Prospective phase II trial of everolimus in PIK3CA amplification/mutation and/or PTEN loss patients with advanced solid tumors refractory to standard therapy

Seung Tae Kim, Jeeyun Lee, Se Hoon Park, Joon Oh Park, Young Suk Park, Won Ki Kang, Ho Yeong Lim, Seung Tae Kim, Jeeyun Lee, Se Hoon Park, Joon Oh Park, Young Suk Park, Won Ki Kang, Ho Yeong Lim

Abstract

Background: We designed a single-arm, open-label phase II trial of everolimus in PIK3CA amplification/mutation and/or PTEN loss patients with advanced solid tumors refractory to standard therapy (#NCT02449538).

Methods: Everolimus was administered orally at a daily dose of 10 mg continuously (28-day cycles). Treatment was continued until progression of the disease or intolerable toxicity was observed. Based on Simon's two-stage optimal design, 10 patients were treated with everolimus during the first stage.

Results: The median age of the patients was 55.5 years (range, 42-72), and the median Eastern Cooperative Oncology Group (ECOG) performance status (PS) was 2 (range, 1-2). Most of the patients (50.0%) had gastric cancer (GC) as the site of their primary tumor followed by colorectal cancer (CRC), pancreatic cancer, and cholangiocarcinoma. Patients received everolimus as a third-line (3 patients), fourth-line (4 patients), fifth-line (1 patient) or sixth-line (2 patients) treatment. Complete or partial responses were not observed in any of the patients. Four patients showed stable disease, resulting in a disease control rate of 40%. The median PFS was 1.6 months (95% CI, 0.8-2.4 months). Grade 3 or greater hematologic/non-hematologic toxicity was not observed. Grade 2 diarrhea and stomatitis were reported in one patient each. There were no treatment-related deaths. There was less than one response out of the 10 initial patients during the first stage, and the study did not progress to the second stage.

Conclusions: The study did not meet its primary objective of demonstrating the anti-tumor activity of everolimus in PIK3CA amplification/mutation and/or PTEN loss patients with advanced solid tumors refractory to standard therapy. Further investigation using other genomic candidates and new-generation mTOR inhibitors is warranted in patients with treatment-refractory cancer.

Trial registration: # NCT02449538 , April 2015.

Keywords: PIK3CA amplification/mutation; PTEN loss; everolimus.

Figures

Fig. 1
Fig. 1
Progression free survival of enrolled patients

References

    1. Shaw AT, Kim DW, Nakagawa K, Seto T, Crino L, Ahn MJ, De Pas T, Besse B, Solomon BJ, Blackhall F, et al. Crizotinib versus chemotherapy in advanced ALK-positive lung cancer. N Engl J Med. 2013;368(25):2385–2394. doi: 10.1056/NEJMoa1214886.
    1. Sosman JA, Kim KB, Schuchter L, Gonzalez R, Pavlick AC, Weber JS, McArthur GA, Hutson TE, Moschos SJ, Flaherty KT, et al. Survival in BRAF V600-mutant advanced melanoma treated with vemurafenib. N Engl J Med. 2012;366(8):707–714. doi: 10.1056/NEJMoa1112302.
    1. Sekulic A, Migden MR, Oro AE, Dirix L, Lewis KD, Hainsworth JD, Solomon JA, Yoo S, Arron ST, Friedlander PA, et al. Efficacy and safety of vismodegib in advanced basal-cell carcinoma. N Engl J Med. 2012;366(23):2171–2179. doi: 10.1056/NEJMoa1113713.
    1. Ciriello G, Miller ML, Aksoy BA, Senbabaoglu Y, Schultz N, Sander C. Emerging landscape of oncogenic signatures across human cancers. Nat Genet. 2013;45(10):1127–1133. doi: 10.1038/ng.2762.
    1. Yarden Y, Sliwkowski MX. Untangling the ErbB signalling network. Nat Rev Mol Cell Biol. 2001;2(2):127–137. doi: 10.1038/35052073.
    1. Liu P, Cheng H, Roberts TM, Zhao JJ. Targeting the phosphoinositide 3-kinase pathway in cancer. Nat Rev Drug Discov. 2009;8(8):627–644. doi: 10.1038/nrd2926.
    1. Engelman JA. Targeting PI3K signalling in cancer: opportunities, challenges and limitations. Nat Rev Cancer. 2009;9(8):550–562. doi: 10.1038/nrc2664.
    1. Laplante M, Sabatini DM. mTOR signaling in growth control and disease. Cell. 2012;149(2):274–293. doi: 10.1016/j.cell.2012.03.017.
    1. Burris HA., 3rd Overcoming acquired resistance to anticancer therapy: focus on the PI3K/AKT/mTOR pathway. Cancer Chemother Pharmacol. 2013;71(4):829–842. doi: 10.1007/s00280-012-2043-3.
    1. Hudes G, Carducci M, Tomczak P, Dutcher J, Figlin R, Kapoor A, Staroslawska E, Sosman J, McDermott D, Bodrogi I, et al. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med. 2007;356(22):2271–2281. doi: 10.1056/NEJMoa066838.
    1. Motzer RJ, Escudier B, Oudard S, Hutson TE, Porta C, Bracarda S, Grunwald V, Thompson JA, Figlin RA, Hollaender N, et al. Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial. Lancet. 2008;372(9637):449–456. doi: 10.1016/S0140-6736(08)61039-9.
    1. Baselga J, Campone M, Piccart M, Burris HA, 3rd, Rugo HS, Sahmoud T, Noguchi S, Gnant M, Pritchard KI, Lebrun F, et al. Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer. N Engl J Med. 2012;366(6):520–529. doi: 10.1056/NEJMoa1109653.
    1. Yao JC, Shah MH, Ito T, Bohas CL, Wolin EM, Van Cutsem E, Hobday TJ, Okusaka T, Capdevila J, de Vries EG, et al. Everolimus for advanced pancreatic neuroendocrine tumors. N Engl J Med. 2011;364(6):514–523. doi: 10.1056/NEJMoa1009290.
    1. Mabuchi S, Altomare DA, Cheung M, Zhang L, Poulikakos PI, Hensley HH, Schilder RJ, Ozols RF, Testa JR. RAD001 inhibits human ovarian cancer cell proliferation, enhances cisplatin-induced apoptosis, and prolongs survival in an ovarian cancer model. Clin Cancer Res. 2007;13(14):4261–4270. doi: 10.1158/1078-0432.CCR-06-2770.
    1. Dormond O, Madsen JC, Briscoe DM. The effects of mTOR-Akt interactions on anti-apoptotic signaling in vascular endothelial cells. J Biol Chem. 2007;282(32):23679–23686. doi: 10.1074/jbc.M700563200.
    1. Buzzoni R, Pusceddu S, Bajetta E, De Braud F, Platania M, Iannacone C, Cantore M, Mambrini A, Bertolini A, Alabiso O, et al. Activity and safety of RAD001 (everolimus) in patients affected by biliary tract cancer progressing after prior chemotherapy: a phase II ITMO study. Ann Oncol. 2014;25(8):1597–1603. doi: 10.1093/annonc/mdu175.
    1. Ohtsu A, Ajani JA, Bai YX, Bang YJ, Chung HC, Pan HM, Sahmoud T, Shen L, Yeh KH, Chin K, et al. Everolimus for previously treated advanced gastric cancer: results of the randomized, double-blind, phase III GRANITE-1 study. J Clin Oncol. 2013;31(31):3935–3943. doi: 10.1200/JCO.2012.48.3552.
    1. Rodrigues HV, Ke D, Lim J, Stephen B, Bellido J, Janku F, Zinner R, Tsimberidou A, Hong D, Piha-Paul S, et al. Phase I combination of pazopanib and everolimus in PIK3CA mutation positive/PTEN loss patients with advanced solid tumors refractory to standard therapy. Investig New Drugs. 2015;33(3):700–709. doi: 10.1007/s10637-015-0238-2.
    1. Park JH, Ryu MH, Park YS, Park SR, Na YS, Rhoo BY, Kang YK. Successful control of heavily pretreated metastatic gastric cancer with the mTOR inhibitor everolimus (RAD001) in a patient with PIK3CA mutation and pS6 overexpression. BMC Cancer. 2015;15:119. doi: 10.1186/s12885-015-1139-7.
    1. Seront E, Pinto A, Bouzin C, Bertrand L, Machiels JP, Feron O. PTEN deficiency is associated with reduced sensitivity to mTOR inhibitor in human bladder cancer through the unhampered feedback loop driving PI3K/Akt activation. Br J Cancer. 2013;109(6):1586–1592. doi: 10.1038/bjc.2013.505.
    1. Hollander MC, Blumenthal GM, Dennis PA. PTEN loss in the continuum of common cancers, rare syndromes and mouse models. Nat Rev Cancer. 2011;11(4):289–301. doi: 10.1038/nrc3037.
    1. Shi Y, Gera J, Hu L, Hsu JH, Bookstein R, Li W, Lichtenstein A. Enhanced sensitivity of multiple myeloma cells containing PTEN mutations to CCI-779. Cancer Res. 2002;62(17):5027–5034.
    1. Steelman LS, Navolanic PM, Sokolosky ML, Taylor JR, Lehmann BD, Chappell WH, Abrams SL, Wong EW, Stadelman KM, Terrian DM, et al. Suppression of PTEN function increases breast cancer chemotherapeutic drug resistance while conferring sensitivity to mTOR inhibitors. Oncogene. 2008;27(29):4086–4095. doi: 10.1038/onc.2008.49.
    1. Guertin DA, Sabatini DM. Defining the role of mTOR in cancer. Cancer Cell. 2007;12(1):9–22. doi: 10.1016/j.ccr.2007.05.008.
    1. Shaw RJ, Cantley LC. Ras, PI(3)K and mTOR signalling controls tumour cell growth. Nature. 2006;441(7092):424–430. doi: 10.1038/nature04869.
    1. Alessi DR, Pearce LR, Garcia-Martinez JM. New insights into mTOR signaling: mTORC2 and beyond. Sci Signal. 2009;2(67):pe27. doi: 10.1126/scisignal.267pe27.
    1. Markman B, Dienstmann R, Tabernero J. Targeting the PI3K/Akt/mTOR pathway--beyond rapalogs. Oncotarget. 2010;1(7):530–543. doi: 10.18632/oncotarget.188.
    1. Ogita S, Lorusso P. Targeting phosphatidylinositol 3 kinase (PI3K)-Akt beyond rapalogs. Target Oncol. 2011;6(2):103–117. doi: 10.1007/s11523-011-0176-7.
    1. Janes MR, Vu C, Mallya S, Shieh MP, Limon JJ, Li LS, Jessen KA, Martin MB, Ren P, Lilly MB, et al. Efficacy of the investigational mTOR kinase inhibitor MLN0128/INK128 in models of B-cell acute lymphoblastic leukemia. Leukemia. 2013;27(3):586–594. doi: 10.1038/leu.2012.276.
    1. Naing A, Aghajanian C, Raymond E, Olmos D, Schwartz G, Oelmann E, Grinsted L, Burke W, Taylor R, Kaye S, et al. Safety, tolerability, pharmacokinetics and pharmacodynamics of AZD8055 in advanced solid tumours and lymphoma. Br J Cancer. 2012;107(7):1093–1099. doi: 10.1038/bjc.2012.368.
    1. Pike KG, Malagu K, Hummersone MG, Menear KA, Duggan HM, Gomez S, Martin NM, Ruston L, Pass SL, Pass M. Optimization of potent and selective dual mTORC1 and mTORC2 inhibitors: the discovery of AZD8055 and AZD2014. Bioorg Med Chem Lett. 2013;23(5):1212–1216. doi: 10.1016/j.bmcl.2013.01.019.
    1. Janku F, Hong DS, Fu S, Piha-Paul SA, Naing A, Falchook GS, Tsimberidou AM, Stepanek VM, Mouldrt SL, Lee JJ, Luthra R, Zinner RG, Broaddus RR, Wheler JJ, Kurzrock R. PIK3CA, and PTEN Aberrations in Early-Phase Trials with PI3K/AKT/mTOR Inhibitors: Experience with 1,656 Patients at MD Anderson Cancer Center. Cell Rep. 2014;6(2):377–387. doi: 10.1016/j.celrep.2013.12.035.

Source: PubMed

Patrocinadores e Colaboradores

Condições médicas

Intervenções de drogas

3
Se inscrever