Efficacy and Biomarker Analysis of Neoadjuvant Immune Checkpoint Blockade in Urothelial Cancer

Findings from the ABACUS trial

Results from a single-arm phase II study investigating two cycles of atezolizumab before cystectomy in 95 patients with muscle-invasive urothelial cancer show the pathological complete response (pCR) rate of 31%. So, the study achieved the primary efficacy endpoint. Biomarker analysis shows that activated CD8-positive T cells in the tumour and cytotoxic T cell signature correlate with immune response. The ABACUS study findings are published by Prof. Thomas Powles of the Barts Experimental Cancer Medicine Centre, Barts Cancer Institute, Queen Mary University of London (QMUL), London, UK and colleagues on 4 November 2019 in the Nature Medicine.

Cystectomy is the standard of care for patients with muscle-invasive urothelial cancer of the bladder who are not eligible for neoadjuvant chemotherapy. Outcomes are poor and new treatments are needed.

Antibodies targeting PD-1 or PD-L1 such as atezolizumab, show efficacy in a proportion of metastatic urothelial cancers. Biomarkers may facilitate identification of these responding tumours. Neoadjuvant use of these agents is associated with pCR in a spectrum of tumours, including urothelial cancer.

The neoadjuvant setting enabled sequential tissue sampling and the identification of molecular pathways associated with response and relapse. Three biological responses described in the metastatic setting were initially investigated:

  1. Pre-existing CD8-positive T-cell immunity;
  2. Transforming growth factor (TGF)-β, specifically in tumours with an excluded immune phenotype; and
  3. Tumour mutational burden (TMB) in association with DNA damage repair and cell cycle transcriptional signatures.

Exploratory analysis of DNA alterations was also performed to identify makers of response and resistance.

In the Nature Medicine article, the ABACUS investigators present results from a single-arm phase II study with two cycles of atezolizumab before cystectomy in patients with muscle-invasive urothelial cancer. pCR was the primary endpoint. Secondary endpoints focused on safety, relapse-free survival and biomarker analysis.

Between May 2016 and June 2018, 95 patients were recruited from 21 sites. The median follow-up was 13.1 months. In total, 88 patients were assessable for the primary endpoint; 87 patients had cystectomy. Eight patients did not have cystectomy, which in three cases was treatment related. At the time of analysis, 17 patients had relapsed and 17 patients had died (1 post-operative death and 1 treatment-related death). The median time from starting atezolizumab to surgery was 5.6 weeks.

The pCR rate was 31%; therefore, achieving the study primary efficacy endpoint.

Baseline biomarkers showed that the presence of pre-existing activated T-cells was more prominent than expected and correlated with outcome. Other established biomarkers, such as TMB, did not predict outcome, differentiating this from the metastatic setting. Dynamic changes to gene expression signatures and protein biomarkers occurred with therapy, whereas changes in DNA alterations with treatment were uncommon. Responding tumours showed predominant expression of genes related to tissue repair after treatment, making tumour biomarker interpretation challenging in this group. Stromal factors such as TGF-β and fibroblast activation protein were linked to resistance, as was high expression of cell cycle gene signatures after treatment.

The Experiment Cancer Medicine Centre at Barts Cancer Institute organised and had oversight of all aspects of the study. imCORE (Roche) and Histogenex performed aspects of the biomarker analysis. The QMUL was the sponsor of the study. Roche granted QMUL funding for the study and supplied the study drug.

 

Reference

Powles T, Kockx M, Rodriguez-Vida A, et al. Clinical efficacy and biomarker analysis of neoadjuvant atezolizumab in operable urothelial carcinoma in the ABACUS trial. Nature Medicine; Published online 4 November 2019.