ESMO 2021: Cisplatin-Related Immunomodulation and Efficacy with Atezolizumab + Cisplatin Versus Carboplatin-Based Chemotherapy in Metastatic Urothelial Cancer

(UroToday.com) The European Society of Medical Oncology (ESMO) 2021 annual meeting’s non-prostate cancer mini-oral session included a presentation by Dr. Matthew Galsky discussing results of cisplatin-related immunomodulation and efficacy with atezolizumab + cisplatin versus carboplatin-based chemotherapy in metastatic urothelial cancer. Cisplatin but not carboplatin-based chemotherapy leads to durable disease control in a subset of patients with metastatic urothelial cancer, but the underlying mechanisms remain elusive. Exploratory data from the randomized phase III IMvigor130 study1 suggest improved OS with the addition of atezolizumab to cisplatin but not carboplatin-based chemotherapy. Together, these findings raise the hypothesis that cisplatin may be associated with specific favorable immunomodulatory effects. Furthermore, the effects of cisplatin +/- atezolizumab on overall survival are most prominent in patients with PD-L1 IC-high tumors as depicted in the following table:

 

 Cisplatin-0.jpg 

For the current analysis, single-cell RNA sequencing was performed on peripheral blood mononuclear cells (PMBCs) obtained at Cycle 1 Day 1 and Cycle 3 Day 1 from 70 IMvigor130 patients receiving atezolizumab + platinum and gemcitabine (platinum [cisplatin or carboplatin]/gemcitabine; Arm A) or placebo + platinum/gemcitabine (Arm C):

Cisplatin-1.jpg  

Gene expression profiling of paired pre-/post- neoadjuvant gemcitabine + cisplatin samples were used to study cisplatin-related changes in the tumour microenvironment (tumor microenvironment; n=113).

In IMvigor130 Arm C cisplatin- vs carboplatin-treated patients, on-treatment enrichment of Hallmark TNFα signaling via NFkB and inflammatory response gene sets was observed across all immune cell clusters, with trends even more pronounced in Arm A. Among the top-ranked genes enriched in PBMCs post-cisplatin versus post-carboplatin was NINJ1, which mediates plasma membrane rupture during lytic cell death, releasing damage-associated molecular patterns (eg, HMGB1). In a separate cohort in the neoadjuvant setting, TNFα signaling via NFkB was also enriched in paired tumour samples post- versus pre-gemcitabine + cisplatin chemotherapy:

Cisplatin-2.jpg 

Dr. Galsky concluded his presentation with the following take-home messages:

  • In this exploratory analysis from IMvigor130, PD-L1 IC2/3 status was associated with longer OS in cisplatin- but not carboplatin-treated patients with metastatic urothelial cancer
  • Cisplatin- versus carboplatin-based chemotherapy was associated with increased innate and adaptive immune gene expression – both in circulating immune cells in patients with metastatic urothelial carcinoma enrolled in IMvigor130 and in the tumor microenvironment in neoadjuvant cisplatin + gemcitabine-treated MIBC cohort
  • These data suggest that cisplatin + gemcitabine enhances anti-tumor immunity, particularly when combined with atezolizumab (ie. as seen when comparing IMvigor Arms A and Arm C), potentially through the induction of immunogenic cell death
  • These data may provide fundamental insights regarding the mechanisms underlying durable disease control achieved in the subset of patients with metastatic urothelial carcinoma treated with cisplatin-based chemotherapy +/- atezolizumab 


Presented by: Matthew D. Galsky, MD, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY

Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, @zklaassen_md on Twitter during the 2021 European Society for Medical Oncology (ESMO) Annual Congress 2021, Thursday, Sep 16, 2021 – Tuesday, Sep 21, 2021.

References:

  1. Galsky MD, Arranz Arija JA, Bamias A, et al. Atezolizumab with or without chemotherapy in metastatic urothelial cancer (IMvigor130): A multicentre, randomized, placebo-controlled phase 3 trial. Lancet. 2020 May 16;395(10236):1547-1557.
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