Interim analysis of ibrutinib plus paclitaxel for patients with advanced urothelial carcinoma previously treated with platinum-based chemotherapy.

Daniel E. Castellano Medical Oncology Service, Hospital Universitario 12 de Octubre, Madrid, Spain info_outline Daniel E. Castellano, Rafael Morales-Barrera, Ignacio Duran, Bhumsuk Keam, Ik Joo Chung, Hendrik-Tobias Arkenau, Ulka N. Vaishampayan, Mark Tuthill, Pablo Gajate, Sang Joon Shin, S. Paul Dang, Chia-Hsin Ju, Jennifer Lin, George W. Cole, Danelle Frances James, Oscar Reig

Authors Daniel E. Castellano Medical Oncology Service, Hospital Universitario 12 de Octubre, Madrid, Spain info_outline Daniel E. Castellano, Rafael Morales-Barrera, Ignacio Duran, Bhumsuk Keam, Ik Joo Chung, Hendrik-Tobias Arkenau, Ulka N. Vaishampayan, Mark Tuthill, Pablo Gajate, Sang Joon Shin, S. Paul Dang, Chia-Hsin Ju, Jennifer Lin, George W. Cole, Danelle Frances James, Oscar Reig Organizations Medical Oncology Service, Hospital Universitario 12 de Octubre, Madrid, Spain, Vall d'Hebron Institute, Barcelona, Spain, Department of Medical Oncology, Hospital Universitario Marqués de Valdecilla, Santander, Spain, Department of Internal Medicine, Hemato-Oncology, Seoul National University Hospital, Seoul, South Korea, Chonnam National University Hwasun Hospital, Hwasun, South Korea, Sarah Cannon Research Institute, Cancer Institute, University College London, London, United Kingdom, Wayne State University, Detroit, MI, Oncology Department, Churchill Hospital, Oxford, United Kingdom, Hospital Ramón y Cajal, Madrid, Spain, Division of Medical Oncology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, South Korea, Clearview Cancer Institute, Huntsville, AL, Pharmacyclics LLC, an AbbVie Company, Sunnyvale, CA, Pharmacyclics LLC, Sunnyvale, CA, Clinic and Provincial University Hospital, Barcelona, Spain Abstract Disclosures Research Funding Pharmaceutical/Biotech Company Background: Patients (pts) with advanced urothelial carcinoma (aUC) who progressed after platinum-based chemotherapy (PBCT) have a median overall survival (OS) of ~6 mo on CT and 8-10 mo on novel immune checkpoint inhibitors (ICIs). Treatment (tx) with ibrutinib (ibr), a first-in-class, once-daily inhibitor of Bruton’s tyrosine kinase (BTK) with immunomodulatory properties, plus paclitaxel (pac) may improve outcomes for pts with aUC. Methods: Pts with aUC who had 1-2 prior tx (≥1 PBCT and/or ICIs) formed one cohort of this phase 1b/2 study. Recommended phase 2 dose per phase 1b was ibr 840 mg/d + weekly pac 80 mg/m 2 in 21-d cycles; starting ibr dose of 560 mg/d. nanoString gene expression assay (NanoString Technologies) was used for preliminary assessment of ibr-targeted kinases in baseline tumor biopsies. Results: This interim analysis included the first 29 pts treated (ibr 840/560 mg/d, n = 25/4; median age 67 y). 52% had 2 prior regimens (prior PD-L1 inhibitors, 100%). Median time on study/tx was 7.2/2.3 mo (max tx: 11.5 mo). Unconfirmed overall response rate (ORR) was 41% (complete/partial response: 10%/31%). Disease control rate was 62%. ORR was 71% for 7 pts with only lymph node metastases; ORR was 36% for 14 pts with 1 prior tx and 47% for 15 pts with 2 prior tx. Median duration of response was 4.2 mo (90% CI: 1.9-7.1). Median progression-free survival was 3.6 mo (90% CI: 1.6-5.4). Median OS was 14.7 mo (90% CI: 7.7-15.9). Follow-up is ongoing for durability/survival with 6 pts alive without progression, including 4 still on ibr. 76% of pts had grade ≥3 adverse events (AEs); 4 discontinued ibr + pac due to AEs and 1 had major hemorrhage. Pac exposure was not impacted by ibr; pac geometric mean C max (2066 ng/mL) and AUC 0 -∞ (3813 ng·h/mL) were consistent with historical data. Preliminary tumor biopsy data showed a nonsignificant trend of higher BTK/ITK/BMX expression in tx responders; analyses are ongoing. Conclusions: Ibr + pac shows promising results for ORR/OS in pts with aUC previously treated with PBCT and ICIs. No unexpected safety signals were seen; ibr + pac seemed tolerable. Follow-up of these and additional pts will support the activity and safety of ibr + pac in this study. Clinical trial information: NCT02599324