Phase 2 study of LY3023414 in patients with advanced endometrial cancer harboring activating mutations in the PI3K pathway Journal Article


Authors: Rubinstein, M. M.; Hyman, D. M.; Caird, I.; Won, H.; Soldan, K.; Seier, K.; Iasonos, A.; Tew, W. P.; O’Cearbhaill, R. E.; Grisham, R. N.; Hensley, M. L.; Troso-Sandoval, T.; Sabbatini, P.; Guillen, J.; Selcuklu, S. D.; Zimel, C.; Torrisi, J.; Aghajanian, C.; Makker, V.
Article Title: Phase 2 study of LY3023414 in patients with advanced endometrial cancer harboring activating mutations in the PI3K pathway
Abstract: Background: PI3K pathway activation is common in endometrial cancer. We evaluated the safety and efficacy of the dual PI3K/mTOR inhibitor, LY3023414, in patients with advanced endometrial cancer harboring activating mutations in the PI3K pathway. Methods: We conducted a single-arm phase 2 study of monotherapy LY3023414. Eligible patients had advanced endometrial cancer of any grade, prior management with 1-4 cytotoxic lines, and PI3K pathway activation prospectively defined as a loss-of-function PTEN alteration or activating alteration in PIK3CA, AKT1, PIK3R1, PIK3R2, or MTOR. The primary objective was best overall response rate (ORR) per RECIST 1.1. Results: Twenty-eight patients were treated; histologies included endometroid (39%), carcinosarcoma (25%), serous (21%), and mixed (14%). Patients were heavily pretreated, with a median of 2 prior cytotoxic lines (range, 1-3). The most common alterations involved PIK3CA (68%), PTEN (43%), and PIK3R1 (32%). In the 25 efficacy-evaluable patients, the ORR was 16% (90% CI, 7%-100%), and the clinical benefit rate was 28% (90% CI, 16%-100%). Four patients had a confirmed partial response, and 2 responses lasted for >9 months. The median progression-free survival and overall survival were 2.5 months (95% CI, 1.2-3.0) and 9.2 months (95% CI, 5.0-15.9), respectively. The most common all-grade treatment-related adverse events were anemia (71%), hyperglycemia (71%), hypoalbuminemia (68%), and hypophosphatemia (61%). No correlation between molecular alterations and response was observed. Conclusion: In patients with heavily pretreated advanced endometrial cancer prospectively selected for tumors with activating PI3K pathway mutations, LY3023414 demonstrated modest single-agent activity and a manageable safety profile. © 2019 American Cancer Society
Keywords: signal transduction; adult; clinical article; aged; overall survival; somatic mutation; drug dose reduction; drug efficacy; drug safety; drug withdrawal; hypophosphatemia; liver function; monotherapy; recommended drug dose; side effect; endometrial cancer; endometrioid carcinoma; endometrium cancer; proto oncogene; progression free survival; multiple cycle treatment; phase 2 clinical trial; anemia; nausea; hyperglycemia; tumor suppressor gene; hypoalbuminemia; hypokalemia; hyponatremia; open study; loss of function mutation; pik3ca gene; lymphocyte count; advanced; akt1 gene; carcinosarcoma; pten gene; hyperinsulinemia; dual pi3k/mtor inhibitor; pi3k pathway; response evaluation criteria in solid tumors; pik3r1 gene; fgfr3 gene; human; female; priority journal; article; pi3k signaling pathway; ly3023414; samotolisib
Journal Title: Cancer
Volume: 126
Issue: 6
ISSN: 0008-543X
Publisher: Wiley Blackwell  
Date Published: 2020-03-15
Start Page: 1274
End Page: 1282
Language: English
DOI: 10.1002/cncr.32677
PUBMED: 31880826
PROVIDER: scopus
DOI/URL:
Notes: Article -- Export Date: 1 April 2020 -- Source: Scopus
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