Abstract 754P
Background
Ibr, a once-daily Bruton’s tyrosine kinase (BTK) inhibitor approved for various B-cell malignancies, also inhibits other kinases, such as ITK and ETK (Wang Clin Cancer Res 2018), that are upregulated in UC. In vitro, ibr has been shown to mitigate resistance to pac (Zhang Mol Cancer Ther 2017). The combination of ibr + pac was evaluated in the aUC cohort of the phase 1b/2 study (NCT02599324).
Methods
Ibr + pac was assessed in pts with aUC previously treated with platinum-based chemotherapy who had an ECOG performance status of 0–1. Pts treated with a prior BTK inhibitor were excluded. Pts received once-daily ibr (at a starting dose of 560 mg or recommended phase 2 dose of 840 mg) in combination with weekly IV pac 80 mg/m2 in 21-d cycles until unacceptable toxicity or progressive disease (PD). The primary endpoint was progression-free survival (PFS). Additional endpoints included efficacy (overall response rate [ORR], disease control rate [DCR], and overall survival [OS]), and safety. Biomarker analysis of baseline tumor biopsies was done by NanoString gene expression assay.
Results
63 pts were treated with ibr (560 mg, n=4; 840 mg, n=59) + pac with a median follow-up of 21 mo. Median age was 67 y; 54% of pts had 2 prior therapies. 68% of pts previously had a checkpoint inhibitor. Median PFS was 4 mo (90% CI 3–4); median OS was 8 mo (90% CI 7–10). DCR was 65%, with an ORR of 27% and CR of 5% (Table). Median duration of response (DOR) was 4 mo (90% CI 3–5); maximum DOR was 24 mo. One pt (2%) is still on treatment and 7 pts (11%) are still in follow-up. Grade ≥3 adverse events occurred in 83% of pts; major hemorrhage occurred in 4 pts (6%). Analysis of baseline tumor biopsies (n=43) found that responders (n=18) had a nonsignificant trend toward higher gene expression of ibr targets (BTK, ErbB2, and ITK) vs pts with PD (n=10).
Conclusions
Ibr + pac showed activity in pts with aUC previously treated with platinum-based therapy. No unexpected safety signals were observed. Table: 754P
Best response by prior therapy and organ
| Response, n (%) | 1 prior treatment n=29 | 2 prior treatments n=34 | Lymph node metastasis only n=9 | Liver metastasis n=14 | All pts n=63 |
| ORR | 11 (38) | 6 (18) | 4 (44) | 3 (21) | 17 (27) |
| Complete response | 0 (0) | 3 (9) | 1 (11) | 0 (0) | 3 (5) |
| Partial response | 11 (38) | 3 (9) | 3 (33) | 3 (21) | 14 (22) |
Clinical trial identification
NCT02599324.
Editorial acknowledgement
Medical writing support was provided by Valerie Hilliard, PhD, and funded by Pharmacyclics LLC, an AbbVie Company.
Legal entity responsible for the study
Pharmacyclics LLC, an AbbVie Company.
Funding
Pharmacyclics LLC, an AbbVie Company.
Disclosure
D. Castellano Gauna: Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (self): Roche; Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony: MSD; Honoraria (self): Exelixis; Honoraria (self), Advisory/Consultancy: Pfizer; Advisory/Consultancy: AstraZeneca; Research grant/Funding (self): Astellas; Speaker Bureau/Expert testimony, Research grant/Funding (self): Janssen; Speaker Bureau/Expert testimony: Ipsen. R. Morales-Barrera: Advisory/Consultancy, Travel/Accommodation/Expenses: MSD; Advisory/Consultancy, Travel/Accommodation/Expenses: Sanofi; Advisory/Consultancy, Travel/Accommodation/Expenses: Roche; Advisory/Consultancy, Travel/Accommodation/Expenses: AstraZeneca; Speaker Bureau/Expert testimony: MSD Oncology; Speaker Bureau/Expert testimony: Asofarma; Travel/Accommodation/Expenses: Astellas; Travel/Accommodation/Expenses: J&J; Travel/Accommodation/Expenses: Bayer. I. Duran: Honoraria (self), Advisory/Consultancy, Research grant/Funding (self): Roche; Honoraria (self), Advisory/Consultancy: BMS; Honoraria (self), Advisory/Consultancy: MSD; Honoraria (self), Advisory/Consultancy: Janssen; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Ipsen; Honoraria (self), Advisory/Consultancy: Novartis; Honoraria (self): Astellas; Advisory/Consultancy: Pharmacyclics LLC, an AbbVie Company; Research grant/Funding (self), Travel/Accommodation/Expenses: AstraZeneca. D-Y. Oh: Advisory/Consultancy: Genentech/Roche; Advisory/Consultancy, Research grant/Funding (self): AstraZeneca; Advisory/Consultancy: Novartis; Advisory/Consultancy: Merck Serono; Advisory/Consultancy: Bayer; Advisory/Consultancy: Taiho; Advisory/Consultancy: Aslan; Advisory/Consultancy: Halozyme; Advisory/Consultancy: Zymeworks; Research grant/Funding (self): Array; Research grant/Funding (self): Eli Lilly. T. Arkenau: Research grant/Funding (self), Full/Part-time employment: HCA/Sarah Cannon; Honoraria (self): Roche; Honoraria (self): Guardant; Honoraria (self): Bayer; Honoraria (self): Bicycle; Honoraria (self): Servier. U.N. Vaishampayan: Advisory/Consultancy: BMC; Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (self): Exelixis; Advisory/Consultancy, Speaker Bureau/Expert testimony: Sanofi; Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (self): Pfizer; Advisory/Consultancy: Bayer; Speaker Bureau/Expert testimony, Research grant/Funding (self): BMS. M. Tuthill: Leadership role, Full/Part-time employment: Personalized Medicine Limited; Honoraria (self): Pfizer; Honoraria (self), Travel/Accommodation/Expenses: Janssen; Honoraria (self), Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: BMS; Honoraria (self), Speaker Bureau/Expert testimony: Novartis; Honoraria (self), Speaker Bureau/Expert testimony: Roche; Advisory/Consultancy: Vaccitech; Speaker Bureau/Expert testimony: Lilly; Speaker Bureau/Expert testimony: Oxford Vacmedix; Speaker Bureau/Expert testimony: Astellas; Speaker Bureau/Expert testimony: Genomic Health; Speaker Bureau/Expert testimony: Eisai; Speaker Bureau/Expert testimony: Everything Genetic; Travel/Accommodation/Expenses: Ipsen; Travel/Accommodation/Expenses: EUSA Pharma. P. Gajate Borau: Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Roche. S.P. Dang: Research grant/Funding (self): Oncology Specialties PC. C-H. Ju: Full/Part-time employment: Pharmacyclics LLC, an AbbVie Company; Shareholder/Stockholder/Stock options: AbbVie. E. Chong: Full/Part-time employment: Pharmacyclics LLC, an AbbVie Company. I. Lal: Full/Part-time employment: Pharmacyclics LLC, an AbbVie Company; Full/Part-time employment: Permanente Medical Group (spouse only); Shareholder/Stockholder/Stock options: AbbVie; Shareholder/Stockholder/Stock options: Gilead Sciences; Shareholder/Stockholder/Stock options: Clovis; Shareholder/Stockholder/Stock options: Permanente Medical Group; Shareholder/Stockholder/Stock options: Reviva Pharmaceuticals. G. Cole Jr: Full/Part-time employment: Pharmacyclics LLC, an AbbVie Company; Shareholder/Stockholder/Stock options: AbbVie. O. Reig Torras: Travel/Accommodation/Expenses: Ipsen. All other authors have declared no conflicts of interest.