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      Phase II trial of palbociclib in patients with metastatic urothelial cancer after failure of first-line chemotherapy

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          Abstract

          Background

          The 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.

          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. 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.

          Results

          Twelve 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.

          Conclusions

          Palbociclib 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.

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          Most cited references25

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          Intrinsic subtypes of high-grade bladder cancer reflect the hallmarks of breast cancer biology.

          We sought to define whether there are intrinsic molecular subtypes of high-grade bladder cancer. Consensus clustering performed on gene expression data from a meta-dataset of high-grade, muscle-invasive bladder tumors identified two intrinsic, molecular subsets of high-grade bladder cancer, termed "luminal" and "basal-like," which have characteristics of different stages of urothelial differentiation, reflect the luminal and basal-like molecular subtypes of breast cancer, and have clinically meaningful differences in outcome. A gene set predictor, bladder cancer analysis of subtypes by gene expression (BASE47) was defined by prediction analysis of microarrays (PAM) and accurately classifies the subtypes. Our data demonstrate that there are at least two molecularly and clinically distinct subtypes of high-grade bladder cancer and validate the BASE47 as a subtype predictor. Future studies exploring the predictive value of the BASE47 subtypes for standard of care bladder cancer therapies, as well as novel subtype-specific therapies, will be of interest.
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            Phase II trial of the CDK4 inhibitor PD0332991 in patients with advanced CDK4-amplified well-differentiated or dedifferentiated liposarcoma.

            CDK4 is amplified in > 90% of well-differentiated (WDLS) and dedifferentiated liposarcomas (DDLS). The selective cyclin-dependent kinase 4 (CDK4)/CDK6 inhibitor PD0332991 inhibits growth and induces senescence in cell lines and xenografts. In a phase I trial of PD0332991, several patients with WDLS or DDLS experienced prolonged stable disease. We performed an open-label phase II study to determine the safety and efficacy of PD0332991 in patients with advanced WDLS/DDLS. Patients age ≥ 18 years experiencing disease progression while receiving systemic therapy before enrollment received PD0332991 200 mg orally once per day for 14 consecutive days in 21-day cycles. All were required to have CDK4 amplification by fluorescence in situ hybridization and retinoblastoma protein (RB) expression by immunohistochemistry (≥ 1+). The primary end point was progression-free survival (PFS) at 12 weeks, with 12-week PFS of ≥ 40% considered promising and ≤ 20% not promising. If ≥ nine of 28 patients were progression free at 12 weeks, PD0332991 would be considered active. We screened 48 patients (44 of 48 had CDK4 amplification; 41 of 44 were RB positive). Of those, 30 were enrolled, and 29 were evaluable for the primary end point. Grade 3 to 4 events included anemia (17%), thrombocytopenia (30%), neutropenia (50%), and febrile neutropenia (3%). At 12 weeks, PFS was 66% (90% CI, 51% to 100%), significantly exceeding the primary end point. The median PFS was 18 weeks. There was one partial response. Treatment with the CDK4 inhibitor PD0332991 was associated with a favorable progression-free rate in patients with CDK4-amplified and RB-expressing WDLS/DDLS who had progressive disease despite systemic therapy.
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              Afatinib Activity in Platinum-Refractory Metastatic Urothelial Carcinoma in Patients With ERBB Alterations.

              Somatic mutations and copy number variation in the ERBB family are frequent in urothelial carcinoma (UC) and may represent viable therapeutic targets. We studied whether afatinib (an oral, irreversible inhibitor of the ErbB family) has activity in UC and if specific ERBB molecular alterations are associated with clinical response.
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                Author and article information

                Contributors
                matt_milowsky@med.unc.edu
                Journal
                Br J Cancer
                Br. J. Cancer
                British Journal of Cancer
                Nature Publishing Group UK (London )
                0007-0920
                1532-1827
                8 October 2018
                2 October 2018
                : 119
                : 7
                : 801-807
                Affiliations
                [1 ]ISNI 0000000122483208, GRID grid.10698.36, Division of Hematology/Oncology, Lineberger Comprehensive Cancer Center, , University of North Carolina at Chapel Hill, ; Chapel Hill, NC USA
                [2 ]ISNI 0000 0004 1936 9916, GRID grid.412807.8, Division of Hematology and Oncology, Department of Medicine, Vanderbilt-Ingram Cancer Center, , Vanderbilt University Medical Center, ; Nashville, TN USA
                [3 ]ISNI 0000000086837370, GRID grid.214458.e, Division of Hematology/Oncology, , University of Michigan, ; Ann Arbor, MI USA
                [4 ]ISNI 0000000122483208, GRID grid.10698.36, Lineberger Comprehensive Cancer Center, , University of North Carolina at Chapel Hill, ; Chapel Hill, NC USA
                [5 ]ISNI 0000000122483208, GRID grid.10698.36, Department of Pathology and Laboratory Medicine, , University of North Carolina at Chapel Hill, ; Chapel Hill, NC USA
                Article
                229
                10.1038/s41416-018-0229-0
                6189143
                30293995
                57043758-4919-4a1a-b933-0c7774a5d4c8
                © Cancer Research UK 2018

                This work is published under the standard license to publish agreement. After 12 months the work will become freely available and the license terms will switch to a Creative Commons Attribution 4.0 International (CC BY 4.0).

                History
                : 27 March 2018
                : 9 July 2018
                : 19 July 2018
                Categories
                Article
                Custom metadata
                © Cancer Research UK 2018

                Oncology & Radiotherapy
                bladder cancer,tumour biomarkers,cancer genomics
                Oncology & Radiotherapy
                bladder cancer, tumour biomarkers, cancer genomics

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