Abstract
BackgroundThe majority of urothelial cancers (UC) harbor alterations in retinoblastoma (Rb) pathway genes that can lead to loss of Rb tumour suppressor function. Palbociclib is an oral, selective inhibitor of CDK 4/6 that restores Rb function and promotes cell cycle arrest.MethodsIn this phase II trial, patients with metastatic platinum-refractory UC molecularly selected for p16 loss and intact Rb by tumour immunohistochemistry received palbociclib 125 mg p.o. daily for 21 days of a 28-day cycle. Primary endpoint was progression-free survival at 4 months (PFS4) using a Simon’s two-stage design. Next-generation sequencing including Rb pathway alterations was conducted.ResultsTwelve patients were enrolled and two patients (17%) achieved PFS4 with insufficient activity to advance to stage 2. No responses were seen. Median PFS was 1.9 months (95% CI 1.8–3.7 months) and median overall survival was 6.3 months (95% CI 2.2–12.6 months). Fifty-eight percent of patients had grade ≥3 hematologic toxicity. There were no CDKN2A alterations found and no correlation of Rb pathway alterations with clinical outcome.ConclusionsPalbociclib did not demonstrate meaningful activity in selected patients with platinum-refractory metastatic UC. Further development of palbociclib should only be considered with improved integral biomarker selection or in rational combination with other therapies.
Highlights
The majority of urothelial cancers (UC) harbor alterations in retinoblastoma (Rb) pathway genes that can lead to loss of Rb tumour suppressor function
Immune checkpoint inhibition remains effective in only a subset of patients with metastatic UC, and tumour progression remains inevitable in most patients
Patient characteristics Of 34 patients screened, 25 were eligible based on tumour IHC demonstrating p16 loss and intact Rb (Fig. 1)
Summary
The majority of urothelial cancers (UC) harbor alterations in retinoblastoma (Rb) pathway genes that can lead to loss of Rb tumour suppressor function. METHODS: In this phase II trial, patients with metastatic platinum-refractory UC molecularly selected for p16 loss and intact Rb by tumour immunohistochemistry received palbociclib 125 mg p.o. daily for 21 days of a 28-day cycle. Platinum-based combination chemotherapy was the only effective treatment option for metastatic UC. Additional effective agents are needed for the treatment of this deadly disease and molecularly targeted therapies hold promise for patients with disease progression after platinum-based chemotherapy and/or immunotherapy. The irreversible ErbB family receptor blocker afatinib had significant activity in patients with platinum-refractory UC with HER2 or ERBB3 amplifications.[1] the VEGF2-R antagonist ramucirumab in combination with docetaxel improved progression-free survival (PFS) compared with docetaxel alone in unselected patients with platinum-refractory UC.[2]
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