Phase II Clinical and Translational Study of Everolimus ± Paclitaxel as First-Line Therapy in Cisplatin-Ineligible Advanced Urothelial Carcinoma
Tomi Jun, Noah M Hahn, Guru Sonpavde, Constantine Albany, Gary R MacVicar, Ralph Hauke, Mark Fleming, Theodore Gourdin, Bagi Jana, William K Oh, Patricia Taik, Huan Wang, Ajay Ramakrishnan Varadarajan, Andrew Uzilov, Matthew D Galsky, Tomi Jun, Noah M Hahn, Guru Sonpavde, Constantine Albany, Gary R MacVicar, Ralph Hauke, Mark Fleming, Theodore Gourdin, Bagi Jana, William K Oh, Patricia Taik, Huan Wang, Ajay Ramakrishnan Varadarajan, Andrew Uzilov, Matthew D Galsky
Abstract
Background: Treatment options have been historically limited for cisplatin-ineligible patients with advanced urothelial carcinoma (UC). Given the need for alternatives to platinum-based chemotherapy, including non-chemotherapy regimens for patients with both impaired renal function and borderline functional status, in 2010 (prior to the immune checkpoint blockade era in metastatic UC), we initiated a phase II trial to test the activity of everolimus or everolimus plus paclitaxel in the cisplatin-ineligible setting.
Methods: This was an open-label phase II trial conducted within the US-based Hoosier Cancer Research Network (ClinicalTrials.gov number: NCT01215136). Patients who were cisplatin-ineligible with previously untreated advanced UC were enrolled. Patients with both impaired renal function and poor performance status were enrolled into cohort 1; patients with either were enrolled into cohort 2. Patients received everolimus 10 mg daily alone (cohort 1) or with paclitaxel 80 mg/m2 on days 1, 8, and 15 of each 28-day cycle (cohort 2). The primary outcome was clinical benefit at 4 months. Secondary outcomes were adverse events, progression-free survival (PFS), and 1-year overall survival (OS). Exploratory endpoints included genomic correlates of outcomes. The trial was not designed for comparison between cohorts.
Results: A total of 36 patients were enrolled from 2010 to 2018 (cohort 1, N = 7; cohort 2, N = 29); the trial was terminated due to slow accrual. Clinical benefit at 4 months was attained by 0 (0%, 95% confidence interval [CI] 0-41.0%) patients in cohort 1 and 11 patients (37.9%, 95% CI 20.7-57.7%) in cohort 2. Median PFS was 2.33 (95% CI 1.81-Inf) months in cohort 1 and 5.85 (95% CI 2.99-8.61) months in cohort 2. Treatment was discontinued due to adverse events for 2 patients (29%) in cohort 1 and 11 patients (38%) in cohort 2. Molecular alterations in microtubule associated genes may be associated with treatment benefit but this requires further testing.
Conclusion: Everolimus plus paclitaxel demonstrates clinical activity in cisplatin-ineligible patients with metastatic UC, although the specific contribution of everolimus cannot be delineated. Patients with both impaired renal function and borderline functional status may be difficult to enroll to prospective trials. (ClinicalTrials.gov Identifier NCT01215136).
Keywords: cisplatin-ineligible; everolimus; genomic; paclitaxel; urothelial cancer.
© The Author(s) 2022. Published by Oxford University Press. The data published online to support this summary are the property of the authors. Please contact the authors about reuse rights of the original data.
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References
- Dash A, Galsky MD, Vickers AJ, et al. . Impact of renal impairment on eligibility for adjuvant cisplatin-based chemotherapy in patients with urothelial carcinoma of the bladder. Cancer. 2006;107(3):506-513.
- Galsky MD, Hahn NM, Rosenberg J, et al. . Treatment of patients with metastatic urothelial cancer “unfit” for Cisplatin-based chemotherapy. J Clin Oncol. 2011;29(17):2432-2438.
- De Santis M, Bellmunt J, Mead G, et al. . Randomized phase II/III trial assessing gemcitabine/ carboplatin and methotrexate/carboplatin/vinblastine in patients with advanced urothelial cancer “unfit” for cisplatin-based chemotherapy: phase II–results of EORTC study 30986. J Clin Oncol. 2009;27(33):5634-5639.
- Tickoo SK, Milowsky MI, Dhar N, et al. . Hypoxia-inducible factor and mammalian target of rapamycin pathway markers in urothelial carcinoma of the bladder: possible therapeutic implications. BJU Int. 2011;107(5):844-849.
- Puzio-Kuter AM, Castillo-Martin M, Kinkade CW, et al. . Inactivation of p53 and Pten promotes invasive bladder cancer. Genes Dev. 2009;23(6):675-680.
- Iyer G, Hanrahan AJ, Milowsky MI, et al. . Genome sequencing identifies a basis for everolimus sensitivity. Science. 2012;338(6104):221.
- Dreicer R, Gustin DM, See WA, Williams RD.. Paclitaxel in advanced urothelial carcinoma: its role in patients with renal insufficiency and as salvage therapy. J Urol. 1996;156(5):1606-1608.
- Hu L, Hofmann J, Lu Y, Mills GB, Jaffe RB.. Inhibition of phosphatidylinositol 3’-kinase increases efficacy of paclitaxel in in vitro and in vivo ovarian cancer models. Cancer Res. 2002;62(4):1087-1092.
- Faried LS, Faried A, Kanuma T, et al. . Inhibition of the mammalian target of rapamycin (mTOR) by rapamycin increases chemosensitivity of CaSki cells to paclitaxel. Eur J Cancer. 2006;42(7):934-947.
- Liu Z, Zhu G, Getzenberg RH, Veltri RW.. The upregulation of PI3K/Akt and MAP kinase pathways is associated with resistance of microtubule-targeting drugs in prostate cancer. J Cell Biochem. 2015;116(7):1341-1349.
- Campone M, Levy V, Bourbouloux E, et al. . Safety and pharmacokinetics of paclitaxel and the oral mTOR inhibitor everolimus in advanced solid tumours. Br J Cancer. 2009;100(2):315-321.
- Hurvitz SA, Dalenc F, Campone M, et al. . A phase 2 study of everolimus combined with trastuzumab and paclitaxel in patients with HER2-overexpressing advanced breast cancer that progressed during prior trastuzumab and taxane therapy. Breast Cancer Res Treat. 2013;141(3):437-446.
- Hurvitz SA, Andre F, Jiang Z, et al. . Combination of everolimus with trastuzumab plus paclitaxel as first-line treatment for patients with HER2-positive advanced breast cancer (BOLERO-1): a phase 3, randomised, double-blind, multicentre trial. Lancet Oncol. 2015;16(7):816-829.
- Eisenhauer EA, Therasse P, Bogaerts J, et al. . New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45(2):228-247.
- Zhang Z, Hao K.. SAAS-CNV: a joint segmentation approach on aggregated and allele specific signals for the identification of somatic copy number alterations with next-generation sequencing data. PLoS Comput Biol. 2015;11(11):e1004618.
- Mermel CH, Schumacher SE, Hill B, Meyerson ML, Beroukhim R, Getz G.. GISTIC2.0 facilitates sensitive and confident localization of the targets of focal somatic copy-number alteration in human cancers. Genome Biol. 2011;12(4):R41.
- Lynch AG. Decomposition of mutational context signatures using quadratic programming methods. F1000Res. 2016;5:1253.
- Alexandrov LB, Nik-Zainal S, Wedge DC, et al. ; Australian Pancreatic Cancer Genome Initiative; ICGC Breast Cancer Consortium; ICGC MMML-Seq Consortium; ICGC PedBrain. Signatures of mutational processes in human cancer. Nature. 2013;500(7463):415-421.
- Dobin A, Davis CA, Schlesinger F, et al. . STAR: ultrafast universal RNA-seq aligner. Bioinformatics. 2013;29(1):15-21.
- Liao Y, Smyth GK, Shi W.. featureCounts: an efficient general purpose program for assigning sequence reads to genomic features. Bioinformatics. 2014;30(7):923-930.
- Love MI, Huber W, Anders S.. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. 2014;15(12):550.
- Nicorici D, Şatalan M, Edgren H, et al. . FusionCatcher – a tool for finding somatic fusion genes in paired-end RNA-sequencing data. bioRxiv. 2014. doi:
- Haas BJ, Dobin A, Stransky N, et al. . STAR-fusion: fast and accurate fusion transcript detection from RNA-Seq. bioRxiv. 2017. doi:
- Kim J, Mouw KW, Polak P, et al. . Somatic ERCC2 mutations are associated with a distinct genomic signature in urothelial tumors. Nat Genet. 2016;48(6):600-606.
- Yu EY, Petrylak DP, O’Donnell PH, et al. . Enfortumab vedotin after PD-1 or PD-L1 inhibitors in cisplatin-ineligible patients with advanced urothelial carcinoma (EV-201): a multicentre, single-arm, phase 2 trial. Lancet Oncol. 2021;22(6):872-882.
- Rosenberg JE, Flaig TW, Friedlander TW, et al. . Study EV-103: durability results of enfortumab vedotin plus pembrolizumab for locally advanced or metastatic urothelial carcinoma. JCO. 2020;38(15_suppl):5044.
- Siefker-Radtke AO, Campbell MT, Munsell MF, Harris DR, Carolla RL, Pagliaro LC.. Front-line treatment with gemcitabine, paclitaxel, and doxorubicin for patients with unresectable or metastatic urothelial cancer and poor renal function: final results from a phase II study. Urology. 2016;89:83-89.
- Narayanan S, Lam A, Vaishampayan U, et al. . Phase II study of pazopanib and paclitaxel in patients with refractory urothelial cancer. Clin Genitourin Cancer. 2016;14(5):432-437.
- Niegisch G, Retz M, Thalgott M, et al. . Second-line treatment of advanced urothelial cancer with paclitaxel and everolimus in a German phase II Trial (AUO Trial AB 35/09). Oncology. 2015;89(2):70-78.
- Adib E, Klonowska K, Giannikou K, et al. . Phase II clinical trial of everolimus in a pan-cancer cohort of patients with mTOR pathway alterations. Clin Cancer Res. 2021;27(14):3845-3853.
- Bellmunt J, Lalani AA, Jacobus S, et al. . Everolimus and pazopanib (E/P) benefit genomically selected patients with metastatic urothelial carcinoma. Br J Cancer. 2018;119(6):707-712.
- Patel VG, Oh WK, Galsky MD.. Treatment of muscle-invasive and advanced bladder cancer in 2020. CA Cancer J Clin. 2020;70(5):404-423.
- Gupta S, Sonpavde G, Grivas P, et al. . Defining “platinum-ineligible” patients with metastatic urothelial cancer (mUC). JCO. 2019;37(7_suppl):451.
- Kakinuma T, Ichikawa H, Tsukada Y, Nakamura T, Toh BH.. Interaction between p230 and MACF1 is associated with transport of a glycosyl phosphatidyl inositol-anchored protein from the Golgi to the cell periphery. Exp Cell Res. 2004;298(2):388-398.
- Ning W, Yu Y, Xu H, et al. . The CAMSAP3-ACF7 complex couples noncentrosomal microtubules with actin filaments to coordinate their dynamics. Dev Cell. 2016;39(1):61-74.
- Nagai T, Ikeda M, Chiba S, Kanno S, Mizuno K.. Furry promotes acetylation of microtubules in the mitotic spindle by inhibition of SIRT2 tubulin deacetylase. J Cell Sci. 2013;126(Pt 19):4369-4380.
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