Drug Safety

, Volume 42, Issue 2, pp 247–262 | Cite as

Safety and Tolerability of Phosphatidylinositol-3-Kinase (PI3K) Inhibitors in Oncology

  • Giuseppe Curigliano
  • Rashmi R. ShahEmail author
Review Article


Activation of phosphatidylinositol-3-kinase (PI3K) and downstream signalling by AKT/mammalian target of rapamycin (mTOR) modulates cellular processes such as increased cell growth, cell proliferation and increased cell migration as well as deregulated apoptosis and oncogenesis. The PI3K/AKT/mTOR pathway (particularly Class I PI3K isoforms) is frequently activated in a variety of solid tumours and haematological malignancies, making PI3K an attractive therapeutic target in oncology. Inhibitors of PI3K also have the potential to restore sensitivity to other modalities of treatments when administered as part of combination regimens. Although many PI3K inhibitors have reached different stages of clinical development, only two (idelalisib and copanlisib) have been currently approved for use in the treatment of B cell lymphoma and leukaemias. While these two agents are effective clinically, their use is associated with a number of serious class-related as well as drug-specific adverse effects. Some of these are immune-mediated and include cutaneous reactions, severe diarrhoea with or without colitis, hepatotoxicity and pneumonitis. They also induce various metabolic abnormalities such as hyperglycaemia and hypertriglyceridaemia. Not surprisingly, therefore, many new PI3K inhibitors with a varying degree of target selectivity have been synthesised in expectations of improved safety and efficacy, and are currently under clinical investigations for use in a variety of solid tumours as well as haematological malignancies. However, evidence from early clinical trials, reviewed herein, suggests that these newer agents are also associated not only with class-related but also other serious and unexpected adverse effects. Their risk/benefit evaluations have resulted in a number of them being discontinued from further development. Cumulative experience with the use of PI3K inhibitors under development suggests that, compared with their use as monotherapy, combining them with other anticancer therapies may be a more effective strategy in improving current standard-of-care and clinical outcomes in cancers beyond haematological cancers. For example, combination of alpelisib with fulvestrant has recently demonstrated unexpectedly superior efficacy compared to fulvestrant alone. Furthermore, the immunomodulatory activity of PI3Kδ and PI3Kγ inhibitors also provides unexpected opportunities for their use in cancer immunotherapy, as is currently being tested in several clinical trials.


Compliance with Ethical Standards

Ethical Standards

This is a review of data in the public domain and the authors declare compliance with all ethical standards.


No sources of funding were used to assist in the preparation of this review.

Conflict of Interest

Rashmi Shah (RS) was formerly a Senior Clinical Assessor at the Medicines and Healthcare products Regulatory Agency (MHRA), London, UK, and now provides expert consultancy services to a number of pharmaceutical companies. Giuseppe Curigliano (GC) has received consulting fees from Pfizer, Novartis, Eli Lilly and Roche; travel support from Roche; and lecture payments from Pfizer. RS and GC have no other conflicts of interest that are relevant to the content of this review.

Contributions for Authorship

GC and RS conceived the topic and RS assisted with literature search. RS prepared the first draft and GC revised the first and subsequent drafts. Both GC and RS approved the final version.


  1. 1.
    Porta C, Paglino C, Mosca A. Targeting PI3K/Akt/mTOR signaling in cancer. Front Oncol. 2014;4:64.CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Markman B, Atzori F, Pérez-García J, Tabernero J, Baselga J. Status of PI3K inhibition and biomarker development in cancer therapeutics. Ann Oncol. 2010;21:683–91.CrossRefPubMedGoogle Scholar
  3. 3.
    Fruman DA, Chiu H, Hopkins BD, Bagrodia S, Cantley LC, Abraham RT. The PI3K pathway in human disease. Cell. 2017;170:605–35.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Yip PY. Phosphatidylinositol 3-kinase-AKT-mammalian target of rapamycin (PI3K-Akt-mTOR) signaling pathway in non-small cell lung cancer. Transl Lung Cancer Res. 2015;4:165–76.PubMedPubMedCentralGoogle Scholar
  5. 5.
    Fry MJ. Phosphoinositide 3-kinase signalling in breast cancer: how big a role might it play? Breast Cancer Res. 2001;3:304–12.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Engelman JA, Luo J, Cantley LC. The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism. Nat Rev Genet. 2006;7:606–19.CrossRefPubMedGoogle Scholar
  7. 7.
    Curran E, Smith SM. Phosphoinositide 3-kinase inhibitors in lymphoma. Curr Opin Oncol. 2014;26:469–75.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Wang X, Ding J, Meng LH. PI3K isoform-selective inhibitors: next-generation targeted cancer therapies. Acta Pharmacol Sin. 2015;36:1170–6.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Janku F. Phosphoinositide 3-kinase (PI3K) pathway inhibitors in solid tumors: from laboratory to patients. Cancer Treat Rev. 2017;59:93–101.CrossRefPubMedGoogle Scholar
  10. 10.
    Tzenaki N, Papakonstanti EA. p110δ PI3Kinase pathway: emerging roles in cancer. Front Oncol. 2013;3:40.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Stark AK, Sriskantharajah S, Hessel EM, Okkenhaug K. PI3K inhibitors in inflammation, autoimmunity and cancer. Curr Opin Pharmacol. 2015;23:82–91.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Greenwell IB, Ip A, Cohen JB. PI3K inhibitors: understanding toxicity mechanisms and management. Oncology (Williston Park). 2017;31:821–8.Google Scholar
  13. 13.
    Baselga J. Targeting the phosphoinositide-3 (PI3) kinase pathway in breast cancer. Oncologist. 2011;16(Suppl 1):12–9.CrossRefPubMedGoogle Scholar
  14. 14.
    Zhao W, Qiu Y, Kong D. Class I phosphatidylinositol 3-kinase inhibitors for cancer therapy. Acta Pharm Sin B. 2017;7:27–37.CrossRefPubMedGoogle Scholar
  15. 15.
    Perrotta M, Lembo G, Carnevale D. The multifaceted roles of PI3Kγ in hypertension, vascular biology, and inflammation. Int J Mol Sci. 2016;17:1858.CrossRefPubMedCentralGoogle Scholar
  16. 16.
    Ali K, Soond DR, Pineiro R, Hagemann T, Pearce W, Lim EL, et al. Inactivation of PI(3)K p110δ breaks regulatory T-cell-mediated immune tolerance to cancer. Nature. 2014;510:407–11.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Okkenhaug K, Graupera M, Vanhaesebroeck B. Targeting PI3K in cancer: impact on tumor cells, their protective stroma, angiogenesis, and immunotherapy. Cancer Discov. 2016;6:1090–105.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Vivanco I, Sawyers CL. The phosphatidylinositol 3-kinase AKT pathway in human cancer. Nat Rev Cancer. 2002;2:489–501.CrossRefPubMedGoogle Scholar
  19. 19.
    Brader S, Eccles SA. Phosphoinositide 3-kinase signalling pathways in tumor progression, invasion and angiogenesis. Tumori. 2004;90:2–8.CrossRefPubMedGoogle Scholar
  20. 20.
    Massacesi C, Di Tomaso E, Urban P, Germa C, Quadt C, Trandafir L, et al. PI3K inhibitors as new cancer therapeutics: implications for clinical trial design. Onco Targets Ther. 2016;9:203–10.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Janku F, Yap TA, Meric-Bernstam F. Targeting the PI3K pathway in cancer: are we making headway? Nat Rev Clin Oncol. 2018;15:273–91.CrossRefPubMedGoogle Scholar
  22. 22.
    Dienstmann R, Rodon J, Serra V, Tabernero J. Picking the point of inhibition: a comparative review of PI3K/AKT/mTOR pathway inhibitors. Mol Cancer Ther. 2014;13:1021–31.CrossRefPubMedGoogle Scholar
  23. 23.
    Thorpe LM, Yuzugullu H, Zhao JJ. PI3K in cancer: divergent roles of isoforms, modes of activation and therapeutic targeting. Nat Rev Cancer. 2015;15:7–24.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Millis SZ, Ikeda S, Reddy S, Gatalica Z, Kurzrock R. Landscape of phosphatidylinositol-3-kinase pathway alterations across 19784 diverse solid tumors. JAMA Oncol. 2016;2:1565–73.CrossRefPubMedGoogle Scholar
  25. 25.
    LoRusso PM. Inhibition of the PI3K/AKT/mTOR pathway in solid tumors. J Clin Oncol. 2016;34:3803–15.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    O’Donnell JS, Massi D, Teng MWL, Mandala M. PI3K-AKT-mTOR inhibition in cancer immunotherapy, redux. Semin Cancer Biol. 2018;48:91–103.CrossRefPubMedGoogle Scholar
  27. 27.
    Yehia L, Eng C. 65 years of the double helix: one gene, many endocrine and metabolic syndromes: PTEN-opathies and precision medicine. Endocr Relat Cancer. 2018;25:T121–40.CrossRefPubMedGoogle Scholar
  28. 28.
    Engelman JA. The role of phosphoinositide 3-kinase pathway inhibitors in the treatment of lung cancer. Clin Cancer Res. 2007;13(15 Pt 2):s4637–40.CrossRefPubMedGoogle Scholar
  29. 29.
    Lux MP, Fasching PA, Schrauder MG, Hein A, Jud SM, Rauh C, et al. The PI3K pathway: background and treatment approaches. Breast Care (Basel). 2016;11:398–404.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Keegan NM, Gleeson JP, Hennessy BT, Morris PG. PI3K inhibition to overcome endocrine resistance in breast cancer. Expert Opin Investig Drugs. 2018;27:1–15.CrossRefPubMedGoogle Scholar
  31. 31.
    Burris HA 3rd. Overcoming acquired resistance to anticancer therapy: focus on the PI3K/AKT/mTOR pathway. Cancer Chemother Pharmacol. 2013;71:829–42.CrossRefPubMedGoogle Scholar
  32. 32.
    Fruman DA, Rommel C. PI3Kδ inhibitors in cancer: rationale and serendipity merge in the clinic. Cancer Discov. 2011;1:562–72.CrossRefPubMedGoogle Scholar
  33. 33.
    Rodon J, Tabernero J. Improving the armamentarium of PI3K inhibitors with isoform-selective agents: a new light in the darkness. Cancer Discov. 2017;7:666–9.CrossRefPubMedGoogle Scholar
  34. 34.
    Liu Y, Wan WZ, Li Y, Zhou GL, Liu XG. Recent development of ATP-competitive small molecule phosphatidylinostitol-3-kinase inhibitors as anticancer agents. Oncotarget. 2017;8:7181–200.PubMedGoogle Scholar
  35. 35.
    Bergholz JS, Roberts TM, Zhao JJ. Isoform-selective phosphatidylinositol 3-kinase inhibition in cancer. J Clin Oncol. 2018;36:1339–42.CrossRefPubMedGoogle Scholar
  36. 36.
    Food and Drug Administration. Drug-specific reviews on Drugs@FDA; 2018.
  37. 37.
    European Medicines Agency. Drug-specific assessment reports and labels; 2018.
  38. 38.
    Lampson BL, Brown JR. PI3Kδ-selective and PI3Kα/δ-combinatorial inhibitors in clinical development for B-cell non-Hodgkin lymphoma. Expert Opin Investig Drugs. 2017;26:1267–79.CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Bossaer JB, Chakraborty K. Drug interaction between idelalisib and diazepam resulting in altered mental status and respiratory failure. J Oncol Pharm Pract. 2017;23:470–2.CrossRefPubMedGoogle Scholar
  40. 40.
    Pleyer C, Wiestner A, Sun C. Immunological changes with kinase inhibitor therapy for chronic lymphocytic leukemia. Leuk Lymphoma. 2018. (Epub 2018 May 15).CrossRefPubMedGoogle Scholar
  41. 41.
    Lampson BL, Kasar SN, Matos TR, Morgan EA, Rassenti L, Davids MS, et al. Idelalisib given front-line for treatment of chronic lymphocytic leukemia causes frequent immune-mediated hepatotoxicity. Blood. 2016;128:195–203.CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    de Weerdt I, Koopmans SM, Kater AP, van Gelder M. Incidence and management of toxicity associated with ibrutinib and idelalisib: a practical approach. Haematologica. 2017;102:1629–39.CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Coutre SE, Barrientos JC, Brown JR, de Vos S, Furman RR, Keating MJ, et al. Management of adverse events associated with idelalisib treatment: expert panel opinion. Leuk Lymphoma. 2015;56:2779–86.CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Callahan MK, Postow MA, Wolchok JD. Targeting T cell co-receptors for cancer therapy. Immunity. 2016;44:1069–78.CrossRefPubMedGoogle Scholar
  45. 45.
    Louie CY, DiMaio MA, Matsukuma KE, Coutre SE, Berry GJ, Longacre TA. Idelalisib-associated enterocolitis: clinicopathologic features and distinction from other enterocolitides. Am J Surg Pathol. 2015;39:1653–60.CrossRefPubMedGoogle Scholar
  46. 46.
    Weidner AS, Panarelli NC, Geyer JT, Bhavsar EB, Furman RR, Leonard JP, et al. Idelalisib-associated colitis: histologic findings in 14 patients. Am J Surg Pathol. 2015;39:1661–7.CrossRefPubMedGoogle Scholar
  47. 47.
    Hammami MB, Al-Taee A, Meeks M, Fesler M, Hurley MY, Cao D, et al. Idelalisib-induced colitis and skin eruption mimicking graft-versus-host disease. Clin J Gastroenterol. 2017;10:142–6.CrossRefPubMedGoogle Scholar
  48. 48.
    Yeung CC, Hockenbery DM, Westerhoff M, Coutre SE, Sedlak RH, Dubowy RL, et al. Pathological assessment of gastrointestinal biopsies from patients with idelalisib-associated diarrhea and colitis. Future Oncol. 2018;14:2265–77.CrossRefPubMedGoogle Scholar
  49. 49.
    Haustraete E, Obert J, Diab S, Abbes S, Zini JM, Valade S, et al. Idelalisib-related pneumonitis. Eur Respir J. 2016;47:1280–3.CrossRefPubMedGoogle Scholar
  50. 50.
    Dreyling M, Santoro A, Mollica L, Leppä S, Follows GA, Lenz G, et al. Phosphatidylinositol 3-kinase inhibition by copanlisib in relapsed or refractory indolent lymphoma. J Clin Oncol. 2017;35:3898–905.CrossRefPubMedGoogle Scholar
  51. 51.
    Yang T, Meoli DF, Moslehi J, Roden DM. Inhibition of the α-subunit of phosphoinositide 3-kinase in heart increases late sodium current and is arrhythmogenic. J Pharmacol Exp Ther. 2018;365:460–6.CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    O’Brien S, Hillmen P, Coutre S, Barr PM, Fraser G, Tedeschi A, et al. Safety analysis of four randomized controlled studies of ibrutinib in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma or mantle cell lymphoma. Clin Lymphoma Myeloma Leuk. 2018;18(10):648.e15–657.e15.Google Scholar
  53. 53.
    O’Brien SM, Furman RR, Coutre SE, Flinn IW, Burger J, Blum K, et al. Five-year experience with single-agent ibrutinib in patients with previously untreated and relapsed/refractory chronic lymphocytic leukemia/small lymphocytic leukemia [abstract]. Presented at: 58th American Society of Hematology Annual Meeting; San Diego, CA; December 3–6, 2016. Blood. 2016;128:233.Google Scholar
  54. 54.
    Furman RR, Sharman JP, Coutre SE, Cheson BD, Pagel JM, Hillmen P, et al. Idelalisib and rituximab in relapsed chronic lymphocytic leukemia. N Engl J Med. 2014;370:997–1007.CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    Janku F, Hong DS, Fu S, Piha-Paul SA, Naing A, Falchook GS, et al. Assessing PIK3CA and PTEN in early-phase trials with PI3K/AKT/mTOR inhibitors. Cell Rep. 2014;6:377–87.CrossRefPubMedPubMedCentralGoogle Scholar
  56. 56.
    Zelenetz AD, Barrientos JC, Brown JR, Coiffier B, Delgado J, Egyed M, et al. Idelalisib or placebo in combination with bendamustine and rituximab in patients with relapsed or refractory chronic lymphocytic leukaemia: interim results from a phase 3, randomised, double-blind, placebo-controlled trial. Lancet Oncol. 2017;18:297–311.CrossRefPubMedPubMedCentralGoogle Scholar
  57. 57.
    Food and Drug Administration. FDA alerts healthcare professionals about clinical trials with Zydelig (idelalisib) in combination with other cancer medicines. 14 Mar 2016; 2018.
  58. 58.
    Food and Drug Administration. Zydelig® risk evaluation and mitigation strategy (modified on 26 January 2018); 2018.
  59. 59.
    Novak J, Havrda M, Gaherova L, Spicka J, Kozak T. Clinical case: idelalisib-induced immunoglobulin flare. Immunopharmacol Immunotoxicol. 2017;39:251–2.CrossRefPubMedGoogle Scholar
  60. 60.
    Castillo JJ, Gustine JN, Meid K, Dubeau T, Yang G, Xu L, et al. Idelalisib in Waldenström macroglobulinemia: high incidence of hepatotoxicity. Leuk Lymphoma. 2017;58:1002–4.CrossRefPubMedGoogle Scholar
  61. 61.
    Gryc T, Putz F, Goerig N, Ziegler S, Fietkau R, Distel LV, et al. Idelalisib may have the potential to increase radiotherapy side effects. Radiat Oncol. 2017;12:109.CrossRefPubMedPubMedCentralGoogle Scholar
  62. 62.
    Health Canada. Summary safety review—ZYDELIG (idelalisib)—assessing the potential risk of a rare brain infection (progressive multifocal leukoencephalopathy). 15 Dec 2017; 2017.
  63. 63.
    Martín M, Chan A, Dirix L, O’Shaughnessy J, Hegg R, Manikhas A, et al. A randomized adaptive phase II/III study of buparlisib, a pan-class I PI3K inhibitor, combined with paclitaxel for the treatment of HER2-advanced breast cancer (BELLE-4). Ann Oncol. 2017;28:313–20.CrossRefPubMedGoogle Scholar
  64. 64.
    Younes A, Salles G, Martinelli G, Bociek RG, Barrigon DC, Barca EG, et al. Pan-phosphatidylinositol 3-kinase inhibition with buparlisib in patients with relapsed or refractory non-Hodgkin lymphoma. Haematologica. 2017;102:2104–12.CrossRefPubMedPubMedCentralGoogle Scholar
  65. 65.
    Heudel PE, Fabbro M, Roemer-Becuwe C, Kaminsky MC, Arnaud A, Joly F, et al. Phase II study of the PI3K inhibitor BKM120 in patients with advanced or recurrent endometrial carcinoma: a stratified type I-type II study from the GINECO group. Br J Cancer. 2017;116:303–9.CrossRefPubMedPubMedCentralGoogle Scholar
  66. 66.
    Sarker D, Ang JE, Baird R, Kristeleit R, Shah K, Moreno V, et al. First-in-human phase I study of pictilisib (GDC-0941), a potent pan-class I phosphatidylinositol-3-kinase (PI3K) inhibitor, in patients with advanced solid tumors. Clin Cancer Res. 2015;21:77–86.CrossRefPubMedGoogle Scholar
  67. 67.
    Shapiro GI, Rodon J, Bedell C, Kwak EL, Baselga J, Braña I, et al. Phase I safety, pharmacokinetic, and pharmacodynamic study of SAR245408 (XL147), an oral pan-class I PI3K inhibitor, in patients with advanced solid tumors. Clin Cancer Res. 2014;20:233–45.CrossRefPubMedGoogle Scholar
  68. 68.
    Matulonis U, Vergote I, Backes F, Martin LP, McMeekin S, Birrer M, et al. Phase II study of the PI3K inhibitor pilaralisib (SAR245408; XL147) in patients with advanced or recurrent endometrial carcinoma. Gynecol Oncol. 2015;136:246–53.CrossRefPubMedGoogle Scholar
  69. 69.
    Edelman G, Rodon J, Lager J, Castell C, Jiang J, Van Allen EM, et al. Phase I trial of a tablet formulation of pilaralisib, a pan-class I PI3K inhibitor, in patients with advanced solid tumors. Oncologist. 2018;23:401-e38.CrossRefPubMedPubMedCentralGoogle Scholar
  70. 70.
    Bowles DW, Kochenderfer M, Cohn A, Sideris L, Nguyen N, Cline-Burkhardt V, et al. A randomized, phase II trial of cetuximab with or without PX-866, an irreversible oral phosphatidylinositol 3-kinase inhibitor, in patients with metastatic colorectal carcinoma. Clin Colorectal Cancer. 2016;15(337–44):e2.Google Scholar
  71. 71.
    Mayer IA, Abramson VG, Formisano L, Balko JM, Estrada MV, Sanders ME, et al. A phase Ib study of alpelisib (BYL719), a PI3Kα-specific inhibitor, with letrozole in ER+/HER2- metastatic breast cancer. Clin Cancer Res. 2017;23:26–34.CrossRefPubMedGoogle Scholar
  72. 72.
    Juric D, Rodon J, Tabernero J, Janku F, Burris HA, Schellens JHM, et al. Phosphatidylinositol 3-kinase α-selective inhibition with alpelisib (BYL719) in PIK3CA-altered solid tumors: results from the first-in-human study. J Clin Oncol. 2018;36:1291–9.CrossRefPubMedPubMedCentralGoogle Scholar
  73. 73.
    Flinn IW, O’Brien S, Kahl B, Patel M, Oki Y, Foss FF, et al. Duvelisib, a novel oral dual inhibitor of PI3K-δ, γ, is clinically active in advanced hematologic malignancies. Blood. 2018;131:877–87.CrossRefPubMedPubMedCentralGoogle Scholar
  74. 74.
    Horwitz SM, Koch R, Porcu P, Oki Y, Moskowitz A, Perez M, et al. Activity of the PI3K-δ, γ inhibitor duvelisib in a phase 1 trial and preclinical models of T-cell lymphoma. Blood. 2018;131:888–98.CrossRefPubMedPubMedCentralGoogle Scholar
  75. 75.
    Flinn IW, Patel M, Oki Y, Horwitz S, Foss FF, Allen K, et al. Duvelisib, an oral dual PI3K-δ, γ inhibitor, shows clinical activity in indolent non-Hodgkin lymphoma in a phase 1 study. Am J Hematol. 2018;93:1311–7.CrossRefPubMedPubMedCentralGoogle Scholar
  76. 76.
    Juric D, Krop I, Ramanathan RK, Wilson TR, Ware JA, Sanabria Bohorquez SM, et al. Phase I dose-escalation study of taselisib, an oral PI3K inhibitor, in patients with advanced solid tumors. Cancer Discov. 2017;7:704–15.CrossRefPubMedPubMedCentralGoogle Scholar
  77. 77.
    Tamura K, Kodaira M, Shimizu C, Yonemori K, Yunokawa M, Shimomura A, et al. Phase I study of taselisib in Japanese patients with advanced solid tumors or hormone receptor-positive advanced breast cancer. Cancer Sci. 2018;109:1592–601.CrossRefPubMedPubMedCentralGoogle Scholar
  78. 78.
    Dolly SO, Wagner AJ, Bendell JC, Kindler HL, Krug LM, Seiwert TY, et al. Phase I study of apitolisib (GDC-0980), dual phosphatidylinositol-3-kinase and mammalian target of rapamycin kinase inhibitor, in patients with advanced solid tumors. Clin Cancer Res. 2016;22:2874–84.CrossRefPubMedPubMedCentralGoogle Scholar
  79. 79.
    Powles T, Lackner MR, Oudard S, Escudier B, Ralph C, Brown JE, et al. Randomized open-label phase II trial of apitolisib (GDC-0980), a novel inhibitor of the PI3K/mammalian target of rapamycin pathway, versus everolimus in patients with metastatic renal cell carcinoma. J Clin Oncol. 2016;34:1660–8.CrossRefPubMedPubMedCentralGoogle Scholar
  80. 80.
    Wicki A, Brown N, Xyrafas A, Bize V, Hawle H, Berardi S, et al. First-in human, phase 1, dose-escalation pharmacokinetic and pharmacodynamic study of the oral dual PI3K and mTORC1/2 inhibitor PQR309 in patients with advanced solid tumors (SAKK 67/13). Eur J Cancer. 2018;96:6–16.CrossRefPubMedGoogle Scholar
  81. 81.
    Carlo MI, Molina AM, Lakhman Y, Patil S, Woo K, DeLuca J, et al. A phase Ib study of BEZ235, a dual inhibitor of phosphatidylinositol 3-kinase (PI3K) and mammalian target of rapamycin (mTOR), in patients with advanced renal cell carcinoma. Oncologist. 2016;21:787–8.CrossRefPubMedPubMedCentralGoogle Scholar
  82. 82.
    Seront E, Rottey S, Filleul B, Glorieux P, Goeminne JC, Verschaeve V, et al. Phase II study of dual phosphoinositol-3-kinase (PI3K) and mammalian target of rapamycin (mTOR) inhibitor BEZ235 in patients with locally advanced or metastatic transitional cell carcinoma. BJU Int. 2016;118:408–15.CrossRefPubMedGoogle Scholar
  83. 83.
    Wise-Draper TM, Moorthy G, Salkeni MA, Karim NA, Thomas HE, Mercer CA, et al. A phase Ib study of the dual PI3K/mTOR inhibitor dactolisib (BEZ235) combined with everolimus in patients with advanced solid malignancies. Target Oncol. 2017;12:323–32.CrossRefPubMedPubMedCentralGoogle Scholar
  84. 84.
    Shapiro GI, Bell-McGuinn KM, Molina JR, Bendell J, Spicer J, Kwak EL, et al. First-in-human study of PF-05212384 (PKI-587), a small-molecule, intravenous, dual inhibitor of PI3K and mTOR in patients with advanced cancer. Clin Cancer Res. 2015;21:1888–95.CrossRefPubMedPubMedCentralGoogle Scholar
  85. 85.
    Del Campo JM, Birrer M, Davis C, Fujiwara K, Gollerkeri A, Gore M, et al. A randomized phase II non-comparative study of PF-04691502 and gedatolisib (PF-05212384) in patients with recurrent endometrial cancer. Gynecol Oncol. 2016;142:62–9.CrossRefPubMedGoogle Scholar
  86. 86.
    Papadopoulos KP, Tabernero J, Markman B, Patnaik A, Tolcher AW, Baselga J, et al. Phase I safety, pharmacokinetic, and pharmacodynamic study of SAR245409 (XL765), a novel, orally administered PI3K/mTOR inhibitor in patients with advanced solid tumors. Clin Cancer Res. 2014;20:2445–56.CrossRefPubMedGoogle Scholar
  87. 87.
    Wen PY, Omuro A, Ahluwalia MS, Fathallah-Shaykh HM, Mohile N, Lager JJ, et al. Phase I dose-escalation study of the PI3K/mTOR inhibitor voxtalisib (SAR245409, XL765) plus temozolomide with or without radiotherapy in patients with high-grade glioma. Neuro Oncol. 2015;17:1275–83.CrossRefPubMedPubMedCentralGoogle Scholar
  88. 88.
    Brown JR, Hamadani M, Hayslip J, Janssens A, Wagner-Johnston N, Ottmann O, et al. Voxtalisib (XL765) in patients with relapsed or refractory non-Hodgkin lymphoma or chronic lymphocytic leukaemia: an open-label, phase 2 trial. Lancet Haematol. 2018;5:e170–80.CrossRefPubMedGoogle Scholar
  89. 89.
    Brown KK, Toker A. The phosphoinositide 3-kinase pathway and therapy resistance in cancer. F1000Prime Rep. 2015;7:13.Google Scholar
  90. 90.
    Wang Q, Liu P, Spangle JM, Von T, Roberts TM, Lin NU, et al. PI3K-p110α mediates resistance to HER2-targeted therapy in HER2+, PTEN-deficient breast cancers. Oncogene. 2016;35:3607–12.CrossRefPubMedGoogle Scholar
  91. 91.
    Peng W, Chen JQ, Liu C, Malu S, Creasy C, Tetzlaff MT, et al. Loss of PTEN promotes resistance to T cell-mediated immunotherapy. Cancer Discov. 2016;6:202–16.CrossRefPubMedGoogle Scholar
  92. 92.
    Costa C, Ebi H, Martini M, Beausoleil SA, Faber AC, Jakubik CT, et al. Measurement of PIP3 levels reveals an unexpected role for p110β in early adaptive responses to p110α-specific inhibitors in luminal breast cancer. Cancer Cell. 2015;27:97–108.CrossRefPubMedGoogle Scholar
  93. 93.
    Schwartz S, Wongvipat J, Trigwell CB, Hancox U, Carver BS, Rodrik-Outmezguine V, et al. Feedback suppression of PI3Kα signaling in PTEN-mutated tumors is relieved by selective inhibition of PI3Kβ. Cancer Cell. 2015;27:109–22.CrossRefPubMedGoogle Scholar
  94. 94.
    Mayer IA, Dent R, Tan T, Savas P, Loi S. Novel targeted agents and immunotherapy in breast cancer. Am Soc Clin Oncol Educ Book. 2017;37:65–75.CrossRefPubMedGoogle Scholar
  95. 95.
    Li X, Dai D, Chen B, Tang H, Xie X, Wei W. Efficacy of PI3K/AKT/mTOR pathway inhibitors for the treatment of advanced solid cancers: a literature-based meta-analysis of 46 randomised control trials. PLoS One. 2018;13:e0192464.CrossRefPubMedPubMedCentralGoogle Scholar
  96. 96.
    Hoste G, Slembrouck L, Jongen L, Punie K, Matton T, Vander Borght S, et al. Unexpected benefit from alpelisib and fulvestrant in a woman with highly pre-treated ER-positive, HER2-negative PIK3CA mutant metastatic breast cancer. Clin Drug Investig. 2018;38:1071–5.CrossRefPubMedGoogle Scholar
  97. 97.
    Andre F, Kaufman B, Juric D, Ciruelos EM, Iwata H, Mayer IA, et al. SOLAR-1: a phase III study of alpelisib and fulvestrant in men and postmenopausal women with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2–) advanced breast cancer (BC) progressing on or after aromatase inhibitor (AI) therapy [abstract no. OT2-01-04]. Cancer Res. 2017;77(4 Suppl):OT2-01-04.
  98. 98.
    André F, Ciruelos EM, Rubovszky G, Campone M, Loibl S, Rugo HS, et al. Alpelisib (ALP) + fulvestrant (FUL) for advanced breast cancer (ABC): results of the phase III SOLAR-1 trial. Ann Oncol. 2018;29(suppl_8):mdy424.010 (Abstract LBA3-PR).CrossRefGoogle Scholar
  99. 99.
    Rodon J, Curigliano G, Delord JP, Harb W, Azaro A, Han Y, et al. A phase Ib, open-label, dose-finding study of alpelisib in combination with paclitaxel in patients with advanced solid tumors. Oncotarget. 2018;9:31709–18.CrossRefPubMedPubMedCentralGoogle Scholar
  100. 100.
    Baselga J, Dent SF, Cortés J, Im Y-H, Diéras V, Harbeck N, et al. Phase III study of taselisib (GDC-0032) + fulvestrant (FULV) v FULV in patients (pts) with estrogen receptor (ER)-positive, PIK3CA-mutant (MUT), locally advanced or metastatic breast cancer (MBC): primary analysis from SANDPIPER [abstract no. LBA1006]. J Clin Oncol. 2018;36(suppl):LBA1006.Google Scholar
  101. 101.
    Carroll J. Roche dumps its PhIII PI3K effort on taselisib after researchers track poor survival edge, harsh side effects for breast cancer. Chicago, 3 Jun 2018; 2018.
  102. 102.
    Larkin J, Hodi FS, Wolchok JD. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med. 2015;373:1270–1.CrossRefPubMedGoogle Scholar
  103. 103.
    Hao C, Tian J, Liu H, Li F, Niu H, Zhu B. Efficacy and safety of anti-PD-1 and anti-PD-1 combined with anti-CTLA-4 immunotherapy to advanced melanoma: a systematic review and meta-analysis of randomized controlled trials. Medicine (Baltimore). 2017;96:e7325.CrossRefPubMedPubMedCentralGoogle Scholar
  104. 104.
    Hodi FS, Chiarion-Sileni V, Gonzalez R, Grob JJ, Rutkowski P, Cowey CL, et al. Nivolumab plus ipilimumab or nivolumab alone versus ipilimumab alone in advanced melanoma (CheckMate 067): 4-year outcomes of a multicentre, randomised, phase 3 trial. Lancet Oncol. 2018;19(11):1480–92.CrossRefPubMedGoogle Scholar
  105. 105.
    Collins DC, Chenard-Poirier M, Lopez JS. The PI3K pathway at the crossroads of cancer and the immune system: strategies for next generation immunotherapy combinations. Curr Cancer Drug Targets. 2018;18:355–64.CrossRefPubMedGoogle Scholar
  106. 106.
    Lim EL, Cugliandolo FM, Rosner DR, Gyori D, Roychoudhuri R, Okkenhaug K. Phosphoinositide 3-kinase δ inhibition promotes antitumor responses but antagonizes checkpoint inhibitors. JCI Insight. (Epub 2018 Jun 7).

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Division of Early Drug Development for Innovative TherapyIEO, European Institute of Oncology IRCCSMilanItaly
  2. 2.Department of Oncology and Haematology (DIPO)University of MilanMilanItaly
  3. 3.Pharmaceutical ConsultantGerrards CrossUK

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