poster 7510 long-term efficacy and safety with ibrutinib
TRANSCRIPT
Long-term Efficacy and Safety With Ibrutinib (ibr) in Previously Treated Chronic Lymphocytic Leukemia (CLL): Up to Four Years Follow-up of the RESONATE Study
John C. Byrd1, Peter Hillmen2, Susan O’Brien3, Jacqueline C. Barrientos4, Nishitha M. Reddy5, Steven Coutre6, Constantine S. Tam7, Stephen P. Mulligan8, Ulrich Jaeger9, Paul M. Barr10, Richard R. Furman11, Thomas J. Kipps12, Patrick Thornton13, John M. Pagel14, Jan A. Burger15, Jeffrey Jones1, Sandra Dai16, Remus Vezan16, Danelle F. James16, Jennifer R. Brown17
1The Ohio State University Comprehensive Cancer Center, Columbus, OH; 2The Leeds Teaching Hospitals, St. James Institute of Oncology, Leeds, UK; 3University of California Irvine, Irvine, CA; 4Hofstra Northwell School of Medicine, Hempstead, NY; 5Vanderbilt-Ingram Cancer Center, Nashville, TN; 6Stanford University School of Medicine, Stanford, CA; 7Peter MacCallum Cancer Centre and St. Vincent’s Hospital, Melbourne, Australia; 8Royal North Shore Hospital, Sydney, Australia; 9Division of Hematology and Hemostaseology, Medical University of Vienna, Wien, Austria; 10Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY; 11Weill Cornell Medical College, New York, NY;
12University of California San Diego, Moores Cancer Center, La Jolla, CA; 13Beaumont Hospital, Dublin, Ireland; 14Swedish Cancer Institute Hematologic Malignancies Program, Seattle, WA; 15University of Texas MD Anderson Cancer Center, Houston, TX; 16Pharmacyclics LLC, an AbbVie Company, Sunnyvale, CA; 17CLL Center, Dana-Farber Cancer Institute, Boston, MA
INTRODUCTION• Ibrutinib,afirst-in-class,once-dailyinhibitorofBruton’s
tyrosinekinase,isapprovedintheUSforthetreatmentofpatientswithchroniclymphocyticleukemia/smalllymphocyticlymphoma(CLL/SLL),includingpatientswith del(17p), and allows for treatment withoutchemotherapy.
• In the phase 3 RESONATE™ study of ibrutinib vsofatumumabinpatientswithrelapsedorrefractoryCLL/SLL, ibrutinib significantly improved survival,reducingtheriskofprogressionby78%andtheriskofdeathby57%atprimaryanalysis.1
• WereportupdatedsafetyandefficacyresultsfortheRESONATEtrialwithupto4yearsoffollow-up.
METHODS
Figure 1. PCYC-1112 (RESONATE) Study Design
Key eligibility criteria• CLL/SLL diagnosis• ≥1 prior therapy• ECOG PS 0-1• Measurable nodal disease by CT
Oral ibrutinib 420 mg
once daily until PD or
unacceptable toxicity
n=195
IVofatumumabinitial dose
300 mgfollowed by2000 mgx 11 doses
over 24 weeksn=196
Of 144 subjects
eligible for crossover,
133 received ibrutinib 420 mg
1:1
RANDOMIZE
Endpoints: PFS, OS, ORR, safety
• Theintent-to-treatpopulationwasassessedforlong-termefficacy.
— PFSandORRareperinvestigatorassessment.
• All patients who received ≥1 treatment dose wereincludedinthesafetyanalysis.
• Atinterimanalysis(median9monthsoffollow-up),theDataMonitoringCommitteedeclaredsuperiorityofibrutinibvsofatumumabforprogression-freesurvival(PFS)andoverallsurvival(OS),andaccesstoibrutinibwasrecommendedforallpatientsintheofatumumabarm.
• MultivariateanalysesforPFSintheibrutinibarmwasconductedwiththefollowingpotentialcovariatestobeincludedinthemodel:age,Raistage,ECOGstatus,numberofprior linesof therapy,del(11q),del(17p),β2-microglobulin,LDH,andrefractorystatustopurineanalogs.Covariatesinthefinalmodelwereidentifiedusingforward,backward,andstepwiseselection.
• AnadditionalOSsensitivityanalysiswasperformedperpublishedguidelines2toaddressthebiasintroducedbycrossoverfromofatumumabtoibrutinib.
— Therank-preservingstructuralfailuretimemodel(RPSFTM)3 was used to account for crossover,and represents a randomization-based methodforestimatingcounterfactualsurvival times(i.e.,survivaltimesthatwouldhavebeenobservedintheabsenceofcrossover).
RESULTS
Table 1. Baseline Characteristics
CharacteristicIbrutinib (N=195)
Ofatumumab (N=196)
Median age, years (range) ≥70 years, n (%)
67(30–86)78(40%)
67(37–88)80(41%)
Male, n (%) 129(66%) 137(70%)
ECOG status, n (%)01
79(41%)116(59%)
80(41%)116(59%)
Rai stage III/IV, n (%) 109(56%) 113(58%)
Bulky disease (LN ≥5 cm), n (%) 124(64%) 101(52%)
Median LDH, unit/L (range) 232.0(40.0–1937) 228.0(94.0–1301)
Median β2-microglobulin, mg/L (range) 5.8(1.8–20.2) 5.8(2.0–17.1)
Median number of prior therapies (range)1priortherapy,n(%)2priortherapy,n(%)≥3priortherapies,n(%)
3(1–12)35(18%)57(29%)103(53%)
2(1–13)53(27%)53(27%)90(46%)
Genomic abnormalities, n/N (%)Del(11q)Del(17p)Complexkaryotype*IGHVunmutated†NOTCH1mutationTP53mutationSF3B1mutationBIRC3mutationXP01mutation
63/190(33%)63/195(32%)39/153(25%)98/134(73%)43/154(28%)79/154(51%)47/154(31%)21/154(14%)26/154(17%)
59/191(31%)64/196(33%)33/147(22%)84/133(63%)45/149(30%)68/149(46%)44/149(30%)15/149(10%)12/149(8%)
*Complex karyotype data were reported by investigator. †IGHV mutation status was assessed by a central laboratory.
Table 2. Baseline Characteristics by FISH Subgroups in Ibrutinib Arm
CharacteristicDel(17p)
N=59Del(11q)
N=50
No del(17p)/ no del(11q)
N=81Median number of prior therapies (range)
1-2priortherapies,n(%)≥3priortherapies,n(%)
3(1-10)27(46%)32(54%)
3(1-9)23(46%)27(54%)
2(1-9)42(52%)39(48%)
Bulky disease (LN ≥5 cm), n (%) 37(63%) 37(74%) 48(59%)
IGHV mutation status, n* (%)UnmutatedMutated
34/45(76%)11/45(24%)
27/32(84%)5/32(16%)
37/54(69%)17/54(31%)
Complex karyotype, n** (%)YesNo
19/45(42%)26/45(58%)
9/40(23%)31/40(78%)
10/66(15%)56/66(85%)
*IGHV mutation status was not available for 14, 18, and 27 patients in the del(17p), del(11q), and no del(17p)/no del(11q) subgroups. **Complex karyotype data were not available for 14, 10, and 15 patients in the del(17p), del(11q), and no del(17p)/no del(11q) subgroups.
• BaselinebulkydiseaseandunmutatedIGHVweremorefrequentlyobservedamongthesubgroupwithdel(11q)(Table 2).
• Complexkaryotypeoccurredmorefrequentlyamongpatientswithdel(17p).
Efficacy
Figure 2. Progression-free Survival
PFS
(%
)
0
10
20
30
40
50
60
70
80
90
100
0 3 6 9 12 15 18 21 24 27 30 33 36
Median PFS, months (range)
Hazard ratio (95% CI) 0.133 (0.099-0.178)
IbrutinibNE
Ofatumumab8.11
39 42 45 48 51
196 159 120 66 35 22 18 14 10 9 6 5 5 4 3195 189 179 171 161 154 148 145 136 123 115 110 105 98 53 14 1
Ibrutinib
Ofatumumab
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N at RiskIbrutinib:
Ofatumumab:
Time (month)
• Atamedianfollow-upof44months(range,0.33-53months)foribrutinib,PFSwassignificantlylongerforibrutinibvs.ofatumumabwithhazardratio(HR)of0.133(Figure 2).
— MedianPFSwasnotreachedwithibrutinibvs8.1monthsforofatumumab.
— The3-yearPFSratewas59%withibrutinibvs3%withofatumumab.
Figure 3. Progression-Free Survival for the Ibrutinib Arm by (A) FISH Cytogenetic Category, (B) IGHV Mutation Status, (C) TP53 Mutation Status, and (D) Number of Prior Lines of Therapy
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Time (month)
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Time (month)
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C D
Time (month)
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Del(17p) (n=59)Del (11q)/No Del(17p) (n=50)No Del(17p)/No Del(11q) (n=81)
TP53 Mutation (n=79)No TP53 Mutation (n=75)
≤2 Prior Therapies (n=92)>2 Prior Therapies (n=103)
IGHV Mutated (n=36)IGHV Unmutated (n=98)
• PFSwithibrutinibforthedel(11q)subgrouptrendedtohavethemostfavorableoutcome;however,PFSwasnotstatisticallydifferentforpatientswithdel(17p)(median40.1months)ordel(11q)(medianNR)orwithouttheseFISHabnormalities(medianNR)(Figure 3A).
— 3-yearPFSwas53%forpatientswithdel(17p),66%fordel(11q),and58%forpatientswithouttheseabnormalities.
• NosignificantdifferenceswereobservedinPFSwithibrutinibbetweenpatientswithunmutatedandthosewithmutatedIGHVstatus;medianPFSwasNRineithersubgroup,and3-yearPFSwas63%vs66%,respectively(Figure 3B).
• AmongthepatientswithunmutatedIGHVstatus,3-yearPFSwas55%forpatientswithdel(17p),70%fordel(11q),and63%forpatientswithouttheseFISHabnormalities.
• PFSinpatientswithoutTP53mutationstrendedtohavemorefavorableoutcomevsthosewithTP53mutations(medianPFSNRvs.40.7),thoughthisdifferencewasnotstatisticallydifferent(Figure 3C).
• PFSwasimprovedinpatientswhoreceived≤2priortherapies(62%[57/92]had2prior)comparedwithmoreheavilypretreatedpatientswith>2priortherapies(medianPFSNRvs35.1months)(Figure 3D).
Figure 4. PFS by Baseline Characteristics
All subjects
Refractory disease to purine analogs
Yes
No
Age
< 65 years
≥ 65 years
Rai Stage at baseline
Stage 0-II
Stage III-IV
ECOG at baseline
0
1
Bulky Disease
< 5 cm
≥ 5 cm
Number of prior treatment lines
≤ 2
> 2
Del(17p)
Yes
No
Del(11q)
Yes
No
β2-microglobulin at baseline
≤3.5 mg/L
>3.5 mg/L
391
175
216
152
239
169
222
159
232
163
225
198
193
127
264
122
259
58
298
0.139
0.117
0.154
0.093
0.165
0.094
0.181
0.136
0.141
0.142
0.101
0.120
0.128
0.125
0.138
0.049
0.183
0.081
0.147
(0.104, 0.184)
(0.076, 0.180)
(0.105, 0.226)
(0.057, 0.152)
(0.116, 0.237)
(0.059, 0.152)
(0.127, 0.258)
(0.085, 0.218)
(0.099, 0.202)
(0.089, 0.227)
(0.067, 0.150)
(0.077, 0.186)
(0.085, 0.191)
(0.074, 0.210)
(0.097, 0.196)
(0.024, 0.101)
(0.131, 0.256)
(0.033, 0.200)
(0.107, 0.202)
N Hazard Ratio 95% CI
0.00 0.25 0.50 0.75
Hazard Ratio
1.00 1.25 1.50
Favor Ibrutinib Favor Ofatumumab
• ThesignificantPFSbenefitwithibrutinibwasconsistentacrossbaselinediseaseandpatientcharacteristics(Figure 4).
• InamultivariateanalysisofPFSwithibrutinib,greaternumberofpriorlinesoftherapy(>2vs≤2prior)andelevatedβ2-microglobulin(>3.5mg/Lvs≤3.5mg/L)wereindependentfactorsassociatedwithdecreasedPFS.
Figure 5. Overall Survival By Intent-to-Treat Analysis* and By RPSFT Methodology Adjusting for Crossover
Ibrutinib
Ofatumumab*
Ofatumumab adjusted for cross-over (RPSFTM)
Time (month)
OS
(%)
0
10
20
30
40
50
60
70
80
90
100
0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51
*In the ITT analysis, patients randomized to ofatumumab were not censored at crossover.
• Withthemajorityofpatientsintheofatumumabarm(133/196[68%])crossingovertoibrutinibattimeofanalysis,OSwaslongerforibrutinibvsofatumumab(medianNRforeitherarm)(Figure 5).
— TheOSrateforibrutinibat3yearswas74%.
• AsensitivityanalysisofOSadjustingforcrossoverbasedontheRPSFTmethodalsoshowedOSbenefitwithibrutinibvsofatumumabwithHR=0.37(95%CI:0.22,0.62)(Figure 5).
Figure 6. Cumulative Best Response Over Time for the Ibrutinib Arm
100
90
80
70
60
50
40
30
20
10
0
3 6 9 12 15 18 24 30 36 42
Time (months)
Res
po
nse
Rat
e (%
)
31.0
32.0
58.0
1.0
23.0
70.0
2.0
14.0
75.0
4.0
10.0
76.0
5.0
7.0
77.0
6.0
6.0
1.01.01.06.0
78.0
6.0
76.0
8.0
5.0
3.03.0
8.0
75.0 75.0
9.0
3.0
4.04.0
CR/CRi nPR PR PR-L
ORR = CR + CRi + nPR + PR-L + PR.
TheORRforibrutinibwas91%,withCR/CRirates(9%withcurrentfollow-up)thatincreasedovertime(Figure 6).
Table 3. Sustained Hematologic Improvement*
Baseline Cytopenias Improvement in Patients With Cytopenias at Baseline
Ibrutinib(N=195)
Ofatumumab(N=196)
Ibrutinib Ofatumumab
Hemoglobin 89(46%) 84(43%) 76/89(85%) 55/84(65%)
Platelets 74(38%) 62(32%) 70/74(95%) 42/62(68%)
ANC 41(21%) 37(19%) 39/41(95%) 34/37(92%)
*Sustained hematologic improvement in cytopenias were defined as hemoglobin >11 g/dL or ≥50% increase over baseline levels ≤11 g/dL, platelet counts >100 x 109/L or ≥50% increase over baseline counts ≤100 x 109/L, and ANC >1.5 x 109/L or ≥50% increase over baseline counts ≤1.5 x 109/L, continuously for ≥56 days without blood transfusions or growth factors.
• Withextendedibrutinibtherapy,baselinecytopeniasimprovedinthelargemajorityofpatients(Table 3).
Table 4. Summary of Disposition and Treatment Exposure During Study Treatment Phase
Ibrutinib(N=195)
Ofatumumab(N=196)
Median duration of treatment (range), months 41(0.2-50.1) 5.3(0-9.0)
Patients continuing treatment, n (%) 90(46%) 0
Duration of treatment (randomized therapy), n (%)>0-6months>6-12months>12-24months>24-36months>36-48months>48months
23(12%)13(7%)
25(13%)31(16%)96(49%)
7(4%)
183(93%)8(4%)
————
Primary reason for treatment discontinuation, n (%)DuetoPDDuetoAE/unacceptabletoxicityDuetodeathDuetopatientdecisionDuetoinvestigatordecision
105(54%)53(27%)23(12%)12(6%)7(4%)10(5%)
71(36%)36(18%)7(4%)9(5%)6(3%)13(7%)
• Median treatment duration was 41 months with ibrutinib and 5 months withofatumumab.
• ThemostcommonreasonsfordiscontinuationofibrutinibwerePD(27%)andadverseevents(AEs;12%)(Table 4).
• Among53patientsforwhomPDwastheprimaryreasonfordiscontinuationofibrutinib, 14wereduetotransformation(DLBCL,n=9;Hodgkin’sdisease,n=3;prolymphocyticlymphoma,n=2).
• Among23patientswhodiscontinuedibrutinibtreatmentduetoAEs,themostfrequentAEswerepneumonia(n=3),andanemia,thrombocytopenia,diarrheaandanalincontinence(n=2each).
• Atthetimeofanalysis,46%ofpatientsrandomizedtotheibrutinibarmcontinuedibrutinibtherapywithmedianfollow-upof44months.
Figure 7. Most Common Cumulative Adverse Events (Any Grade ≥20%) for the Ibrutinib Arm
Diarrhea
Fatigue
Cough
Upper Respiratory Tract Infection
Nausea
Pyrexia
Anemia
Neutropenia
Arthralgia
Sinusitis
Pneumonia
Peripheral Edema
Increased Tendency to Bruise
Muscle Spasm
Urinary Tract Infection
Vomiting
Constipation
Headache
Thrombocytopenia
Hypertension
0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100%
Grade 1
Grade 2
Grade 3
Grade 4
Grade 5
• ThemostcommonAEsofanygradewereconsistentwithpriorreportswithibrutinib(Figure 7).
• Themostcommongrade≥3hematologicAEsincludedneutropenia(23%),anemia(8%)andthrombocytopenia(8%).
• Themostcommongrade≥3non-hematologicAEsincludedpneumonia(17%),hypertension(8%),urinarytractinfection(6%),anddiarrhea(6%).
• Withamedianfollow-upof44monthsonibrutinibarm,majorhemorrhageoccurredin12patients(6%).
• Atrialfibrillationofanygradewasreportedin22patients(11%)with11patients(6%)experiencinggrade≥3eventsoverthecourseoffollow-up.
Figure 8. Onset of Grade ≥3 Adverse Events of Clinical Interest Over Time
Neutropenia
Anemia
Thrombocytopenia
Pneumonia
Diarrhea
Hypertension
Atrial fibrilation
Fatigue
Arthralgia
Major hemorrhage (combined terms)*
Infections (combined terms)
0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100%
> 0–1 year (n=195)
> 1–2 years (n=160)
> 2–3 years (n=137)
> 3 years (n=103)
*Defined as any hemorrhagic event grade ≥3 or in severity, or that results in one of the following: intraocular bleeding causing vision loss, need for a transfusion of ≥ 2 units of RBC or equivalent, hospitalization or prolongation of hospitalization.
• Mostgrade≥3AEsofinterestweremorecommonduringthefirstyearofibrutinibtreatment(Figure 8).
— Ratesofmostgrade≥3AEsdecreasedfromyear 1 toyears2-3, includingneutropenia(18%vs8%),pneumonia(11%vs4%),andatrialfibrillation(4%vs2%).
• Theprevalenceofany-gradeatrialfibrillationremainedconsistentovertimewithreportedratesof6%,5%,8%,and8%overyears0-1,1-2,2-3,and>3,respectively.
• Theprevalenceofany-gradehypertensionwas8%,15%,23%,and22%overyears0-1,1-2,2-3,and>3,respectively.
• AEsleadingtodiscontinuationwerevaried,butdecreasedovertimefrom6%inyear0-1to4%inyear2-3.
— AEsthatoccurredinmorethan1patientwerepneumonia(n=3;2%)anddiarrhea(n=2,1%).
• AEsleadingtodosereductionremainedconsistentovertime,occurringin6%,9%,4%,7%overyears0-1,1-2,2-3,and>3,respectively.
CONCLUSIONS• Theselong-termresultsfromtheinternationalphase3RESONATEstudyshowthat
extendedtreatmentwithibrutinibistolerableandcontinuestoshowsustainedPFSinpreviouslytreatedpatientswithCLLregardlessofhigh-riskcytogenetics(medianPFSnotreachedwithupto4yearsoffollow-up).
• Traditionalpoorprognosticfactorsforsurvivalwithchemoimmunotherapy,includingdel(17p)anddel(11q),werenotsignificantfactorspredictiveofPFSoutcomeswithibrutinibtherapy.
• OSoutcomeswithibrutinibwerealsosustainedwithextendedfollow-up.
• Withupto4yearsoffollowuponibrutinib,nolong-termsafetysignalshaveemergedandmanytoxicitiesdiminishedovertimeonibrutinibtherapy.
REFERENCES1. ByrdJC,etal. N Engl J Med.2014;371:213-223.
2. Latimer NR and KR Abrams. National Institute for Health and Care Excellence Decision Support Unit Technical Support Document 16;July 2014.Availableathttp://www.nicedsu.org.uk/Treatment-switching-TSD(2973293).htm.
3. RobinsJMandAATsiatis.Commun Stat Theory Methods.1991;20:2609-2631.
DISCLOSURESJCByrd:researchfundingfromGenentech,Acerta,Pharmacyclics;PH:honoraria,consultancy/advisoryrole,andresearchfundingfromRoche,GSK,Janssen,Gilead,AbbVie;honorariaandresearchfundingfromNovartis,PharmacyclicsLLC,anAbbVieCompany;researchfundingfromCelgene;SOB:consultancy/advisoryrolefromAmgen,Astellas,Celgene,GlaxoSmithKlein,Janssen,AptoseBiosciences,Inc,VaniamGroupLLC,AbbVie,Sunesis,Alexion,Gilead,PharmacyclicsLLC,anAbbVieCompany,TGTherapeutics,Pfizer;researchfundingfromProNai,Regeneron,Acerta,Gilead,TGTherapeutics,Pfizer,PharmacyclicsLLC,anAbbVieCompany;JCBarrientos:consultancy/advisory role forAbbVie,Gilead,Janssen,PharmacyclicsLLC,anAbbVieCompany; research funding fromAbbVie,Gilead,PharmacyclicsLLC,anAbbVieCompany;NMR:consultancy/advisoryroleforCelgene,Infinity,Gilead,AbbVie;SC:consultancy/advisoryroleforAbbvie,Gilead,Novartis,Celgene,Janssen,PharmacyclicsLLC,anAbbVieCompany;researchfundingfromAbbVie,PharmacyclicsLLC,anAbbVieCompany,Gilead,Celgene,Novartis;CT:honoraria,consultancy/advisoryrole,andresearchfundingfromJanssen;SPM:consultancy/advisoryrole,honoraria,andspeakersbureauforRoche,AbbVie,Janssen,andGilead;consultancy/advisoryroleandhonorariafromGSK;researchfundingfromRoche,AbbVie,andJanssen;UJ:honoraria,consultancy/advisoryrole,andtravelexpensesforJanssenandRoche;PMB:consultancy/advisoryroleforPharmacyclicsLLC,anAbbVieCompany,AbbVie,Celgene,Novartis,SeattleGeneticsandInfinity,researchfundingfromPharmacyclicsLLC,anAbbVieCompany;RRF:honoraria,consultancy/advisoryrole,speakersbureauforPharmacyclicsLLC,anAbbVieCompany;TJK:consultancy/advisoryroleforAbbVie,Genentech,PharmacyclicsLLC,anAbbVieCompanyandGilead;researchfundingfromAbbVie,Genentech,OncternalandPharmacyclicsLLC,anAbbVieCompany;PT:consultancy/advisoryroleforJanssen,Abbvie;honorariaandtravelaccommodationsfromRoche;JMP:consultancy/advisoryroleforPharmacyclicsLLC,anAbbVieCompanyandGilead;JAB:honoraria,travelexpenses,andconsulting/advisoryrolewithGlead,TGTheraputics,PharmacyclicsLLC,anAbbVieCompany,Novartis,Janssen;researchfundingfromPharmacyclicsLLC,anAbbVieCompany;JJ:consultancy/advisoryroleandresearchfundingfromPharmacyclicsLLC,anAbbVieCompany,AbbVie,andJanssen;SD,RV, DFJ:employmentwithPharmacyclics,LLC,anAbbVieCompany;equityownershipwithAbbVie;JRB:consultancy/advisoryroleforGilead,PharmacyclicsLLC,anAbbVieCompany,Janssen,Roche/Genentech,Celgene,SunPharma,InfinityPharmaceuticals,AstraZeneca,Redx,AstellasPharma,AbbVie;honorariafromJanssenOncology,AbbVie;researchfundingfromGileadSciences.
Poster presented at the ASCO Annual Meeting 2017, June 2-6, 2017, Chicago, IL.
Poster 7510
CopiesofthisposterobtainedthroughQuickResponse(QR)Codeareforpersonaluseonlyandmaynotbereproducedwith-outpermissionfromASCO®andtheauthorofthisposter
ACKNOWLEDGMENTSThisstudywassponsoredbyPharmacyclicsLLC,anAbbVieCompany.TheauthorsthankDrJorisDielsofJanssenandDrSuzyVanSandenofHEMAR,Janssen-CilagLtd(Beerse,Belgium)ongeneratingthecrossover-adjustedOSanalysisusingtheRPSFTmethod.
EditorialsupportwasprovidedbySkyeGeherin,PhD,andfundedbyPharmacyclicsLLC,anAbbVieCompany.
OPEN
ORIGINAL ARTICLE
Extended follow-up and impact of high-risk prognostic factorsfrom the phase 3 RESONATE study in patients withpreviously treated CLL/SLLJR Brown1,23, P Hillmen2,23, S O’Brien3, JC Barrientos4, NM Reddy5, SE Coutre6, CS Tam7, SP Mulligan8, U Jaeger9, PM Barr10,RR Furman11, TJ Kipps12, F Cymbalista13, P Thornton14, F Caligaris-Cappio15, J Delgado16, M Montillo17, S DeVos18, C Moreno19,JM Pagel20, T Munir2, JA Burger3, D Chung21, J Lin21, L Gau21, B Chang21, G Cole21, E Hsu21, DF James21 and JC Byrd22
In the phase 3 RESONATE study, ibrutinib demonstrated superior progression-free survival (PFS), overall survival (OS) and overallresponse rate (ORR) compared with ofatumumab in relapsed/refractory CLL patients with high-risk prognostic factors. We reportupdated results from RESONATE in these traditionally chemotherapy resistant high-risk genomic subgroups at a median follow-upof 19 months. Mutations were detected by Foundation One Heme Panel. Baseline mutations in the ibrutinib arm included TP53(51%), SF3B1 (31%), NOTCH1 (28%), ATM (19%) and BIRC3 (14%). Median PFS was not reached, with 74% of patients randomized toibrutinib alive and progression-free at 24 months. The improved efficacy of ibrutinib vs ofatumumab continues in all prognosticsubgroups including del17p and del11q. No significant difference within the ibrutinib arm was observed for PFS across mostgenomic subtypes, although a subset carrying both TP53 mutation and del17p had reduced PFS compared with patients withneither abnormality. Reduced PFS or OS was not evident in patients with only del17p. PFS was significantly better for ibrutinib-treated patients in second-line vs later lines of therapy. The robust clinical activity of ibrutinib continues to show ongoing efficacyand acceptable safety consistent with prior reports, independent of various known high-risk mutations.
Leukemia advance online publication, 21 July 2017; doi:10.1038/leu.2017.175
INTRODUCTIONThe last decade has seen remarkable advances in therapy ofchronic lymphocytic leukemia (CLL) with the advent of combina-tion chemotherapy (fludarabine and cyclophosphamide (FC))1,2
and then chemoimmunotherapy with rituximab (FCR).3,4 Indeed, asubset of low-risk patients with IGHV-mutated disease may beessentially cured by FCR, but still may suffer the toxic effects ofchemotherapy. However, patients with higher-risk geneticabnormalities (IGHV unmutated) experience inferior outcomeswith a median progression-free survival (PFS) of 4.2 years,5 whilethose with the highest-risk factor, del(17)(p13.1) [del17p], have amedian PFS of ∼ 1 year.3 Shorter remissions particularly in high-risksubgroups, and poor survival with conventional salvage regimensafter FCR relapse,6,7 present a need for novel therapies for CLL.Bruton’s tyrosine kinase (BTK) has emerged as an attractive
target with the observation that the genetic disease, X-linkedagammaglobulinemia, in which BTK is inactivated, results in thefailure of B cells to develop, with few other complications outsideof infectious morbidity that is clinically manageable.8 Ibrutinib is aonce-daily, first-in-class, covalent inhibitor of BTK, which bindsirreversibly to Cys481 in BTK with an IC50 of 0.5 nM9 allowing for
once-daily, oral administration with sustained enzyme inhibition.RESONATE was a randomized comparison of ibrutinib toofatumumab in previously treated CLL patients, many with high-risk prognostic factors. The first report of this trial demonstratedthat ibrutinib significantly improved PFS, overall survival (OS), andoverall response rates (ORR) compared with ofatumumab, and wasacceptably tolerated,10 leading to ibrutinib’s approval for pre-viously treated CLL and del17p CLL.Ibrutinib shows marked efficacy in genetically high-risk CLL,
particularly del17p,11 known to confer a very poor prognosis inaddition to TP53 mutation.12 Whole exome sequencing studieshave identified recurrent mutations particularly in NOTCH1,13 ATM,SF3B114,15 and BIRC3.16 These mutations, enriched in previouslytreated CLL, are associated with poor prognosis in retrospectivestudies.17 In the CLL8 study, both TP53 and SF3B1 mutations wererisk factors for reduced PFS, but only TP53 for reduced OS,18 andNOTCH1 mutation was associated with lack of benefit from theaddition of CD20 monoclonal antibody in two studies.18,19 Inretrospective studies, NOTCH1 mutation has also been associatedwith increased risk of Richter transformation (RT).20,21 Here, wereport updated results with up to 2-year follow-up from the
1Dana-Farber Cancer Institute, Boston, MA, USA; 2St James Institute of Oncology, Leeds, UK; 3MD Anderson Cancer Center, Houston, TX, USA; 4Hofstra Northwell School ofMedicine, Hempstead, NY, USA; 5Vanderbilt-Ingram Cancer Center, Nashville, TN, USA; 6Stanford University School of Medicine, Stanford, CA, USA; 7Peter MacCallum CancerCentre and St Vincent’s Hospital, Melbourne, Australia; 8Royal North Shore Hospital, Sydney, Australia; 9Medical University of Vienna, Vienna, Austria; 10University of RochesterCancer Center, Rochester, NY, USA; 11Weill Cornell Medical College/New York Presbyterian Hospital, New York, NY, USA; 12UCSD Moores Cancer Center, San Diego, CA, USA;13Hôpital Avicenne, Paris, France; 14Beaumont Hospital, Dublin, Ireland; 15Universita Vita-Salute San Raffaele, Milan, Italy; 16Hospital Clinic, Barcelona, Spain; 17Niguarda CancerCenter Niguarda Hospital, Milan, Italy; 18David Geffen School of Medicine at UCLA, Los Angeles, CA, USA; 19Hospital de la Santa Creu Sant Pau, Barcelona, Spain; 20Swedish CancerInstitute, Seattle, WA, USA; 21Pharmacyclics LLC, an AbbVie Company, Sunnyvale, CA, USA and 22The Ohio State University Medical Center, Columbus, OH, USA. Correspondence:Dr JR Brown, Division of Hematologic Malignancies, Dana-Farber Cancer Institute, 450 Brookline Ave, Boston, MA 02215, USA.E-mail: [email protected] authors.Received 17 February 2017; revised 11 May 2017; accepted 23 May 2017; accepted article preview online 8 June 2017
Leukemia (2017), 1–9
www.nature.com/leu
RESONATE trial, including subgroup analysis for baseline high-riskgenetic features. We find that the marked benefit of ibrutinibcontinues and is preserved in all evaluable genetic subgroups.
MATERIALS AND METHODSStudy designRESONATE is a multicenter, international, open-label, randomized, phase 3study that compares the efficacy and safety of ibrutinib to ofatumumab, aspreviously described (NCT01578707).10 At the time of this update, 123patients randomized to ofatumumab received ibrutinib in crossover. SeeSupplementary Appendix for details.
PatientsAll patients provided written informed consent. The study was approvedby the institutional review board or ethics committee at each participatinginstitution and conducted in accordance with the Declaration of Helsinkiand the International Conference on Harmonization Guidelines for GoodClinical Practice.
ProceduresUpdated efficacy data from this analysis, including PFS and ORR, were byinvestigator assessment. Procedural details have been describedpreviously10 and can be found in Supplementary Appendix.
Mutation IdentificationIn order to make our results applicable to general practice, all mutationanalyses were performed by a clinically available, FDA-approved targetednext generation sequencing panel that is being increasingly used in clinicalpractice, the Foundation One Heme Panel. This panel has a mediansequencing depth 500X and reports variant allele frequencies ofapproximately 1% or higher22 (see Supplementary Appendix for details).As is typical in clinical practice, matched germline testing was notperformed; known common polymorphisms were removed based onthose identified in the 1000 Genomes Project (dbSNP135). Putativemutations were evaluated based on COSMIC v62; all candidate mutationsof any detected allele frequency, classified as known, likely, or unknown,were counted as a mutation. Of note, 138 of 140 TP53 mutations identifiedwere classified as known or likely to have a functional effect.
Statistical analysisPlease see Supplementary Appendix for additional details on outcomesmeasures.10
RESULTSBaseline patient characteristicsPatients in the ibrutinib (n= 195) and ofatumumab (n= 196) armshad a median of three and two prior therapies, respectively, with53 vs 46% of patients receiving study therapy in the fourth line oftherapy or beyond; 18% of ibrutinib- and 27% of ofatumumab-treated patients had received only one prior therapy (Table 1);approximately 32% of ibrutinib patients had del17p, and 32% haddel(11)(q22.3) [del11q].Consistent with this relapsed higher-risk population, the
frequencies of TP53, NOTCH1, SF3B1 and BIRC3 mutations werehigh compared with other studies.16,18,23 Most notably, 51% ofibrutinib and 46% of ofatumumab patients carried mutations inTP53. Of 195 ibrutinib patients, 154 had TP53 samples available. Of45 ibrutinib patients with del17p and a sample available foranalysis, 84% (n= 38) had coexistent TP53 mutation, consistentwith prior reports;24 of 79 ibrutinib patients with mutated TP53,52% (n= 41) carried this mutation in the absence of del17p. In theibrutinib arm, 39 of 153 (25%) evaluable patients had complexkaryotype (CK); of 47 del17p patients in the ibrutinib arm withkaryotype data reported, 20 (43%) had CK.
Patient dispositionWith a median 19-month follow-up (maximum 26 months onstudy), 145 (74%) patients on the ibrutinib arm continue ibrutinibon study. Fifty (26%) patients discontinued ibrutinib (19 (10%) dueto progressive disease (PD), 13 (7%) due to adverse events (AE)and 10 (5%) due to death; Supplementary Table 1).
EfficacyIbrutinib showed significant improvement in PFS compared withofatumumab (median not reached (NR) vs 8.1 months; HR 0.106;Figure 1a) with the benefit of ibrutinib apparent for all clinical andgenetic subgroups (Supplementary Figure 1). Median PFS was NRon the ibrutinib arm in any prognostic subgroup including del17p(Figure 1b) and del11q. Second-line ibrutinib PFS outcomes weresignificantly improved compared with those in later lines oftherapy (P = 0.0348) (Figure 1c). Supplementary Figure 2 showsPFS for ibrutinib by one, two, three and ⩾ four prior therapies.
Table 1. Baseline characteristics
Characteristic Ibrutinib(n= 195)
Ofatumumab(n= 196)
Median age, years (range) 67 (30–86) 67 (37–88)⩾ 70 years, n (%) 40% 41%Male, n (%) 66% 70%Rai stage III/IV, n (%) 56% 58%Median number of prior therapies(range), n (%)
3 (1–12) 2 (1–13)
1 18% 27%2 29% 27%⩾ 3 53% 46%
Del17p, n/N (%) 63/195 (32%) 64/196 (33%)Del11q, n/N (%) 63/190 (33%) 59/191 (31%)Trisomy 12, n/N (%) 22/138 (16%) 27/145 (19%)Complex karyotype, n/N (%) 39/153 (25%) 33/147 (22%)CD38 (⩾ 30%), n/N (%) 69/160 (43%) 69/155 (45%)
IGHV, n/N (%)Unmutated 98/134 (73%) 83/132 (63%)Mutated 36/134 (27%) 49/132 (37%)
Gene mutations, n (%) Ibrutinib(n= 154)a
Ofatumumab(n=149)a
ATMMutated 30 (19%) 33 (22%)Not mutated 124 (81%) 116 (78%)
NOTCH1Mutated 43 (28%) 45 (30%)Not mutated 111 (72%) 104 (70%)
SF3B1Mutated 47 (31%) 44 (30%)Not mutated 107 (69%) 105 (70%)
TP53Mutated 79 (51%) 68 (46%)Not mutated 75 (49%) 81 (54%)
MYD88Mutated 3 (2%) 3 (2%)Not mutated 151 (98%) 146 (98%)
BIRC3Mutated 21 (14%) 15 (10%)Not mutated 133 (86%) 134 (90%)
aNumber of samples assessed.
Extended follow-up/prognostic factors in RESONATEJR Brown et al
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The 24-month PFS rate was 74% for the ibrutinib arm. The18-month PFS with ibrutinib was similar regardless of baselinegenetic factors including unmutated IGHV, del17p, del11q, CK ormutations including NOTCH1, BIRC3 and ATM (Table 2). With SF3B1mutation, a trend toward a lower 18-month PFS rate was seen inthe ibrutinib arm (P= 0.1424); however, when all data were takeninto account by log-rank test (P= 0.3349), this trend was lessapparent. The presence of del17p or del11q did not confer inferiorPFS outcomes compared with PFS in patients with neitherdeletion (P= 0.2160; Figure 2a). Those with any del17p/TP53alteration (carrying either one or both abnormalities) did not showsignificantly inferior PFS compared with those with neitherabnormality (P= 0.1306; Figure 3a). Interestingly, however, anexploratory subset analysis focusing on patients with both del17pand TP53mutation (n= 38) compared with patients with neither ofthese abnormalities (n= 68) showed worse PFS in the subsetcarrying both abnormalities (P= 0.0381; Figure 2b). Althoughsurvival assessment by CK status was somewhat limited due tomissing CK data in 22% of patients, available data suggest that PFSwas not significantly different in ibrutinib patients with known CKrelative to those without CK (Figure 3b). Among ofatumumab-treated patients, unmutated IGHV (P= 0.0436) and presence ofdel11q (P= 0.0654) had a lower 18-month PFS rate (Table 2) andNOTCH1 mutation was associated with a worse overall PFS (log-rank P= 0.0064); conversely, the presence of a NOTCH1 mutation
did not negatively impact the efficacy of ibrutinib (Table 2;Supplementary Table 2).A limited multivariate Cox proportional hazards regression
analysis (MVA) was performed including the following candidatefactors: age, Rai stage, ECOG, number of prior therapies, del11q,del17p, β2-microglobulin, and disease refractory to purine analo-gues. Gene mutations (for example, TP53 alone) and CK were notincluded in the MVA due to missing data in ~23% of patients in theibrutinib and ofatumumab arms. Del17p, del11q and β2-micro-globulin were considered significant prognostic factors for PFS in allpatients. No significant prognostic factors were identified withcurrent follow-up when the MVA was limited to the ibrutinib arm.Eighty-six percent of patients randomized to ibrutinib were alive
at the time of analysis. Of patients randomized to ofatumumab,77% were alive with the majority of these patients (108/196)continuing crossover therapy with ibrutinib. Crossover wasinstituted ~ 4 months after the last patient was randomized, andOS analyses showed consistent benefit with ibrutinib in the naïveintent-to-treat comparison and when OS was adjusted forcrossover (based on rank preserving structural failure time modelmethodology), with a significant reduction in the risk of death ofapproximately 64% for ibrutinib vs ofatumumab (SupplementaryFigure 3). OS was similar between ibrutinib subgroups includingdel17p without del11q, del11q without del17p, neither deletion(Supplementary Figure 4) and del17p and/or TP53 (Figure 4a for
PFS,
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Median Time (mo)Hazard Ratio(95% CI)Log-Rank P-value
8.11 NE0.106
(0.075-0.151)<0.0001
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Ibrutinib withlymphocytosis (n=133)
Ibrutinib withoutlymphocytosis (n=59)
Ofatumumab withlymphocytosis (n=24)
Ofatumumab withoutlymphocytosis (n=166)
Months
PFS,
% Ibrutinibwithout
lymphocytosis
Ibrutinibwith
lymphocytosis
Median Time (mo)Hazard Ratio(95% CI)Log-Rank P-value
NE NE0.503
(0.271-0.932)0.0259
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Ibrutinib 1 prior therapy (n=35)Ibrutinib >1 prior therapy (n=160)Ofatumumab 1 prior therapy (n=53) Ofatumumab >1 prior therapy (n= 143)
Ibrutinib >1 Ibrutinib 1
Median Time (mo)Hazard Ratio(95% CI)Log-Rank P-value
NE NE3.294
(1.019-10.65)0.0348
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Ibrutinibwithoutdel17p
Ibrutinibwith
del17p
Median Time (mo)Hazard Ratio(95% CI)Log-Rank P-value
NE NE1.421
(0.771-2.620)0.2575
Figure 1. PFS in patient subgroups. (a) Overall PFS; Po0.0001 for the comparison of ibrutinib vs ofatumumab. (b) PFS in patients with del17pCLL; P= 0.2575 for ibrutinib-treated patients with and without del17p and P= 0.0582 for ofatumumab-treated patients with and withoutdel17p. (c) PFS in patients with 1 vs 41 prior therapy; P= 0.0348 for ibrutinib-treated patients with 1 prior line vs 41 prior line of therapy andP= 0.2761 for ofatumumab-treated patients with 1 prior line vs 41 prior line of therapy. (d) PFS in patients who did or did not developlymphocytosis; P= 0.0259 for ibrutinib-treated patients with and without lymphocytosis at baseline and P= 0.0095 for ofatumumab-treatedpatients with and without lymphocytosis.
Extended follow-up/prognostic factors in RESONATEJR Brown et al
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any alteration vs none, log-rank P= 0.1903). No significantdifference in OS benefit was observed for ibrutinib-treatedpatients with respect to known CK, although data were limited(P= 0.1610; Figure 4b). The OS 18-month point estimate was 86%in the ibrutinib arm: 83% for the del17p subgroup, 89% for thedel11q subgroup, 85% for those with neither deletion, and 79%
for those with CK. There was a trend towards improved OS forpatients on the ibrutinib arm treated in a second-line setting (HR2.874, P= 0.1324) compared with those salvaged in later lines oftherapy (Supplementary Figure 5).Lymphocytosis occurred in 69% of ibrutinib-treated patients
and was typically transient, resolving with continued ibrutinib
Table 2. 18-month PFS rate and ORR by subgroup
Subgroup 18-month PFSa ORR, n/N (%)a,d
Ibrutinib (N= 195) Ofatumumab (N= 196) Ibrutinib (N= 195) Ofatumumab (N= 196)
Overall 76% 8% 90% 25%
Median number of prior therapies1 91%c 11% 35/35 (100%)c 14/53 (26%)2 76%c 0% 141/160 (88%)c,b 35/143 (24%)b
⩾ 3 71%c 4%
Del11qYes 83% 0% 57/63 (90%) 7/59 (12%)c
No 73% 10% 114/127 (90%) 42/132 (32%)c
Del17pYes 71% 7% 56/63 (89%) 13/64 (20%)g
No 79% 8% 120/132 (91%) 36/132 (27%)g
Complex karyotypeYes 72% 0% 35/39 (90%) 2/33 (6%)c
No 80% 10% 102/114 (89%) 38/114 (33%)c
Trisomy 12 77% 0% 21/22 (95%) 8/27 (30%)
CD38 (⩾ 30%) 78% 0% 65/69 (94%) 21/69 (30%)
IGHVUnmutated 77% 0% 90/98 (92%) 22/83 (27%)Mutated 74% 15% 32/36 (89%) 12/49 (24%)
Gene mutations Ibrutinib (N= 154) Ofatumumab (N= 149) Ibrutinib (N= 154) Ofatumumab (N= 149)
ATMMutated 78% 0 28/30 (93%) 8/33 (24%)Not mutated 73% 8% 113/124 (91%) 32/116 (28%)
NOTCH1Mutated 72% 0c 40/43 (93%) 13/45 (29%)Not mutated 74% 11%c 101/111 (91%) 27/104 (26%)
SF3B1Mutated 65%e 10% 45/47 (96%) 10/44 (23%)Not mutated 79%e 0 96/107 (90%) 30/105 (29%)
TP53Mutated 66%f 0 72/79 (91%) 13/68 (19%)g
Not mutated 81%f 9% 69/75 (92%) 27/81 (33%)g
MYD88Mutated 0 0 2/3 (67%) 1/3 (33%)Not mutated 73% 8% 139/151 (92%) 39/146 (27%)
BIRC3Mutated 81% 0 20/21 (95%) 4/15 (27%)Not mutated 72% 9% 121/133 (91%) 36/134 (27%)
aPo0.0001 (Z test) ibrutinib vs ofatumumab for 18-mo PFS rate. Mutated subgroup for MYD88 was not assessed. Po0.05 within ofatumumab arm for 18-moPFS rate (Z test) for IGHV (Unmutated vs Mutated). Po0.0001 for ORR (Fisher’s exact test) ibrutinib vs ofatumumab, except for MYD88. bRepresents ⩾ 2 priortherapy. cPo0.05 within an arm for overall PFS (log-rank test) and ORR (Fisher’s exact test). dIncludes PR-L. eP= 0.1424 for SF3B1mutated vs not mutated withinthe ibrutinib arm; P= 0.3349 for overall PFS (log-rank test). fP= 0.0672 for TP53 mutated vs not mutated within the ibrutinib arm. gP= 0.3793 for del17p andP= 0.0638 for TP53 mutated vs not mutated within the ofatumumab arm.
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therapy in 87% of patients with a median duration of 14.1 weeks.PFS appeared better for those who developed lymphocytosis vsthose who did not (Figure 1d); a previous study has reported non-inferior outcomes between patients with or without persistentlymphocytosis.25 Ibrutinib patients with mutated IGHV showed aslight trend to greater initial increase in absolute lymphocytecount (ALC) compared with those with unmutated IGHV(Supplementary Figure 6), with apparent slower resolution inpatients with mutated IGHV vs those with unmutated IGHV similarto a previous report (Po0.001).26
The best ORR increased in the ibrutinib arm with 90% ofpatients now attaining PR with lymphocytosis (PR-L) or better, ascompared with 83 vs 23% (ibrutinib vs ofatumumab, Po0.0001)by investigator assessment at interim analysis.10 ORR was higher inthe ibrutinib arm in all evaluable subgroups compared withofatumumab (Po0.0001). In addition, the complete response (CR)rate improved with 7% of patients demonstrating CR (9 (5%)) orcomplete response with incomplete blood count recovery (CRi; 4(2%)) compared with 2% at interim analysis. The latest CR/CRi wasachieved in the ibrutinib arm at 17.5 months. One patient onofatumumab achieved CR at 8 months. The ORR was 100% inibrutinib-treated patients with only one prior therapy as comparedwith 88% with ⩾ 2 prior therapies (P= 0.0275, Table 2). No
difference was seen in ORR within the ibrutinib arm amongpatients with or without various genetic mutations. On theofatumumab arm, patients with del11q and CK had a significantlylower ORR compared with those without del11q and CK(P= 0.0038 and P= 0.0015, respectively) (Table 2).Twenty-eight ibrutinib patients progressed including patients
who discontinued due to AE and later progressed. Of the 28patients who progressed, 20 had CLL progression (without RT) and8 had RT, of which 6 developed large cell lymphoma and 2Hodgkin disease (5 ofatumumab patients progressed with RT,including 1 after crossover to ibrutinib). Clonal relationship of theRT to prior CLL was unknown. Of the 8 ibrutinib-treated patientswith RT (6 within 1 year, 2 within two years), baseline mutationswere available for 6 patients and reported as follows: NOTCH1(n= 2), BIRC3 (n= 1), TP53 (n= 5), SF3B1 (n= 1), or ATM (n= 1).Other high-risk features were observed in these RT patients,including del17p (n= 4), del11q (n= 2), and CK (n= 3), and in non-RT PD patients (n= 20) including del17p (n= 9), del11q (n= 4), CK(n= 5), NOTCH1 (n= 7), TP53 (n= 11), SF3B1 (n= 10). At the time ofanalysis, 12 of 28 patients who progressed had died (including 8patients with non-RT progression and 4 with RT). Seventeen of 28patients had received subsequent anticancer therapy (including11 patients with non-RT progression and 6 with RT). The mostcommon subsequent therapies were regimens containing ofatu-mumab (n= 6), R-CHOP (n= 4) or R ± EPOCH (n= 4). Of 14 patientswho discontinued ibrutinib due to PD and received subsequentanticancer therapy, 6 had RT: 2 died, and 3 were alive at time ofanalysis on subsequent therapy (See Supplementary Table 3 for
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del17p yes and TP53 mutation yes (n=38)no del 17p or TP53 mutation (n=68)del17p yes or TP53 mutation yes (n=48)
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a
b
Figure 2. PFS with ibrutinib by cytogenetics (FISH)/mutationalassociation. (a) PFS in patients by del17p/del11q CLL subgroups;the del17p subgroup contains patients with del17p with or withoutdel11q (P= 0.2160 comparing all three groups). (b) PFS in patientsby del17p/TP53 CLL subgroups (P= 0.1737 for both del17p and TP53mutation vs either del17p or TP53 mutation; P= 0.0381 for bothdel17p and TP53 mutation vs neither; P= 0.5022 for either del17p orTP53 mutation vs no del17p or TP53 mutation).
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CK Yes (n=39)CK No (n=114)
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Median Time (mo)Hazard Ratio(95% CI)Log-Rank P-value
CK Yes
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NE1.529
(0.741-3.157)0.2476
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del17p and/orTP53 mutation (n=86)
No del17p orTP53 mutation (n=68)
Median Time (mo)Hazard Ratio(95% CI)Log-Rank p-value
No del17p orTP53 mutation
(n=68)
NE
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(n=86)
NE0.590
(0.295-1.179)0.1306
Figure 3. PFS with ibrutinib by del17p/TP53 status and complexkaryotype. (a) PFS with ibrutinib in patients by any del17p/TP53alteration vs none. (b) PFS with ibrutinib in all patients with orwithout complex karyotype.
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details). Eight with non-RT PD received subsequent anticancertherapy, and 3 were alive at analysis.
SafetyThe longer-term safety profile of ibrutinib in this randomizedphase 3 study was consistent with the 3-year follow-up from thephase 2 study.27 The most common cumulative AE of any graderemains diarrhea, now 54 from 48% at interim analysis, followedby fatigue (34 vs 28%), nausea (31 vs 26%) and fever (30 vs 24%)(Table 3). The most common (410%) infections included upperrespiratory tract infections (25% any grade, 0.5% grade ⩾ 3),sinusitis (19% any grade, 0.5% grade ⩾ 3), pneumonia (17% anygrade, 12% grade ⩾ 3), and urinary tract infections (14% anygrade, 4% grade ⩾ 3). Pneumocystis jirovecii pneumonia (grade 3)occurred in 1 patient (0.5%). Seven patients (4%) had grade 5infections, which included pneumonia (n= 4), sepsis (n= 2) andneutropenic sepsis (n= 1) (Supplementary Table 1); none of thesegrade 5 infections were considered related to study treatment.Nineteen patients (10%) in the ibrutinib arm had receivedprophylactic growth factor support, and 131 patients (67%) hadreceived some form of anti-infective prophylaxis, most commonlywith antiviral agents including aciclovir (n= 53; 27%) andvalaciclovir (n= 52; 27%). The most common antibiotic agentsused for prophylaxis included trimethoprim-sulfamethoxazole(n= 47; 24%) and levofloxacin (n= 16; 8%).New onset of diarrhea, atrial fibrillation (AF), arthralgia and
grade ⩾ 3 infection decreased over time (Table 4). Grade ⩾ 3bleeding events were infrequent with three additional events overapproximately 1-year follow-up since interim analysis, includinggrade 3 epistaxis and spontaneous psoas hematoma (the latterduring concomitant enoxaparin and clopidogrel) and grade 4subdural hematoma (post-traumatic event, resolved and patientrestarted and continues ibrutinib). Any grade AF occurred in 13(7%) patients (grade 1 (n= 2), grade 2 (n= 4), grade 3 (n= 7)) withthe median time to onset of first event being 5.1 months). Eight(62%) of these patients resolved their AF event (median 3 days toresolution, range 1–42), and all received thromboprophylaxis that
Figure 4. Overall survival with ibrutinib by del17p/TP53 status andcomplex karyotype. (a) Overall survival with ibrutinib in patients byany del17p/TP53 alteration vs none. (b) Overall survival withibrutinib in all patients with or without complex karyotype.
Table 3. Most common cumulative AEs for ibrutinib (⩾15%) at interim analysis (IA) and current data cut
Adverse event Any grade, n (%) (N= 195) Grade 3-4, n (%) (N= 195) Grade 5, n (%) (N= 195)
IA data (medianfollow-up of9.4 mo)a
Updated data (medianfollow-up of19 mo)b
IA data (medianfollow-up of9.4 mo)a
Updated data(median follow-up of
19 mo)b
IA data (medianfollow-up of9.4 mo)a
Updated data(median follow-up of
19 mo)b
Diarrhea 93 (47.7) 105 (53.8) 8 (4.1) 9 (4.6) 0 0Fatigue 54 (27.7) 67 (34.4) 4 (2.1) 7 (3.6) 0 0Nausea 51 (26.2) 61 (31.3) 3 (1.5) 3 (1.5) 0 0Pyrexia 46 (23.6) 58 (29.7) 3 (1.5) 3 (1.5) 0 0Cough 38 (19.5) 51 (26.2) 0 1 (0.5) 0 0Neutropenia 42 (21.5) 50 (25.6) 32 (16.4) 38 (19.5) 0 0Anemia 44 (22.6) 49 (25.1) 9 (4.6) 12 (6.2) 0 0Upper respiratorytract infection
31 (15.9) 49 (25.1) 1 (0.5) 1 (0.5) 0 0
Peripheral edema 22 (11.3) 38 (19.5) 0 0 0 0Sinusitis 21 (10.8) 37 (19.0) 1 (0.5) 1 (0.5) 0 0Arthralgia 34 (17.4) 36 (18.5) 2 (1.0) 3 (1.5) 0 0Muscle spasms 25 (12.8) 36 (18.5) 0 1 (0.5) 0 0Constipation 30 (15.4) 35 (17.9) 0 0 0 0Headache 27 (13.8) 33 (16.9) 2 (1.0) 3 (1.5) 0 0Pneumonia 19 (9.7) 33 (16.9) 13 (6.7) 20 (10.3) 3 (1.5) 4 (2.1)Thrombocytopenia 33 (16.9) 33 (16.9) 11 (5.6) 11 (5.6) 0 0Vomiting 28 (14.4) 33 (16.9) 0 0 0 0
Abbreviation: IA, interim analysis. aRepresents cumulative AEs as of interim analysis data cut with median follow-up of 9.6 months. bRepresents totalcumulative AEs (including all IA data) with median follow-up of 19 months, maximum follow-up of 24 months.
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included aspirin, low molecular weight heparin, direct oralanticoagulants or combinations thereof (Supplementary Table 4).One patient with AF had a major hemorrhagic event that was thegrade 3 spontaneous psoas hematoma described above.
DISCUSSIONEfficacy with ibrutinib remained high at this 2-year follow-up ofthe RESONATE study, with 74% of patients alive and progression-free. Patients on the ibrutinib arm treated after only one priortherapy experienced improved efficacy compared with thosesalvaged after ⩾ second-line therapy. Phase 3 data in treatment-naive patients without del17p also suggest high efficacy in thefrontline setting with significantly improved PFS and OS comparedwith chlorambucil with a median 19-month follow-up.28 Takentogether, the results from this study as well as from studies ofibrutinib in frontline therapy27,28 suggest that the best resultsoccur when ibrutinib has been used earlier in the treatmentcourse. This observation has also been true of other therapieshistorically, including chemoimmunotherapy with FCR, perhapsreflecting the accumulation of multiple and broad mechanisms ofdrug resistance over time with treatment. The outcome ofongoing randomized trials using standard combination chemoim-munotherapy vs ibrutinib-containing regimens in the upfrontsetting will be required to determine the true extent of ibrutinibbenefit in that setting as compared with the early relapsed setting.Tolerability to ibrutinib was well maintained in this relapsed
patient population with extended treatment. The most commonside effects were similar to those at interim analysis with only aslight increase in the cumulative event rate despite the additionalyear of therapy. Specifically, the rate of new infection, diarrhea andarthralgia appeared lower later in follow-up when compared withthe first 6 months, consistent with a recent report of long-termfollow-up with ibrutinib at the Ohio State University, in whichpatients who discontinued for reasons other than progression didso relatively early, followed by a plateau.29 Severe (grade ⩾ 3)bleeding events were infrequent with three events occurringduring the additional follow-up period, with two of these eventsoccurring in the context of concomitant anticoagulation and in apost-traumatic setting, respectively. Recent studies have reportedreduced ristocetin-30and collagen-31 mediated platelet aggrega-tion in patients treated with ibrutinib. Grade ⩾ 3 bleeding eventswith ibrutinib were uncommon in these reports. With regard to AF,the median time of onset of 5.1 months in our study was similar to3.8 months reported in the largest cohort of ibrutinib-treated CLLpatients with AF (n= 56).32 Further, hypertension has been notedthroughout the ibrutinib treatment course including at latertimes.27,28 Thus, ongoing monitoring of toxicity, particularly in
patients who may remain on ibrutinib for many years, remainsimportant.Prior non-randomized trials have reported that RT tends to
occur early in the course of ibrutinib treatment29,33,34 followed bya plateau in incidence. In this study, which followed patients onlyuntil disease progression, more events of RT were reported in theibrutinib arm compared with the ofatumumab arm (8 patients vs 5patients, respectively, with 6 and 4 patients with RT in the firstyear of follow-up), but these frequencies reflect a median PFS (andtherefore of follow-up) of 8.1 months on ofatumumab vs ongoingfollow-up in most patients on ibrutinib. Previous reports of threerandomized controlled CLL trials have identified a similarincidence of RT on the ibrutinib and control arms; there were 3patients with RT on the placebo arm vs 0 on the ibrutinib arm ofHELIOS,35 1 RT on the chlorambucil arm vs 0 on the ibrutinib armof RESONATE-2,28 and 2 RT cases on each arm of RESONATE attime of primary analysis.10 Moreover, the 4% rate of RT in theibrutinib arm of our current analysis is not different from historicalrates reported with other CLL regimens.36–38 Patients whodeveloped RT in the ibrutinib arm had frequent adverse genomicfeatures at baseline, including del17p, NOTCH1, and TP53abnormalities, which are known to be associated with, and maycontribute to, the development of RT. Thus, the risk of RT withibrutinib treatment does not appear to be higher compared withother treatment regimens in CLL, and likely reflects the naturalhistory of high-risk, relapsed/refractory disease.For the first time, we report randomized efficacy outcomes with
ibrutinib in high-risk FISH-defined genetic subgroups in additionto more novel high-risk gene mutations. Ibrutinib markedlyimproved PFS and ORR in all genetic subgroups over ofatumu-mab. In particular, with an additional year of follow-up, patients onibrutinib with either del17p or TP53 mutation did not showmarkedly worse PFS than those without these genetic abnorm-alities, although in an exploratory analysis, the presence of bothabnormalities was associated with a decrease in the PFS curve.Notably, similar to prior reports,39 41/2 of patients with TP53mutations did not have del17p – such patients experience pooroutcomes to chemotherapy regimens,40 yet TP53 mutationaltesting is not standardly performed in the United States. The3-year update of the phase 2 data demonstrated that patientswith del17p have significantly lower PFS (median 28 months) thanpatients with del11q or neither of these anomalies, where themedian PFS was NR.27 In that study, TP53mutation was not tested,but it is likely that most patients with del17p had TP53 mutation,as previously reported;24 thus, these findings are likely consistentwith the emerging decrease in PFS observed in the current studyfor patients with both abnormalities. In a subsequent efficacyanalysis of patients with del17p from the same study, patientswithout CK appeared to experience the most favorable PFS/OS
Table 4. Adverse events of interest for ibrutinib-treated patients by time of event onset
Adverse eventa 0–6 months, n/N* (%)(N= 195)
46–12 months, n/N* (%)(N= 172)
412–18 months, n/N* (%)(N= 159)
418–24 months, n/N* (%)(N=136)
Atrial fibrillation 7/195 (4%) 7/171 (4%) 2/156 (1%) 0/133 (0%)Arthralgia 34/195 (17%) 5/153 (3%) 3/140 (2%) 2/115 (2%)Diarrhea 92/195 (47%) 17/142 (12%) 12/131 (9%) 4/110 (4%)Hypertension 10/195 (5%) 8/165 (5%) 7/144 (5%) 2/120 (2%)Bleeding 84/195 (43%) 28/141 (20%) 16/127 (13%) 10/103 (10%)BleedingXgrade 3 1/195 (o1%) 1/172 (o1%) 2/159 (1%) 0/135 (0%)Infection 147/195 (75%) 83/135 (61%) 57/110 (52%) 18/91 (20%)InfectionXgrade 3 40/195 (21%) 22/166 (13%) 11/155 (7%) 5/133 (4%)
n, number of patients who were treated and had an event onset for a given AE within each exposure period. N*, number of patients who were treated and atrisk for event onset for a given AE in each exposure period; patients whose AE started in the previous time period and continued into the current or next timeperiod(s) are not considered at risk for event onset in the current exposure period for that AE. N, number of patients who were treated in each exposureperiod. aIncludes any severity grade unless specified as Xgrade 3.
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outcomes.41 Consistent with these findings, investigators at MDAnderson Cancer Center and Ohio State University havepreviously reported that CK adversely affects ibrutiniboutcomes.29,42 This finding was not observed yet in this study,but may be due to incomplete data or still relatively shortfollow-up.Analysis of other relevant prognostic genes including SF3B1,
BIRC3, ATM and NOTCH1 revealed no difference in progressionoutcomes between ibrutinib patients with or without thesemutations at 19 months follow-up. In contrast, NOTCH1-mutatedpatients randomized to ofatumumab fared significantly worsethan their non-mutated counterparts, perhaps consistent withprevious reports in which NOTCH1mutations were associated withlack of benefit of CD20 antibody therapies.18,19 It should be notedthat, in order to make our results relevant to clinical practice, weused a clinically available next generation sequencing panelapplied only to tumor, and because of that, the analysis may belimited by the absence of comparison to matched germline, whichmay result in some rare germline variants being counted assomatic mutations. In addition, all mutations detected in the NGSpanel, which has a detection limit of approximately 1% allelefrequency, were included in the clinical analysis, yet at present, itis unknown whether a cutoff should be applied for a minimumallele frequency when assessing these mutations in relation toclinical outcome. Given this uncertainty, we chose to err on theside of including any detected candidate mutation, particularly asprior literature does suggest that even tiny TP53 mutated clonesare associated with poor outcome.39,43 Ultimately, detailedscientific studies with large uniformly treated datasets will berequired to determine whether an allele frequency cutoff wouldbe more appropriate.In this study, patients who developed lymphocytosis experi-
enced longer PFS compared with those who did not. In a 3-yearfollow-up of treatment-naïve and relapsed/refractory patients withCLL/SLL, Byrd et al. reported similar PFS outcomes in patients withand without persistent lymphocytosis at one year of ibrutinibtherapy.27 Woyach et al. have also reported similar outcomesamong patients with or without persistent lymphocytosis treatedwith ibrutinib, although a trend towards improved PFS was seen inpatients who achieved PR-L.25 An association between prolongedlymphocytosis and favorable prognostic features was alsoobserved, with ibrutinib responders with prolonged treatment-related lymphocytosis more likely to carry favorable prognosticmarkers including del13q and mutated IGHV.25 Taken together,these data suggest that prolonged lymphocytosis is associatedwith favorable prognostic factors that are associated with longerresponse, but ultimately longer follow-up is warranted to establisha definite correlation.Ultimately, given the low number of PFS events in patients
treated with ibrutinib, the follow-up is still too short to definitivelyknow whether subgroups characterized by higher-risk mutations,including del17p, will have reduced PFS. Meanwhile, the majorityof relapsed CLL patients treated on this trial continue to doextremely well, underscoring the significant impact of ibrutinib inaltering the course of relapsed CLL.
CONFLICT OF INTERESTJRB has received honoraria from Celgene, Gilead, Infinity, Genentech/Roche, Janssen,Pharmacyclics, Pfizer and Sub BioPharma, has served in an advisory role for Celgene,Gilead, Infinity, Genentech, Janssen, Pfizer and Pharmacyclics, and has beenreimbursed for expenses by Gilead, Sun BioPharma, Pfizer and Janssen. PH hasserved as a consultant for Roche, Glaxo Smith Kline, Janssen, Gilead, and AbbVie,received honoraria from AbbVie, Gilead, Glaxo Smith Kline, Roche, Novartis,Pharmacyclics and Janssen, and research funding from Roche, Novartis, Glaxo SmithKline, Janssen, Gilead, AbbVie, Celgene, Pharmacyclics. SOB has served as aconsultant and received honoraria from Pharmacyclics and Janssen, and receivedresearch funding from Pharmacyclics. JCBarrientos has served as a consultant toGilead, AbbVie, and Janssen, and received research funding from AbbVie and Gilead.
NMR has served as a consultant for Celgene, Infinity, Gilead, and AbbVie. SEC hasserved in an advisory role for Janssen and Pharmacyclics, and has received researchfunding from AbbVie and Pharmacyclics. CT has received honoraria from Janssen,research funding from Janssen, and has served in an advisory role for Janssen. SPMhas served as a consultant for and received honoraria from AbbVie, Gilead, GlaxoSmith Kline, Janssen, Roche, received research funding from AbbVie, Janssen, Roche,participated in speakers’ bureau for AbbVie, Gilead, Janssen, Roche. UJ has served asa consultant, and received honoraria and reimbursements from Janssen and Roche.PMB has served as a consultant for Pharmacyclics, AbbVie and received researchfunding from Pharmacyclics. RRF has received honoraria from Pharmacyclics, and hasserved in an advisory role and on Speakers’ Bureaus for Pharmacyclics. TJK has servedas a consultant for AbbVie, Genentech, Gilead, and received research funding fromAbbVie, Genentech, Pharmacyclics. FC has received research funding from Janssen,honoraria from Gilead, Janssen, Mundipharma and AbbVie, has consulted for Gilead,Janssen and AbbVie, and been reimbursed by Janssen, and Roche. PT has served as aconsultant for Janssen. FCC has received honoraria and served as a consultant forCelgene, Janssen, Pharmacyclics. JD has received honoraria from and served as aconsultant for Gilead, Novartis, Glaxo Smith Kline, Janssen, Roche, and receivedresearch funding from Infinity, Roche. MM has received honoraria from and served ina consultancy role for Roche, Gilead, and Janssen, and received honoraria fromNovartis. SDV and CM have no relevant conflicts of interest to disclose. JMP hasserved as a consultant for Gilead and Pharmacyclics, and received research fundingfrom Pharmacyclics, AbbVie, and TG Therapeutics. TM has received honoraria fromPharmacyclics, Gilead, and Alexion and has served as a consultant for Morphosys. JABhas served as a consultant for Janssen, Portola, has received research funding fromGilead, Pharmacyclics, and reimbursement from Janssen, Roche. DC is employed byPharmacyclics and has stock/ownership in Gilead and AbbVie. JL, LG, BC, GC, EH, DFJare employed by Pharmacyclics and have stock/ownership in AbbVie. JCByrd has norelevant conflict of interest to disclose.
ACKNOWLEDGEMENTSManuscript developed with editorial support from Nexus GG Science LLC funded byPharmacyclics LLC, an AbbVie Company. The study was sponsored by Pharmacyclics.All authors and their research teams collected the data. Pharmacyclics designed thestudy, confirmed the accuracy of the data, and compiled it for analysis. The authorshad full access to the data and analyses for the compilation of this report. JRB wrotethe first draft of this manuscript, which was subsequently reviewed, modified, andapproved in its final version by all authors. All authors vouch for the accuracy andcompleteness of the data reported and the fidelity of the study to the protocol(previously published at NEJM.org).
AUTHOR CONTRIBUTIONSJRB wrote the first draft of the manuscript and all authors carefully reviewed themanuscript and approved the final version. The corresponding author had fullaccess to all of the data and final responsibility to submit for publication.
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Extended follow-up/prognostic factors in RESONATEJR Brown et al
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T h e n e w e ngl a nd j o u r na l o f m e dic i n e
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original article
Ibrutinib versus Ofatumumab in Previously Treated Chronic Lymphoid Leukemia
J.C. Byrd, J.R. Brown, S. O’Brien, J.C. Barrientos, N.E. Kay, N.M. Reddy, S. Coutre, C.S. Tam, S.P. Mulligan, U. Jaeger, S. Devereux, P.M. Barr, R.R. Furman,
T.J. Kipps, F. Cymbalista, C. Pocock, P. Thornton, F. Caligaris-Cappio, T. Robak, J. Delgado, S.J. Schuster, M. Montillo, A. Schuh, S. de Vos, D. Gill, A. Bloor, C. Dearden, C. Moreno, J.J. Jones, A.D. Chu, M. Fardis, J. McGreivy, F. Clow,
D.F. James, and P. Hillmen, for the RESONATE Investigators*
The authors’ full names, academic de-grees, and affiliations are listed in the Ap-pendix. Address reprint requests to Dr. Byrd at B302 Starling-Loving Hall, 320 W. 10th Ave., Columbus, OH 43210, or at [email protected].
*A complete list of investigators in the Study of Ibrutinib versus Ofatumumab in Pa-tients with Relapsed or Refractory Chron-ic Lymphocytic Leukemia (RESONATE) is provided in the Supplementary Ap-pendix, available at NEJM.org.
This article was published on May 31, 2014, at NEJM.org.
DOI: 10.1056/NEJMoa1400376Copyright © 2014 Massachusetts Medical Society.
A BS TR AC T
Background
In patients with chronic lymphoid leukemia (CLL) or small lymphocytic lymphoma (SLL), a short duration of response to therapy or adverse cytogenetic abnormalities are associated with a poor outcome. We evaluated the efficacy of ibrutinib, a cova-lent inhibitor of Bruton’s tyrosine kinase, in patients at risk for a poor outcome.
Methods
In this multicenter, open-label, phase 3 study, we randomly assigned 391 patients with relapsed or refractory CLL or SLL to receive daily ibrutinib or the anti-CD20 antibody ofatumumab. The primary end point was the duration of progression-free survival, with the duration of overall survival and the overall response rate as sec-ondary end points.
Results
At a median follow-up of 9.4 months, ibrutinib significantly improved progression-free survival; the median duration was not reached in the ibrutinib group (with a rate of progression-free survival of 88% at 6 months), as compared with a median of 8.1 months in the ofatumumab group (hazard ratio for progression or death in the ibrutinib group, 0.22; P<0.001). Ibrutinib also significantly improved overall survival (hazard ratio for death, 0.43; P = 0.005). At 12 months, the overall survival rate was 90% in the ibrutinib group and 81% in the ofatumumab group. The overall response rate was significantly higher in the ibrutinib group than in the ofatum-umab group (42.6% vs. 4.1%, P<0.001). An additional 20% of ibrutinib-treated pa-tients had a partial response with lymphocytosis. Similar effects were observed regardless of whether patients had a chromosome 17p13.1 deletion or resistance to purine analogues. The most frequent nonhematologic adverse events were diarrhea, fatigue, pyrexia, and nausea in the ibrutinib group and fatigue, infusion-related reactions, and cough in the ofatumumab group.
Conclusions
Ibrutinib, as compared with ofatumumab, significantly improved progression-free survival, overall survival, and response rate among patients with previously treated CLL or SLL. (Funded by Pharmacyclics and Janssen; RESONATE ClinicalTrials.gov number, NCT01578707.)
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Chronic lymphoid leukemia (CLL) is characterized by a variable natural history that is partly predicted by clinical and ge-
nomic features.1 Therapy for CLL has evolved from monotherapy with alkylating agents to che-moimmunotherapy.2,3 Each of the combination regimens has shown prolonged rates of progres-sion-free survival, as compared with similar reg-imens that do not contain antibodies.
Treatment of patients with relapsed CLL of-ten includes regimens such as bendamustine and rituximab,4 ofatumumab,5 or investigational agents.6-8 Ofatumumab was approved by the Food and Drug Administration (FDA) and the European Medicines Agency on the basis of a single-group study involving patients who had re-sistance to fludarabine and alemtuzumab therapy; with an overall response rate of 58%,5 ofatum-umab has been recommended in international consensus guidelines as a therapeutic option for patients with previously treated CLL.9,10
A short duration of response to initial therapy or adverse cytogenetic abnormalities have been associated with a poor outcome among patients receiving conventional therapy.9,11,12 Identifying new therapies that prolong survival remains an important need for these patients.
Ibrutinib (Imbruvica, Pharmacyclics and Jans-sen) is a first-in-class, oral covalent inhibitor of Bru ton’s tyrosine kinase, an essential enzyme in B-cell receptor signaling, homing, and adhe-sion.13-15 On the basis of response rates in single-group, phase 2 studies, ibrutinib was recognized by the FDA as a breakthrough therapy and was granted accelerated approval for patients with mantle-cell lymphoma (in November 2013) and CLL (in February 2014) who had received at least one previous therapy. Among patients with re-lapsed or refractory CLL or small lymphocytic lymphoma (SLL), those who received ibrutinib had a response rate of 71%, according to investigator assessment, and a progression-free survival rate of 75% at 2 years.13 In this study, drug toxicity did not result in the discontinuation of ibrutinib in most patients. On the basis of early results of the phase 2 trial, we initiated a multicenter, open-label, randomized, phase 3 trial, the Study of Ibrutinib versus Ofatumumab in Patients with Relapsed or Refractory Chronic Lymphocytic Leu-kemia (RESONATE), to compare once-daily oral ibrutinib with an active control single-agent ther-apy, ofatumumab, in patients with relapsed or re-fractory CLL or SLL.
Me thods
Patients
Patients with CLL or SLL requiring therapy16 were eligible for enrollment if they had received at least one previous therapy and were considered to be inappropriate candidates for purine analogue treatment because they had a short progression-free interval after chemoimmunotherapy or be-cause they had coexisting illnesses, an age of 70 years or more, or a chromosome 17p13.1 deletion (Text S1 in the Supplementary Appendix, avail-able with the full text of this article at NEJM.org). Patients were required to have an Eastern Coop-erative Oncology Group (ECOG) performance status17 of less than 2 (on a scale from 0 to 5, with higher scores indicating greater disability), an absolute neutrophil count of at least 750 cells per microliter, a platelet count of at least 30,000 cells per microliter, and adequate liver and kidney function. Patients requiring warfarin or strong CYP3A4/5 inhibitors were excluded. All patients provided written informed consent.
Study Oversight
The study was approved by the institutional re-view board or independent ethics committee at each participating institution and was conducted in accordance with the provisions of the Declara-tion of Helsinki and the International Conference on Harmonization Guidelines for Good Clinical Practice. The study was sponsored by Pharma-cyclics and Janssen. All the authors and their re-search teams collected the data. Representatives of Pharmacyclics designed the study, confirmed the accuracy of the data, and compiled the data for analysis; Janssen representatives had no ac-tive role in the study. The authors had full access to the data and analyses for the compilation of this report. The first author wrote the first draft of the manuscript, which was reviewed, modi-fied, and approved in its final version by all the authors. Editorial assistance was provided by two professional medical editors funded by Pharma-cyclics. All the authors vouch for the accuracy and completeness of the data reported and the fidelity of the study to the protocol (available at NEJM.org) and made the decision to submit the manuscript for publication.
Study Review
An independent review committee, whose mem-bers were unaware of study-group assignments and
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lymphocyte counts, assessed progression and re-sponse. An independent data and safety monitor-ing committee evaluated safety and reviewed data from the protocol-specified interim analysis.
Randomization and Treatment
From June 2012 through April 2013, we enrolled 391 patients at 67 sites in the United States, Aus-tralia, and seven European countries. Patients were randomly assigned to receive either oral ibrutinib (at a dose of 420 mg once daily) until disease pro-gression or the occurrence of unacceptable toxic effects or intravenous ofatumumab for up to 24 weeks at an initial dose of 300 mg at week 1, fol-lowed by a dose of 2000 mg weekly for 7 weeks and then every 4 weeks for 16 weeks, consistent with local labeling. Patients were stratified ac-cording to whether they had resistance to purine analogue chemoimmunotherapy (defined as no response or a relapse within 12 months after the last dose of a purine analogue) and whether they had a chromosome 17p13.1 deletion.
During this study, promising data from the phase 2 trial13 led investigators to request, and the steering committee to recommend, crossover of patients in the ofatumumab group to the ibru-tinib group. This revision was supported by the data and safety monitoring committee and was discussed with health authorities. Approximately 4 months after the last patient underwent ran-domization, a protocol amendment allowed pa-tients in the ofatumumab group who had disease progression, as confirmed by an independent re-view committee, to receive ibrutinib.
Study End Points
The primary end point was the duration of pro-gression-free survival, as assessed by the inde-pendent review committee, according to the cri-teria of the International Workshop on Chronic Lymphocytic Leukemia.11 (Details regarding cri-teria for a complete response, partial response, stable disease, and progressive disease are pro-vided in Table S1 in the Supplementary Appendix.) On the basis of a clarification adopted in 2012, treatment-related lymphocytosis was not consid-ered to be progressive disease.11 Key secondary end points included the duration of overall survival and the response rate. The criteria of the Interna-tional Workshop on Chronic Lymphocytic Leuke-mia require the use of computed tomography (CT) to evaluate response and persistent improvement for at least 2 months to confirm response.11
Patients were monitored weekly for the first 8 weeks, every 4 weeks until month 6, and then every 12 weeks, with full response assessments performed every 12 weeks. Toxicity was graded according to the criteria of the National Cancer Institute Common Terminology Criteria for Ad-verse Events, version 4.0; the criteria of the Inter-national Workshop on Chronic Lymphocytic Leu-kemia were used to evaluate hematologic toxicity. Reports of eye-related adverse events were collected proactively on the basis of preclinical toxicology studies in dogs that revealed corneal abnormali-ties in animals receiving ibrutinib at a dose of 150 mg per kilogram of body weight per day (equivalent dose in humans, 81 mg per kilogram per day).18-20 Pathologists at a central laboratory assessed the results of interphase fluorescence in situ hybridization (FISH) to evaluate cytogenetic factors (a procedure that was also performed at local site laboratories), measurements of serum β2-microglobulin, and mutational analysis of im-munoglobulin heavy-chain variable (IGHV) genes. (The presence of unmutated genes is usually as-sociated with a poorer response to therapy and a worse outcome.)
Statistical Analysis
The primary end point, progression-free survival, was used in the calculation of the study sample size. The number of required events was based on a target hazard ratio for progression or death of 0.60, as calculated with the use of a two-sided log-rank test at an alpha level of 0.05, with a study power of at least 90%. The efficacy bound-ary (two-sided P<0.028) was crossed at the pre-planned interim analysis, and the results from that analysis are presented in this report. The primary analysis was a two-sided log-rank test stratified according to the presence or absence of the chromosome 17p13.1 deletion and the disease refractory status at randomization. The type I error was controlled through adjustment of the signifi-cance level with the use of the O’Brien–Fleming boundary21 for the interim analysis and with the use of a hierarchical closed-testing procedure for primary and ordered secondary end points.
R esult s
Patients
The baseline characteristics of the patients were generally well balanced between the two study groups (Table 1, and Table S2 in the Supplemen-
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tary Appendix). The majority of patients had ad-vanced-stage disease. Patients in the ibrutinib group had undergone a median of three previous therapies, and those in the ofatumumab group had
undergone a median of two previous therapies. The majority of patients had received previous treat-ment with purine analogues, alkylating agents, and anti-CD20 antibodies, which were frequently ad-
Table 1. Characteristics of the Patients at Baseline.*
CharacteristicIbrutinib(N = 195)
Ofatumumab(N = 196)
Patients with small lymphocytic lymphoma — no. (%) 10 (5) 8 (4)
Median age (range) — yr 67 (30–86) 67 (37–88)
Male sex — no. (%) 129 (66) 137 (70)
Cumulative Illness Rating Scale score >6 — no. (%)† 38 (32) 39 (32)
Creatinine clearance <60 ml/min — no. (%) 62 (32) 61 (31)
Median hemoglobin (range) — g/dl 11 (7–16) 11 (6–16)
Median platelet count (range) — per mm3 116,500 (20,000–441,000)
122,000 (23,000–345,000)
Median lymphocyte count (range) — per mm3 29,470(90–467,700)
29,930(290–551,030)
ECOG performance status — no. (%)‡
0 79 (41) 80 (41)
1 116 (59) 116 (59)
Bulky disease ≥5 cm — no. (%)§ 124 (64) 101 (52)
Interphase cytogenetic abnormalities — no. (%)
Chromosome 11q22.3 deletion 63 (32) 59 (30)
Chromosome 17p13.1 deletion ¶ 63 (32) 64 (33)
β2-microglobulin >3.5 mg/liter — no. (%) 153 (78) 145 (74)
Previous therapies
Median no. (range) 3 (1–12) 2 (1–13)
≥3 — no. (%) 103 (53) 90 (46)
Type of therapy — no. (%)
Alkylator 181 (93) 173 (88)
Bendamustine 84 (43) 73 (37)
Purine analogue 166 (85) 151 (77)
Anti-CD20 183 (94) 176 (90)
Alemtuzumab 40 (21) 33 (17)
Allogeneic transplantation 3 (2) 1 (1)
Median time from last therapy (range) — mo 8 (1–140) 12 (0–184)
Resistance to purine analogues — no. (%)‖ 87 (45) 88 (45)
* There were no significant differences between the two groups at baseline, except with respect to the presence of bulky disease of 5 cm or more (P = 0.04) and the median time from last therapy (P = 0.02).
† Scores on the Cumulative Illness Rating Scale range from 0 to 52, with higher scores indicating worse health status. Scores on this test were required only for patients 65 years of age or older, and coexisting illnesses were not included in the scoring.
‡ Scores on the Eastern Cooperative Oncology Group (ECOG) performance status range from 0 to 5, with higher scores indicating greater disability.
§ Measurement was based on the largest diameter of the longest lymph node at screening, according to the assessment of the independent review committee.
¶ Patients were stratified at randomization according to the presence or absence of this genetic abnormality.‖ Resistance was defined as no response or a relapse within 12 months after the last dose of a CD20-based chemoimmuno-
therapy regimen that included a purine analogue.
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Ibrutinib vs. Ofatumumab in CLL
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ministered in combination. The percentage of pa-tients with bulky disease (≥5 cm) was higher in the ibrutinib group than in the ofatumumab group (64% vs. 52%). Approximately 57% of the patients in the two study groups had a deletion at either chromosome 17p13.1 or chromosome 11q22.3. The median follow-up time was 9.4 months (range, 0.1 to 16.6), and 86% of patients were still receiv-ing ibrutinib at the time of this analysis (Fig. S1 in the Supplementary Appendix).
EfficacyProgression-free SurvivalIbrutinib significantly prolonged the duration of progression-free survival, with the median not reached at a median follow-up of 9.4 months, as compared with a median duration of progression-free survival of 8.1 months with ofatumumab. The hazard ratio for progression or death in the ibrutinib group was 0.22 (95% confidence inter-val [CI], 0.15 to 0.32; P<0.001) (Fig. 1A). This rep-resents a 78% reduction in the risk of progression or death among patients treated with ibrutinib, as compared with ofatumumab. At 6 months, 88% of patients in the ibrutinib group were still alive with no disease progression, as compared with 65% in the ofatumumab group. The effect of ibrutinib on progression-free survival was ob-served regardless of baseline clinical characteris-tics or molecular features (Fig. 2).
Among patients with a chromosome 17p13.1 deletion, the median duration of progression-free survival was not reached in the ibrutinib group, as compared with a median of 5.8 months in the ofatumumab group (hazard ratio for progression or death, 0.25; 95% CI, 0.14 to 0.45). At 6 months, 83% of the patients with this deletion in the ibrutinib group, as compared with 49% of those with this deletion in the ofatumumab group, were alive with no disease progression. Richter’s transformation (CLL that has evolved into an ag-gressive, rapidly growing large-cell lymphoma) was confirmed in two patients in each study group. Prolymphocytic leukemia developed in an addi-tional patient in the ibrutinib group.
Overall SurvivalIbrutinib, as compared with ofatumumab, signifi-cantly prolonged the rate of overall survival (haz-ard ratio for death in the ibrutinib group, 0.43; 95% CI, 0.24 to 0.79; P = 0.005), with the risk of death reduced by 57% (Fig. 1B). At 12 months, the overall survival rate was 90% in the ibrutinib
group and 81% in the ofatumumab group. At the time of this analysis, 57 patients in the ofatumumab group had crossed over to receive ibrutinib after confirmed disease progression. The survival effect was based on an analysis in which data were cen-sored at the time of crossover. At 12 months, the survival effect was also observed in the uncensored sensitivity analysis (hazard ratio for death, 0.39; P = 0.001), with an overall survival rate of 90% in the ibrutinib group and 79% in the ofatumumab group (Fig. S2 in the Supplementary Appendix).
Prog
ress
ion-
free
Sur
viva
l (%
)
100
80
90
70
60
40
30
10
50
20
00 3 6 9 12 15
Months
B
A
Hazard ratio for progressionor death, 0.22 (95% CI, 0.15–0.32)
P<0.001 by log-rank test
No. at RiskIbrutinibOfatumumab
195196
183161
11683
3815
71 0
Ibrutinib
Ofatumumab
Ove
rall
Surv
ival
(%)
100
80
90
70
60
40
30
10
50
20
00 3 6 9 12 18
Months
Hazard ratio for death, 0.43 (95% CI, 0.24–0.79)P=0.005 by log-rank test
No. at RiskIbrutinibOfatumumab
195196
191183
184164
11588
3221
15
53
Ibrutinib
Ofatumumab
Figure 1. Progression-free and Overall Survival.
The durations of progression-free survival (Panel A) and overall survival (Panel B) were significantly longer in the ibrutinib group than in the ofa-tumumab group. At a median follow-up of 9.4 months, the median duration of progression-free survival was not reached in the ibrutinib group (with a rate of progression-free survival of 88% at 6 months), as compared with a median of 8.1 months in the ofatumumab group; the median duration of overall survival was not reached in either study group.
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The difference in overall survival supporting the superiority of ibrutinib was preserved in all the subgroups defined according to pretreatment and genetic features (Fig. S3 in the Supplemen-tary Appendix).
ResponseThe independently assessed response rate was significantly higher in the ibrutinib group than
in the ofatumumab group (Fig. 3A). Overall, 43% of the patients in the ibrutinib group had a par-tial response, as compared with 4% in the ofa-tumumab group (odds ratio, 17.4; 95% CI, 8.1 to 37.3; P<0.001). In addition, 20% of the patients receiving ibrutinib had a partial response with lymphocytosis (resulting in a 63% response rate). Lymphocytosis was observed in 69% of the pa-tients who were treated with ibrutinib and was
0.03 1 3 5 10
OfatumumabBetter
Ibrutinib Better
All patients
Disease refractory to purine analogues
Yes
No
Chromosome 17p13.1 deletion
Yes
No
Age
<65 yr
≥65 yr
Sex
Male
Female
Race
White
Nonwhite
Geographic region
United States
Europe or other
Rai stage at baseline
0, I, or II
III or IV
ECOG score at baseline
0
1
Bulky disease
<5 cm
≥5 cm
No. of prior treatment regimens
<3
≥3
Chromosome 11q22.3 deletion
Yes
No
β2-microglobulin at baseline
≤3.5 mg/liter
>3.5 mg/liter
Hazard Ratio (95% CI)No. of PatientsSubgroup
391
175
216
127
264
152
239
266
125
351
40
192
199
169
222
159
232
163
225
198
193
122
259
58
298
0.001
0.21 (0.14–0.31)
0.18 (0.10–0.32)
0.24 (0.15–0.40)
0.25 (0.14–0.45)
0.19 (0.12–0.32)
0.17 (0.09–0.31)
0.24 (0.15–0.40)
0.22 (0.13–0.35)
0.21 (0.11–0.40)
0.21 (0.14–0.31)
0.27 (0.07–0.96)
0.12 (0.07–0.23)
0.34 (0.21–0.56)
0.19 (0.10–0.37)
0.22 (0.13–0.35)
0.26 (0.14–0.48)
0.18 (0.11–0.30)
0.24 (0.13–0.44)
0.19 (0.12–0.31)
0.19 (0.10–0.36)
0.21 (0.13–0.34)
0.14 (0.06–0.29)
0.26 (0.16–0.40)
0.05 (0.01–0.39)
0.21 (0.14–0.33)
Figure 2. Subgroup Analyses of Progression-free Survival.
Shown are forest plots of hazard ratios for death or disease progression among subgroups of patients in the ibrutinib group and the ofatumumab group. The size of the circle is proportional to the size of the subgroup. The dashed vertical line indicates the overall treatment effect for all patients. The only test for heterogeneity that was significant was for geo-graphic region (P = 0.02), although the treatment effect remained significant within each region (P<0.001). The Rai staging system ranges from 0 (low risk) to I or II (intermediate risk) to III or IV (high risk). The Eastern Cooperative Oncology Group (ECOG) score ranges from 0 to 5, with higher scores indicating greater disability. Race was self-reported.
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Ibrutinib vs. Ofatumumab in CLL
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not considered to be disease progression.11 The condition resolved in 77% of these patients dur-ing follow-up. In a recent study, patients with a partial response with lymphocytosis had rates of progression-free survival that were similar to those in patients with a partial response.22 Inves-tigator-assessed response rates were higher than independently assessed response rates in the two study groups (Fig. 3B).
Safety
Treatment exposure was longer among patients receiving ibrutinib than among those receiving ofatumumab (median duration, 8.6 months [range, 0.2 to 16.1] vs. 5.3 months [range, 0 to 7.4]). The profiles of cumulative adverse events that occurred in at least 10% of the patients are pre-sented without adjustment for duration of expo-sure in Table 2. The most frequent nonhemato-logic adverse events that occurred in at least 20% of the patients were diarrhea, fatigue, pyrexia, and nausea in the ibrutinib group and fatigue, infusion-related reactions, and cough in the ofa-tumumab group. Overall, 57% of the patients in the ibrutinib group and 47% of the patients in the ofatumumab group had at least one adverse event of grade 3 or higher. Serious adverse events are summarized in Table S3 in the Supplementary Appendix. Adverse events of grade 3 or higher that occurred more frequently in the ibrutinib group than in the ofatumumab group included diarrhea (4% vs. 2%) and atrial fibrillation (3% vs. 0%); the latter event required cessation of ther-apy in one patient. An additional four patients in the ibrutinib group and one patient in the ofa-tumumab group had grade 1 or 2 atrial fibrilla-tion. Bleeding-related adverse events of any grade (most commonly, petechiae, and including ecchy-moses) were more common in the ibrutinib group than in the ofatumumab group (44% vs. 12%). Major hemorrhage (any hemorrhagic event of grade 3 or higher or resulting in transfusion of red cells or in hospitalization) was reported in two patients (1%) in the ibrutinib group (includ-ing one patient with a subdural hematoma) and three patients (2%) in the ofatumumab group.
Other adverse events that were more com-monly noted among patients receiving ibrutinib than among those receiving ofatumumab includ-ed rash (8% vs. 4%), pyrexia (24% vs. 15%), and blurred vision (10% vs. 3%); all these events were generally grade 1 or 2 in severity. The incidence of cataracts was 3% and 1%, respectively. Infec-
tions of any grade were more common in the ibrutinib group (70% vs. 54%), whereas the fre-quency of infections of grade 3 or higher was similar in the two study groups (24% vs. 22%) (Table S4 in the Supplementary Appendix). Infu-sion reactions, peripheral sensory neuropathy, urticaria, night sweats, and pruritus were more common in the ofatumumab group. Basal-cell and squamous-cell carcinomas were reported in 4% of the patients in the ibrutinib group and in 2% in the ofatumumab group; nonskin cancers
32%
3% 10%
63/195
5/195 20/1964%
78%
8/196
153/196
39/19520%
63%
43%
83/195
2% 11%1% 1%
14%
4/195 22/195 2/195 1/19627/196
83%
23%
54%
106/196
30/19515%
4/1962%
68%
21%41/196
132/195
Bes
t Res
pons
e (%
)
100
80
90
70
60
40
30
10
50
20
0
Ibrutinib(N=195)
PR+LPR
SD PD
Ofatumumab(N=196)
PR SD PD
B Investigator Assessment
A Independent Assessment
Bes
t Res
pons
e (%
)
100
80
90
70
60
40
30
10
50
20
0
Ibrutinib(N=195)
Ofatumumab(N=196)
PR+LPR
SD PDCR/CRi PR+LPR
CR/CRi SD PD
Figure 3. Best Response to Therapy, as Assessed by Independent Reviewers and by Investigators.
Shown are rates of patients’ best response to therapy, according to inde-pendent assessment (Panel A) and investigator assessment (Panel B) with respect to complete response (CR), complete response with incomplete he-matopoietic recovery (CRi), partial response (PR), partial response with lymphocytosis (PR+L), stable disease (SD), and progressive disease (PD). Data were unknown, missing, or could not be evaluated for 5 patients in the ibrutinib group in both the independent assessment and the investi-gator assessment and for 15 patients in the ofatumumab group in the independent assessment and 17 patients in the group in the investigator assessment.
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were seen in 3% and 1% of the patients, respec-tively.
Discontinuation of treatment because of ad-verse events occurred in 4% of the patients in each study group. Fatal events occurred in 4% of
the patients in the ibrutinib group and in 5% of those in the ofatumumab group (Table S5 in the Supplementary Appendix). These events were most commonly infectious in nature. Adverse events resulting in dose reductions occurred in
Table 2. Adverse Events.*
Adverse EventIbrutinib (N = 195)
Ofatumumab(N = 191)
Any Grade
Grade 3 or 4
Any Grade
Grade 3 or 4
number of patients (percent)
Any adverse event occurring during treatment 194 (99) 99 (51) 187 (98) 74 (39)
Diarrhea 93 (48) 8 (4) 34 (18) 3 (2)
Fatigue 54 (28) 4 (2) 57 (30) 3 (2)
Nausea 51 (26) 3 (2) 35 (18) 0
Pyrexia 46 (24) 3 (2) 28 (15) 2 (1)
Anemia 44 (23) 9 (5) 33 (17) 15 (8)
Neutropenia 42 (22) 32 (16) 28 (15) 26 (14)
Cough 38 (19) 0 44 (23) 2 (1)
Thrombocytopenia 33 (17) 11 (6) 22 (12) 8 (4)
Arthralgia 34 (17) 2 (1) 13 (7) 0
Upper respiratory tract infection 31 (16) 1 (1) 20 (10) 3 (2)
Constipation 30 (15) 0 18 (9) 0
Vomiting 28 (14) 0 12 (6) 1 (1)
Headache 27 (14) 2 (1) 11 (6) 0
Petechiae 27 (14) 0 2 (1) 0
Muscle spasm 25 (13) 0 16 (8) 0
Dyspnea 23 (12) 4 (2) 20 (10) 1 (1)
Peripheral edema 22 (11) 0 15 (8) 0
Back pain 22 (11) 2 (1) 12 (6) 1 (1)
Sinusitis 21 (11) 1 (1) 12 (6) 0
Dizziness 22 (11) 0 10 (5) 0
Contusion 21 (11) 0 6 (3) 0
Stomatitis 21 (11) 1 (1) 4 (2) 1 (1)
Pain in limb 20 (10) 1 (1) 8 (4) 0
Pneumonia 19 (10) 13 (7) 13 (7) 9 (5)
Urinary tract infection 19 (10) 7 (4) 10 (5) 1 (1)
Myalgia 19 (10) 1 (1) 7 (4) 0
Blurred vision 19 (10) 0 6 (3) 0
Night sweats 10 (5) 1 (1) 24 (13) 0
Peripheral sensory neuropathy 8 (4) 0 24 (13) 0
Infusion-related reaction 0 0 53 (28) 6 (3)
* Listed are all adverse events that occurred in at least 10% of the patients in either group. Five patients in the ofatum u-mab group did not receive a study drug. All serious adverse events are listed in Tables S3 and S4 in the Supplementary Appendix.
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Ibrutinib vs. Ofatumumab in CLL
n engl j med nejm.org 9
4% of the patients treated with ibrutinib, with only diarrhea (which occurred in three patients) leading to a dose reduction in more than one patient. Changes in creatinine levels from base-line were similar in the two study groups, with a decrease in creatinine clearance of any grade observed in 16% of the patients in the ibrutinib group and in 17% of those in the ofatumumab group.
Discussion
Among patients with relapsed CLL or SLL, in-cluding those who had a short duration of re-sponse to prior therapy or who had adverse cyto-genetic abnormalities, ibrutinib was superior to ofatumumab with respect to progression-free survival, overall survival, and response rate at a median follow-up of 9.4 months. The positive ef-fect of ibrutinib was observed in subgroups of patients with a high-risk chromosome 17p13.1 deletion and with resistance to previous purine analogue therapy. Similar benefits with respect to progression-free survival were observed re-gardless of age, clinical stage, and factors such as status with respect to mutations in IGHV. The effect of ibrutinib on overall survival was signifi-cant, an effect that was robust despite the cross-over of 57 patients to the ibrutinib group after they had disease progression while receiving ofa-tumumab; this effect was also observed in sub-group and sensitivity analyses.
Except for a few differences, our findings are largely similar to those of other trials of ibruti-nib or ofatumumab. In each of the two groups in our study, the response rate as determined by independent assessors was lower than the re-sponse rate as determined by investigators. In the phase 2 study of ibrutinib monotherapy,13 in which response was assessed by investigators, the response rate was 71%, which is similar to the 70% response rate assessed by investigators in our study. The independently assessed re-sponse rate in the ofatumumab group in our study appears to be lower than that in the piv-otal study that was based on 1996 National Cancer Institute guidelines for CLL,23 which did not require CT scanning to confirm response.24 This difference may be due in part to the re-quirement in our study for serial CT scanning, which was performed every 12 weeks, to con-
firm response. Another ofatumumab study that compared response assessment between patients who underwent CT scanning and those who did not undergo CT scanning showed substantial differences in the rates of response between the two subgroups, with lower response rates seen in the group that underwent CT scanning.25 Furthermore, the investigator-assessed response rate among patients in the ofatumumab group in our study (21%) was similar to the rate (23%) in a recent study that used 2008 criteria of the International Workshop on Chronic Lymphocytic Leukemia.26 Reassuringly, the results with respect to progression-free survival in the ofatumumab group in our study (median, 8.1 months) are similar to those in historical reports (median, approximately 6 months).5
Previous reports of ofatumumab therapy showed that patients with refractory CLL had a median survival of 12 months26 and 15 months,5
with no plateau in deaths. With a median fol-low-up of 9.4 months in our study, an early separation in the curves for overall survival fa-vored ibrutinib; however, the median was not reached in either study group. At later time points, the survival curve for ofatumumab began to flatten, which may in part be a reflection of the influence of ibrutinib on patients in the ofa-tumumab group who crossed over to ibrutinib therapy.
Ibrutinib was associated with toxic effects that were expected on the basis of the results of phase 2 studies. It appears that the drug can be safely administered even in a heavily pretreated and elderly population with baseline coexisting conditions, such as the one in our study. In the ibrutinib group, 32% of the patients had a de-creased creatinine clearance, 64% had cytope-nias, and 32% had a score on the Cumulative Illness Rating Scale of more than 6 (ranging from 0 to 52, with higher scores indicating worse health status). Toxic effects did not result in frequent dose reductions or treatment discon-tinuations.
One strength of a randomized, controlled trial is that background disease-related compli-cations may be differentiated from a treatment effect with a new agent. However, it is important to note that patients in the ibrutinib group had a reporting period for adverse events that was more than 3 months longer than that in the
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T h e n e w e ngl a nd j o u r na l o f m e dic i n e
n engl j med nejm.org10
ofatumumab group (median duration, 8.6 months vs. 5.3 months), and no exposure-adjusted analy-sis of adverse events was performed.
The frequencies of renal complications and increased creatinine levels were similar in the two study groups. Although the overall rate of infections was higher in the ibrutinib group, the frequency of infections of grade 3 or higher did not differ significantly between the two groups. Ocular symptoms were collected proactively and were reported more frequently among patients in the ibrutinib group, including a small propor-tion of patients who reported blurred vision. The development of cataracts in 3% of the patients receiving ibrutinib (as compared with 1% in the control group) bears noting, since longer expo-sure may be associated with an increased risk.
Atrial fibrillation of any grade was noted in 10 patients in the ibrutinib group, as compared with 1 patient in the ofatumumab group, and led to the discontinuation of ibrutinib in 1 patient. Potential reasons for the higher rate of atrial fibrillation among patients receiving ibrutinib are being explored. In clinical studies in which serial electrocardiographic studies were performed, no evidence of arrhythmias was observed among patients receiving ibrutinib.13,27
An adverse event of interest with ibrutinib from early studies was major hemorrhage, includ-ing subdural hematoma. In our study, we excluded patients requiring warfarin but not those requir-ing other forms of anticoagulation. The rate of major hemorrhage was similar in the two study
groups, with one subdural hematoma noted in a patient receiving ibrutinib. Although mild bleed-ing episodes were more common in the ibrutinib group, adherence to appropriate drug-withhold-ing guidelines perioperatively and precautions regarding the use of antiplatelet agents and anti-coagulants resulted in no unexpected major bleed-ing complications in the ibrutinib group. Further studies of the mechanism of bleeding, includ-ing bruising, that was observed among patients receiving ibrutinib have been conducted28 or are planned.
In conclusion, ibrutinib was superior to ofa-tumumab in difficult-to-treat patients with re-lapsed or refractory CLL or SLL, as measured by progression-free survival, overall survival, and response. The improvement was observed across all subgroups that were examined, including patients who were resistant to chemoimmuno-therapy and those with a chromosome 17p13.1 deletion, which confirms single-agent ibrutinib as an effective therapy for CLL or SLL. Phase 3 studies examining the effect of ibrutinib in pre-viously untreated patients with CLL or SLL are on-going (ClinicalTrials.gov numbers, NCT02048813 and NCT01722487).
Supported by Pharmacyclics and Janssen.Disclosure forms provided by the authors are available with
the full text of this article at NEJM.org.We thank the patients and their families; Jennifer Lin for
assistance with data analysis and interpretation; Christine Barker for trial management; and Patricia Gosling, Ph.D., of Pharma cyclics and Karen Pemberton, Ph.D., funded by Pharma-cyclics, for their editorial assistance in the preparation of the manuscript.
AppendixThe authors are as follows: John C. Byrd, M.D., Jennifer R. Brown, M.D., Ph.D., Susan O’Brien, M.D., Jacqueline C. Barrientos, M.D., Neil E. Kay, M.D., Nishitha M. Reddy, M.B., B.S., Steven Coutre, M.D., Constantine S. Tam, M.D., Stephen P. Mulligan, M.B., B.S., Ph.D., Ulrich Jaeger, M.D., Steve Devereux, M.D., Paul M. Barr, M.D., Richard R. Furman, M.D., Thomas J. Kipps, M.D., Florence Cymbalista, M.D., Christopher Pocock, M.D., Ph.D., Patrick Thornton, M.D., Federico Caligaris-Cappio, M.D., Tadeusz Robak, M.D., Julio Delgado, M.D., Stephen J. Schuster, M.D., Marco Montillo, M.D., Anna Schuh, M.D., Sven de Vos, M.D., Devinder Gill, M.D., Adrian Bloor, Ph.D., F.R.C.Path., Claire Dearden, M.D., Carol Moreno, M.D., Jeffrey J. Jones, M.D., Alvina D. Chu, M.D., Maria Fardis, Ph.D., Jesse McGreivy, M.D., Fong Clow, D.Sc., Danelle F. James, M.D., and Peter Hillmen, M.B., Ch.B., Ph.D.
The authors’ affiliations are as follows: Ohio State University Comprehensive Cancer Center, Columbus (J.C. Byrd, J.J.J.); Dana–Farber Cancer Institute, Boston (J.R.B.); M.D. Anderson Cancer Center, Houston (S.O.); Hofstra North Shore–LIJ School of Medicine, Hemp-stead (J.C. Barrientos), University of Rochester Cancer Center, Rochester (P.M.B.). and New York–Presbyterian Hospital and Weill Cornell Medical College, New York (R.R.F.) — all in New York; Mayo Clinic, Rochester, MN (N.E.K.); Vanderbilt–Ingram Cancer Center, Nashville (N.M.R.); Stanford University School of Medicine and Stanford Cancer Institute, Stanford (S.C.), Moores UCSD Can-cer Center, San Diego (T.J.K.), David Geffen School of Medicine at UCLA, Los Angeles (S.V.), and Pharmacyclics, Sunnyvale (A.D.C., M.F., J.M., F.C., D.F.J.) — all in California; Peter MacCallum Cancer Centre and St. Vincent’s Hospital, Melbourne, VIC (C.S.T.), Royal North Shore Hospital, Sydney, NSW (S.P.M.), and Princess Alexandra Hospital, Brisbane, QLD (D.G.) — all in Australia; Medical Uni-versity of Vienna, Vienna (U.J.); Kings College Hospital, National Health Service (NHS) Foundation Trust Denmark Hill, London (S.D.), East Kent Hospitals, Canterbury (C.P.), Oxford Biomedical Research Centre, Oxford (A.S.), Christie NHS Foundation Trust Hematology and Transplant Unit, Manchester (A.B.), Royal Marsden Hospital and the Institute of Cancer Research, Sutton (C.D.), and Leeds Teach-ing Hospitals, St. James Institute of Oncology, Leeds (P.H.) — all in the United Kingdom; Hôpital Avicenne, Paris (F.C.); Beaumont Hospital, Dublin, Ireland (P.T.); Universita Vita-Salute San Raffaele (F.C-C.) and Niguarda Ca’ Granda Hospital (M.M.), Milan; Medical University of Lodz and Copernicus Memorial Hospital, Lodz, Poland (T.R.); Hospital Clinic (J.D.) and Hospital de la Santa Creu Sant Pau (C.M.), Barcelona; and Abramson Cancer Center of the University of Pennsylvania, Philadelphia (S.J.S.).
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Ibrutinib vs. Ofatumumab in CLL
n engl j med nejm.org 11
References1. Hallek M. Chronic lymphocytic leuke-mia: 2013 update on diagnosis, risk strat-ification and treatment. Am J Hematol 2013;88:803-16.2. Hallek M, Fischer K, Fingerle-Rowson G, et al. Addition of rituximab to fludara-bine and cyclophosphamide in patients with chronic lymphocytic leukaemia: a randomised, open-label, phase 3 trial. Lancet 2010;376:1164-74.3. Goede V, Fischer K, Busch R, et al. Obinutuzumab plus chlorambucil in pa-tients with CLL and coexisting condi-tions. N Engl J Med 2014;370:1101-10.4. Fischer K, Cramer P, Busch R, et al. Bendamustine combined with rituximab in patients with relapsed and/or refracto-ry chronic lymphocytic leukemia: a multi-center phase II trial of the German Chronic Lymphocytic Leukemia Study Group. J Clin Oncol 2011;29:3559-66.5. Wierda WG, Kipps TJ, Mayer J, et al. Ofatumumab as single-agent CD20 im-munotherapy in f ludarabine-refractory chronic lymphocytic leukemia. J Clin Oncol 2010;28:1749-55. [Erratum, J Clin Oncol 2010;28:3670.]6. Badoux XC, Keating MJ, Wen S, et al. Phase II study of lenalidomide and ritux-imab as salvage therapy for patients with relapsed or refractory chronic lymphocytic leukemia. J Clin Oncol 2013;31:584-91.7. Chen CI, Bergsagel PL, Paul H, et al. Single-agent lenalidomide in the treat-ment of previously untreated chronic lym-phocytic leukemia. J Clin Oncol 2011; 29:1175-81.8. Ferrajoli A, Lee BN, Schlette EJ, et al. Lenalidomide induces complete and par-tial remissions in patients with relapsed and refractory chronic lymphocytic leuke-mia. Blood 2008;111:5291-7.9. Eichhorst B, Dreyling M, Robak T, Montserrat E, Hallek M. Chronic lym-phocytic leukemia: ESMO Clinical Prac-tice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2011;22:Suppl 6:vi50-vi54.10. Zelenetz AD, Wierda WG, Abramson JS, et al. Non-Hodgkin’s lymphomas, ver-sion 1.2013. J Natl Compr Canc Netw 2013;11:257-72.
11. Hallek M, Cheson B, Catovsky D, et al. Response assessment in chronic lympho-cytic leukemia treated with novel agents causing an increase of peripheral blood lymphocytes. Blood 2012 June 4 (e-letter) (http://bloodjournal.hematologylibrary .org/content/111/12/5446/reply).12. Zelenetz AD, Abramson JS, Advani RH, et al. NCCN Clinical Practice Guide-lines in Oncology: non-Hodgkin’s lym-phomas. J Natl Compr Canc Netw 2010;8: 288-334.13. Byrd JC, Furman RR, Coutre SE, et al. Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia. N Engl J Med 2013;369:32-42. [Erratum, N Engl J Med 2014;370:786.]14. Honigberg LA, Smith AM, Sirisawad M, et al. The Bruton tyrosine kinase in-hibitor PCI-32765 blocks B-cell activation and is efficacious in models of autoim-mune disease and B-cell malignancy. Proc Natl Acad Sci U S A 2010;107:13075-80.15. Ponader S, Chen SS, Buggy JJ, et al. The Bruton tyrosine kinase inhibitor PCI-32765 thwarts chronic lymphocytic leuke-mia cell survival and tissue homing in vi-tro and in vivo. Blood 2012;119:1182-9.16. Hallek M, Cheson BD, Catovsky D, et al. Guidelines for the diagnosis and treat-ment of chronic lymphocytic leukemia: a report from the International Workshop on Chronic Lymphocytic Leukemia updat-ing the National Cancer Institute–Work-ing Group 1996 guidelines. Blood 2008; 111:5446-56. [Erratum, Blood 2008;112: 5259.]17. Oken MM, Creech RH, Tormey DC, et al. Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 1982;5:649-55.18. Byrd JC, O’Brien S, James DF. Ibruti-nib in relapsed chronic lymphocytic leu-kemia. N Engl J Med 2013;369:1278-9.19. Neffendorf JE, Gout I, Hildebrand GD. Ibrutinib in relapsed chronic lym-phocytic leukemia. N Engl J Med 2013; 369:1277.20. Rushworth SA, MacEwan DJ, Bowles KM. Ibrutinib in relapsed chronic lym-phocytic leukemia. N Engl J Med 2013; 369:1277-8.
21. O’Brien PC, Fleming TR. A multiple testing procedure for clinical trials. Bio-metrics 1979;35:549-56.22. Woyach JA, Smucker K, Smith LL, et al. Prolonged lymphocytosis during ibru-tinib therapy is associated with distinct molecular characteristics and does not indicate a suboptimal response to thera-py. Blood 2014;123:1810-7.23. Cheson BD, Bennett JM, Grever M, et al. National Cancer Institute-sponsored Working Group guidelines for chronic lymphocytic leukemia: revised guidelines for diagnosis and treatment. Blood 1996; 87:4990-7.24. Lemery SJ, Zhang J, Rothmann MD, et al. U.S. Food and Drug Administration approval: ofatumumab for the treatment of patients with chronic lymphocytic leu-kemia refractory to fludarabine and alem-tuzumab. Clin Cancer Res 2010;16:4331-8.25. Flinn IW, Harwin WN, Ward P, et al. Phase II trial of ofatumumab (OFA) for older patients and patients who refuse fludarabine-based regimens with previ-ously untreated chronic lymphocytic leu-kemia (CLL) or small lymphocytic lympho-ma (SLL). Blood 2012;120:719. abstract.26. Moreno C, Montillo M, Panayiotis P, et al. A multicenter, phase IV observation-al study of ofatumumab in chronic lym-phocytic leukemia (CLL): a European Re-search Initiative on CLL (ERIC) study. Blood 2013;122:1645. abstract.27. Advani RH, Buggy JJ, Sharman JP, et al. Bruton tyrosine kinase inhibitor ibrutinib (PCI-32765) has significant activity in pa-tients with relapsed/refractory B-cell ma-lignancies. J Clin Oncol 2013;31:88-94.28. Farooqui M, Lozier J, Valdez J, et al. Ibrutinib (PCI 32765) rapidly improves platelet counts in chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) patients and has minimal ef-fects on platelet aggregation. Blood 2014; https://ash.confex.com/ash/2012/ webprogram/Paper50250.html. abstract.
Copyright © 2014 Massachusetts Medical Society.
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Updated Efficacy Including Genetic and Clinical Subgroup Analysis and Safety in the Phase 3 RESONATETM Trial Comparing Ibrutinib With Ofatumumab in Previously Treated Chronic Lymphocytic
Leukemia/Small Lymphocytic Lymphoma (CLL/SLL) Jennifer R. Brown, MD, PhD1, Peter Hillmen, MB ChB, PhD2, Susan O’Brien, MD3, Jacqueline C. Barrientos, MD4, Nishitha M. Reddy, MBBS, MScl5, Steven Coutre, MD6, Constantine S. Tam, MD7, Stephen P. Mulligan, MBBS, MD, FRACP, FRCPA8, Ulrich Jaeger, MD9, Paul M. Barr, MD10, Richard R. Furman, MD11, Thomas J. Kipps, MD12, Florence Cymbalista, MD13,
Patrick Thornton, MD14, Federico Caligaris-Cappio, MD15, Julio Delgado, MD16, Marco Montillo, MD17, Sven DeVos, MD18, Carol Moreno, MD19, John Pagel, MD, PhD20, Jan A. Burger, MD, PhD3, Devon Chung, BS21, Jennifer Lin, MA, MS21, Linda Gau, MS21, Betty Chang, PhD21, Danelle F. James, MD, MAS21, John C. Byrd, MD22 1Dana-Farber Cancer Institute, Boston, MA; 2St. James Institute of Oncology, Leeds, UK; 3MD Anderson Cancer Center, Houston, TX; 4North Shore-LIJ Cancer Institute, Lake Success, NY; 5Vanderbilt-Ingram Cancer Center, Nashville, TN; 6Stanford University School of Medicine, Stanford, CA; 7Peter MacCallum Cancer Centre and St. Vincent’s Hospital, Melbourne, Australia;8Royal North Shore Hospital, Sydney, Australia; 9Medical University of Vienna, Vienna, Austria; 10University of Rochester Cancer Center, Rochester, NY; 11Weill Cornell Medical College/New York Presbyterian
Hospital, New York, NY; 12UCSD Moores Cancer Center, San Diego, CA; 13Hôpital Avicenne, Paris, France; 14Beaumont Hospital, Dublin, Ireland; 15Universita Vita-Salute San Raffaele, Milan, Italy 16Hospital Clinic, Barcelona, Spain; 17Niguarda Cà Granda Hospital, Milan, Italy; 18David Geffen School of Medicine at UCLA, Los Angeles, CA; 19Hospital de la Santa Creu Sant Pau, Barcelona, Spain; 20Fred Hutchinson Cancer Center, Seattle, WA; 21Pharmacyclics, Inc., Sunnyvale, CA; 22The Ohio State University Medical Center, Columbus, OH
ABSTRACTBackground: Prognostic factors underlying CLL/SLL are not fully understood. Ibrutinib
(Imbruvica®) is a first-in-class, once-daily, orally administered covalent inhibitor of Bruton’s
tyrosine kinase FDA-approved for CLL patients who have received ≥1 prior therapy and
patients with del17p CLL.
Objective: Update efficacy data relative to genetic features and prior treatment for the phase 3
RESONATETM study of ibrutinib vs. ofatumumab and safety data.
Methods: Patients received 420 mg oral ibrutinib daily until disease progression or
unacceptable toxicity or IV ofatumumab for up to 24 weeks. The primary endpoint was inde-
pendent review committee-assessed PFS. At interim analysis (median follow-up, 9.4 months),
the independent Data Monitoring Committee recommended ibrutinib access for patients
randomized to ofatumumab.
Results: 391 patients were randomized to ibrutinib (n=195) or ofatumumab (n=196). Median
age was 67 years (40% ≥70 years); 57% had Rai stage III/IV disease. Median number of prior
therapies was 3 (ibrutinib) vs. 2 (ofatumumab). Approximately 32% had del17p, 32% del11q,
24% (72/300) complex cytogenetics (≥3 abnormalities), and 68% (181/266) unmutated
IGHV. Median follow-up was 16 months. Ibrutinib significantly extended investigator-
assessed PFS vs. ofatumumab (median NR vs. 8.1 months, HR 0.106, P<0.0001). OS was
significantly longer for ibrutinib vs. ofatumumab (18-month OS 85% vs. 78%), despite
crossover of 122 patients (62%) from ofatumumab to ibrutinib (censored at crossover).
Best investigator-assessed ORR was significantly higher for ibrutinib vs. ofatumumab
(90% vs. 25%; P<0.0001). Ibrutinib significantly improved 12-month PFS and ORR regardless
of baseline genetics, complex cytogenetics, or number of prior therapies (P<0.001 for
all). Patients receiving ibrutinib with 1 prior therapy had better 12-month PFS (94% vs.
82%; P=0.01) and responses (100% vs. 88%; P=0.04) than those receiving ibrutinib in later
lines. Treatment-emergent lymphocytosis and del17p did not significantly impact 12-month
PFS for ibrutinib. The most common AEs for ibrutinib included diarrhea (37% grade [G]
1, 10% G2, 4% G3), fatigue (18% G1, 12% G2, 3% G3), and nausea (24% G1, 6% G2, 2% G3).
The most frequent grade 3/4 AEs for ibrutinib included neutropenia (18%), pneumonia
(9%), thrombocytopenia (6%), anemia (6%), and hypertension (6%). 7% of ibrutinib-treated
patients experienced any-grade atrial fibrillation. 47 patients (24%) discontinued ibrutinib,
including 17 (9%) for progressive disease and 13 (7%) for AEs.
Conclusions: Ibrutinib significantly improved investigator-assessed PFS, OS, and ORR
compared with ofatumumab in previously treated patients with CLL/SLL, including those
with high-risk genetic factors. Early (second-line) ibrutinib treatment improved outcomes vs.
its use in later lines of therapy.
INTRODUCTION• The implications of various prognostic factors and new genetic markers associated
with high risk in CLL/SLL are not yet fully understood. • Mutations in the genes Notch1 and SF3B1 have been identified in 4% and 15%,
respectively, of patients with CLL and are associated with poor outcomes.1
• Ibrutinib (Imbruvica®), a first-in-class Bruton’s tyrosine kinase inhibitor, is a once-daily single agent approved by the US FDA for CLL patients who have received ≥1 prior therapy and for patients with 17p deletion CLL.
• The phase 3 RESONATETM (PCYC-1112) study of ibrutinib vs. ofatumumab demonstrated a 78% reduction in risk of progression by IRC and 56% reduction in risk of death, prompting the independent data monitoring committee to recommend that all patients randomized to ofatumumab be provided access to ibrutinib.
• We report updated efficacy results for the phase 3 RESONATETM study, with median treatment duration of 16 months, relative to genetic features and prior treatment exposure, and provide updated adverse event (AE) data.
METHODS
Figure 1. PCYC-1112 (RESONATETM) Study Design
Oral ibrutinib 420 mg
once daily until PD or
unacceptable toxicity
n=195Key eligibility criteria
• CLL/SLL diagnosis
• ≥1 prior therapy
• ECOG PS 0-1
• Measurable nodal
disease by CT
Endpoints: PFS, OS, ORR, safety
RANDOMIZE1:1
122 patients (62%)
crossover
to ibrutinib 420 mg
once daily
following PD
IV ofatumumab initial
dose of 300 mg
followed by 2000 mg
x 11 doses over 24 weeks
n=196
• Progression-free survival (PFS) and response assessments were conducted per IWCLL criteria with the 2012 clarification for treatment-related lymphocytosis and are presented per investigator assessment.
• Longer term follow-up safety data focused on ibrutinib. Ofatumumab treatment (and AE reporting period) were complete at publication of interim analysis.2,3
• Analysis of IGHV was performed by a central laboratory; complex karyotype was determined by the investigator.
• The entire coding regions of Notch1, SF3B1, MYD88, and TP53 were sequenced by next generation sequencing.
RESULTS
Table 1. Baseline Characteristics
Characteristicibrutinib (N=195)
ofatumumab (N=196)
Median age, years (range) ≥70 years
67 (30-86)40%
67 (37-88)41%
Male 66% 70%
Rai stage III/IV 56% 58%
Median number of prior therapies (range)12 ≥3
3 (1-12)18%29%53%
2 (1-13)28%27%46%
Del17p 32% 33%
Del11q 63/190 (33%) 59/191 (31%)
Trisomy 12 22/138 (16%) 27/145 (19%)
Complex karyotype 39/153 (25%) 32/145 (22%)
CD38 (≥30%) 69/160 (43%) 69/155 (45%)
IGHV UnmutatedMutated
98/134 (73%)36/134 (27%)
83/132 (63%)49/132 (37%)
Novel Gene Mutationsibrutinib (n=121)
ofatumumab (n=145)
NOTCH1MutatedNot mutated
35 (29%)86 (71%)
44 (30%)101 (70%)
SF3B1Mutated Not mutated
37 (31%)84 (69%)
44 (30%) 101 (70%)
TP53MutatedNot mutated
61 (50%)60 (50%)
67 (46%)78 (54%)
MYD88MutatedNot mutated
3 (2%)
118 (98%)
3 (2%)
142 (98%)
Figure 2. Survival Outcomes
Progression-Free SurvivalA B Overall Survival
ofatumumabn=196
Median PFS (mo) 8.1
Hazard Ratio
(95% CI)
Log-Rank P value
ibrutinibn=195
NR
0.106
(0.073-0.153)
<0.001
0 6 12 18 24
Months
Pro
gre
ssio
n-F
ree
Su
rviv
al
(%)
0
10
20
30
40
50
60
70
80
90
100
ibrutinib
ofatumumab
Median Time (mo) NR NR
Hazard Ratio 0.434
(95% CI) (0.238-0.789)
Log-Rank P value 0.0049
ofatumumabn=196
ibrutinibn=195
40
50
60
70
80
90
100
0
10
20
30
0 6 12 18
Months
Ov
era
ll S
urv
iva
l (%
)
24
First patientcrossover
Ibrutinib (n = 195, 16 events)
Ofatumumab (n = 196, 33 events)Red tics indicate crossover patients
Interim analysis at 18 months
Overall SurvivalC
Ov
era
ll S
urv
ival
(%)
Months
6 12 18 240
10
20
30
40
50
60
70
80
90
100
0
ibrutinib
Longer-term analysis at 24 months
• Median follow-up was 16 months vs. 12 months for ibrutinib vs. ofatumumab.• Ibrutinib treatment significantly lengthened PFS (median not reached vs. 8.1 mo,
HR=0.106, 95% CI 0.073-0.153, P<0.001).• 12-month PFS rate was significantly improved for ibrutinib vs. ofatumumab (84% vs.
18%, P<0.001).
Overall Survival• OS was significantly improved for ibrutinib vs. ofatumumab at time of interim analysis
(HR=0.43, P=0.005), when 57 patients had crossed over following IRC confirmed PD. After the IA, the additional patients randomized to ofatumumab were allowed to cross over to ibrutinib at investigator discretion and were censored for OS.
• 12-month OS rate was 90% for ibrutinib. • 168 of 195 patients randomized to ibrutinib were alive at the time of analysis with a
median follow-up of 16 months.
Figure 3. Best Overall Response*
100%90%*
4% CRCRinPRPR-LPR
2%
<1%3%
2%
6%1%
25%*
53%
14%22%
8%
74%
ORR SD
ibrutinib(N=195†)
PD ORR SD
ofatumumab(N=196†)
PD
80%
60%
40%
20%
0%
ORR = CR + CRi + nPR + PR-L + PR.*P<0.0001 for ibrutinib vs. ofatumumab. †5 patients for ibrutinib and 17 for ofatumumab were nonevaluable for response but included in denominator (ITT population).
• Median time to initial response was 3 months for both ibrutinib (range, 2-17) and ofatumumab (range, 2-9) consistent with the first scheduled CT assessment.
• Median time to best response was 5 months (range, 2-17) for ibrutinib and 3 months (range, 2-9) for ofatumumab.
• Median time to CR/CRi with ibrutinib was 11 months (range, 6-17).• 1 patient receiving ofatumumab achieved CR at 8 months.
Figure 4. Cumulative Best Response to ibrutinib Over Time
31
59
72
7981 82
88914
2322
1410 8 7 6
1815129630
0
10
20
30
40
50
60
70
80
90
100CR/PR
PR-L
SD
Pati
en
ts W
ith
Re
spo
nse
(%
)
Months From Initiation of Study Treatment
31
Complete responses and partial responses
Partial response with lymphocytosis
Stable disease
• Most patients experienced a transient increase in blood lymphocyte counts that frequently resolved with continued ibrutinib treatment and patients achieved deeper responses.
Figure 5. PFS by Cytogenetic Abnormalities and Prognostic Features
All patientsNumber of prior CLL/SLL therapies
12≥3
del17pYesNo
del13q (0 or 1)YesNo
del11qYesNo
LymphocytosisYesNo
IGHVMutatedUnmutated
Trisomy 12YesNo
Complex karyotypeYesNo
CD38<30%≥30%
391
89109193
127264
184122
122259
157225
85181
49234
72228
177138
Hazard RatioNo. of PatientsSubgroup
0.00 0.25 0.50
Favors ibr Favors ofa
0.75 1.00 1.25 1.50
Table 2. PFS and ORR by Subgroup
Subgroup
12-Month PFS* ORR*
ibrutinib
(N=195)
ofatumumab
(N=196)
ibrutinib
(N=195)
ofatumumab
(N=196)
Median number of
prior therapies
1
2
≥3
35 (94%)†
57 (84%)†
103 (80%)†
54 (22%)
52 (30%)
90 (10%)
35 (100%)†
45/57 (79%)†
80/103 (78%)†
13/54 (24%)
17/52 (33%)
14/90 (16%)
Lymphocytosis 133 (89%) 24 (9%)† 110/133 (83%) 0/24 (0%)†
Del11q
Yes
No
63 (89%)
127 (81%)
59 (8%)†
132 (24%)†
50/63 (79%)
106/127 (83%)
6/59 (10%)†
38/132 (29%)†
Del17p
Yes
No
63 (79%)
132 (86%)
64 (17%)†
132 (19%)†
54/63 (86%)
106/132 (80%)
12/64 (19%)
32/132 (24%)
Trisomy 12 22 (86%) 27 (15%) 21/22 (95%) 7/27 (26%)
CD38 ≥30% 69 (87%) 69 (15%) 59/69 (86%) 18/69 (26%)
Complex karyotype
Yes
No
39 (72%)
114 (86.5%)
33 (3%)†
114 (20.5%)†
29/39 (74%)
98/114 (86%)
1/33 (3%)†
36/114 (32%)†
IGHV
Unmutated
Mutated
98 (86%)
36 (86%)
83 (13%)†
49 (29%)†
84/98 (86%)
27/36 (75%)
19/83 (23%)
12/49 (24%) *P<0.001 for 12-month PFS (P-value based on Z test) and P<0.0001 for ORR (P-value based on Fisher’s exact test), except for 2 prior therapy and trisomy 12 where P=0.0005. †P<0.05 within an arm for overall PFS (P-value based on unstratified log-rank test) and ORR (P-value based on Fisher’s exact test).
Table 3. PFS and ORR by Gene Mutation at Baseline (n=266)
Novel Gene
Mutations
12-Month PFS ORR
ibrutinib
(n=121)
ofatumumab
(n=145)
ibrutinib
(n=121)
ofatumumab
(n=145)
NOTCH1
Mutated*
Not mutated*
85%
90.5%
11%†
23%†
29 (83%)
68 (79%)
10 (23%)
23 (23%)
SF3B1
Mutated*
Not mutated*
86.5%
90%
16%
21%
31 (84%)
66 (79%)
10 (23%)
23 (23%)
TP53
Mutated*
Not mutated*
88%
90%
16%
22.5%
49 (80%)
48 (80%)
11 (16%)
22 (28%)
MYD88
Mutated
Not mutated*
100%
89%
33%
19%
2 (67%)
95 (81%)
1 (33%)
32 (23%)
*P<0.001 except for MYD88 mutated where P=0.014 for 12-month PFS (P-value based on Z test) and P<0.0001 for ORR except for MYD88 mutated where P=1.0000 (P-value based on Fisher’s exact test). †P<0.05 within an arm for overall PFS (P-value based on unstratified log-rank test).
• 12-month PFS rate and ORR were significantly improved with ibrutinib vs. ofatumumab regardless of baseline genetics, including del17p, del11q, and genetic mutations (e.g., SF3B1 and Notch1), complex karyotype, or number of prior therapies.
• Notch1, complex karyotype, unmutated IGHV, del17p, and del11q were associated with inferior PFS for patients treated with ofatumumab.
• Significant difference in PFS with and without del17p for ofatumumab- (P=0.039) but not ibrutinib-treated (P=0.396) patients (Figure 6).
• Patients in the ibrutinib arm treated in second-line therapy experienced better outcomes (P=0.046) than those salvaged in later lines of therapy. (Figure 7).
• ORR was 100% for ibrutinib-treated patients receiving 1 prior therapy vs. 2 (79%) or ≥3 (78%) prior therapies (P=0.002).
• There was no significant difference in ORR or PFS in ibrutinib-treated patients with and without lymphocytosis (Figure 8).
Figure 6. No Significant Difference in PFS With or Without Del17p for ibru-tinib
Median PFS (mo)
ibrutinibdel17p, no
NR
Hazard Ratio
(95% CI)
Log-Rank P value
ibrutinibdel17p, yes
NR
1.314
(0.698-2.473)
0.396
8.2
ofatumumab,del17p, no
5.9
1.413
(1.017-1.963)
0.039
ofatumumabdel17p, yes
N at Riskibrutinib del17p, yes 63 59 53 52 47 26 5 2ibrutinib del17p, no 132 128 124 117 107 43 4 1
ofatumumab del17p, yes 64 45 29 15 9 2ofatumumab, del17p, no 132 113 86 48 20
Pro
gre
ssio
n-F
ree
Su
rviv
al
(%)
0
10
20
30
40
50
60
70
80
90
100
0 3 6 9 12 15 18 21 24
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ibrutinib del17p, noibrutinib del17p, yes
ofatumumab, del17p, noofatumumab del17p, yes
Figure 7. Significant Difference in PFS With 1 vs. >1 Prior Therapy for ibru-tinib
Median PFS (mo)
ibrutinib>1 priortherapy
NR
Hazard Ratio
(95% CI)
Log-Rank P value
ibrutinib1 prior
therapy
NR
3.108
(0.959-10.07)
0.046
8.0
ofatumumab>1 priortherapy
8.2
1.238
(0.870-1.763)
0.235
ofatumumab1 prior
therapy
Pro
gre
ssio
n-F
ree
Su
rviv
al
(%)
Months
ibrutinib 1 prior therapy
ibrutinib >1 prior therapy
ofatumumab 1 prior therapy
ofatumumab >1 prior therapy0
10
20
30
40
50
60
70
80
90
100
0 3 6 9 12 15 18 21 24
N at Riskibrutinib 1 prior therapy 35 35 34 33 30 17 2 1
ibrutinib >1 prior therapy 160 152 143 136 124 52 7 2ofatumumab 1 prior therapy 54 46 35 19 9
ofatumumab >1 prior therapy 142 112 80 44 20 2
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Figure 8. No Significant Difference in PFS With or Without Lymphocytosis for ibrutinib
Pro
gre
ssio
n-F
ree
Su
rviv
al
(%)
Months
0
10
20
30
40
50
60
70
80
90
100
0 3 6 9 12 15 18 21 24
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N at Riskibrutinib lymphocytosis, yes 133 130 126 120 113 49 5 3ibrutinib lymphocytosis, no 59 55 49 48 40 20 4
ofatumumab lymphocytosis, yes 24 17 9 3 1 0ofatumumab lymphocytosis, no 166 140 106 60 28 2
ibrutinib lymphocytosis, yesibrutinib lymphocytosis, no
ofatumumab lymphocytosis, yesofatumumab lymphocytosis, no
ibrutiniblymphocytosis,
yes
ibrutiniblymphocytosis,
no
Median PFS (mo)
Hazard Ratio
(95% CI)
Log-Rank P value
NRNR
0.584
(0.308-1.107)
0.096
Table 4. Characteristics of Patients With Progressive Disease
Baseline CharacteristicRT
(n=8)
Non-RT PD
(n=18)
No PD
(n=169)
Del17p 50% 44% 30%
Del11q 25% 17% 34%
Complex karyotype 38% 28% 18%
Median β2-microglobulin, mg/L (range)
11 (4-17) 7 (4-20) 6 (2-16)
Median LDH, U/L (range) 359 (185-1937) 311 (183-787) 227 (40-841)
Median number of prior therapies (range)
3 (2-6) 3.5 (1-8) 3 (1-12)
Massive lymphadenopathy ≥10 cm*
25% 17% 3%
*By IRC CT scan. RT, Richter’s Transformation.
Table 5. Treatment Discontinuation
ibrutinib
(N=195)
ofatumumab
(N=196)
Patients continuing treatment 148 (76%) 0
Patients who completed and crossed over* — 93 (47%)
Patients who discontinued and crossed over* — 29 (15%)
Patients who discontinued treatment
Due to PD
Due to AE/unacceptable toxicity
Due to death
Due to patient decision
Due to investigator decision
47 (24%)
17 (9%)
13 (7%)
10 (5%)
3 (2%)†
4 (2%)‡
42 (21%)
38 (19%)
7 (4%)
9 (5%)
6 (3%)
11 (6%)
*Completed and discontinued refer to 24 weeks of planned ofatumumab.†2 patients went to commercial ibrutinib. ‡1 patient went to stem cell transplant.
• 76% of patients randomized to ibrutinib continue treatment on study; 2 additional patients discontinued to go on commercial ibrutinib.
• Median treatment duration was 16 months for ibrutinib vs. 5 months for ofatumumab.
Figure 9. Most Common Cumulative AEs for ibrutinib by Preferred Term (≥15%)
Diarrhea
0% 20% 40% 60% 80% 100%
Grade 1
Grade 2
Grade 3
Grade 4
Fatigue
Nausea
Pyrexia
Anemia
Cough
Neutropenia
Upper respiratory tract infection
Arthralgia
Peripheral edema
Constipation
Muscle spasms
Sinusitis
Thrombocytopenia
Vomiting
Pneumonia
• The most frequently reported preferred terms were diarrhea, fatigue, cytopenia, constipation, and pneumonia over the 16-month follow-up.
• Most AEs were grade 1.• The most frequent grade 3/4 AEs for ibrutinib were neutropenia (18%), pneumonia
(9%), thrombocytopenia (6%), anemia (6%), hypertension (6%).• Over 16 months of follow-up, atrial fibrillation of any grade occurred in 13 (7%) ibrutinib-
treated patients, which includes 3 additional patients reported since interim analysis. — 1 patient discontinued due to atrial fibrillation.
— Of note, prior medical history of atrial fibrillation was reported more frequently for ibrutinib (5.6%) vs. ofatumumab (2.6%).
• Bleeding AEs occurred in 48% of patients, the majority were grade 1 (40%), with grade 2 events reported in 6%, grade 3 (2%), and grade 4 (1%). The most frequently reported terms were petechiae, contusion, and increased tendency to bruise.
— Grade ≥3 bleeding events included grade 3 epistaxis (n=1), grade 3 spontaneous hematoma (n=1), and grade 4 subdural hematoma (n=1).
— There were no grade 5 events.
• Tumor lysis syndrome (TLS) occurred in 2 patients randomized to ibrutinib and was not considered related to treatment by investigator. Both patients experienced TLS in the setting of disease progression on study days 534 and 242, 5 days and 11 days, respectively, after discontinuation of ibrutinib.
• Dose reductions due to an AE occurred in 6% of ibrutinib-treated patients.• Discontinuations due to AE/unacceptable toxicity occurred in 7% of ibrutinib-
treated patients.
CONCLUSIONS• Ibrutinib significantly improved PFS, OS, and ORR relative to ofatumumab in patients
with CLL/SLL who had received ≥1 prior therapy.• Patients in the ibrutinib arm treated after only 1 prior therapy experienced better
outcomes than those salvaged in later lines of therapy, while the presence of del17p did not confer inferior outcomes in ibrutinib-treated patients.
• The updated results with 16 months of follow-up for ibrutinib-treated patients are consistent with previously published phase 2 single-agent results.4
• These results provide further evidence of the robust clinical activity of ibrutinib in patients with CLL regardless of high-risk baseline genetics.
REFERENCES1. Wang et al. N Engl J Med. 2011;365:2497-2506.2. Byrd et al. N Engl J Med. 2014;371:213-223.3. Barrientos et al. Hematologic and Immunologic Function and Patient Well-Being for the Phase III RESONATE Study of ibrutinib vs ofatumumab in
Relapsed/Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma. ASH 2014 (Abstract #4696).
4. Byrd et al. N Engl J Med. 2013;369:32-42.
ACKNOWLEDGMENTSWe thank the patients who par tic ipated in the study and their suppor tive fami l ies , and the investigators and clinical research staff from the study centers. This study was sponsored by Pharmacyclics, Inc. Editorial support was provided by Luana Atherly-Henderson, PhD, CMPP, and funded by Pharmacyclics, Inc.
Poster 13
Poster presented at the 11th HOPA Annual Conference, March 25-28, 2015, Austin, TX