Introduction:

Patients with predominant variant histologies (pVH) of bladder tumors, usually defined as involving >50% of the tumor specimen, are typically excluded from clinical trials, and for these patients there is no standard neoadjuvant therapy, defining an unmet medical need.

We aimed to evaluate the activity of preoperative pembrolizumab in patients with muscle-invasive bladder carcinoma (MIBC) and variant histologies, enrolled within the PURE-01 study (NCT02736266).

Methods:

In the PURE-01 study, 3 courses of 200 mg pembrolizumab, every 3 weeks, preceding radical cystectomy (RC) were administered in clinical T2-4aN0M0 MIBC. The amended study design included patients with pVH. Pathologic complete response (pT0) in intention-to-treat population was the primary endpoint. Logistic regression models evaluated clinical variables (clinical T-stage and histology) and biomarkers in association with the pathologic response. Biomarker analyses included PD-L1 expression using the combined positive score (CPS, Dako 22C3 antibody) and comprehensive genomic profiling (FoundationONE assay).

Results:

From 02/2017 to 06/2019, 114 patients have been enrolled: 34 (29.8%) presented with VH, including 19 (16.7%) with pVH (Figure). In total, the pT0-rate was 36.8% (95% confidence interval [CI]: 28-46.4) and the pT</=1 rate was 55.3% (95%CI: 45.7-64.6). The majority of pVH patients presented with squamous-cell carcinoma (SCC, N=7), and 6/7 (85.7%) had a downstaging to pT</=1, with one pT0; 2/3 lymphoepithelioma-like (LEL) variants had a pT0 response. None of the remaining 9 pVH had a response. On multivariable logistic regression analyses, tumor mutational burden (TMB) and CPS were associated with pT</=1 response (p=0.015 and p=0.032, respectively), together with the clinical T-stage (p=0.004), regardless of tumor histology (pVH: p=0.32; VH: p=0.92).

Differences in genomic alterations between pVH and UC subgroups involved RB1 (36.8% vs 22.5%, respectively) and ERBB2 copy number alterations (25% vs 7.5%, respectively), whereas FGFR3 alterations were equally observed across the histologic subgroups: 15.5%, 13.3% and 17.5% in pVH, VH, and UC, respectively.

Conclusion:

The updated PURE-01 results confirm the activity of neoadjuvant pembrolizumab in MIBC. Patients with SCC and LEL features should be considered for inclusion in neoadjuvant immunotherapy trials. PD-L1 CPS and TMB may predict the pathological response to pembrolizumab and provide a rationale for selecting patients according to these features instead of the histological bladder cancer subtypes. Furthermore, pVH tumors revealed different opportunities for targeted therapies and a non-overlapping genomic alterations landscape compared to UC or VH.

Funding: Merck