 cycles of pembrolizumab prior to radical cystectomy(PURE-01). PURE-01 was successful as all patients tolerated therapy, and 42% achieved a pathologic complete response with 55% downstaged to Stage I or less. Yet, half of tumors did not respond and could have potentially benefited from the addition of a second agent targeting a complimentary pathway. In BC, the FGFR pathways, predominately driven by FGFR3, are altered in up to half of BCs and are often associated with resistance to both chemotherapy and immunotherapy. One agent, rogaratinib, is an oral pan FGFR-inhibitor that demonstrated a 73% disease control rate (complete, partial and stable disease) in patients with advanced BC with FGFR1-4 overexpression. We hypothesize over-expression of FGFR genes, pathways and subtypes are enriched in ICB non-responders. Therefore, if FGFR-responsive tumors could be identified prior to treatment, combination of ICB with FGFR targeting therapy may improve the overall response resulting in a significantly improved survival. From our collaborator Dr. Necchi, 100 pre-treatment TURBT samples have been identified of patients accrued to PURE-01 study. From FFPE slides, tumors will be macrodissected and extraction of RNA will be performed using the Qiagen AllPrep FFPE RNA/DNA extraction methods. RNA will be quantified and analyzed for purity. Libraries will be constructed using Illumina platform TruSeq TotalRNA library construction followed by next generation sequencing. After alignment, trimming and differential expression analysis, we will compare differential expression of FGFR1-4, evaluate for FGFR-fusions and develop tumor subtyping to determine the frequency of “luminal” and luminal-papillary tumors between responders and non-responders to ICB. We will also compare FGFR expression with PDL1 immunohistochemistry, total mutation burden (TMB) and targeted gene sequencing analysis to identify FGFR3 mutations already performed on these tumors. Given published data on response and tolerability to rogaratinib in advanced BC, an increased frequency of FGFR alterations (expression, mutations, and/or subtype) in pembrolizumab non-responders would provide preliminary data to support a clinical trial of neoadjuvant therapy with ICB and rogaratinib for patients with MIBC overexpressing FGFs, FGF alterations or luminal subtype and FGFR alterations may be a biomarker of combination therapy.