Phase II, 2-stage, 2-arm, PIK3CA mutation stratified trial of MK-2206 in recurrent endometrial cancer Journal Article
| Authors: | Myers, A. P.; Konstantinopoulos, P. A.; Barry, W. T.; Luo, W.; Broaddus, R. R.; Makker, V.; Drapkin, R.; Liu, J.; Doyle, A.; Horowitz, N. S.; Meric-Bernstam, F.; Birrer, M.; Aghajanian, C.; Coleman, R. L.; Mills, G. B.; Cantley, L. C.; Matulonis, U. A.; Westin, S. N. |
| Article Title: | Phase II, 2-stage, 2-arm, PIK3CA mutation stratified trial of MK-2206 in recurrent endometrial cancer |
| Abstract: | Endometrial cancers have high rates of phosphoinositide 3-kinase (PI3K) pathway alterations. MK-2206 is an allosteric inhibitor of AKT, an effector kinase of PI3K signals. We hypothesized patients with tumors harboring PIK3CA mutations would be more likely to benefit from MK-2206 than those without PIK3CA mutation. A Phase II study was performed in patients with recurrent endometrial cancer; all histologies except carcinosarcoma were eligible. Up to two prior chemotherapy lines were permitted, excluding prior treatment with PI3K pathway inhibitors. The first 18 patients were treated with MK-2206 200 mg weekly. Due to unacceptable toxicity, dose was reduced to 135 mg. Co-primary endpoints were objective response rate (ORR) and progression-free survival at 6 months (6moPFS). Thirty-seven patients were enrolled (one ineligible). By somatic PIK3CA mutation analysis, nine patients were mutant (MT) [one with partial response (PR)/6moPFS, two with 6moPFS]. Twenty-seven patients were wild-type (WT) (one PR and four 6moPFS). Most common toxicities were rash (44%), fatigue (41%), nausea (42%) and hyperglycemia (31%). Grade 3 and 4 toxicities occurred in 25 and 17% of patients, respectively. Exploratory analysis found serous histology had greater 6moPFS as compared to all other histologies (5/8 vs. 2/28, p = 0.003). PTEN expression was associated with median time to progression (p = 0.04). No other significant associations with PI3K pathway alterations were identified. There is limited single agent activity of MK-2206 in PIK3CA MT and PIK3CA WT endometrial cancer populations. Activity was detected in patients with serous histology and due to their poor outcomes warrants further study (NCT01307631). © 2019 UICC |
| Keywords: | treatment; endometrial cancer; endometrioid; serous; pi3k/akt |
| Journal Title: | International Journal of Cancer |
| Volume: | 147 |
| Issue: | 2 |
| ISSN: | 0020-7136 |
| Publisher: | John Wiley & Sons |
| Date Published: | 2020-07-15 |
| Start Page: | 413 |
| End Page: | 422 |
| Language: | English |
| DOI: | 10.1002/ijc.32783 |
| PUBMED: | 31714586 |
| PROVIDER: | scopus |
| PMCID: | PMC7214201 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 1 June 2020 -- Source: Scopus |
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