ESMO 2021: Cisplatin (Cis)-Related Immunomodulation and Efficacy with Atezolizumab + Cis- vs Carboplatin-Based Chemotherapy in Metastatic Urothelial Cancer (mUC)

( chemotherapy is associated with improved responses and more durable outcomes than carboplatin in mUC, though the mechanisms for this are poorly characterized. An exploratory subset analysis of the IMvigor130 trial suggested that the addition of atezolizumab to cisplatin-based chemotherapy had more efficacy (hazard ratio for overall survival 0.73 (0.54 – 0.98) with cisplatin versus 0.91 (0.74-1.10) with carboplatin in cisplatin-treated patients rather than carboplatin treated patients. Dr. Galsky and colleagues hypothesized that perhaps cisplatin is associated with more favorable immunomodulatory effects that predispose tumors to greater response with immune checkpoint blockade.


First, the authors examined the impact of PD-L1 staining intensity prior to treatment on outcome. As shown in the slide below, patients with high PD-L1 staining (Ventana SP142 assay) tumors tended to have longer survival when treated with cisplatin +/- atezolizumab, but this was not the case with carboplatin.

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Unfortunately, the investigators did not have access to on treatment tumor tissue. So, they hypothesized that single cell analysis of peripheral blood mononuclear cells may show evidence of immunogenic cell death in cisplatin treated patients, but not carboplatin treated patients. This would potentially manifest as expression upregulation of RNA signatures of innate and adaptive immunity at the cycle 3 day 1 timepoint relative to pre-treatment. A total of 142 samples underwent single cell RNA-sequencing. The authors also analyzed a separate cohort of 113 neoadjuvant muscle-invasive bladder cancer samples prior to and after treatment with cisplatin.

The slide below illustrates the gene sets enriched in cisplatin treated samples from the IMvigor130 data set (up-regulated gene sets in cisplatin-treated samples in red). Overall, enrichment of TNF-alpha and interferon-response gene sets was seen with cisplatin treatment, and this was also observed in the neoadjuvant cohort.

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Dr. Galsky concluded that in this exploratory analysis, PD-L1 pre-treatment expression was associated with overall survival in patients on IMvigor130 who received cisplatin chemotherapy. Cisplatin-treated patients, in contrast to those treated with carboplatin, had evidence of up-regulated innate and adaptive immune gene expression in circulating blood cells. These findings may suggest a mechanism whereby a subset of patients on this study achieved durable disease control with cisplatin-based chemotherapy +/- atezolizumab.

Presented by: Matthew Galsky, MD, medical oncologist and director of Genitourinary Medical Oncology at the Tisch Cancer Institute, Icahn School of Medicine at Mt. Sinai, New York, New York, USA

Written by: Alok Tewari, MD, PhD – Genitourinary Medical Oncologist, Instructor in Medicine, Dana-Farber Cancer Institute, Harvard Medical School, Twitter: @aloktewar during the 2021 European Society for Medical Oncology (ESMO) Annual Congress 2021, Thursday, Sep 16, 2021 – Tuesday, Sep 21, 2021.