Phase Ib study of binimetinib with paclitaxel in patients with platinum-resistant ovarian cancer: Final results, potential biomarkers, and extreme responders Journal Article


Authors: Grisham, R. N.; Moore, K. N.; Gordon, M. S.; Harb, W.; Cody, G.; Halpenny, D. F.; Makker, V.; Aghajanian, C. A.
Article Title: Phase Ib study of binimetinib with paclitaxel in patients with platinum-resistant ovarian cancer: Final results, potential biomarkers, and extreme responders
Abstract: Purpose: Epithelial ovarian cancer (EOC) is a molecularly diverse disease. MEK inhibition targets tumors harboring MAPK pathway alterations and enhances paclitaxel-induced apoptosis in EOC. This phase Ib study evaluated the MEK inhibitor binimetinib combined with paclitaxel in patients with platinum-resistant EOC. Patients and Methods: Patients received intravenous weekly paclitaxel with oral binimetinib in three different administration schedules. Outcomes were assessed by RECIST and CGIC CA-125 response criteria. Tumor samples were analyzed using next-generation sequencing. Results: Thirty-four patients received >= 1 binimetinib dose. A 30-mg twice-a-day continuous or 45-mg twice-aday intermittent binimetinib dose was deemed the recommended phase II dose (RP2D) in combination with 80 mg/m(2) i.v. weekly paclitaxel. Rate of grade 3/4 adverse events was 65%. The best overall response rate was 18%-one complete (CR) and four partial responses (PR)-among 28 patients with RECIST-measurable disease. Eleven patients achieved stable disease (SD), yielding a clinical benefit rate (CR+PR+SD) of 57%. Response rates, per both RECIST and CA-125 criteria, were highest in the 45-mg twice-a-day continuous cohort and lowest in the 45-mg twice-a-day intermittent cohort. All four evaluable patients with MAPK pathway-altered tumors experienced clinical benefit. Conclusions: The combination of binimetinib and intravenous weekly paclitaxel was tolerable in this patient population. The RP2D of binimetinib in combination with paclitaxel was 30 mg twice a day as a continuous or 45 mg twice a day as an intermittent dose. Although response rates were modest, a higher clinical benefit rate was seen in patients harboring alterations affecting the MAPK pathway. (C) 2018 AACR.
Keywords: survival; chemotherapy; topotecan; apoptosis; carcinoma; braf mutation; trial; expression; pegylated liposomal doxorubicin; activated protein-kinase; grade serous
Journal Title: Clinical Cancer Research
Volume: 24
Issue: 22
ISSN: 1078-0432
Publisher: American Association for Cancer Research  
Date Published: 2018-11-15
Start Page: 5525
End Page: 5533
Language: English
ACCESSION: WOS:000450349300006
DOI: 10.1158/1078-0432.Ccr-18-0494
PROVIDER: wos
Notes: Article -- Source: Wos
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MSK Authors
  1. Vicky Makker
    72 Makker
  2. Rachel Nicole Grisham
    34 Grisham