ASCO GU 2023: Co-Primary Endpoint Analysis of HCRN GU 16-257: Phase 2 Trial of Gemcitabine, Cisplatin, plus Nivolumab with Selective Bladder Sparing in Patients with Muscle-Invasive Bladder Cancer (MIBC)

(UroToday.com) The 2023 American Society of Clinical Oncology Genitourinary (ASCO GU) cancers symposium held in San Francisco, CA between February 16^th and 18^th was host to a urothelial carcinoma rapid abstract session. Dr. Matt Galsky presented the co-primary endpoint analysis of HCRN GU 16-256, a phase II trial of gemcitabine, cisplatin, plus nivolumab with selective bladder sparing in patients with muscle-invasive bladder cancer.

Dr. Galsky began his presentation by recapping that cisplatin-based neoadjuvant chemotherapy (NAC) yields pathologic complete responses (pCR) in approximately 30 to 40% of patients with muscle invasive bladder cancer (MIBC).¹ Furthermore, patients with pCR have significantly better survival outcomes.

Unfortunately, as of date, a pCR can only be determined after the bladder has already been removed. One bladder-sparing paradigm that has been proposed it to treat MIBC patients with “neoadjuvant” chemotherapy, following which patients are clinically re-staged. Those with a clinical CR would avoid a radical cystetomy, whereas those without a CR would proceed to surgery. 

Historical barriers to the adoption of this bladder-sparing paradigm include:

1. Paucity of prospective studies
2. Lack of rigorous methods to measure and define clinical CR
3. Limited understanding of the role of “delayed” cystectomy in patients with local recurrence
4. Suboptimal systemic therapeutic regimens
5. Absence of biomarkers to refine decision making

As such, Dr. Galsky and colleagues designed the HCRN GU16-257 trial. As demonstrated in the figure below, this trial included patients with cT2-4aN0M0 cisplatin-eligible patients. All patients received the combination of gemcitabine + cisplatin + nivolumab for 4 cycles. Afterwards, patients were clinically restaged using cystoscopy, biopsies, urine cytology, and MRI. Patients with a clinical CR were offered either a radical cystectomy or no cystectomy (with a further 8 cycle of nivolumab akin to adjuvant ICI in patients post-cystectomy), per patient choice. Patients without a clinical CR proceeded to surgery.

The co-primary endpoints were:

1. Clinical CR rate
2. Performance of clinical CR in predicting treatment benefit, as defined by:
   1. 2-year metastasis-free if no cystectomy
   2. pCR in immediate cystectomy

This trial recruited 76 patients of whom 72 underwent clinical re-staging. Of these 72 re-staged patients, 33 (43%) had a clinical response and 32/33 chose against proceeding with cystectomy.

The plot below demonstrates the outcomes of patients achieving a clinical CR (n=33), with 9 patients eventually undergoing a delayed radical cystectomy, often after evidence of local recurrence, with 2/33 patients developing metastases. The median follow-up for these patients with a clinical CR was 30 months (range: 18 to 42 months). The bladder-intact MFS in this patient cohort is demonstrated below:

Patients with a clinical CR had significantly better MFS and OS as demonstrated in the KM curves below. Clinical CR predicted treatment benefit with appositive predictive value of 0.96 (95% CI: 0.89 – 1.0).

Analysis of TMB, including RB1, ATM, ERCC2, FANCC, and TP53, demonstrated that bladder-intact MFS in the overall cohort was significantly improved for patients with higher TMBs (>10):

Dr. Galsky concluded his presentation as follows:

• Gemcitabine, cisplatin, plus nivolumab after TURBT was associated with a clinical CR rate of 43%
• Standardized clinical response assessment with a uniform complete CR definition identified patients with particularly favorable outcomes and facilitated bladder sparing
• These findings may help advance a more personalized approach to the management of MIBC leveraging clinical response-based risk stratification

Presented by: Matt D. Galsky, MD, FASCO, Professor of Medicine, Director of Genitourinary Medical Oncology, The Tisch Cancer Institute, Mount Sinai, New York, NY

Written by: Rashid Sayyid, MD, MSc – Society of Urologic Oncology (SUO) Clinical Fellow at The University of Toronto, @rksayyid on Twitter during the 2023 American Society of Clinical Oncology Genitourinary (ASCO GU) Cancers Symposium, San Francisco, CA, February 16th – February 18th, 2023

Reference:

1. Pfister C, et al. Dose-Dense Methotrexate, Vinblastine, Doxorubicin, and Cisplatin or Gemcitabine and Cisplatin as Perioperative Chemotherapy for Patients With Nonmetastatic Muscle-Invasive Bladder Cancer: Results of the GETUG-AFU V05 VESPER Trial. J Clin Oncol 2022;40(18):2013-2022.