487 Background: Tumors deficient in DNA mismatch repair (dMMR) exhibit a microsatellite unstable phenotype characterized by high tumor mutational burden and an immunogenic tumor microenvironment. Despite the histology-agnostic approval of pembrolizumab for advanced dMMR/MSI cancers, responsiveness of dMMR/MSI upper tract urothelial cancers (UTUC) to immune checkpoint (IC) blockade remains largely unknown. Methods: Consecutive records of patients (pts) from a single institution with locally advanced unresectable or metastatic dMMR/MSI UTUC who received IC therapy were analyzed. The primary endpoint was assessment of objective response rate (ORR) using RECIST v1.1. Secondary endpoints were progression-free survival (PFS) and overall survival (OS) using the Kaplan-Meier technique. dMMR/MSI status was evaluated by immunohistochemistry (IHC) and/or polymerase chain reaction (PCR). Results: Ten pts were identified with locally advanced unresectable (N = 3) or metastatic (N = 7) dMMR/MSI UTUC who received therapy with IC blockade (pembrolizumab = 7, nivolumab = 2, atezolizumab = 1). Median age was 65.5 (range = 46 – 90). Six pts were male. Seven pts had germline dMMR. MSI was detected by PCR in three pts and dMMR by IHC in seven pts (PMS2/MLH1 loss = 4, MSH2 loss = 1, MLH1 loss = 1, MSH6 loss = 1). Five pts received systemic chemotherapy (2 cisplatin based, 1 carboplatin based, 2 other) prior to IC therapy with two pts (40%) achieving partial response (PR). At a median follow-up of 15.5 months (range: 2 – 43 months), all pts were alive, and none experienced disease progression. PFS and OS at 15.5 months were 100%. The observed ORR was 90% (CI, 55.5%, 99.8%), including 8 pts who achieved complete remission (CR). The median time to best response was 4 months (range: 2 – 8 months). Toxicity leading to treatment discontinuation: 1 (grade 3) pancytopenia, 1 (grade 2) pneumonitis, 1 (grade 2) SICCA-like symptoms. Conclusions: Immunotherapy with IC inhibitors demonstrates excellent clinical activity in advanced dMMR/MSI UTUC. Further studies integrating these agents earlier in the disease course are warranted in this rare but important subgroup. Given the extremely high complete response rate in this population consideration of preference to IC therapy as initial therapy should be entertained if these findings are validated.

TPS4612 Background: MTAP-deficiency occurs primarily due to homozygous loss in chromosome 9p21 and is seen in approximately 25% of urothelial cancers. MTAP-deficiency portends aggressive biology with poorer outcomes than in MTAP-proficient tumors; for example, in the IMvigor210 data, MTAP-deficient patients had median overall survival of 8.0 months, compared to 11.3 months in MTAP-proficient patients (p = 0.042). MTAP-deficient tumors lack salvage nucleotide synthesis pathways and thus are uniquely sensitive to anti-folate agents; however, in prior clinical work with pemetrexed in these tumors, responses are relatively short-lived. In-vivo data has suggested that pemetrexed can increase tumor infiltrating T-cells, macrophages, dendritic cells, and PD-L1 expression in MTAP-deficient tumors and decrease myeloid-derived suppressor cells (MDSCs). As such, it was postulated that sequential treatment with anti-folate chemotherapy (pemetrexed) and immune checkpoint inhibition (avelumab) would improve responses in MTAP-deficient urothelial cancer. Methods: A prospective phase II trial of patients with advanced MTAP-deficient urothelial cancer is being conducted under IRB-approved protocol NCT03744793. This study will enroll 25 patients at a single site (The University of TX, MD Anderson Cancer Center). Key eligibility criteria include patients with advanced MTAP-deficient urothelial cancer with measurable disease in second-line or beyond. MTAP-deficiency is confirmed with CLIA-approved IHC or NGS. Patients are stratified as being IO-pretreated versus IO-naïve. All patients receive a lead-in cycle of pemetrexed (500 mg/m2) followed by combination pemetrexed (500 mg/m2) and avelumab (10 mg/kg) IV every three weeks until disease progression, patient withdrawal, or unacceptable toxicity. Three biopsies per patient with tissue collection at trial baseline, on single agent pemetrexed, and on combination pemetrexed-avelumab are performed. The primary objective of this trial is to evaluate response rate with sequential pemetrexed and avelumab in MTAP-deficient urothelial cancer. Imaging response assessment is done via RECIST v1.1. Secondary objectives are to evaluate progression-free survival (PFS) and overall survival (OS), as well as to perform correlative studies evaluating the effect of this therapy on immune cells and tumor microenvironment. This correlative work includes but is not limited to evaluation of peripheral T-cells, tumor-infiltrating T-cells, macrophages, and MDSCs. Interim analyses for futility and safety occur in cohorts of 5 patients and are performed based on Bayesian sequential methods. Fifteen patients have been enrolled thus far. Clinical trial information: NCT03744793.

Objectives: Multimodal kidney-preserving (MKP) strategies may be an option for patients with localised or locally advanced high-risk upper tract urothelial carcinoma (UTUC) who have a relative contraindication for nephroureterectomy (NU). Materials and methods:We studied patients with UTUC who were managed with MKP strategies, consisting of systemic anticancer therapy, with or without local/ topical strategies after endoscopic control of intraluminal tumours. Primary end points were overall survival (OS) and progression-free survival (PFS).Results: Fourteen patients received MKP treatment between August 2013 and April 2020. Median baseline estimated glomerular filtration rate was 43 mL/min/1.73m 2 .MKP was mainly pursued to avoid dialysis (10/14, 71%), followed by low performance status and/or comorbidities (2/14, 14%). All patients had received systemic therapy: chemotherapy (64%) and immunotherapy (36%). Endoscopic control and/or laser ablation was feasible in 7 (50%) patients. Calculated overall risk of non-organ confined disease was 35%. Predicted 2-year and 5-year relapse-free probability (RFP) was 74% (24-92%) and 62% (10-85%), respectively. Median follow-up was 31 months (95% CI: 22.6, NE), median OS was 48.1 months (95% CI: 48.1, NE) and 2-year OS probability was 0.89 (95% CI: 0.71, 1). Median metastases-free survival was 48.1 months (95% CI: 26.8, NE), median PFS was 22.4 months (95% CI: 15.6, NE) and 2-year PFS probability was 0.48 (0.26, 0.89). Conclusion:Management of high-risk localised or locally advanced UTUC with MKP strategies was associated with good tolerance, preservation of renal function, and comparable PFS and OS to predicted in vulnerable patients. Prospective studies with more patients are needed to evaluate these possible benefits relative to current standards.

428 Background: Bilateral TGCT offers a unique opportunity to elucidate a stem cell versus genetic origin of cancer (Coffey, 2008). Comparison of the epigenetics and genetics of disparate tumors in either synchronous or metachronous bilateral TGCT from the same patients is feasible and may be informative. Methods: We examined the clinical characteristics and natural history of 37 patients with bilateral TGCT. We performed reduced representation bisulfite sequencing (RRBS) of FFPE DNA and whole exon sequencing (WES) of 5 of those patients whose tumor samples were available for the study. Results: We identified 37 patients with bilateral TGCT, who underwent their first orchiectomy between January 1984 and April 2022 and the second between August 1997 and April 2022. Thirty-five (95%) of these patients are still alive. Seven patients had synchronous, while 30 had metachronous bilateral TGCT. There were 13 bilateral seminomas, 14 bilateral nonseminomas, and 10 bilateral seminoma and nonseminoma. For those patients with metachronous bilateral TGCT, the median time between the two TGCT was 59 months (range 6-400). WES revealed a mutation in 189 (<1%) out of about 20,000 genes in the 10 paired samples from 5 patients. A total of 2 genes were mutated in more than 1 sample: KIT (n=4), and KRAS (n=2). Although one patient with synchronous bilateral seminomas shared KIT mutation, another did not with KIT and KRAS mutations (Table). RRBS showed a similar methylation profile in the 2 metachronous nonseminomas, which did not share any genetic mutations in the WES study. Conclusions: The clinical course of our patients with synchronous and metachronous bilateral TGCT and the results of our RRBS and WES reaffirmed that a preponderance of TGCT was curable and alluded to whether its epigenetic vs genetic origins might be causative or contributory to its general curability vs potential lethality. Coffey J et al. Somatic KIT mutations occur predominantly in seminoma germ cell tumors and are not predictive of bilateral disease: report of 220 tumors and review of literature. Genes Chromosomes Cancer 2008;47:34-42. [Table: see text]

Colorectal cancer (CRC) is expected to cause over 50,000 deaths in 2018, making it the 3rd leading cause of cancer-related death in the United States. The cause of CRC is controlled by several factors, including environmental and genetic roles. Lynch syndrome (LS) is a genetic disorder increasing an individual's risk for developing colorectal cancer by as much as 80%. LS is frequently underdiagnosed and most often found after a CRC diagnosis.