Phase II, 2-stage, 2-arm, PIK3CA mutation stratified trial of MK-2206 in recurrent endometrial cancer

Andrea P. Myers, Panagiotis A. Konstantinopoulos, William T. Barry, Weixiu Luo, Russell R. Broaddus, Vicky Makker, Ronny Drapkin, Joyce Liu, Austin Doyle, Neil S. Horowitz, Funda Meric-Bernstam, Michael Birrer, Carol Aghajanian, Robert L. Coleman, Gordon B. Mills, Lewis C. Cantley, Ursula A. Matulonis, Shannon N. Westin

    Research output: Contribution to journalArticle

    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).

    Original languageEnglish (US)
    JournalInternational Journal of Cancer
    DOIs
    StateAccepted/In press - Jan 1 2019

    Fingerprint

    Endometrial Neoplasms
    Mutation
    1-Phosphatidylinositol 4-Kinase
    Histology
    Carcinosarcoma
    MK 2206
    Exanthema
    Hyperglycemia
    Nausea
    Disease-Free Survival
    Fatigue
    Phosphotransferases
    Drug Therapy
    Population
    Neoplasms

    Keywords

    • endometrial cancer
    • endometrioid
    • PI3K/AKT
    • serous
    • treatment

    ASJC Scopus subject areas

    • Oncology
    • Cancer Research

    Cite this

    Myers, A. P., Konstantinopoulos, P. A., Barry, W. T., Luo, W., Broaddus, R. R., Makker, V., ... Westin, S. N. (Accepted/In press). Phase II, 2-stage, 2-arm, PIK3CA mutation stratified trial of MK-2206 in recurrent endometrial cancer. International Journal of Cancer. https://doi.org/10.1002/ijc.32783

    Phase II, 2-stage, 2-arm, PIK3CA mutation stratified trial of MK-2206 in recurrent endometrial cancer. / Myers, Andrea P.; Konstantinopoulos, Panagiotis A.; Barry, William T.; Luo, Weixiu; Broaddus, Russell R.; Makker, Vicky; Drapkin, Ronny; Liu, Joyce; Doyle, Austin; Horowitz, Neil S.; Meric-Bernstam, Funda; Birrer, Michael; Aghajanian, Carol; Coleman, Robert L.; Mills, Gordon B.; Cantley, Lewis C.; Matulonis, Ursula A.; Westin, Shannon N.

    In: International Journal of Cancer, 01.01.2019.

    Research output: Contribution to journalArticle

    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 2019, 'Phase II, 2-stage, 2-arm, PIK3CA mutation stratified trial of MK-2206 in recurrent endometrial cancer', International Journal of Cancer. https://doi.org/10.1002/ijc.32783
    Myers, Andrea P. ; Konstantinopoulos, Panagiotis A. ; Barry, William T. ; Luo, Weixiu ; Broaddus, Russell R. ; Makker, Vicky ; Drapkin, Ronny ; Liu, Joyce ; Doyle, Austin ; Horowitz, Neil S. ; Meric-Bernstam, Funda ; Birrer, Michael ; Aghajanian, Carol ; Coleman, Robert L. ; Mills, Gordon B. ; Cantley, Lewis C. ; Matulonis, Ursula A. ; Westin, Shannon N. / Phase II, 2-stage, 2-arm, PIK3CA mutation stratified trial of MK-2206 in recurrent endometrial cancer. In: International Journal of Cancer. 2019.
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    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).",
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    AU - Luo, Weixiu

    AU - Broaddus, Russell R.

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    AU - Doyle, Austin

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