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Advanced urothelial carcinoma: Ibrutinib in combination with Paclitaxel has activity - Final analysis of a phase Ib/II study


Ibrutinib ( Imbruvica ), 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 urothelial carcinoma.
In vitro, Ibrutinib has been shown to mitigate resistance to Paclitaxel ( Zhang Mol Cancer Ther 2017 ).

The combination of Ibrutinib + Paclitaxel was evaluated in the advanced urothelial carcinoma cohort of the phase 1b/2 study.

The combination of Ibrutinib and Paclitaxel was assessed in patients with advanced urothelial carcinoma previously treated with Platinum-based chemotherapy who had an ECOG performance status of 0–1.
Patients treated with a prior BTK inhibitor were excluded.
Patients received once-daily Ibrutinib ( at a starting dose of 560 mg or recommended phase 2 dose of 840 mg ) in combination with weekly IV Paclitaxel 80 mg/m2 in 21-days cycles until unacceptable toxicity or progressive disease.

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.

63 patients were treated with Ibrutinib ( 560 mg, n=4; 840 mg, n=59 ) + Paclitaxel with a median follow-up of 21 months.
Median age was 67 years; 54% of patients had 2 prior therapies; 68% of patients previously had a checkpoint inhibitor.

Median progression-free survival was 4 months ( 90% CI 3–4 ); median overall survival was 8 months ( 90% CI 7–10 ).

Disease control rate was 65%, with an overall response rate of 27% and complete response ( CR ) of 5%.

Median duration of response ( DOR ) was 4 months ( 90% CI 3–5 ); maximum DOR was 24 months.

One patient ( 2% ) is still on treatment and 7 patients ( 11% ) are still in follow-up.

Grade 3 or more adverse events occurred in 83% of patients; major hemorrhage occurred in 4 patients ( 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 ) versus patients with progression disease ( n=10 ).

In conclusion, Ibrutinib + Paclitaxel showed activity in patients with advanced urothelial carcinoma previously treated with Platinum-based therapy.
No unexpected safety signals were observed. ( Xagena )

Source: European Society for Medical Oncology ( ESMO ) Virtual Meeting, 2020

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