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|Ref Type||Journal Article|
|Authors||Myers AP, Konstantinopoulos PA, Barry WT, Luo W, Broaddus RR, Makker V, Drapkin R, Liu J, Doyle A, Horowitz NS, Meric-Bernstam F, Birrer M, Aghajanian C, Coleman RL, Mills GB, Cantley LC, Matulonis UA, Westin SN|
|Title||Phase II, 2-stage, 2-arm, PIK3CA mutation stratified trial of MK-2206 in recurrent endometrial cancer.|
|Journal||International journal of cancer|
|Date||2019 Nov 12|
|Abstract Text||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).|
|Molecular Profile||Treatment Approach|
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|PIK3CA mutant||endometrial cancer||no benefit||MK2206||Phase II||Actionable||In a Phase II trial, MK2206 demonstrated limited benefit in endometrial cancer patients regardless of PIK3CA status, with partial responses in 6% (2/37) of patients, 19% (7/37; 5 with serous histology) remaining progression-free for at least 6 mo, and a median progression-free survival (PFS) of 2.0 mo in the overall population, and partial responses in 11% (11/9), 33% (3/9) progression-free for 6 mo, and a median PFS of 1.7 mo in the group of patients with PIK3CA mutations (PMID: 31714586; NCT01307631).||31714586|