ASCO 2021: PrE0807: A Phase Ib Feasibility Trial of Neoadjuvant Nivolumab Without or with Lirilumab in Cisplatin-Ineligible Patients with Muscle-Invasive Bladder Cancer

( Neoadjuvant cisplatin-based chemotherapy prior to radical cystectomy improves overall survival (OS) in muscle-invasive bladder cancer, but about half of patients are cisplatin-unfit or refuse it. Neoadjuvant immune checkpoint inhibitors can induce a high pathologic complete response rate (ypT0N0). The combination of anti-PD-1 (nivolumab) and anti-KIR (lirilumab) is hypothesized to be safe and has significant activity based on the complementary and possibly synergistic roles in regulating adaptive and innate immune response in muscle-invasive bladder cancer.  KIR2DL modulates the immune microenvironment pathways and lirilumab is a fully human antibody that targets KIR2DL. At the 2021 American Society of Clinical Oncology (ASCO) annual meeting, Dr. Petros Grivas and colleagues presented the results of this phase Ib trial.

This is a phase Ib multi-institutional trial in patients with localized muscle-invasive bladder cancer treated with two neoadjuvant doses (4 weeks apart) of nivolumab alone (480 mg) in cohort 1 or nivolumab (480 mg) + lirilumab (240 mg) in cohort 2 prior to radical cystectomy without adjuvant therapy. Cohorts were enrolled sequentially and were not randomized. Key eligibility criteria included stage cT2-4aN0-1M0, ≥20% tumor content at TURBT, and cisplatin-ineligibility (Galsky criteria) or refusal. The primary endpoint was safety manifested as the rate of  ≥ grade 3 treatment-related adverse events assessed in each cohort with CTCAE v5.0. Key secondary endpoints included the percentage of patients who had radical cystectomy > 6 weeks after last neoadjuvant dose due to treatment-related adverse events, CD8+ T cell density at radical cystectomy, ypT0N0 and < ypT2N0 rates, CD8+ T cell density change between TURBT and radical cystectomy, recurrence-free survival (RFS) and biomarkers in tumor tissue, blood, and urine. The trial design for PrE0907 is as follows:


Among 43 patients enrolled (13 cohort 1, 30 cohort 2), the median age was 75 (51-89), 67% were men, all had performance status ECOG 0-1. Patients were cisplatin-ineligible due to impaired renal function (47%) and hearing loss (37%), while 14 % refused cisplatin. At baseline, 37 patients had cT2 stage, two had cN1, and three cNx disease. In cohort 1 and 2, 13 and 29 patients, respectively, completed intended neoadjuvant treatment, and 41/43 underwent radical cystectomy (12/13 cohort 1, 29/30 cohort 2). One patient progressed to metastatic disease prior to radical cystectomy (cohort 1) and one withdrew consent prior to being treated (cohort 2). Additionally, 1 patient was found to have cervical cancer at radical cystectomy. The median time from the last neoadjuvant dose to radical cystectomy was 27 (95% CI 24-29) days. There was no radical cystectomy delayed > 6 weeks from treatment completion due to treatment-related adverse events. Grade 3 treatment-related adverse events occurred in 0% with nivolumab and 6.7% (90%CI 1.2-19.5%) in nivolumab + lirilumab (1: arthralgia, 1: gout, 2: hip pain) that all resolved, and there were no Grade 4/5 treatment-related adverse events occurred. Of 40 patients with muscle-invasive bladder cancer and radical cystectomy, ypT0N0 rates for nivolumab and nivolumab + lirilumab were 8% and 18%, while < ypT2N0 rates were 17% and 29%, respectively. Data on RFS and OS, and biomarker data were not yet mature.

Dr. Grivas concluded his presentation of the PrE0807 trial with the following summary points:

  • Neoadjuvant nivolumab alone and nivolumab + lirilumab combination prior to radical cystectomy were safe, feasible, and well-tolerated in cisplatin-ineligible patients with muscle-invasive disease
  • ypT0N0 rates were unexpectedly low, especially with nivolumab alone
  • The 2-year RFS as well as blood, urine, and tissue-based marker assessment
  • Two phase 3 trials (NCT03661320; NCT04209114) are evaluating the peri-operative role of nivolumab + chemotherapy +/- Linrodostat in cisplatin-fit and nivolumab +/- Bempeg in cisplatin unfit patients and are also assessing biomarkers

Clinical trial information: NCT03532451

Presented By: Petros Grivas, MD, Ph.D., University of Washington, Fred Hutchinson Cancer Research Center, Seattle Cancer Care Alliance, Seattle, WA

Written By: Zachary Klaassen, MD, MSc, Urologic Oncologist, Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, Twitter: @zklaassen_md at the 2021 American Society of Clinical Oncology (ASCO) Annual Meeting, Virtual Annual Meeting #ASCO21, June, 4-8, 2021

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