DUTRENEO Trial: A randomized phase II trial of DUrvalumab and TREmelimumab versus chemotherapy as a NEOadjuvant approach to muscle-invasive urothelial bladder cancer (MIBC) patients (pts) prospectively selected by an interferon (INF)-gamma immune signature.

Abstract

5012 Background: Cisplatin-based neoadjuvant chemotherapy (CT) followed by radical cystectomy (RC) is a standard treatment for MIBC. PD-1/L1 inhibitors as single agent induce pathological complete responses (pCR) in this setting. Predictors of response are still ill defined. DUTRENEO trial aimed to prospectively explore the activity of anti-PDL1 + anti-CTLA4 vs CT in pts selected according to a tumor pro-inflammatory IFN-gamma signature (tumor immune score, TIS). Methods: Cisplatin-eligible pts with urothelial MIBC (cT2-T4a, N≤1, M0) candidates to RC were classified as “hot” or “cold” according to a tumor TIS determined by Nanostring technology. Patients with "hot" tumors were randomized to DU 1500 mg + TRE 75 mg every 4 weeks x 3 cycles or standard cisplatin-based CT (GEMCIS or MVACdd). Pts in the “cold” arm received standard CT. Primary endpoint was to achieve ≥8 pCR in the DU+TRE arm. PDL1 expression was assessed using immunohistochemistry. Results: 61 pts were recruited in 10 sites between oct-2018 and dec-2019. Pts randomized in the “hot” arms received standard CT (n = 22) or DU+TRE (n = 23) and had a pCR rate of 8/22 pts (36.4%) vs 8/23 pts (34.8%), respectively [OR = 0.923 (0.26 – 3.24)]. In the “cold” arm, 16 pts received CT obtaining a pCR rate of 68.8% (11/16 pts). There were more PDL1 low tumors in the "cold" TIS arm (10/12, 83.3%). pCR rate by PDL1 status is shown in the table. One pt in the DU+TRE arm refused RC. Full treatment was delivered to 81.3% of CT "cold" vs 59.1% of CT "hot" vs 73.9% in the DU+TRE arm pts. Grade 3-4 toxicities were more frequent in the CT arms. Conclusions: The combination of DU+TRE is safe and active in MIBC patients in the neoadjuvant setting. Nevertheless prospective stratification by a pro-inflammatory IFN-gamma signature failed to select patients more likely to benefit from IO vs CT in this context. Further studies are required to guide treatment selection. Clinical trial information: NCT03472274 . [Table: see text]

Rationale and Outcomes for Neoadjuvant Immunotherapy in Urothelial Carcinoma of the Bladder

“…In contrast to studies with anti-PD1/PD-L1 monotherapy, complete response to ipilimumab plus nivolumab in the NABUCCO trial was independent of baseline CD8 + presence or T-effector signatures [32]. However, recent results from the randomized phase II DUTRENEO trial did not demonstrate enhanced antitumor efficacy in selected patients treated with the combination durvalumab + tremelimumab on the basis of tumor inflammation signature (ie, 18 genes) [37]. Second, PD-L1-positive status evaluated as a CPS correlated separately with pCR in patients who received preoperative pembrolizumab.…”

Three vs. Four Cycles of Neoadjuvant Chemotherapy for Localized Muscle Invasive Bladder Cancer Undergoing Radical Cystectomy: A Retrospective Multi-Institutional Analysis

“…While The PURE-01 trial reported that pembrolizumab was associated with a 37% complete response (pT0) after neoadjuvant therapy, the ABACUS trial showed that atezolizumab yielded a complete response rate of 31%. Conversely, preoperative combination of ipilimumab + nivolumab ( 18 ), cisplatin plus gemcitabine plus pembrolizumab ( 19 ), durvalumab + tremelimumab ( 20 ), was associated with a complete pathologic response rate of 46%, 44, 34.8%, respectively. Combination of 4 cycles of cisplatin-gemcitabine plus 4 cycles of nivolumab in the BLASST-1 trial was able to yield a complete pathologic response rate in 20 of 41 of patients or 49% of patients ( 21 ).…”

Society for Immunotherapy of Cancer (SITC) clinical practice guideline on immunotherapy for the treatment of urothelial cancer

“…Pembrolizumab is also being tested in a randomized phase III trial as adjuvant therapy after radical surgery in patients with muscle-invasive (node-positive) urothelial carcinoma. This trial, AMBASSADOR, is enrolling patients with ≥ypT2 disease and/or nodal involvement at radical surgery after neoadjuvant chemotherapy, or ≥ypT3 disease after no neoadjuvant chemotherapy and 91 However, all other monotherapy and combination studies in table 4 did not identify a significant response correlation with tumor or IC PD-L1 status.…”