Management of Relapsed/Refractory Follicular Lymphoma

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1 April 2018 Volume 16, Issue 4, Supplement 10 Mngement of Relpsed/Refrctory Folliculr Lymphom n How I Tret Relpsed/Refrctory Folliculr Lymphom: An Expert Perspective n Highlights from: The 2017 Americn Society of Hemtology Annul Meeting nd Exposition December 9-12, 2017 Atlnt, Georgi Peter Mrtin, MD, MS Associte Professor of Medicine Jon nd Snford I. Weill Deprtment of Medicine Weill Cornell Medicl College New York, New York ON THE WEB: hemtologyndoncology.net Indexed through the Ntionl Librry of Medicine (PubMed/MEDLINE), PubMed Centrl (PMC), nd EMBASE

2 How I Tret Relpsed/Refrctory Folliculr Lymphom Peter Mrtin, MD, MS Associte Professor of Medicine Jon nd Snford I. Weill Deprtment of Medicine Weill Cornell Medicl College New York, New York H&O Wht re the first-line tretment options for folliculr lymphom? PM Some ptients with newly dignosed folliculr lymphom do not need tretment t the time of dignosis. 1 When tretment is indicted, there re severl different pproches, depending on mix of lymphom-relted nd ptient-relted detils. 2 The most evluted tretment in the first-line setting of folliculr lymphom is rituximb, with or without chemotherpy. 3-5 Recently, the monoclonl ntibody obinutuzumb ws pproved in combintion with chemotherpy. 6 There my be mintennce therpy fter the initil therpy. 7 H&O How often do ptients with folliculr lymphom develop relpsed/refrctory disese? PM Some ptients, prticulrly those with erly-stge disese, might be cured with existing therpies. Additionlly, some ptients might remin in remission for long period without clinicl evidence of recurrence. However, most ptients with folliculr lymphom will eventully relpse. H&O Wht re the second-line tretment options, nd how effective re they? PM There re t lest s mny options for the secondline setting s for the first-line. After relpse or progression, the first question is whether tretment is required. 8 Very often, the nswer is no, nd symptomtic ptients with slowly progressive disese cn be observed, just s they my hve been when the lymphom ws originlly dignosed. Among ptients who do hve indictions for therpy, the first question is whether the folliculr lymphom is trnsformed or still indolent. Trnsformed disese requires tretment tht is more intense. If the folliculr lymphom is not trnsformed, then it is necessry to devise tretment pln bsed, gin, on severl lymphom-relted nd ptient-relted fctors. In the relpsed/refrctory setting, there re dditionl dt to consider: the ptient s previous therpy nd response. Options include single-gent rituximb nd rituximb plus chemotherpy. 9 In ddition, the US Food nd Drug Administrtion (FDA) hs pproved severl regimens for relpsed/refrctory folliculr lymphom. Bendmustine, with or without obinutuzumb, is pproved for ptients with rituximb-refrctory folliculr lymphom. 10,11 Ibritumomb tiuxetn is lso pproved for previously treted indolent lymphom, but it is seldom used. 12 More intensive options include utologous stem cell trnsplnt, 4 prticulrly for ptients who relpsed very erly fter first-line immunochemotherpy. H&O Do ptients in need of third-line tretment pose ny prticulr chllenges? PM There re chllenges in treting these ptients, lthough they do not necessrily reflect the line of therpy. A ptient who hs received 2 prior lines of therpy my hve ccumulted some tretment-relted toxicity nd my hve more resistnt tumor. There re severl different scenrios in this setting. For exmple, ptient might receive tretment with rituximb nd remin in remission for 5 yers, nd then receive n dditionl course of rituximb tht leds to nother 5-yer remission. This cse obviously differs from ptient who relpses quickly fter 2 lines of therpy. In the third-line setting, there is the potentil for more tretmentresistnt tumor. Ptients in need of third-line tretment my be older nd hve more comorbid conditions thn newly dignosed ptient. H&O Wht re the third-line tretment pproches, nd is there stndrd of cre? PM Options used in the first-line nd second-line setting cn lso be used in the third-line setting. In ddition, the FDA hs pproved 2 gents specificlly for third-line tretment: the phosphoinositide 3 (PI3)-kinse inhibitors copnlisib nd idellisib. 13,14 There is no stndrd of cre. The tretment choices re bsed on the prticulr ptient scenrio. All of these options hve resonble roles, depending on the context. 2 Clinicl Advnces in Hemtology & Oncology Volume 16, Issue 4, Supplement 10 April 2018

3 H&O Do dt support the use of ibrutinib in folliculr lymphom? PM Ibrutinib is not pproved by the FDA for folliculr lymphom, so ny use would be off-lbel. Currently, the evidence for ibrutinib, prticulrly s monotherpy, in folliculr lymphom is not very strong. Clinicl trils suggested tht ibrutinib works 20% to 30% of the time. 15 The durtion of response ws fir. I do not use ibrutinib frequently in ptients with folliculr lymphom. Ibrutinib my hve ctivity in combintion with other drugs in relpsed/refrctory folliculr lymphom. The phse 3 SELENE tril (A Phse III Study of Ibrutinib in Combintion With Either Bendmustine nd Rituximb [BR] or Rituximb, Cyclophosphmide, Doxorubicin, Vincristine, nd Prednisone [R-CHOP] in Ptients With Previously Treted Folliculr Lymphom or Mrginl Zone Lymphom) is combining chemotherpy nd rituximb, with or without ibrutinib. 16 This tril my led to new pprovl for ibrutinib nd chnge prctice ptterns. H&O How do the gols of therpy differ in certin settings? PM It is importnt to define the gol of third-line tretment. In pproximtely 80% of ptients with folliculr lymphom, longevity is comprble with tht seen in people without the disese. Some of these ptients my die from lymphom or relted complictions, but their life is not necessrily shortened by the disese. In these cses, the gol of every line of therpy should be to mintin qulity of life by minimizing interference from symptoms of lymphom nd side effects of therpy. In 20% of ptients with folliculr lymphom, the disese will significntly shorten life. For these ptients, it my be necessry to consider tretments tht re more intense nd/or ssocited with more significnt side effects. The gol is to help ptients live longer, nd the best therpy is debtble. A rndomized, phse 3 intergroup tril in higher-risk folliculr lymphom is compring 3 rms: chemotherpy, n immunomodultory drug plus n nti-cd20 gent, nd PI3-kinse inhibitor plus n nti-cd20 gent. 17 H&O When ptient hs received 2 prior lines of n nti-cd20 therpy nd develops relpsed/ refrctory disese, is it time to chnge to therpy with different mechnism of ction? PM My initil nswer is yes. There re, however, some controversil dt suggesting tht obinutuzumb cn work in ptients who re refrctory to rituximb. 18 Under some circumstnces, it might be resonble to tret ptient who is refrctory to rituximb with obinutuzumb plus bendmustine. Ptients who re refrctory to nti-cd20 therpy nd chemotherpy will probbly require tretment with therpies tht hve different mechnisms of ction. For exmple, the PI3-kinse inhibitors hve been effective in erly trils. 19 H&O Wht is unique bout the PI3-kinse inhibitor copnlisib? PM Copnlisib is pproved by the FDA for the tretment of ptients with folliculr lymphom tht hs relpsed fter 2 prior lines of therpy or is refrctory to 2 prior lines of therpy. 13 Copnlisib differs from the other PI3-kinse inhibitors in severl wys. For exmple, copnlisib inhibits both the lph nd delt isoforms, wheres the others re specific to delt. Copnlisib is dministered weekly by intrvenous infusion, nd the others re dministered orlly. Outside of phse 3 tril, it is hrd to compre the efficcy of different PI3-kinse inhibitors. However, it is cler tht the side effect profile of copnlisib is unique. The lph inhibition cn result in hyperglycemi nd hypertension. The phrmcokinetic properties my result in lower rtes of utoimmune or inflmmtory issues. H&O Wht did the CHRONOS-1 tril show? PM The open-lbel, multicenter, interntionl phse 2 CHRONOS-1 tril (Open-Lbel, Uncontrolled Phse II Tril of Intrvenous PI3K Inhibitor BAY in Ptients With Relpsed, Indolent or Aggressive Non- Hodgkin s Lymphoms) evluted copnlisib in ptients with indolent non-hodgkin lymphom (NHL) tht hd relpsed following 2 prior lines of therpy (including rituximb). 20 The study enrolled pproximtely 140 ptients. Most ptients hd folliculr lymphom, nd 60% were refrctory to their previous line of therpy. Copnlisib ws clerly ctive. The response rte ws pproximtely 60%, nd the medin progression-free survivl ws bout 1 yer. Alph inhibition cn result in trnsient hyperglycemi nd hypertension, nd these dverse events were mong the most common in the study. In ddition, there were some serious dverse events, including infection. Approximtely 16% of ptients stopped copnlisib owing to dverse events. H&O How do you view the efficcy dt for copnlisib s single gent for relpsed folliculr lymphom? PM Copnlisib clerly hs ctivity s single gent in this ptient popultion. This popultion ws hevily pretreted, nd most ptients were refrctory to their prior line of therpy. The response rte nd progression-free survivl were sufficient for FDA pprovl. 13 Outside of Clinicl Advnces in Hemtology & Oncology Volume 16, Issue 4, Supplement 10 April

4 phse 3 tril, it is hrd to know how copnlisib compres with other gents. H&O How is copnlisib dministered? PM Unlike other medictions currently in development, copnlisib is dministered by intrvenous infusion once weekly. The dosing schedule is 3 weeks on followed by 1 week off. At time when mny new drugs re dministered orlly, it will be interesting to see if the intrvenous dosing improves or reduces effective drug delivery in rel-world setting. H&O Are the dverse events mngeble? PM The FDA lbel lists the dverse events nd describes how to mnge them. I mentioned hyperglycemi, which peks bout 5 to 8 hours fter infusion, nd hypertension. The FDA lbel sttes tht ptient s levels of serum glucose nd blood pressure should be under control before initition of copnlisib. If this is done, then ptients re unlikely to develop post-tretment hyperglycemi or hypertension. Ptients re probbly t higher risk of overtretment thn undertretment. If ptient s glucose level is norml when strting copnlisib, ny rise should be trnsient nd will resolve with dequte fluid intke nd urintion. Similrly, if ptient strts tretment with norml blood pressure, then hypertension should resolve quickly. In other words, ptients should tke their usul ntihypertensive medictions on the dy of the infusion. With ny PI3-kinse inhibitor, there is some risk for inflmmtory or utoimmune rections, such s liver enzyme bnormlities, pneumonitis, nd colitis. Copnlisib ppers to be ssocited with reltively low rte of these rections, but ptients should be crefully monitored for them. If ny of these events occur, copnlisib should be stopped. Ptients receiving tretment with PI3-kinse inhibitors my be t risk for infection becuse of the intensity of their prior therpies, s well s the PI3-kinse inhibition itself. The infections might be severe nd cn be uncommon; they include Pneumocystis pneumoni. It is resonble to consider use of prophylxis to void opportunistic infections. H&O Wht hs been lerned from follow-up nlyses of the CHRONOS-1 tril, s presented t the 2017 ASH meeting? PM Anlyses of the CHRONOS-1 tril presented t the 2017 Americn Society of Hemtology (ASH) meeting were helpful in tht they confirmed the efficcy nd side effect profile. 21,22 There were no new side effects of prticulr concern. Autoimmune rections, which might be expected to rise with longer tretment, were not significntly more common thn suggested by erly dt. Efficcy ws similr with longer follow-up. The durtion of response decresed slightly with longer-term follow-up, which is common. H&O Are there ny other ongoing studies of copnlisib? PM There re severl other CHRONOS trils. CHRO- NOS-3 is phse 3 study evluting copnlisib in combintion with rituximb in relpsed, indolent NHL. 23 The phse 3 CHRONOS-4 tril is evluting copnlisib in combintion with stndrd immunochemotherpy in relpsed, indolent NHL. 24 These multiple CHRONOS studies will provide more rndomized dt bout copnlisib, which is ultimtely the best wy to lern bout the efficcy nd dverse events relted to prticulr drug. H&O Do you hve ny other suggestions for the clinicl use of copnlisib? PM In generl, we should im to prctice evidence-bsed medicine. Copnlisib is pproved by the FDA for the third-line tretment of folliculr lymphom. It should be used on-lbel, nd monitored ccording to the lbel directions. This pproch should led to results tht re similr to those seen in clinicl trils. Disclosure Dr Mrtin hs consulted for Byer, Giled, Acert, Jnssen, Roche, Settle Genetics, nd Kite. 1. Freedmn A. Folliculr lymphom: 2015 updte on dignosis nd mngement. Am J Hemtol. 2015;90(12): Regn PM, Friedberg JW. Folliculr lymphom: first-line tretment without chemotherpy for folliculr lymphom. Curr Tret Options Oncol. 2015;16(7): Fowler N. Frontline strtegy for folliculr lymphom: re we redy to bndon chemotherpy? Hemtology Am Soc Hemtol Educ Progrm. 2016;2016(1): Jiménez-Ubieto A, Grnde C, Cbllero D, et l. Autologous stem cell trnsplnttion for folliculr lymphom: fvorble long-term survivl irrespective of pretrnsplnttion rituximb exposure. Biol Blood Mrrow Trnsplnt. 2017;23(10): Nstoupil LJ, Sinh R, Byrtek M, et l. Comprison of the effectiveness of frontline chemoimmunotherpy regimens for folliculr lymphom used in the United Sttes. Leuk Lymphom. 2015;56(5): FDA pproves obinutuzumb for previously untreted folliculr lymphom. US Food nd Drug Administrtion. Drugs/ApprovedDrugs/ucm htm. Updted November 16, Accessed Mrch 16, Zhng L, Ghielmini M, Cheson BD, Ujjni C. Pros nd cons of rituximb mintennce in folliculr lymphom. Cncer Tret Rev. 2017;58: Chen Q, Ayer T, Nstoupil LJ, Rose AC, Flowers CR. Compring the costeffectiveness of rituximb mintennce nd rdioimmunotherpy consolidtion versus observtion following first-line therpy in ptients with folliculr lymphom. Vlue Helth. 2015;18(2): Subrmnin J, Cvengh J, Desi B, Jcobs I. Rituximb in the tretment of folliculr lymphom: the future of biosimilrs in the evolving therpeutic lndscpe. Cncer Mng Res. 2017;9: Clinicl Advnces in Hemtology & Oncology Volume 16, Issue 4, Supplement 10 April 2018

5 10. Drug pprovl pckge: Trend: (bendmustine hydrochloride). U.S. Food nd Drug Administrtion. nd/2008/trend_022249_toc.cfm. Posted My 8, Accessed Mrch 16, Obinutuzumb. U.S. Food nd Drug Administrtion. Drugs/InformtionOnDrugs/ApprovedDrugs/ucm htm. Updted Februry 26, Accessed Mrch 16, Drug pprovl pckge: Zevlin (ibritumomb tiuxetn) injection. U.S. Food nd Drug Administrtion. nd/2002/125019_0000_zevlintoc.cfm. Posted December 5, Accessed Mrch 16, Drug pprovl pckge: ALIQOPA (copnlisib). U.S. Food nd Drug Administrtion. toc.cfm. Posted October 16, Accessed Mrch 16, Drug pprovl pckge. Zydelig (idellisib) tblets. U.S. Food nd Drug Administrtion Orig1s000TOC.cfm. Posted August 13, Accessed Mrch 16, Brtlett NL, Costello BA, LPlnt BR, et l. Single-gent ibrutinib in relpsed or refrctory folliculr lymphom: phse 2 consortium tril. Blood. 2018;131(2): Fowler NH, Hiddemnn W, Leonrd J, et l. A phse III study of ibrutinib in combintion with either bendmustine nd rituximb (BR) or rituximb, cyclophosphmide, doxorubicin, vincristine, nd prednisone (R-CHOP) in ptients with previously treted folliculr lymphom or mrginl zone lymphom [ASCO bstrct TPS8601]. J Clin Oncol. 2015;33(suppl 15). 17. CliniclTrils.gov. Obinutuzumb with or without PI3K-delt inhibitor TGR-1202, lenlidomide, or combintion chemotherpy in treting ptients with relpsed or refrctory grde I-III folliculr lymphom. ct2/show/nct Identifier: NCT Accessed Mrch 29, Dhillon S. Obinutuzumb: review in rituximb-refrctory or -relpsed folliculr lymphom. Trget Oncol. 2017;12(2): Jbbour E, Ottmnn OG, Deininger M, Hochhus A. Trgeting the phosphoinositide 3-kinse pthwy in hemtologic mlignncies. Hemtologic. 2014;99(1): Dreyling M, Sntoro A, Mollic L, et l. Phosphtidylinositol 3-kinse inhibition by copnlisib in relpsed or refrctory indolent lymphom. J Clin Oncol. 2017;35(35): Dreyling M, Sntoro A, Mollic L, et l. Updted sfety nd efficcy from the copnlisib CHRONOS-1 tril in ptients with relpsed or refrctory indolent B-cell lymphom: low incidence of lte-onset severe toxicities [ASH bstrct 2777]. Blood. 2017;130(suppl 1). 22. Dreyling M, Pnyiotidis P, Egyed M, et l. Efficcy of copnlisib monotherpy in ptients with relpsed or refrctory mrginl zone lymphom: subset nlysis from the CHRONOS-1 tril [ASH bstrct 4053]. Blood. 2017;130(suppl 1). 23. CliniclTrils.gov. Copnlisib nd rituximb in relpsed indolent B-cell non- Hodgkin s lymphom (inhl) (CHRONOS-3). show/nct Identifier: NCT Accessed Mrch 15, CliniclTrils.gov. Study of copnlisib in combintion with stndrd immunochemotherpy in relpsed indolent non-hodgkin s lymphom (inhl) (CHRONOS-4). Identifier: NCT Accessed Mrch 15, Highlights in Folliculr Lymphom From the 2017 Americn Society of Hemtology Annul Meeting nd Exposition Commentry by Peter Mrtin, MD, MS Updted Sfety nd Efficcy From the Copnlisib CHRONOS-1 Tril in Ptients With Relpsed or Refrctory Indolent B-Cell Lymphom: Low Incidence of Lte-Onset Severe Toxicities This updted nlysis of the phse 2 CHRONOS-1 study (Open-Lbel, Uncontrolled Phse II Tril of Intrvenous PI3K Inhibitor BAY in Ptients With Relpsed, Indolent or Aggressive Non-Hodgkin s Lymphoms) indicted tht with 8 dditionl months of follow-up since the primry nlysis, copnlisib continued to demonstrte strong efficcy nd mngeble toxicity in ptients with relpsed or refrctory indolent B-cell lymphom. 1,2 Independent rdiologic review ssessed the objective response rte. 3 The study enrolled 142 ptients with relpsed or refrctory disese fter t lest 2 prior lines of tretment. Copnlisib ws dministered t fixed dose of 60 mg. Among these ptients, 104 hd folliculr lymphom, 23 hd mrginl zone lymphom (MZL), 8 hd smll lymphocytic lymphom, nd 6 hd lymphoplsmcytoid/ Wldenström mcroglobulinemi. The medin durtion of tretment ws 26 weeks (rnge, weeks) in this updted follow-up vs 22 weeks (rnge, weeks) in the primry nlysis. 1,2 The objective response rte ws 58.5% overll (n=83; 95% CI, ) nd 57.7% in ptients with folliculr lymphom (n=60; 95% CI, ). Complete responses occurred in 14.1% of ptients overll (n=20) nd 16.4% of ptients with folliculr lymphom (n=17). The medin durtion of response ws 12.2 months (rnge, months) vs 22.6 months (rnge, months) in the primry nlysis. 1,2 Rtes of medin progression-free survivl were similr with both nlyses, t 11.3 months (rnge, months) t follow-up nd 11.2 months (rnge, months) in the primry nlysis (Figure 1). 1,2 The medin overll survivl hd not been reched. 1 The most common ll-grde tretment-emergent dverse events (AEs) were trnsient hyperglycemi (49.3%) nd trnsient hypertension (29.6%). 1 These Clinicl Advnces in Hemtology & Oncology Volume 16, Issue 4, Supplement 10 April

6 rtes were similr to those reported in the primry nlysis. 2 Serious AEs occurred in 52.1% of ptients (n=74) in the follow-up nlysis vs 50.0% of ptients (n=71) in the primry nlysis. However, few serious AEs occurred in more thn 3 ptients ech. 1,2 Similrly, grde 3/4 tretment-emergent AEs remined primrily unchnged from the primry nlysis, even with the longer follow-up. The individul grde 3/4 tretmentemergent AEs tht incresed did so by only 1 ptient. 1,2 The uthors concluded tht the promising efficcy nd mngeble sfety support the use of copnlisib in this ptient popultion. 1. Dreyling M, Sntoro A, Mollic L, et l. Updted sfety nd efficcy from the copnlisib CHRONOS-1 tril in ptients with relpsed or refrctory indolent B-cell lymphom: low incidence of lte-onset severe toxicities [ASH bstrct 2777]. Blood. 2017;130(suppl 1). 2. Dreyling M, Sntoro A, Mollic L, et l. Phosphtidylinositol 3-kinse inhibition by copnlisib in relpsed or refrctory indolent lymphom. J Clin Oncol. 2017;35(35): Cheson BD, Pfistner B, Juweid ME, et l; Interntionl Hrmoniztion Project on Lymphom. Revised response criteri for mlignnt lymphom. J Clin Oncol. 2007;25(5): Commentry: This updted nlysis of the CHRONOS-1 tril included dt for 8 more months of follow-up. There were no new side effects of concern. Rtes of ll-grde tretmentemergent AEs were similr to those reported in the primry nlysis. Although rtes of utoimmune rections might hve been expected to increse, they were not more common thn in the erlier nlysis. Efficcy ws lso similr. The durtion of response decresed slightly, which would be expected becuse more ptients relpse s time goes on. High Complete Response Rtes With Pembrolizumb in Combintion With Rituximb in Ptients With Relpsed Folliculr Lymphom: Results of n Open-Lbel, Phse 2 Study The combintion of pembrolizumb with rituximb in ptients with relpsed folliculr lymphom showed cliniclly meningful efficcy nd tolerble sfety profile in phse 2 tril. 1 Pembrolizumb nd rituximb could ct synergisticlly in folliculr lymphom by ctivting both innte nd dptive immune responses. 2 Thirty ptients with grde 1 to 3 folliculr lymphom tht hd relpsed fter t lest 1 prior line of therpy nd ws sensitive to rituximb were treted with rituximb nd pembrolizumb for up to 16 cycles. The response ssessment ws performed with the Lugno clssifiction. 3 The ptients medin ge ws 64 yers (rnge, yers). The medin follow-up ws 13.8 months. The overll response rte (ORR) ws 67%, nd the complete response rte ws 50% (Figure 2). The medin progression-free survivl ws 11.4 months (rnge, 8.25 months to not reched). The medin durtion of response ws 14.1 months (rnge, 11 months to not reched). No deths occurred. An nlysis of 19 tumors indicted tht progrmmed deth lignd 1 (PD-L1) expression levels were not ssocited with response to therpy (P=.71). An nlysis of immune cell gene signtures in 18 ptients indicted n ssocition between the CD8-positive T-effector score nd complete response. Among ptients with high levels of CD8 T-effector cells, 67% experienced complete Survivl Probbility O Censored Medin progression-free survivl: 11.3 months (rnge, ) Months Number of ptients t risk Figure 1. Medin progression-free survivl in follow-up nlysis of the phse 2 CHRONOS-1 study, which evluted copnlisib in ptients with relpsed or refrctory indolent B-cell lymphom. CHRONOS-1, Open-Lbel, Uncontrolled Phse II Tril of Intrvenous PI3K Inhibitor BAY in Ptients With Relpsed, Indolent or Aggressive Non-Hodgkin s Lymphoms. Adpted from Dreyling M et l. ASH bstrct Blood. 2017;130(suppl 1). 1 6 Clinicl Advnces in Hemtology & Oncology Volume 16, Issue 4, Supplement 10 April 2018

7 (%) Best Response in Ech Ptient Complete Response Prtil Response Stble Disese Disese Progression * * Figure 2. Responses mong ptients with relpsed folliculr lymphom who received pembrolizumb plus rituximb. Ptients with n erly relpse (<24 months) fter frontline tretment. Adpted from Nstoupil L et l. ASH bstrct 414. Blood. 2017;130(suppl 1). 1 response. Among those with low levels, the complete response rte ws 25%. Peripherl blood interferon gmm gene signtures were ssocited with percent chnge in tumor size in response to tretment with pembrolizumb nd rituximb in both 10-gene pnel (P=.016) nd 28-gene pnel (P=.023). This correltion must be prospectively vlidted in lrger study. All-cuse grde 3/4 AEs were dirrhe (3%), trnsminitis (3%), nd nuse/vomiting (7%). Immunerelted AEs occurring in more thn 1 ptient included dirrhe (grde 1/2, n=11; grde 3, n=1), trnsminitis (grde 1, n=7), pneumonitis (grde 2, n=2), hypothyroidism (grde 1, n=2), nd rsh (grde 1/2, n=7). Six ptients discontinued therpy, ll becuse of immune-relted AEs. 1. Nstoupil L, Westin JR, Fowler J, et l. High complete response rtes with pembrolizumb in combintion with rituximb in ptients with relpsed folliculr lymphom: results of n open-lbel, phse II study [ASH bstrct 414]. Blood. 2017;130(suppl 1). 2. Görgün G, Smur MK, Cowens KB, et l. Lenlidomide enhnces immune checkpoint blockde-induced immune response in multiple myelom. Clin Cncer Res. 2015;21(20): Cheson BD, Fisher RI, Brrington SF, et l; Allince, Austrlsin Leukemi nd Lymphom Group; Estern Coopertive Oncology Group; Europen Mntle Cell Lymphom Consortium; Itlin Lymphom Foundtion; Europen Orgnistion for Reserch; Tretment of Cncer/Dutch Hemto-Oncology Group; Grupo Espñol de Médul Óse; Germn High-Grde Lymphom Study Group; Germn Hodgkin s Study Group; Jpnese Lymphom Study Group; Lymphom Study Assocition; NCIC Clinicl Trils Group; Nordic Lymphom Study Group; Southwest Oncology Group; United Kingdom Ntionl Cncer Reserch Institute. Recommendtions for initil evlution, stging, nd response ssessment of Hodgkin nd non-hodgkin lymphom: the Lugno clssifiction. J Clin Oncol. 2014;32(27): Commentry: This study is interesting, in tht folliculr lymphom would seemingly be n idel trget for immunotherpy. It is slow-growing lymphom tht cn spontneously regress for resons likely relted to nti-tumor immune effects. Occsionlly, there re spontneous responses. The thought would be tht therpy tht intercts with the immune system would work well in folliculr lymphom. Interestingly, pembrolizumb nd other PD-1 inhibitors do not seem to work well in indolent non-hodgkin lymphom. This study evluted whether combining pembrolizumb with rituximb might improve outcome, which is n interesting hypothesis. The chllenge is in distinguishing the benefits of rituximb from those resulting from the synergy between rituximb nd pembrolizumb. The results from this phse 2 tril re minly hypothesisgenerting, but they re reltively promising. Phrmcodynmic Study of Copnlisib in Ptients With Non-Hodgkin s Lymphom nd Advnced Solid Tumors: Confirmtion of On-Trget PI3K Inhibitory Activity This phse 1 study ssessed dose-dependent phrmcodynmics of copnlisib on plsm exposure in ptients with non-hodgkin lymphom (NHL) or solid tumors, demonstrting dose-dependent, on-trget phrmcodynmics nd mngeble sfety profile. 1 Inhibition of the phosphoinositide 3 (PI3)-kinse cn be therpeuticlly efficcious for relpsed or refrctory B-cell lymphoms. Copnlisib is pn-clss 1 PI3-kinse inhibitor tht Clinicl Advnces in Hemtology & Oncology Volume 16, Issue 4, Supplement 10 April

8 predominntly inhibits PI3-kinse lph nd PI3-kinse delt nd hs previously demonstrted efficcy in NHL. 2 Ptients with NHL (n=33) hd received t lest 1 prior chemoimmunotherpy or immunotherpy, nd those with solid tumors (n=30) hd dvnced nd/or refrctory disese. All ptients hd tumors with PIK3CA or PTEN ltertion of t lest 30%. A totl of 63 ptients were treted with copnlisib t dose of either 0.4 mg/kg or 0.8 mg/kg. The reserchers ssessed phrmcodynmics vi biomrkers relted to PI3-kinse signling, including pakt in pltelet-rich plsm nd the ps6 ribosoml protein Ser235/236 in pired tumor tissues. Tretment with copnlisib resulted in decrese of 50% or higher in pakt in pltelet-rich plsm during the initil 2 cycles of therpy, with sustined response for 24 hours fter dministrtion of the drug. Pired tumor biopsies from bseline nd t dy 15 showed greter inhibition of pakt nd ps6 ribosoml protein t the dose of 0.8 mg/kg (n=16) vs 0.4 mg/kg (n=14; P=.05). Plsm exposure to copnlisib incresed ccording to dose (Figure 3). In the cohort of ptients with NHL, 2 ptients (6.1%) hd complete response. Both of these ptients hd received 0.8 mg/kg of copnlisib. Among the 5 ptients with NHL who experienced prtil response (15.2%), 4 hd received the higher dose of copnlisib. Nine ptients with NHL were not ssessed or not evluble. In the cohort of ptients with solid tumors, 1 ptient (3.3%), who ws treted with the higher dose, experienced prtil response. All-grde tretment-emergent AEs occurred in 59 ptients (93.7%). The most common of these events were hyperglycemi (50.8%), hypertension (42.9%), nuse (38.1%), ftigue (38.1%), dirrhe (33.3%), nd nemi (28.6%). The uthors concluded tht this phrmcodynmic nlysis indicted on-trget modultion by copnlisib nd showed dose-dependency of phrmcodynmic mesurements. The higher dose of 0.8 mg/kg ws more efficcious thn the lower dose. 1. Morschhuser F, Awd A, Mchiels JP, et l. Phrmcodynmic study of copnlisib in ptients with non-hodgkin s lymphom nd dvnced solid tumors: confirmtion of on-trget PI3K inhibitory ctivity [ASH bstrct 1256]. Blood. 2017;130(suppl 1). 2. Dreyling M, Sntoro A, Mollic L, et l. Phosphtidylinositol 3-kinse inhibition by copnlisib in relpsed or refrctory indolent lymphom. J Clin Oncol. 2017;35(35): C mx (µg/l) mg/kg (n=33) C mx 0.8 mg/kg (n=27) Figure 3. C mx plsm exposure of copnlisib fter the first infusion on cycle 1, dy 1. Adpted from Morschhuser F et l. ASH bstrct Blood. 2017;130(suppl 1). 1 Commentry: Some hve suggested tht intermittent delt isoform inhibition might reduce the incidence of inflmmtory side effects reltive to tht seen with more continuous inhibition. The phrmcokinetics of copnlisib re intermittent rther thn sustined in delt isoform inhibition, llowing some periodic remittnce of the PI3-kinse inhibition. This should reduce the incidence of the inflmmtory side effects tht re seen with more sustined PI3-kinse inhibition. The phrmcokinetics of copnlisib my llow it to be dministered intermittently. It is not so much the trget, but rther the intermittent dministrtion, tht chnges the side effect profile. Pooled Sfety Anlysis From Phse 1 nd 2 Studies for Ptients With Relpsed Indolent Non-Hodgkin s Lymphom Treted With Intrvenous Copnlisib Dr Pier Luigi Zinzni nd collegues presented pooled sfety nlysis from four phse 1 nd phse 2 trils of copnlisib monotherpy in 168 ptients with indolent NHL. 1-5 In these trils, copnlisib ws dministered intermittently insted of continuously. All ptients hd previously received rituximb, nd 99.4% hd received prior lkylting gents. The medin number of prior lines of therpy ws 3 (rnge, 1-10). The medin durtion of tretment ws 22 weeks (rnge, weeks). Dose reductions, interruptions, or delys occurred in 76.2% of ptients (Figure 4). Dose modifictions owing to tretment-emergent AEs occurred in 68.5% of ptients, with typicl incidence rnging from 10% to 30% per cycle. Discontinution of copnlisib owing to tretment-emergent AEs occurred in 24.4% of ptients 8 Clinicl Advnces in Hemtology & Oncology Volume 16, Issue 4, Supplement 10 April 2018

9 Dose reduction Dose interruption or dely Discontinution Figure 4. Dose reductions, interruptions, delys, or discontinutions in pooled sfety nlysis of phse 1 nd 2 trils evluting copnlisib monotherpy in ptients with indolent non-hodgkin lymphom. Adpted from Zinzni PL et l. ASH bstrct Blood. 2017;130(suppl 1). 1 Ptients (%) (n=168) 2 (n=161) 3 (n=146) 4 (n=125) 5 (n=105) 6 (n=91) 7 (n=71) 8 (n=62) Cycle Number (ptients t risk) 9 (n=53) 10 (n=48) 11 (n=36) 12 (n=30) (n=41), with n incidence of pproximtely 2% to 3% per cycle nd n even distribution cross tretment cycles. All-grde tretment-emergent AEs occurred in 98.8% of ptients (n=166), the most common of which were hyperglycemi (50.6%), dirrhe (35.7%), nd hypertension (34.5%). The most common grde 3 tretment-emergent AEs were hyperglycemi (31.5%), hypertension (26.8%), nd neutropeni (8.3%). The most common grde 4 tretment-emergent AEs were neutropeni (11.9%) nd hyperglycemi (6.0%). Grde 3/4 hyperglycemi nd grde 3 hypertension were typiclly infusion-relted, trnsient, nd symptomtic. Serious tretment-emergent AEs occurred in 48.2% of ptients (n=81). Tretmentemergent AEs were more common nd severe in the first tretment cycle. The prevlence of tretment-emergent AEs remined firly constnt throughout the period of observtion, suggesting tht copnlisib is not ssocited with lte-onset or cumultive toxicities. 1. Zinzni PL, Ptnik MM, Morschhuser F, et l. Pooled sfety nlysis from phse I nd II studies for ptients with relpsed indolent non-hodgkin s lymphom treted with intrvenous copnlisib [ASH bstrct 4042]. Blood. 2017;130(suppl 1). 2. Ptnik A, Applemn LJ, Tolcher AW, et l. First-in-humn phse I study of copnlisib (BAY ), n intrvenous pn-clss I phosphtidylinositol 3-kinse inhibitor, in ptients with dvnced solid tumors nd non-hodgkin s lymphoms. Ann Oncol. 2016;27(10): Dreyling M, Sntoro A, Mollic L, et l. Phosphtidylinositol 3-kinse inhibition by copnlisib in relpsed or refrctory indolent lymphom. J Clin Oncol. 2017;35(35): Dreyling M, Sntoro A, Mollic L, et l. Copnlisib in ptients with relpsed or refrctory indolent B-cell lymphom (CHRONOS-1) [ICML bstrct 108]. Hemtol Oncol. 2017;35(S2). 5. Morschhuser F, Awd A, Mchiels JP, et l. Phrmcodynmic study of copnlisib in ptients with non-hodgkin s lymphom nd dvnced solid tumors: confirmtion of on-trget PI3K inhibitory ctivity [ASH bstrct 1256]. Blood. 2017;130(suppl 1). Commentry: This pooled sfety nlysis focused on trils in which copnlisib ws dministered intermittently insted of continuously. The sfety profile of intermittent copnlisib ppered tolerble nd is in some wys better thn continuous inhibitors lthough the hyperglycemi nd hypertension require some ttention. Results From Phse 1/2 Study of INCB050465, Potent nd Highly Selective PI3Kδ Inhibitor, in Ptients With Relpsed or Refrctory B-Cell Mlignncies Dr Andres Forero-Torres nd collegues presented results of the dose-escltion nd monotherpy expnsion cohorts of the phse 1/2 CITADEL-101 tril of INCB nd itcitinib in ptients with previously treted B-cell mlignncies. 1 Results indicted tolerble Clinicl Advnces in Hemtology & Oncology Volume 16, Issue 4, Supplement 10 April

10 sfety profile nd suggested clinicl efficcy. 1 This nlysis evluted 72 ptients with bseline tumor subtypes of NHL, Hodgkin lymphom, chronic lymphocytic leukemi, nd Wldenström mcroglobulinemi. The NHL subtypes were diffuse lrge B-cell lymphom (DLBCL), folliculr lymphom, mntle cell lymphom, nd MZL. Forty-three ptients hd received 3 or more prior systemic regimens. The ptients medin ge ws 66 yers (rnge, yers). The protocol begn with single-ptient cohort receiving 5 mg of INCB once dily. Next ws 3-plus-3 design, with doses of 10 mg/dy to 45 mg/dy. An evlution of phrmcokinetics/phrmcodynmics led to expnsion of the 20-mg once dily nd 30-mg once dily cohorts. The tretment schedule ws modified to once weekly dosing fter week 9. The medin durtion of exposure ws 16.4 weeks (rnge, weeks). Response ws evluble in 69 ptients (96%). Objective responses occurred t ll doses, except 5 mg dily. Objective response rtes were 53% in NHL, 33% in chronic lymphocytic leukemi, 20% in Hodgkin lymphom, nd not evluble in Wldenström mcroglobulinemi. Among ptients with NHL, 93% of the responses occurred by the first evlution t week 9. No dose-limiting toxicities were reported. Discontinution of therpy occurred in 76% of ptients, most frequently owing to disese progression (40%) nd tretment-emergent AEs (19%). Tretment-emergent AEs lso resulted in dose interruption (42%) nd dose reduction (6%). Among the 16 ptients with NHL who received once-weekly dosing, none discontinued therpy bsed on tretment-emergent AEs. The most common non-hemtologic, ll-grde, tretment-emergent AEs were nuse (36%) nd dirrhe/colitis (36%). Grde 3/4 hemtologic tretment-emergent AEs included neutropeni (grde 3, 14%; grde 4, 6%) nd thrombocytopeni (grde 3, 4%; grde 4, 6%). All-grde serious tretmentemergent AEs occurred in 40% of ptients, nd included dirrhe/colitis (11%). The uthors concluded tht INCB demonstrted mngeble sfety profile in ptients with relpsed or refrctory B-cell mlignncies. Clinicl efficcy ws promising, prticulrly in ptients with NHL. Responses were rpid, deep, nd durble. Reference 1. Forero-Torres A, Rmchndren R, Ycoub A, et l. Results from phse 1/2 study of INCB050465, potent nd highly selective PI3Kδ inhibitor, in ptients with relpsed or refrctory B-cell mlignncies (CITADEL-101) [ASH bstrct 410]. Blood. 2017;130(suppl 1). Commentry: This tril evluted the PI3-kinse delt inhibitor INCB An interesting spect of this tril is tht tretment begn with dily dose, nd then switched to weekly dosing fter 9 weeks. The hypothesis is tht it my be possible to mintin efficcy with less frequent dosing, which could reduce side effects nd keep ptients sfely on tretment for longer durtions. The clinicl efficcy ws promising, prticulrly in ptients with indolent NHL. Efficcy of Copnlisib Monotherpy in Ptients With Relpsed or Refrctory Mrginl Zone Lymphom: Subset Anlysis From the CHRONOS-1 Tril Dr Mrtin Dreyling nd collegues presented updted efficcy results on the subset of ptients with MZL enrolled in the phse 2 CHRONOS-1 tril. 1,2 Among the 142 ptients enrolled in CHRONOS-1, 16.2% hd MZL. Their medin ge ws 69 yers (rnge, yers), nd their medin prior lines of therpy ws 3. The objective response rte ws ssessed vi independent rdiologic review fter t lest 4 tretment cycles. 3 Most ptients in this subset hd nodl MZL (65.2%), nd 4 ptients ech (17.4%) hd mucos-ssocited lymphoid tissue lymphom or splenic MZL. Ptients received medin of 5.8 cycles of therpy, with medin durtion of tretment of 23 weeks (rnge, weeks). Dose interruptions or delys occurred in 91.3%, nd dose modifictions were reported in 95.7%. The objective response rte ws 69.6%. Complete responses occurred in 13.0% of ptients, ll of whom hd splenic MZL. Among the ptients with nodl MZL, 80.0% experienced n objective tumor response (Figure 5). At the time of dt cut-off, the medin durtion of response hd not been reched (rnge, months). Responses ppered rpid nd durble, nd 73.9% of ptients experienced reduction in the trget lesion from bseline. This reduction ws t lest 50% in 60.9%. Responses t 9 months were estimted in 85.0% of ptients. Across the overll CHRONOS-1 study popultion, t lest 1 tretment-emergent AE occurred in 98.6% of ptients, nd 52.1% of ptients experienced t lest 1 serious tretment-emergent AE. The most common ll-grde tretment-emergent AEs were hyperglycemi (50.7%), dirrhe (33.8%), decresed neutrophil count (31.7%), ftigue (31.0%), nd hypertension (30.3%). The uthors concluded tht these results indicte promising efficcy for copnlisib monotherpy in ptients with relpsed or refrctory MZL. Responses were rpid nd durble, nd the overll sfety profile ws mngeble. 1. Dreyling M, Pnyiotidis P, Egyed M, et l. Efficcy of copnlisib monotherpy in ptients with relpsed or refrctory mrginl zone lymphom: subset nlysis from the CHRONOS-1 tril [ASH bstrct 4053]. Blood. 2017;130(suppl 1). 10 Clinicl Advnces in Hemtology & Oncology Volume 16, Issue 4, Supplement 10 April 2018

11 Best Chnge in Trget Lesion Size From Bseline (%) Individul Ptients (n=19) Figure 5. Percent best chnge from bseline in trget lesion size mong ptients with mrginl zone lymphom treted with copnlisib in the CHRONOS-1 tril. CHRONOS-1, Open-Lbel, Uncontrolled Phse II Tril of Intrvenous PI3K Inhibitor BAY in Ptients With Relpsed, Indolent or Aggressive Non-Hodgkin s Lymphoms. Adpted from Dreyling M et l. ASH bstrct Blood. 2017;130(suppl 1) Dreyling M, Sntoro A, Mollic L, et l. Phosphtidylinositol 3-kinse inhibition by copnlisib in relpsed or refrctory indolent lymphom. J Clin Oncol. 2017;35(35): Cheson BD, Pfistner B, Juweid ME, et l. Revised response criteri for mlignnt lymphom. J Clin Oncol. 2007;25(5): Commentry: PI3-kinse inhibitors hve ctivity in MZL, s ws shown in this tril. It is expected tht PI3-kinse inhibitors would be effective in this setting. The results from this tril re encourging. The chllenge is to obtin FDA pprovl of drug specificlly for MZL. CC-122, Novel Cereblon Modulting Agent, in Combintion With Obinutuzumb in Ptients With Relpsed nd Refrctory B-Cell Non-Hodgkin Lymphom Dr Jen-Mrie Michot presented updted sfety nd efficcy results for phse 1 tril of obinutuzumb combined with CC-122 in ptients with relpsed/refrctory B-cell NHL. 1 Dt were gthered from n dditionl 12 months of follow-up. Preliminry results from this tril showed promising efficcy in ptients with relpsed/refrctory B-cell NHL. 2 The study evluted 44 ptients with relpsed/refrctory NHL: 19 ptients with DLBCL, 24 with folliculr lymphom, nd 1 with MZL. 1 CC-122 ws dministered in esclted orl doses, nd the intrvenous dose of obinutuzumb ws fixed t 1000 mg. The medin durtion of tretment ws 23.6 weeks (rnge, weeks). The ORR cross cohorts ws 68%, nd the complete response rte ws 27%. Among ll ptients, the medin progression-free survivl ws 11.3 months. In ptients with DLBCL, the ORR ws 47% nd the complete response rte ws 11%. In ptients with folliculr lymphom/ MZL, the ORR ws 84% nd the complete response rte ws 40%. At 12 months, rtes of overll response, complete response, nd progression-free survivl did not differ mong ptients with folliculr lymphom tht hd relpsed erly or tht ws refrctory to both rituximb nd chemotherpy s compred with the rest of the cohort. Dose reductions of CC-122, which occurred in 32% of ptients, were ll owing to AEs. Dose interruptions occurred in 84% of ptients, mostly owing to AEs. Dose-limiting toxicities consisted of 1 cse of grde 4 neutropeni nd nother of grde 5 tumor flres. The most common grde 3/4 tretment-emergent AEs were neutropeni (55%) nd thrombocytopeni (26%). 1. Michot JM, Boubdll R, Doorduijn JK, et l. CC-122, novel cereblon modulting gent, in combintion with obinutuzumb (GA101) in ptients with relpsed nd refrctory (R/R) B-cell non-hodgkin lymphom (NHL) [ASH bstrct 411]. Blood. 2017;130(suppl 1). 2. Michot JM, Doorduijn JK, Boubdllh R, et l. A phse 1b study of CC-122 in combintion with obinutuzumb (GA101) in relpsed or refrctory diffuse lrge B-cell lymphom nd indolent non-hodgkin lymphom [ASH bstrct 4199]. Blood. 2016;128(suppl 1). Commentry: There re other mechnisms of ction tht clerly hve ctivity in folliculr lymphom, beyond nti- CD20, cytotoxic chemotherpy, nd PI3-kinse inhibition. Immunomodultory drugs (IMiDs), such s lenlidomide, trget cereblon nd hve ctivity in folliculr lymphom. In the future, it is possible tht lenlidomide will be FDA-pproved for the tretment of folliculr lymphom. CC-122, which more specificlly trgets cereblon, my be nother option. It is not yet known how CC-122 differs from IMiDs. In erly clinicl trils, CC-122 hd ctivity in ptients with non-hodgkin lymphoms, s expected. Clinicl Advnces in Hemtology & Oncology Volume 16, Issue 4, Supplement 10 April

12