Efficacy of immune checkpoint blockade in patients with advanced upper tract urothelial cancer and mismatch repair deficiency or microsatellite instability (MSI).

Abstract

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.

Mismatch repair deficiency and microsatellite instability in urothelial carcinoma: a systematic review and meta-analysis

“…We found that dMMR and MSI-H metastatic UC is responsive to ICI, with included studies reporting ORRs of 50%–90%, 35 36 39 101 deep responses 35 36 39 101 121 126 164 and long durations of response 121 123 126 132 ( online supplemental tables S3 and S4 ). These data show that dMMR and MSI-H may be predictive biomarkers for response to ICI in UC, which has already been prospectively demonstrated in solid tumours.…”

Revisiting Treatment of Metastatic Urothelial Cancer: Where Do Cisplatin and Platinum Ineligibility Criteria Stand?

“…Microsatellite instability, DNA mismatch repair status, and tumor mutational burden have also been associated with response to immunotherapy [ 13 , 102 ]. A classic example of the identification of relevant genetic signatures is the relation between high interferon gamma expression and response to nivolumab in CheckMate 275 [ 103 ].…”

“…Patients with alterations in epigenetic modifiers, such as KDM6A and ARID1A, can benefit from trials of EZH2 inhibitors. Patients with tumors showing high microsatellite instability, high TMB or deficient mismatch repair, might benefit more from enrollment in immunotherapy trials [ 102 ]. Although not compared head-to-head with EVP in patients with FGFR alterations, the combination of erdafitinib plus cetrelimab in the NORSE trial showed an ORR of 54.5% and a median OS of 20.8 months [ 39 ].…”

Clinical and Biological Differences between Upper Tract Carcinoma and Bladder Urothelial Cancer, Including Implications for Clinical Practice

“…In the phase 2 mono-arm TROPHY-U-01, 113 patients with metastatic UC and disease progression after prior platinum-based and anti PD(L)-1 therapies were allocated to receive sacituzumab govitecan, an anti-Trop2 antibody conjugated to SN-38 (an active metabolite of irinotecan) [84]. While the inclusion criteria allowed for the admission of patients with UTUC, no data for this population have been published.…”