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Expert Opinion on Pharmacotherapy Volume 17, 2016 - Issue 2
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Drug Evaluations

Idelalisib for the treatment of non-Hodgkin lymphoma

Solomon A. GrafDepartment of Medicine, University of Washington, Seattle, WA, USA;Fred Hutchinson Cancer Research Center, Seattle, WA, USA;Veterans Affairs Puget Sound Health Care System, Seattle, WA, USACorrespondence[email protected]
&
Ajay K. GopalDepartment of Medicine, University of Washington, Seattle, WA, USA;Fred Hutchinson Cancer Research Center, Seattle, WA, USA
Pages 265-274 | Received 29 Sep 2015, Accepted 16 Dec 2015, Published online: 28 Jan 2016

References

  • Papers of special note have been highlighted as either of interest (•) or of considerable interest (••) to readers.
  • Global Burden of Disease Cancer C, Fitzmaurice C, Dicker D, et al.. The global burden of cancer 2013. JAMA Oncol. 2015;1:505–527.
  • Jaffe ES. The 2008 WHO classification of lymphomas: implications for clinical practice and translational research. Hematology Am Soc Hematol Educ Program. 2009;2009(1):523–531.
  • Martin P, Chadburn A, Christos P, et al. Outcome of deferred initial therapy in mantle-cell lymphoma. J Clin Oncol. 2009;27:1209–1213.
  • Solal-Celigny P, Bellei M, Marcheselli L, et al. Watchful waiting in low-tumor burden follicular lymphoma in the rituximab era: results of an F2-study database. J Clin Oncol. 2012;30:3848–3853.
  • Goede V, Fischer K, Busch R, et al. Obinutuzumab plus chlorambucil in patients with CLL and coexisting conditions. N Engl J Med. 2014;370:1101–1110.
  • Hillmen P, Robak T, Janssens A, et al. Chlorambucil plus ofatumumab versus chlorambucil alone in previously untreated patients with chronic lymphocytic leukaemia (COMPLEMENT 1): a randomised, multicentre, open-label phase 3 trial. Lancet. 2015;385:1873–1883.
  • Chaudhry M, Cheson BD. What is the status of novel anti-CD20 antibodies for chronic lymphocytic leukemia and are they set to leave rituximab in the shadows? Expert Rev Hematol. 2015;8(6):733–742.
  • Fowler NH, Davis RE, Rawal S, et al. Safety and activity of lenalidomide and rituximab in untreated indolent lymphoma: an open-label, phase 2 trial. Lancet Oncol. 2014;15:1311–1318.
  • Treon SP, Soumerai JD, Branagan AR, et al. Lenalidomide and rituximab in Waldenstrom’s macroglobulinemia. Clin Cancer Res. 2009;15:355–360.
  • Witzig TE, Wiernik PH, Moore T, et al. Lenalidomide oral monotherapy produces durable responses in relapsed or refractory indolent non-Hodgkin’s Lymphoma. J Clin Oncol. 2009;27:5404–5409.
  • Witzig TE, Nowakowski GS, Habermann TM, et al. A comprehensive review of lenalidomide therapy for B-cell non-Hodgkin lymphoma. Ann Oncol. 2015;26:1667–1677.
  • Coiffier B, Osmanov EA, Hong X, et al. Bortezomib plus rituximab versus rituximab alone in patients with relapsed, rituximab-naive or rituximab-sensitive, follicular lymphoma: a randomised phase 3 trial. Lancet Oncol. 2011;12:773–784.
  • Friedberg JW, Vose JM, Kelly JL, et al. The combination of bendamustine, bortezomib, and rituximab for patients with relapsed/refractory indolent and mantle cell non-Hodgkin lymphoma. Blood. 2011;117:2807–2812.
  • Chen CI, Kouroukis CT, White D, et al. Bortezomib is active in patients with untreated or relapsed Waldenstrom’s macroglobulinemia: a phase II study of the national cancer institute of canada clinical trials group. J Clin Oncol. 2007;25:1570–1575.
  • Ghobrial IM, Xie W, Padmanabhan S, et al. Phase II trial of weekly bortezomib in combination with rituximab in untreated patients with Waldenstrom Macroglobulinemia. Am J Hematol. 2010;85:670–674.
  • Assouline SE, Chang J, Cheson BD, et al. Phase 1 dose-escalation study of IV ixazomib, an investigational proteasome inhibitor, in patients with relapsed/refractory lymphoma. Blood Cancer J. 2014;4:e251.
  • Awan FT, Flynn JM, Jones JA, et al. Phase I dose escalation trial of the novel proteasome inhibitor carfilzomib in patients with relapsed chronic lymphocytic leukemia and small lymphocytic lymphoma. Leuk Lymphoma. 2015;56(10):2834–2840.
  • Fowler N, Davis E. Targeting B-cell receptor signaling: changing the paradigm. Hematology Am Soc Hematol Educ Program. 2013;2013:553–560.
  • Advani RH, Buggy JJ, Sharman JP, et al. Bruton tyrosine kinase inhibitor ibrutinib (PCI-32765) has significant activity in patients with relapsed/refractory B-cell malignancies. J Clin Oncol. 2013;31:88–94.
  • Friedberg JW, Sharman J, Sweetenham J, et al. Inhibition of Syk with fostamatinib disodium has significant clinical activity in non-Hodgkin lymphoma and chronic lymphocytic leukemia. Blood. 2010;115:2578–2585.
  • Herman SE, Gordon AL, Wagner AJ, et al. Phosphatidylinositol 3-kinase-delta inhibitor CAL-101 shows promising preclinical activity in chronic lymphocytic leukemia by antagonizing intrinsic and extrinsic cellular survival signals. Blood. 2010;116:2078–2088.

• First report idelalisib activity in primary CLL cell lines.

  • Hoellenriegel J, Meadows SA, Sivina M, et al. The phosphoinositide 3ʹ-kinase delta inhibitor, CAL-101, inhibits B-cell receptor signaling and chemokine networks in chronic lymphocytic leukemia. Blood. 2011;118:3603–3612.
  • Vanhaesebroeck B, Welham MJ, Kotani K, et al. P110delta, a novel phosphoinositide 3-kinase in leukocytes. Proc Natl Acad Sci U S A. 1997;94:4330–4335.

• First descriptions of the leukocyte expression of the p110delta isoform of phosphatidylinositol 3-kinase.

  • Chantry D, Vojtek A, Kashishian A, et al. p110delta, a novel phosphatidylinositol 3-kinase catalytic subunit that associates with p85 and is expressed predominantly in leukocytes. J Biol Chem. 1997;272:19236–19241.

• First descriptions of the leukocyte expression of the p110delta isoform of phosphatidylinositol 3-kinase.

  • Vanhaesebroeck B, Ali K, Bilancio A, et al. Signalling by PI3K isoforms: insights from gene-targeted mice. Trends Biochem Sci. 2005;30:194–204.
  • Lannutti BJ, Meadows SA, Herman SE, et al. CAL-101, a p110delta selective phosphatidylinositol-3-kinase inhibitor for the treatment of B-cell malignancies, inhibits PI3K signaling and cellular viability. Blood. 2011;117:591–594.
  • Sciences G. Idelalisib Package Insert. 2014.
  • Somoza JR, Koditek D, Villasenor AG, et al. Structural, biochemical, and biophysical characterization of idelalisib binding to phosphoinositide 3-kinase delta. J Biol Chem. 2015;290:8439–8446.
  • Jin F, Robeson M, Zhou H, et al. Abstract 4633: Pharmacokinetics, metabolism and excretion of idelalisib. Cancer Research. 2014;74:4633.
  • Ramanathan S, Jin F, Sharma S, et al. Clinical pharmacokinetic and pharmacodynamic profile of idelalisib. Clin Pharmacokinet. 2015 Aug. [Epub ahead of print].
  • Flinn IW, Kahl BS, Leonard JP, et al. Idelalisib, a selective inhibitor of phosphatidylinositol 3-kinase-delta, as therapy for previously treated indolent non-Hodgkin lymphoma. Blood. 2014;123:3406–3413.

•• Reports of idelalisib monotherapy phase 1 dose escalation studies.

  • Jin F, Robeson M, Zhou H, et al. The pharmacokinetics and safety of idelalisib in subjects with severe renal impairment. Blood. 2013;122:5572–5572.
  • Jin F, Robeson M, Zhou H, et al. The pharmacokinetics and safety of idelalisib in subjects with moderate or severe hepatic impairment. J Clin Pharmacol. 2015;55:944–952.
  • Jin F, Robeson M, Zhou H, et al. Clinical drug interaction profile of idelalisib in healthy subjects. J Clin Pharmacol. 2015;55:909–919.
  • Jin F, Robeson M, Zhou H, et al. Evaluation of the effect of idelalisib on the QT/QTc interval in healthy subjects. Blood. 2013;122:5573–5573.
  • Brown JR, Byrd JC, Coutre SE, et al. Idelalisib, an inhibitor of phosphatidylinositol 3-kinase p110delta, for relapsed/refractory chronic lymphocytic leukemia. Blood. 2014;123:3390–3397.

•• Reports of idelalisib monotherapy phase 1 dose escalation studies.

  • Furman RR, Byrd JC, Flinn IW et al. Interim results from a phase I study of CAL-101, a selective oral inhibitor of phosphatidylinositol 3-kinase p110d isoform, in patients with relapsed or refractory hematologic malignancies. ASCO Meet Abstr. 2010;28:3032.

•• First study to report clinical activity of idelalisib in hematologic malignancies.

  • Kahl BS, Spurgeon SE, Furman RR, et al. A phase 1 study of the PI3Kdelta inhibitor idelalisib in patients with relapsed/refractory mantle cell lymphoma (MCL). Blood. 2014;123:3398–3405.

•• Reports of idelalisib monotherapy phase 1 dose escalation studies.

  • Herman SE, Niemann CU, Farooqui M, et al. Ibrutinib-induced lymphocytosis in patients with chronic lymphocytic leukemia: correlative analyses from a phase II study. Leukemia. 2014;28:2188–2196.
  • Cheson BD, Byrd JC, Rai KR, et al. Novel targeted agents and the need to refine clinical end points in chronic lymphocytic leukemia. J Clin Oncol. 2012;30:2820–2822.
  • Furman RR, De Vos S, Leonard JP, et al. A phase 1 study of the selective PI3Kδ inhibitor idelalisib (GS-1101) in combination with therapeutic anti-CD20 antibodies (Rituximab or Ofatumumab) in patients with relapsed or refractory chronic lymphocytic leukemia. Blood. 2013;122:4180–4180.
  • De Vos S, Furman RR, Barrientos JC, et al. Idelalisib, a selective inhibitor of PI3Kδ, in combination with bendamustine, fludarabine or chlorambucil in patients with relapsed or refractory (R/R) Chronic Lymphocytic Leukemia (CLL). Blood. 2013;122:2878–2878.
  • Coutre SE, Leonard JP, Furman RR et al. Combinations of the selective phosphatidylinositol 3-kinase-delta (PI3Kdelta) inhibitor GS-1101 (CAL-101) with rituximab and/or bendamustine are tolerable and highly active in patients with relapsed or refractory chronic lymphocytic leukemia (CLL): results from a phase I study. ASH Annu Meet Abstr. 2012;120:191.
  • Cheah CY, Nastoupil LJ, Neelapu SS, et al. Lenalidomide, idelalisib, and rituximab are unacceptably toxic in patients with relapsed/refractory indolent lymphoma. Blood. 2015;125:3357–3359.

•• These studies showed unexpected and prohibitive toxicities with idelalisib, lenalidomide, and rituximab combination therapies.

  • Smith SM, Pitcher B, Jung S-H, et al. Unexpected and serious toxicity observed with combined idelalisib, lenalidomide and rituximab in relapsed/refractory B cell lymphomas: alliance A051201 and A051202. Blood. 2014;124:3091–3091.

•• These studies showed unexpected and prohibitive toxicities with idelalisib, lenalidomide, and rituximab combination therapies.

  • Gopal AK, Kahl BS, De Vos S, et al. PI3Kdelta inhibition by idelalisib in patients with relapsed indolent lymphoma. N Engl J Med. 2014;370:1008–1018.

•• Pivotal phase II study of idelalisib in indolent B-NHL.

  • Gopal AK, Kahl BS, De Vos S, et al. Mature follow up from a phase 2 study of PI3K-delta inhibitor idelalisib in patients with double (Rituximab and Alkylating agent)-refractory indolent B-Cell Non-Hodgkin Lymphoma (iNHL). Blood. 2014;124:1708–1708.
  • Gopal AK, Davies AJ, Flinn IW, et al. Idelalisib monotherapy and durable responses in patients with relapsed or refractory Small Lymphocytic Lymphoma (SLL). Blood. 2015;126:2743–2743.
  • Miller BW, Przepiorka D, De Claro RA, et al. FDA approval: idelalisib monotherapy for the treatment of patients with follicular lymphoma and small lymphocytic lymphoma. Clin Cancer Res. 2015;21:1525–1529.
  • Casulo C, Byrtek M, Dawson KL, et al. Early relapse of follicular lymphoma after rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone defines patients at high risk for death: an analysis from the national lymphocare study. J Clin Oncol. 2015;33:2516–2522.
  • Gopal AK, Kahl BS, Flowers C, et al. Activity of idelalisib in high-risk follicular lymphoma with early relapse following front line immunochemotherapy. Blood. 2015;126:2744–2744.
  • Furman RR, Sharman JP, Coutre SE, et al. Idelalisib and rituximab in relapsed chronic lymphocytic leukemia. N Engl J Med. 2014;370:997–1007.

•• Pivotal phase III study of idelalisib plus rituximab in CLL.

  • O’Brien SM, Lamanna N, Kipps TJ, et al. A phase 2 study of idelalisib plus rituximab in treatment-naive older patients with chronic lymphocytic leukemia. Blood. 2015;126(25):2686–2694.

•• Phase II study showing excellent activity and tolerability of idelalisib plus rituximab in treatment-naïve CLL.

  • Jones JA, Wach M, Robak T, et al. Results of a phase III randomized, controlled study evaluating the efficacy and safety of idelalisib (IDELA) in combination with ofatumumab (OFA) for previously treated chronic lymphocytic leukemia (CLL). ASCO Meet Abstr. 2015;33:7023.
  • Coutre S, Leonard J, Flowers C, et al. Idelalisib monotherapy and durable responses in patients with relapsed or refractory Waldenstroms Macroglobulinemia (WM). ASCO Meet Abstr. 2015;33:8532.
  • Barr PM, Saylors GB, Spurgeon SEF, et al. Phase 2 trial of GS-9973, a selective syk inhibitor, and idelalisib (idela) in chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphoma (NHL). ASCO Meet Abstr. 2014;32:7059.
  • Czuczman MS, Knecht H, Auer R, et al. A phase 3, randomized, double-blind, placebo-controlled study evaluating the efficacy and safety of idelalisib (GS-1101) in combination with bendamustine and rituximab for previously treated indolent non-Hodgkin lymphomas (iNHL). ASCO Meet Abstr. 2014;32:TPS8621.
  • Salles GA, Ervin TJ, Dichmann R, et al. A phase 3, randomized, double-blind, placebo-controlled study evaluating the efficacy and safety of idelalisib in combination with rituximab for previously treated indolent non-Hodgkin lymphomas (iNHL). ASCO Meet Abstr. 2014;32:TPS8620.
  • Eradat HA, Robak T, Delgado J, et al. A phase 3, randomized, double-blind, placebo-controlled study evaluating the efficacy and safety of idelalisib (GS-1101) in combination with bendamustine and rituximab for previously treated chronic lymphocytic leukemia (CLL). ASCO Meet Abstr. 2014;32:TPS7127.
  • Salles GA, Lamanna N, Amin BR, et al. A phase 3, randomized, double-blind, placebo-controlled study evaluating the efficacy and safety of idelalisib in combination with bendamustine and rituximab for previously untreated chronic lymphocytic leukemia. ASCO Meet Abstr. 2014;32:TPS7123.
  • Coutre SE, Barrientos JC, Brown JR, et al. Management of adverse events associated with idelalisib treatment: expert panel opinion. Leuk Lymphoma. 2015;56(10):2779–2786.

•• Expert panel review of toxicities associated with idelalisib.

  • Shanafelt TD, Borah BJ, Finnes HD, et al. Impact of ibrutinib and idelalisib on the pharmaceutical cost of treating chronic lymphocytic leukemia at the individual and societal levels. J Oncol Pract. 2015;11:252–258.

• Cost analysis of idelalisib that illuminates the potential for financial toxicity.

  • Kantarjian H, Steensma D, Rius Sanjuan J, et al. High cancer drug prices in the United States: reasons and proposed solutions. J Oncol Pract. 2014;10:e208–211.
  • De Rooij MF, Kuil A, Kater AP, et al. Ibrutinib and idelalisib synergistically target BCR-controlled adhesion in MCL and CLL: a rationale for combination therapy. Blood. 2015;125:2306–2309.
  • Zoellner AK, Bayerl S, Hutter G, et al. Temsirolimus inhibits cell growth in combination with inhibitors of the B-cell receptor pathway. Leuk Lymphoma. 2015;56(12):3393–3400.
  • Choudhary GS, Al-Harbi S, Mazumder S, et al. MCL-1 and BCL-xL-dependent resistance to the BCL-2 inhibitor ABT-199 can be overcome by preventing PI3K/AKT/mTOR activation in lymphoid malignancies. Cell Death Dis. 2015;6:e1593.
  • Burke RT, Meadows S, Loriaux MM, et al. A potential therapeutic strategy for chronic lymphocytic leukemia by combining Idelalisib and GS-9973, a novel spleen tyrosine kinase (Syk) inhibitor. Oncotarget. 2014;5:908–915.
  • Da Roit F, Engelberts PJ, Taylor RP, et al. Ibrutinib interferes with the cell-mediated anti-tumor activities of therapeutic CD20 antibodies: implications for combination therapy. Haematologica. 2015;100:77–86.
  • Kritharis A, Sharma J, Evens AM. Current therapeutic strategies and new treatment paradigms for follicular lymphoma. Cancer Treat Res. 2015;165:197–226.
  • Maddocks KJ, Ruppert AS, Lozanski G, et al. Etiology of ibrutinib therapy discontinuation and outcomes in patients with chronic lymphocytic leukemia. JAMA Oncol. 2015;1:80–87.

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