Clinical Outcomes of Platinum-Ineligible Patients with Advanced Urothelial Carcinoma Treated with First-Line PD1/L1 Inhibitors - Beyond the Abstract

To our knowledge, this is the first study to evaluate the efficacy of PD1/L1 blockade in the first-line setting for platinum-ineligible (i.e. ineligible for both cisplatin and carboplatin) advanced urothelial carcinoma (aUC) in the real world. This is a multicenter retrospective study of 79 patients with aUC who were considered platinum-ineligible at the discretion of the treating medical oncologist due to: 1) those with both renal dysfunction (CrCl<60 ml/min) and poor ECOG performance status [PS]=2, 2) CrCl <30 ml/minute or 3)  ECOG-PS=3, 4) elderly or 5) severe comorbidities that were deemed prohibitive for platinum-based chemotherapy. A recent presentation (Gupta et al) reported consensus criteria for platinum-eligibility, which are also arbitrary but similar to the criteria that we employed.

The efficacy of those agents appeared similar to previous reports from phase II trials that enrolled cisplatin-ineligible patients regardless of PD-L1 expression status.  The objective response rate was 27.9%, the median overall survival was 45 weeks, and the median failure-free survival was 16 weeks. However, grade ≥3 treatment-related toxicities appeared more common (31.7%) comparing with the cisplatin-ineligible first-line aUC cohorts of IMvigor210 and Keynote-052 trials (16% for each trial).  The higher rate of treatment-related toxicities may be attributed to the fact that the platinum-ineligible patient population included in our study may be characterized as frailer than in these trials.

Hence, careful selection of platinum-ineligible patients for first-line PD1/L1 inhibitor therapy is warranted since this population remains poorly defined and may tolerate toxicities poorly. For example, a combination of biomarkers may warrant validation to facilitate patient selection, e.g. PD-L1 expression, tumor mutation burden (TMB), gene-expression subtyping, neutrophil/Lymphocyte ratio (NLR). Larger and prospective studies of new agents informed by predictive biomarkers are needed in platinum-ineligible aUC.

Financial Disclosures

Guru Sonpavde: research grants from Boehringer-Ingelheim, Bayer, Onyx-Amgen, grants, and advisory board fees from Pfizer, advisory board for Genentech,  advisory board for Novartis, research grants and advisory board for Merck, research grants and advisory board for Sanofi, advisory board and steering committee of trial for Seattle Genetics/Astellas, speaking fees from Clinical Care Options, grants, trial steering committee, advisory board and travel fees from Astrazeneca, writing fees from UpToDate, advisory board for Exelixis, advisory board and travel costs from Bristol-Myers-Squibb (BMS), research grants and advisory board Janssen, advisory board for Amgen, advisory board for Eisai, advisory board for NCCN, research grants from Celgene, speaking fees from Physicians Education Resource, Onclive, Research to Practice, Steering committee of trials sponsored by Bavarian Nordic, Debiopharm, QED.

Written by: Guru Sonpavde, MD, Bladder Cancer Director, Dana-Farber Cancer Institute, Associate Professor of Medicine, Harvard Medical School, Boston, MA

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