Introduction:

Neoadjuvant cisplatin-based combination chemotherapy improves survival in cisplatin-eligible patients (pts) with muscle invasive bladder cancer (MIBC). However, an unmet need exists in cisplatin-ineligible pts with muscle invasive urothelial carcinoma (MIUC) who are offered upfront surgery. Neoadjuvant immune checkpoint inhibitors (ICIs) followed by radical surgery of MIUC appears safe and active although the benefit may not extend to the majority of pts. The combination of gemcitabine, carboplatin (GCa) and and a PD1/L1 inhibitor has been demonstrated to be safe and active in cisplatin-ineligible metastatic urothelial carcinoma. In the neoadjuvant setting, combination GCa and a PD1/L1 inhibitor may improve outcomes by delivering early systemic therapy to pts with cisplatin-ineligible MIUC. We hypothesized that the combination of GCa and avelumab, a PD-L1 inhibitor, may improve pathologic complete remissions (pCR) and clinical outcomes compared to upfront surgery for MIUC (S2011, NCT04871529).

Methods:

The S2011 multicenter, randomized (1:1), open-label phase II trial compares the combination of GCa and avelumab as neoadjuvant therapy followed by surgery vs. upfront surgery for cisplatin-ineligible MIUC including MIBC and high-risk upper tract urothelial carcinoma. Adjuvant therapy following surgery is deferred to investigator. Eligibility requires predominant urothelial component and cisplatin-ineligibility (≥1 of: Zubrod performance status [PS]=2, creatinine clearance [CrCl] 30 to <60 ml/min, neuropathy >grade 1, hearing loss >grade 1, congestive heart failure >grade 2). The primary objective is pCR. The stratification factors include clinical stage, Zubrod-PS and CrCl. A total of 178 evaluable pts will be enrolled for the trial to have a power of 90% (1-sided alpha 0.05) to detect pCR rate improvement from 15% to 35%. The secondary objectives are toxicities, resectability rates, surgical complications, event-free survival and overall survival. Correlative studies include tumor molecular profiling, blood immune studies, circulating tumor-DNA profiling and radiomics.  

Results:

Conclusion:

Funding: NIH/NCI grants U10CA180888, U10CA180819, U10CA180821, U10CA180820, U10CA180868; and in part byEMD Serono (CrossRef Funder ID: 10.13039/100004755), as part of an alliance between the healthcare business of Merck KGaA, Darmstadt, Germany and Pfizer.