Neoadjuvant PD-L1 inhibitor therapy found safe, effective

November 14, 2018

“The results with neoadjuvant atezolizumab are preliminary but promising in this area of high unmet need,” says researcher Thomas Powles, MD.

Results from a phase II study show that neoadjuvant therapy with the programmed death-ligand 1 (PD-L1) inhibitor atezolizumab (Tecentriq) prior to cystectomy is safe, well-tolerated, and associated with a meaningful pathologic complete response (pCR) rate in patients with operable muscle-invasive bladder cancer ineligible for cisplatin-based chemotherapy.

The safety and efficacy of atezolizumab in this clinical setting is being evaluated in ABACUS, an investigator-initiated clinical trial. At the American Society of Clinical Oncology annual meeting in Chicago, Thomas Powles, MD, of Barts Cancer Centre, London, reported outcomes for 68 patients with T2-T4aN0M0 disease who received one or two cycles of atezolizumab. Data from this study was also presented at the European Society for Medical Oncology annual congress in Munich.

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A pCR in ≥20% of patients was a co-primary endpoint for the study. It was achieved in 29% of the 68 patients and in 40% considering the subset of 25 patients with a PD-L1 positive tumor. The pCR rates in the subgroups of patients with T2 and T3/T4 disease were 35% (17/48) and 15% (3/20), respectively. A single patient had significant progression of disease.

The adverse events recorded were consistent with those expected in patients receiving two cycles of atezolizumab. There were no increased safety signals for surgery following atezolizumab.

“Neoadjuvant cisplatin-based chemotherapy is routinely used prior to cystectomy for patients with T2-T4a N0M0 bladder cancer and is associated with a pCR rate of 30% to 40%. A large proportion of patients cannot have this neoadjuvant chemotherapy. Therefore, this alternative approach seems attractive,” said Dr. Powles.

Next:"Longer follow-up in larger patient samples is needed"“The results with neoadjuvant atezolizumab are preliminary but promising in this area of high unmet need. Still, longer follow-up in larger patient samples is needed," Dr. Powles added.

Patients enrolled in ABACUS had transitional cell histology, residual disease after transurethral resection of bladder tumor (TURBT), no evidence of nodal or distant metastasis, and were not fit for chemotherapy. They received up to two cycles of atezolizumab, 1,200 mg given after TURBT and 3 weeks later. Patients underwent cystectomy no more than 8 weeks after TURBT. Cross-sectional imaging (computed tomography/magnetic resonance imaging) was performed before receiving atezolizumab and before cystectomy.

A total of 74 patients were enrolled; 59 patients received two cycles of atezolizumab and 15 patients received a single cycle. Only 67 patients went on to cystectomy, but the efficacy analysis included one patient who did not go on to surgery because of disease progression.

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The rate of pCR and increase in CD8 count were being analyzed as co-primary endpoints. Radiologic response was a secondary endpoint.

“Because of the short period of therapy, we felt it would be challenging to achieve pCRs,” Dr. Powles explained.

Sequential analyses of biomarkers from pathological specimens obtained at TURBT and surgery showed upregulation of PD-L1 and of CD8. The percentage of patients with a PD-L1 positive tumor increased from 35% at baseline to 73% after atezolizumab treatment.

“We don't know the importance of these findings from an outcome perspective, but they show the dynamic biology of the disease and are underpinning the mode of action of atezolizumab in bladder cancer,” Dr. Powles said.

“More detailed analyses of the biomarkers are ongoing.”

The radiologic imaging showed that disease was stable or reduced in size after treatment with atezolizumab. There was no major change in tumor size among patients with T4 disease.

Treatment-related grade 3/4 adverse events included fatigue (3%), transaminitis (4%), anorexia (1%), and pyrexia (1%).  There was one treatment-related death that was due to cardiovascular disease. There were no postoperative deaths, and surgery was essentially safe.

Dr. Powles is a consultant to and receives honoraria from Roche/Genentech and other companies with marketed or investigational products for bladder carcinoma. Several of his co-authors have a disclosure related to Roche/Genentech and/or other pharmaceutical companies.