Neoadjuvant pembrolizumab ‘worthwhile’ for some invasive bladder cancers
medwireNews: Neoadjuvant pembrolizumab therapy results in an “impressively high” pathologic complete response (pCR) rate among patients with programmed cell death ligand 1 (PD-L1)-positive muscle-invasive bladder carcinoma (MIBC), researchers say.
“This study indicates that pembrolizumab could be a worthwhile neoadjuvant therapy” in specific groups of patients with MIBC, Andrea Nechhi (Istituto Nazionale dei Tumori, Milan, Italy) and co-authors remark.
The PURE-01 study included 50 patients with MIBC, predominantly of urothelial carcinoma histology. Of these, 54% had a clinical (c)T3 tumor, 42% had a cT2 tumor, and 4% had cT2-3N1 disease.
All but one patient completed the planned three cycles of pembrolizumab 200 mg given every 3 weeks before radical cystectomy. The patient who discontinued pembrolizumab experienced a grade 3 transaminase increase but still underwent radical cystectomy without delay. There were only two other cases of grade 3 or higher adverse events (hyperkalemia and diarrhea), neither of which delayed surgery.
Following radical cystectomy, 21 (42.0%) patients achieved a pathologic complete response (pT0), while a further six patients had residual pTa, pTis, or pT1 stage tumors, resulting in 27 (54.0%) patients overall being downstaged to nonmuscle invasive tumors.
The researchers found that patients with PD-L1-positive tumors had a better response to treatment than those with PD-L1-negative tumors.
Specifically, just over half (54.3%) of the 35 patients with a PD-L1 combined positive score (CPS) at or above 10% achieved a pCR, compared with just 13.3% of the 15 patients with a CPS below 10%.
There was also a nonlinear association between tumor mutation burden (TMB) and pCR whereby a pretreatment score of at least 15 mutations/Mb was associated with a high rate of pCR, the team notes.
Furthermore, gene expression analyses in pretherapy lesions showed that patients who achieved a pCR had significantly higher expression in 18 of 22 genes analyzed than patients with a pT2 stage or higher posttherapy.
The genes with differential expression were involved in interferon gamma signaling, antigen presentation, T-cell functional differentiation to cytolytic effectors, and included chemokines and chemokine receptors, inhibitory receptors and ligands, and the immunosuppressive gene IDO1, Necchi et al report.
Analysis of paired tumor samples taken pre- and post-pembrolizumab from 14 patients with nonresponding tumors (pT≥2) showed that TMB fell significantly during treatment, from 11.0 mutations/Mb before pembrolizumab to 5.7 mutations/Mb post-therapy.
In addition, there was an overall increase in expression of genes involved in the promotion of adaptive immunity, negative regulation, and innate resistance to anti–PD-1 therapy in post-therapy lesions compared with baseline lesions.
Writing in the Journal of Clinical Oncology, Necchi and co-authors conclude that their findings “will encourage the clinical development of new neoadjuvant therapies and allow for more patients with MIBC to receive multimodality therapy.”
By Laura Cowen
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