Complete Response To Tislelizumab In A Muscle- Invasive Urothelial Carcinoma After Surgery Associated With Tumor Mutational Burden High: A Case Report


 Muscle-invasive urothelial carcinoma (MIUC) is a highly aggressive urothelial carcinoma. Radical cystectomy (RC) is standard of treatment, but still more than 50% patients with cancer invading the muscularis propria or involving the regional lymph nodes will have metastatic recurrence. In CheckMate274 study, programmed cell death-1 (PD-1) inhibitor nivolumab as adjuvant treatment has shown effective for patients with MIUC. Tislelizumab is an anti-human PD-1 monoclonal IgG4 antibody which was specifically engineered to minimize FcɣR macrophage binding to abrogate antibody-dependent phagocytosis. But there is no report of tislelizumab as adjuvant treatment in MIUC currently. Here, we report a case of MIUC in a patient with PD-L1-negative, microsatellite stable (MSS), high tumor mutational burden (TMB-H) obtained complete response (CR) receiving tislelizumab therapy after surgery. Progression-free survival (PFS) exceeded 6 months since tislelizumab treatment. To our knowledge, this is the first reported case of MIUC patient with PD-L1-negative, MSS and TMB-H who responded well to tislelizumab as adjuvant treatment. However, we still need more studies to assess the efficacy of tislelizumab as adjuvant treatment in MIUC and to confirm that TMB is a predicted biomarker of tislelizumab for efficacy.

is the rst reported case of MIUC patient with PD-L1-negative, MSS and TMB-H who responded well to tislelizumab as adjuvant treatment. However, we still need more studies to assess the e cacy of tislelizumab as adjuvant treatment in MIUC and to con rm that TMB is a predicted biomarker of tislelizumab for e cacy.

Short Report
Urothelial carcinoma (UC) is the most common tumor of genitourinary malignancy with considerable mortality in the world [1]. Muscle-invasive urothelial carcinoma (MIUC) is a highly aggressive UC. Radical cystectomy (RC) is standard of treatment, but still more than 50% of patients with cancer invading the muscularis propria or involving the regional lymph nodes will have metastatic recurrence [2]. The CheckMate274 study shows that patients with PD-L1 ≥ 1% of high-risk primary invasive UC can bene t from the adjuvant treatment of programmed cell death-1 (PD-1) inhibitor nivolumab [3]. Tislelizumab is an anti-human PD-1 monoclonal IgG4 antibody which was speci cally engineered to minimize Fc R macrophage binding to abrogate antibody-dependent phagocytosis [4]. And tislelizumab has been approved in China to treat patients locally advanced or metastatic UC. But there is no report of tislelizumab as adjuvant treatment in MIUC currently. Here, we report a case of MIUC with PD-L1-negative, microsatellite stable (MSS), high tumor mutational burden (TMB-H) obtained complete response (CR) receiving tislelizumab therapy after surgery. The patient refused chemotherapy due to poor physical conditions. As an alternative, precise treatment was considered, PD-L1 IHC assay (SP263) and a pan-panel 539 genes next-generation sequencing (NGS) analysis was performed on formalin-xed and para n-embedded specimens and white blood cell. The status of microsatellite instability (MSI) was evaluated as MSS based on NGS, and TMB was calculated to be 21.28 Muts/Mb and evaluated as TMB-H. Meanwhile, 37 somatic genetic mutations (Supplementary Table S1) and 6 germline mutations (Supplementary Table S2 In NCT04004221/CTR20170071 study, tislelizumab has shown antitumor activity in patients with previously treated metastatic PD-L1 -positive UC with 24% ORR as second-line treatment [5]. Based on the data of this research, tislelizumab had been approved in China to treat patients with high PD-L1 expression with locally advanced or metastatic UC who have failed platinum containing chemotherapy.
However, the e cacy of tislelizumab as a postoperative adjuvant treatment in MIUC has not yet been reported. In our case, the residual lesions obtained CR after receiving tislelizumab as adjuvant treatment, and PFS lasted for 6 months. This shows that tislelizumab is effective in the adjuvant treatment of MIUC.
NCT04004221/CTR20170071 study results had shown that treatment-experienced patients with PD-L1positive UC can bene t from tislelizumab [5]. However, clinical bene t from tislelizumab was only observed in patients with PD-L1-negative UC with 18% ORR in CTR20160872 study [6]. Only 4 UC patients with PD-L1-positive were enrolled to this trial may be the reason for this phenomenon. This also indicates that UC patients with PD-L1-negative can bene t from tislelizumab. Besides PD-L1 expression, MSI and TMB have also been regarded as a predictive biomarker of immunotherapy response. Our patient was PD-L1-negative, MSS and only TMB-H. Residual lesions attained complete remission after tislelizumab treatment. This indicates that tislelizumab might be a promising treatment option for MIUC patients with PD-L1-negative, MSS and TMB-H.
To our knowledge, this is the rst reported case of MIUC patient with PD-L1-negative, MSS and TMB-H who responded well to tislelizumab as adjuvant treatment. However, we still need more studies to assess the e cacy of tislelizumab as adjuvant treatment in MIUC and to con rm that TMB is a predicted biomarker for e cacy.

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