658MO Cisplatin (cis)-related immunomodulation and efficacy with atezolizumab (atezo) + cis- vs carboplatin (carbo)-based chemotherapy (chemo) in metastatic urothelial cancer (mUC)

Galsky, Matt D.; Guan, Xingying; Banchereau, Romain; Wang, L.; Zhu, Jun; Yu, Haocheng; Rishipathak, Deepali; Hajaj, Emma; Herbst, R.; Davis, Ian D.; Grande, Enrique; Bamias, Aristotelis; Santis, Maria De; Arranz, José Ángel; Kikuchi, Eiji; Zhang, J.; Lee, C.; Shen, Xuzhuang; Black, Peter C.; Mariathasan, Sanjeev

doi:10.1016/j.annonc.2021.08.054

Cited by 13 publications

(3 citation statements)

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“… 2 3 Cisplatin-based chemotherapy has been shown to exert distinct immunomodulatory effects in patients with mUC, 8 and a recent study demonstrated that measures of pretreatment adaptive immunity, specifically PD-L1 expression on immune cells in the tumor microenvironment, was associated with a higher likelihood of durable disease control. 15 Somatic mutations in DDR genes have also been associated with increased sensitivity to cisplatin-based chemotherapy, as they induce DNA damage which is repaired primarily by the nucleotide excision repair pathway. 16 DDR alterations, specifically those causing deficiencies in the mismatch repair pathway, are also linked to response to ICIs across multiple cancer types, 17 thought to be driven by enhanced mutagenicity and neoantigen exposure.…”

Section: Discussionmentioning

confidence: 99%

“… 19 While combination trials with platinum-based chemotherapy plus PD-1/PD-L1 blockade in patients with mUC have not demonstrated significant improvements in overall survival, these trials included patients receiving both cisplatin-based and carboplatin-based chemotherapy which may be associated with different immunomodulatory effects. 15 Analyses of ongoing randomized studies will be needed to better understand the contribution of individual treatment components.…”

Section: Discussionmentioning

confidence: 99%

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Antitumor immunity as the basis for durable disease-free treatment-free survival in patients with metastatic urothelial cancer

Anker,

Pal,

Kim-Schulze

et al. 2023

J Immunother Cancer

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Cisplatin-based chemotherapy has been associated with durable disease control in a small subset of patients with metastatic urothelial cancer. However, the mechanistic basis for this phenomenon has remained elusive. Antitumor immunity may underlie these exceptional responders. In a phase II trial evaluating a phased schedule of gemcitabine and cisplatin followed by gemcitabine and cisplatin with ipilimumab for metastatic urothelial cancer, 4 of 36 patients achieved durable disease-free treatment-free survival (DDFTFS) and remain in remission over 5 years after enrolment on the study. We sought to identify the genomic and immunological mechanisms associated with functional cures of such patients. Whole exome sequencing was performed on pretreatment archival tumor tissue. Neoantigen prediction and ranking were performed using a novel pipeline. For a subset of patients with available biospecimens, selected peptides were tested for neoantigen-specific T cell reactivity in peripheral blood CD4+and CD8+T cells cultured with autologous antigen-presenting cells at baseline, postchemotherapy, and postchemotherapy and ipilimumab timepoints. Multiplex assays of serum protein analytes were also assessed at each time point. Serum proteomic analysis revealed that pretreatment, patients achieving DDFTFS demonstrated an immune activated phenotype with elevations in TH1 adaptive immunity, costimulatory molecules, and immune checkpoint markers. After combination cisplatin-based chemotherapy and ipilimumab treatment, DDFTFS patients again displayed enrichment for markers of adaptive immunity, as well as T cell cytotoxicity. CD27 was uniquely enriched in DDFTFS patients at all timepoints. Neoantigen reactivity was not detected in any patient at baseline or post two cycles of chemotherapy. Both CD4+and CD8+neoantigen-specific T cell reactivity was detected in two of two DDFTFS patients in comparison to zero of five non-DDFTFS patients after combination cisplatin-based chemotherapy and ipilimumab treatment. Antitumor immunity may underlie functional cures achieved in patients with metastatic urothelial cancer treated with cisplatin-based chemotherapy and immune checkpoint blockade. Probing the mechanistic basis for DDFTFS may facilitate the identification of biomarkers, therapeutic components, and optimal treatment sequences necessary to extend this ultimate goal to a larger subset of patients.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Antitumor immunity as the basis for durable disease-free treatment-free survival in patients with metastatic urothelial cancer

Anker,

Pal,

Kim-Schulze

et al. 2023

J Immunother Cancer

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“…A recent study suggested that only cisplatin and gemcitabine doublet, rather than carboplatin and gemcitabine doublet, had such a synergic effect. 43 However, our study did not include patients treated with cisplatin, and further larger real-world study is required to refine the existing evidence.…”

Section: Discussionmentioning

confidence: 99%

First-line Immune Checkpoint Inhibitor Versus Immune Checkpoint Inhibitor With Chemotherapy for Cisplatin-ineligible Metastatic Urothelial Carcinoma: Evidence From a Real-world, Multicenter Analysis

Lin

Huang

et al. 2022

Journal of Immunotherapy

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Immune checkpoint inhibitors (ICIs) are widely used for first-line cisplatin-ineligible patients with metastatic urothelial carcinoma (mUC). However, whether to use ICIs as monotherapy or in combination with chemotherapy is still uncertain. We retrospectively analyzed cisplatin-ineligible patients with mUC who underwent first-line ICI monotherapy or ICI plus chemotherapy at 2 medical centers in Taiwan from 2016 to 2021. We calculated the objective response rate, progression-free survival, and overall survival (OS) using the Kaplan-Meier method and Cox regression model for multivariable analysis. In total, 130 patients were enrolled and categorized into 2 groups: an ICI monotherapy group [immunotherapy (IO), n=101] and an ICI plus noncisplatin chemotherapy group [immunotherapy and chemotherapy (IC), n=29]. The median OS of patients in the IO and IC groups was 19.5 and 9.7 months (P=0.33). Among patients with high programmed cell death ligand-1–expressing tumors, the median OS was significantly prolonged in the IO group compared with the IC group (not reached vs. 6.3 mo, P=0.02). First-line ICI monotherapy demonstrated robust antitumor activity in cisplatin-ineligible patients with mUC. Combining noncisplatin chemotherapy with ICI did not improve clinical outcomes.

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Precision Medicine in Urothelial Carcinoma: Current Markers to Guide Treatment and Promising Future Directions

Miller,

Galsky

2023

Curr. Treat. Options in Oncol.

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658MO Cisplatin (cis)-related immunomodulation and efficacy with atezolizumab (atezo) + cis- vs carboplatin (carbo)-based chemotherapy (chemo) in metastatic urothelial cancer (mUC)

Cited by 13 publications

References 0 publications

Antitumor immunity as the basis for durable disease-free treatment-free survival in patients with metastatic urothelial cancer

Antitumor immunity as the basis for durable disease-free treatment-free survival in patients with metastatic urothelial cancer

First-line Immune Checkpoint Inhibitor Versus Immune Checkpoint Inhibitor With Chemotherapy for Cisplatin-ineligible Metastatic Urothelial Carcinoma: Evidence From a Real-world, Multicenter Analysis

Precision Medicine in Urothelial Carcinoma: Current Markers to Guide Treatment and Promising Future Directions

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