ASCO 2020: DUTRENEO Trial: A Randomized Phase II Trial of DUrvalumab and TREmelimumab versus Chemotherapy as a NEOadjuvant Approach to Muscle-Invasive Bladder Cancer Patients Prospectively Selected by an Interferon-Gamma Immune Signature

(UroToday.com) Cisplatin-based neoadjuvant chemotherapy followed by radical cystectomy yields a 30 to 40% pathological complete response rate and also provides a survival benefit of 5% for patients with muscle-invasive bladder cancer.¹ It is currently considered the standard of care for these patients.

However, in the same setting, treatment with new immune checkpoint inhibitors has resulted in a pathological complete response rate of 12 to 46%.^2,3 It appears that tumors that overexpressed PDL-1 have a higher likelihood of achieving a complete pathological response. Importantly, the predictors of these responses are still lacking and need to be defined.^2,3

It has been shown that the expression of specific genes might select for a response to immune checkpoint inhibitors.^4,5 Patients can be classified as “hot” or “cold” by using a TIS score based on 18-gene IFN-y signaling related expression.⁶

The present study aimed to prospectively assess the activity of an anti-PDL-1 (Durvalumab) + anti-CTLA4 (TREmelimumab) Versus chemotherapy in urothelial bladder cancer patients prospectively selected by TIS score. The study design is shown in Figure 1.

Figure 1:

The primary study objective was to measure anti-tumor activity manifested as a complete pathological response. Secondary objectives included overall survival, disease-free survival, and toxicity profile. In addition, there was an exploratory objective to measure biomarker response in tumor samples.  The baseline patient characteristics are shown in Table 1, and the treatment-related adverse events are shown in Figure 2.

Table 1 – Baseline characteristics:

Figure 2 – Treatment-related adverse events:

The Cisplatin dose intensity and surgical outcomes are shown in Table 2. The overall response in the intention to treat population demonstrated a pathological complete response rate of 68.8% in the cold chemotherapy arm, 36.4% in the hot chemotherapy arm and 34.8% in the combined immune checkpoint inhibitor treatment arm, as shown in Table 3.

Table 2 – Cisplatin dose intensity and surgical outcome:

Table 3 – Responses in the intention to treat population:

Patients with high PD L1 expression in their tumor cells demonstrated a higher pathological complete response rate when treated with immune checkpoint inhibitors, but not when treated with chemotherapy, as shown in Figure 3. Lastly, Figure 4 demonstrates the pathological complete response rate stratified by histology.

Figure 3 – Pathological complete response rate by PD-L1 expression tumor cells:

Figure 4 - Pathological complete response rate by histology:

The authors concluded that the pathological complete response rate in tumors selected by the TIS score with DU+TRE was 34.8% in the intention to treat population. The safety profile of the combination of DU+TRE treatment seems better than with chemotherapy. However, the role of a prospective selection using the TIS score remains uncertain. The authors stated that ongoing biomarker studies and the second stage phase of this DUTERENEO study would provide more refined information in the near future.

Presented by: Enrique Grande, MD, Anderson Cancer Center Madrid, Madrid, Spain

Written by: Hanan Goldberg, MD, MSc., Urology Department, SUNY Upstate Medical University, Syracuse, NY, USA, Twitter: @GoldbergHanan, at 

References:

1. Neoadjuvant chemotherapy in invasive bladder cancer: update of a systematic review and meta-analysis of individual patient data advanced bladder cancer (ABC) meta-analysis collaboration. European urology 2005; 48(2): 202-5; discussion 5-6.
2. Necchi A, Raggi D, Gallina A, et al. Updated Results of PURE-01 with Preliminary Activity of Neoadjuvant Pembrolizumab in Patients with Muscle-invasive Bladder Carcinoma with Variant Histologies. European urology 2020; 77(4): 439-46.
3. 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 2019; 25(11): 1706-14.
4. Ayers M, Lunceford J, Nebozhyn M, et al. IFN-γ-related mRNA profile predicts clinical response to PD-1 blockade. The Journal of clinical investigation 2017; 127(8): 2930-40.
5. Necchi A, Anichini A, Raggi D, et al. Pembrolizumab as Neoadjuvant Therapy Before Radical Cystectomy in Patients With Muscle-Invasive Urothelial Bladder Carcinoma (PURE-01): An Open-Label, Single-Arm, Phase II Study. Journal of Clinical Oncology 2018; 36(34): 3353-60.
6. Danaher P, Warren S, Lu R, et al. Pan-cancer adaptive immune resistance as defined by the Tumor Inflammation Signature (TIS): results from The Cancer Genome Atlas (TCGA). Journal for ImmunoTherapy of Cancer 2018; 6(1): 63.