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).

Keywords: PI3K/AKT; endometrial cancer; endometrioid; serous; treatment.

Conflict of interest statement

Conflict of Interest Statement

APM reports employment by Novartis. PAK reports personal fees for consulting from Merck, Pfizer, AstraZeneca, Tesaro and Vertex. WB reports research funding to his institution from Pfizer. VM reports personal fees for consulting from EISAI Pharma, Merck, Karyopharm, IBM Watson and research funding for her institution from AstraZeneca, EISAI Pharma, Merck, Lilly, Karyopharm, Takeda, and Roche/Genentech. RD reports personal fees for consulting from Repare Therapeutics and Siamab Therapeutics. JL reports personal fees for consulting from Mersana, Clovis Oncology, Tesaro and Roche/Genentech and research funding to her institution from 2X Oncology, Agenus, AstraZeneca, Arch Oncology, Boston Biomedical, Bristol-Myers Squibb, Clovis Oncology, CytomX Therapeutics, Surface Oncology, Regeneron, Roche/Genentech, and Vigeo Therapeutics. FMB reports personal feeds for consulting from Pieris, Dialectica, Sumitomo Dainippon, Samsung Bioepis, Aduro, OrigiMed, Xencor, Jackson Laboratory, Zymeworks, Kolon Life Science, and Parexel International, and advisor to Inflection Biosciences, GRAIL, Darwin Health, Spectrum, Mersana, Seattle Genetics, and Immunomedics. FMB reports receiving commercial research grants from Novartis, AstraZeneca, Calithera, Aileron, Bayer, Jounce, CytoMx, eFFECTOR, Zymeworks, PUMA Biotechnology, Curis, Millennium, Daiichi Sankyo, Abbvie, Guardant Health, Takeda, and GlaxoSmithKline as well as grants and travel related fees from Taiho and Seattle Genetics. CA reports personal fees from Tesaro, Immunogen, Clovis Oncology, Mateon Therapeutics, Eisai/Merck and grants from Clovis Oncology, Roche/Genentech, AbbVie, AstraZeneca; RLC reports personal fees for consulting from Abbvie, AstraZeneca, Clovis Oncology, Janssen, Immunogen, Tesaro, Array, Genmab, Gamamab, and research funding from Abbvie, AstraZeneca, Clovis Oncology, Roche/Genentech, Janssen, and Merck. GBM reports personal fees for consulting from AstraZeneca, Chrysalis (travel reimbursement only), ImmunoMET, Ionis, Mills Institute for Personalized Care (travel reimbursement only), Nuevolution (travel reimbursement only), PDX Pharma, SignalChem LifeSciences, Symphogen, and Tarveda. GBM reports research support from Adelson Medical Research Foundation, AstraZeneca, Breast Cancer Research Foundation, Ionis, Karus Therapeutics, Komen Research Foundation, Nanostring, Ovarian Cancer Research Foundation, Pfizer, Takeda/Millennium, and Prospect Creek Foundation. GBM reports stock options in Catena Pharmaceuticals, ImmunoMet, SignalChem LifeSciences, Spindle Top Ventures and Tarveda. GBM reports licensed technology with Myriad Genetics (HRD assay) and Nanostring (DSP).LCC reports personal fees and other from Agios Pharmaceuticals, Cell Signaling, Novo Nordisk, Petra Pharma, Pfizer. LCC holds equity in and receives compensation from Agios Pharmaceuticals and Petra Pharmaceuticals. LCC receives research support from Petra Pharma and Sanofi USA. LCC reports other from EIP Pharma, Petra Pharma, Volastra, and Faeth. LCC reports licensed technology to Agios Pharmaceticals, Beth Israel Deaconess Medical Center, Genesys Research Institute, Clear Coat Holding, and Cornell University, California Institute of Biological Research. UAM reports personal fees for consulting from 2X Oncology, Mersana, Novartis, Clovis Oncology, Fujifilm, Geneos, Lilly, Merck, Myriad Genetics and research funding to her institution from Merck and Novartis. SNW reports personal fees for consulting from AstraZeneca, Circulogene, Clovis Oncology, Merck, Novartis, Pfizer, Roche/Genentech, Takeda, Tesaro, and research funding to her institution from ArQule, AstraZeneca, Bayer, Clovis Oncology, Cotinga Pharmaceuticals, Novartis, Roche/Genentech, and Tesaro. WL, RRB, NSH, MB, and AD report no conflict of interest.

© 2019 UICC.

Figures

Figure 1:

Study schema

Figure 2:

Progression free and overall survival by PIK3CA mutation status

Figure 2:

Progression free and overall survival by PIK3CA mutation status

Figure 3:

Time on treatment based on molecular aberrations. Off treatment reasons are provided at the end of each plot (P, progressive disease); T, unacceptable toxicity; W, patient withdrawal; C, patient continue on treatment)

Figure 3:

Time on treatment based on molecular aberrations. Off treatment reasons are provided at the end of each plot (P, progressive disease); T, unacceptable toxicity; W, patient withdrawal; C, patient continue on treatment)

Figure 3:

Time on treatment based on molecular aberrations. Off treatment reasons are provided at the end of each plot (P, progressive disease); T, unacceptable toxicity; W, patient withdrawal; C, patient continue on treatment)

Figure 3:

Time on treatment based on molecular aberrations. Off treatment reasons are provided at the end of each plot (P, progressive disease); T, unacceptable toxicity; W, patient withdrawal; C, patient continue on treatment)

Figure 3:

Time on treatment based on molecular aberrations. Off treatment reasons are provided at the end of each plot (P, progressive disease); T, unacceptable toxicity; W, patient withdrawal; C, patient continue on treatment)

Figure 3:

Time on treatment based on molecular aberrations. Off treatment reasons are provided at the end of each plot (P, progressive disease); T, unacceptable toxicity; W, patient withdrawal; C, patient continue on treatment)