Neoadjuvant atezolizumab plus chemotherapy shows promise in MIBC

Combining the immunotherapy atezolizumab (Tecentriq) with the chemotherapy doublet of gemcitabine and cisplatin (GC) in the neoadjuvant setting showed strong potential in patients with muscle-invasive bladder cancer (MIBC), according to results published in the Journal of Clinical Oncology.¹

The triplet regimen met the primary end point of the study by inducing a pathologic response in 69% of patients, including a 41% pathologic complete response rate.

“Compared with the historical control of neoadjuvant chemotherapy alone and despite low PD-L1 positivity (10%) in the cohort, the addition of atezolizumab to GC resulted in a high rate of non–muscle-invasive downstaging (69%), which correlated with improved relapse-free survival and overall survival,” lead study author Samuel A. Funt, MD, a medical oncology at Memorial Sloan Kettering Cancer Center, and coauthors wrote. No patients failed to undergo timely radical cystectomy because of toxicity, and no unexpected safety signals were observed during treatment or postoperatively.”

The study enrolled patients with cT2 to T4aN0M0 node-negative MIBC who were eligible for RC. Overall, there were 39 evaluable patients enrolled across 5 institutions.

The median patient age was 65 years (range, 58-69), 85% were male, and 64% were current or former smokers. Only 2 patients had prior BCG. The ECOG performance status was 0 for 59% of patients and 1 for 41% of patients. The PD-L1 immune cells score was IC2/3 (≥5%) for 10% (n = 4) of patients and IC0/1 (<5%) for 90% (n = 35) of patients.

Regarding histology at presentation, the majority of patients had either pure urothelial carcinoma not otherwise specified (61.5%), or urothelial carcinoma with squamous differentiation (23.1%). The clinical T stage at presentation was T2N0 for 79% of patients, T3N0 for 18% of patients, and T4aN0 for 3% of patients.

Patients were treated with a single lead-in dose of atezolizumab and 2 weeks later started concurrent GC and atezolizumab over four 21-days cycles followed by RC. Patients could also be treated with 1 final dose of atezolizumab 3 weeks after receiving their last dose of atezolizumab while awaiting RC.

Twenty-seven (69%) patients achieved a pathologic response, defined as pathologic downstaging to non-MIBC (<pT2N0) at RC. Fourteen of the 27 patients reached <pT2N0 in first stage and 13 reached pT2N0in second stage. Sixteen (41%) of the patients were complete responders, defined as downstaging to pT0N0.

PD-L1 was not predictive of achieving a pathologic response. All 4 PD-L1–positive patients achieved pathologic downstaging to pT2N0. Among the PD-L1–negative subgroup, 68% reached <pT2N0.

The median time from the final dose of chemotherapy to RC was 7.8 weeks (range, 5.1-17). Thirty-six (92%) of the 39 evaluable patients received all 4 planned cycles of GC.

The researchers reported that adverse events (AEs) were manageable and did not compromise surgical resection. The most frequently occurring grade 3/4 AEs were neutropenia (36%), lymphopenia (16%), and anemia (11%). All were related to GC chemotherapy. There were no new safety signals regarding grade 3/4 immune-related AEs as compared with those reported in prior studies of atezolizumab. Two patients were treated with high-dose steroids for immune-related AEs.

Funt et al wrote that, going forward, biomarkers should be key component to the design of future studies of this triplet regimen.

“The need for improved biomarkers beyond programmed death-ligand 1 and the association of non–muscle-invasive downstaging and improved outcomes have implications for future trial design.”

Reference

1. Funt SA, Lattanzi M, Whiting K, et al. Neoadjuvant atezolizumab with gemcitabine and cisplatin in patients with muscle-invasive bladder cancer: a multicenter, single-arm, phase II trial [published online ahead of print January 28, 2022]. J Clin Oncol. 2022. doi: 10.1200/JCO.21.01485