V O L U M E 3 1 䡠 N U M B E R 2 9 䡠 O C T O B E R 1 0 2 0 1 3
`
`JOURNAL OF CLINICAL ONCOLOGY
`
`O R I G I N A L R E P O R T
`
`Andre Goy, John Theurer Cancer
`Center at Hackensack University Medi-
`cal Center, Hackensack; Lei Zhang,
`Sherri Cicero, and Tommy Fu, Celgene,
`Summit, NJ; Rajni Sinha, Emory Univer-
`sity Winship Cancer Institute, Atlanta,
`GA; Michael E. Williams, University of
`Virginia Health System, Charlottesville,
`VA; Sevgi Kalayoglu Besisik, Istanbul
`University Faculty of Medicine, Istanbul,
`Turkey; Johannes Drach, Medical
`University of Vienna, Vienna, Austria;
`Radhakrishnan Ramchandren, Karma-
`nos Cancer Institute, Detroit, MI; and
`Thomas E. Witzig, Mayo Clinic,
`Rochester, MN.
`
`Published online ahead of print at
`www.jco.org on September 3, 2013.
`
`Supported by Celgene.
`
`Presented in part at the 54th American
`Society of Hematology Meeting and
`Exposition, Atlanta, GA, December
`8-11, 2012.
`
`Authors’ disclosures of potential con-
`flicts of interest and author contribu-
`tions are found at the end of this
`article.
`
`Clinical trial information: NCT00737529.
`
`Corresponding author: Andre Goy, MD,
`John Theurer Cancer Center at Hacken-
`sack University Medical Center, 20
`Prospect Ave, Hackensack, NJ 07601;
`e-mail: agoy@humed.com.
`
`© 2013 by American Society of Clinical
`Oncology
`
`0732-183X/13/3129w-3688w/$20.00
`
`DOI: 10.1200/JCO.2013.49.2835
`
`Single-Agent Lenalidomide in Patients With Mantle-Cell
`Lymphoma Who Relapsed or Progressed After or
`Were Refractory to Bortezomib: Phase II MCL-001
`(EMERGE) Study
`Andre Goy, Rajni Sinha, Michael E. Williams, Sevgi Kalayoglu Besisik, Johannes Drach,
`Radhakrishnan Ramchandren, Lei Zhang, Sherri Cicero, Tommy Fu, and Thomas E. Witzig
`Listen to the podcast by Dr Till at www.jco.org/podcasts
`
`A
`
`B
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`S
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`T
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`R
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`A
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`C
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`T
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`Purpose
`Although dose-intensive strategies or high-dose therapy induction followed by autologous
`stem-cell transplantation have improved the outcome for patients with mantle-cell
`lymphoma
`(MCL), most eventually relapse and subsequently respond poorly to additional therapy. Bort-
`ezomib (in the United States) and temsirolimus (in Europe) are currently the only two treatments
`approved for relapsed disease. Lenalidomide is an immunomodulatory agent with proven
`tumoricidal and antiproliferative activity in MCL. The MCL-001 (EMERGE) trial
`is a global,
`multicenter phase II study examining the safety and efficacy of lenalidomide in patients who had
`relapsed or were refractory to bortezomib.
`
`Patients and Methods
`Lenalidomide 25 mg orally was administered on days 1 through 21 every 28 days until disease
`progression or intolerance. Primary end points were overall response rate (ORR) and duration of
`response (DOR); secondary end points included complete response (CR) rate, progression-free
`survival (PFS), overall survival (OS), and safety.
`
`Results
`In all, 134 patients were enrolled with a median age of 67 years and a median of four prior
`therapies (range, two to 10 prior therapies). The ORR was 28% (7.5% CR/CR unconfirmed) with
`rapid time to response (median, 2.2 months) and a median DOR of 16.6 months (95% CI, 7.7 to
`26.7 months). Median PFS was 4.0 months (95% CI, 3.6 to 5.6 months), and median OS was 19.0
`months (95% CI, 12.5 to 23.9 months). The most common grade 3 to 4 adverse events were
`neutropenia (43%), thrombocytopenia (28%), anemia (11%), pneumonia (8%), and fatigue (7%).
`Conclusion
`The MCL-001 study demonstrated durable efficacy of lenalidomide with a predictable safety
`profile in heavily pretreated patients with MCL who had all relapsed or progressed after or were
`refractory to bortezomib.
`
`J Clin Oncol 31:3688-3695. © 2013 by American Society of Clinical Oncology
`
`INTRODUCTION
`
`Mantle cell lymphoma (MCL) is an uncommon
`subtype of non-Hodgkin lymphoma (NHL),1 ac-
`counting for 3% to 6% of NHL.2-4 Median age at
`diagnosis is mid to late 60s and patients typically
`present with advanced-stage disease.2,5-7 Al-
`though overall survival (OS) has improved over
`the last two decades, MCL remains challenging,
`especially in the relapsed/refractory setting in
`which median OS is approximately 1 to 2 years
`with current therapies.8-10
`
`Combination chemotherapy and immuno-
`therapy is the foundation of first-line MCL treat-
`ment and, when feasible, dose-intensive/induction
`strategies followed by high-dose therapy and au-
`tologous stem-cell transplantation (HDT-ASCT)
`consolidation have improved outcomes.8,11-15 Al-
`ternative options in older patients or those with co-
`morbidities include less intensive strategies (eg,
`bendamustine plus rituximab), some of which may
`incorporate maintenance strategies to improve du-
`ration of disease control.9,16-18 Following relapse,
`there are limited options, with minimal benefit from
`
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`Lenalidomide in Relapsed/Refractory MCL Postbortezomib (MCL-001)
`
`standard chemotherapy or HDT-ASCT, because patients often be-
`come chemotherapy resistant.13,19,20 Two therapeutic agents are
`currently approved in the relapsed/refractory setting: bortezomib
`(a proteasome inhibitor; United States) and temsirolimus (a mam-
`malian target of rapamycin complex 1 inhibitor; Europe).21,22 Both
`are limited by intravenous administration and short duration of
`response (DOR),23-27 substantiating the need for novel alternatives
`for these patients.
`Lenalidomide (Revlimid; Celgene, Summit, NJ) is an immuno-
`modulatory agent initially studied in multiple myeloma and myelo-
`dysplastic syndromes.28-31 Preclinical studies showed antitumor and
`antiproliferative activities in leukemia and lymphoma, including
`MCL.32-34 Two phase II studies (NHL-002 and NHL-003) reported
`clinical activity of lenalidomide in heavily pretreated patients with
`relapsed/refractory aggressive NHL,35,36 including MCL.37,38 With a
`similar dosing schema (25 mg per day orally for 21 of 28 days),
`responses were consistent between studies, including 35% overall
`response rate (ORR) for both (12% to 13% complete response [CR]),
`median DOR of 6.2 months (NHL-002) and 10.6 months (NHL-003),
`and median progression-free survival (PFS) of 4.0 months (NHL-002)
`and 3.7 months (NHL-003) across all histologies.35,36 Interestingly,
`higher and more durable responses were seen in MCL versus other
`NHL subtypes. Patients with MCL in NHL-002 showed 53% ORR
`(20% CR), median DOR of 13.7 months, and median PFS of 5.6
`months.36 Central review in the NHL-003 study showed 35% ORR
`(12% CR/ CR unconfirmed [CRu]), median DOR of 16.3 months,
`and median PFS of 8.8 months.38 Responses were independent of
`baseline characteristics or prior therapies; most common grade 3 to 4
`adverse events (AEs) for patients with MCL in NHL-002 and NHL-
`003 were neutropenia (40% and 46%) and thrombocytopenia (33%
`and 30%), respectively.37,38 On the basis of these encouraging results
`and limited treatment options in relapsed/refractory MCL, the MCL-
`001 (EMERGE) phase II study was designed to examine the safety and
`efficacy of single-agent lenalidomide in heavily pretreated patients
`who had relapsed, progressed, or were refractory to bortezomib.
`
`PATIENTS AND METHODS
`
`Patients
`The institutional review board or independent ethics committee at each
`participating institution reviewed and approved the study protocol, amend-
`ments, and patient’s written informed consent before study initiation. Study
`design and conduct were in accordance with ethical principles of Good Clini-
`cal Practice according to International Conference on Harmonization Har-
`monized Tripartite Guidelines and the Declaration of Helsinki.
`Key inclusion criteria were confirmed MCL diagnosis with cyclin-D1
`overexpression by immunohistochemistry or t(11;14)(q13;q32) translocation
`by fluorescent in situ hybridization, age ⱖ18 years, Eastern Cooperative On-
`cology Group (ECOG) performance score 0 to 2, absolute neutrophil count
`ⱖ 1,500/␮L, platelets ⱖ 60,000/␮L, and adequate organ function. Diagnosis
`criteria included measurable lesion (ⱖ 2 cm by computed tomography [CT]).
`Patientswererequiredtohaveprioranthracyclineormitoxantrone,cyclophos-
`phamide, or rituximab therapy and documented relapsed, refractory, or pro-
`gressive disease (PD) following bortezomib (alone or in combination). The
`definition of relapse was within 1 year of the last dose of bortezomib and
`following an initial CR to a bortezomib-containing regimen. Refractory to
`bortezomib was defined as PD without achieving at least a partial response
`(PR) during treatment after at least two cycles of a bortezomib-containing
`regimen. PD was within 1 year of the last dose of bortezomib after achiev-
`ing a PR to a bortezomib-containing regimen. Patients who relapsed after
`
`HDT-ASCT were eligible, and there was no limitation for the number of
`prior therapies.
`Key exclusion criteria included the presence of CNS disease, creatinine
`clearance (CrCl) ⬍ 30 mL/min, eligibility for HDT-ASCT or allogeneic stem-
`cell transplantation per investigator decision, corticosteroids ⱕ 1 week (⬎ 10
`mg per day prednisone or equivalent), unwillingness to receive contraception
`or prophylaxis for deep vein thrombosis, desquamating rash with prior
`thalidomide, prior exposure to lenalidomide, chemotherapy ⱕ 2 weeks,
`nitrosourea ⱕ 6 weeks, monoclonal antibody ⱕ 8 weeks, radioimmuno-
`conjugate ⱕ 12 weeks, or external radiotherapy ⱕ 3 weeks.
`Study Design
`MCL-001 (EMERGE; NCT00737529) was a global, multicenter, single-
`arm, open-label phase II study of safety and efficacy of single-agent lenalido-
`mide in patients who had relapsed, progressed, or were refractory to
`bortezomib. Primary end points were ORR and DOR; secondary end points
`included safety, CR/CRu, time to response (TTR), time to progression (TTP),
`time to treatment failure (TTF), PFS, and OS.
`Lenalidomide 25 mg (10 mg for CrCl ⱖ 30 to ⬍ 60 mL/min) was
`self-administered orally on days 1 through 21 of each 28-day cycle until PD,
`intolerance, or voluntary withdrawal. Dosing was based on prior NHL studies
`(including MCL)35-37 and approved dosing in multiple myeloma.39
`Dose modification/interruption was planned in the event of grade ⱖ 2
`allergic reaction or hypersensitivity; ⬎ 3⫻ upper limit of normal AST, ALT, or
`bilirubin; grade I or higher tumor lysis syndrome (TLS; by Cairo-Bishop
`grading system40); sustained grade ⱖ 3 neutropenia for ⱖ 7 days or associated
`with fever (ⱖ 38.5°C); thrombocytopenia (platelets ⬍ 50,000/␮L); constipa-
`tion; desquamating (blistering) rash (or grade 4 nondesquamating rash); ve-
`nous thrombosis/embolism; new peripheral neuropathy; tumor flare reaction
`(TFR); or lenalidomide-related nonhematologic AE. Allopurinol 300 mg per
`day or equivalent was recommended for TLS prophylaxis with oral hydration
`during the first 7 days of treatment (or as indicated). Patients at high-risk for
`developing a thromboembolic event (TEE; defined as a history of TEE and/or
`concomitant medication with increased risk and/or known hypercoagulable
`state regardless of thromboembolic history) received prophylaxis (eg, aspirin
`70 to 100 mg per day, low-molecular-weight heparin [LMWH], or warfarin,
`per investigator). Growth factors were not administered as prophylaxis but
`were allowed to treat severe hematologic events. Concomitant anticancer
`therapy was prohibited, although physiologic doses of steroids (ⱕ 10 mg per
`day) not prescribed for MCL were permitted.
`Response and Safety Assessments
`Safety assessments included AEs, pregnancy tests for females of child-
`bearing age, second primary malignancies (SPMs), TLS, and TFR, hematol-
`ogy, serum chemistry, and other laboratory tests. CT scans were performed
`every two cycles (⫾ 7 days) throughout treatment and every 90 days (⫾ 14
`days) after stopping lenalidomide until progression or initiation of subsequent
`antilymphoma therapy. Confirmatory bone marrow aspirate and unilateral
`biopsy was required within 28 days for patients achieving CR (by CT).
`Efficacy analyses were performed in the intent-to-treat patient popula-
`tion as defined in the protocol. Response data were evaluated by investigators
`and an independent review committee (ie, central review) per modified Inter-
`national Workshop Lymphoma Response Criteria.24,41,42 Central reviewers
`prospectively reviewed efficacy data to provide an objective, unbiased inde-
`pendent review of clinical outcomes blinded to institution information, demo-
`graphic information, and investigator assessments. Central reviewers
`consisted of four experts in radiology and hematology/oncology. Two radiol-
`ogists first evaluated medical imaging data in a blinded independent radiology
`review, with adjudication by a third radiologist as needed, followed by an
`independent overall hematologist/oncologist review of radiology results in
`conjunction with pertinent clinical data to determine response. Central re-
`viewers provided the primary efficacy results for this study.
`Statistical Analyses
`Primary efficacy end points were evaluated following six cycles (⫾ 1
`month) of lenalidomide or on treatment discontinuation. Patients discontin-
`uing before achieving a response or who switched to another therapy were
`considered nonresponders. Response rates were calculated with two-sided
`
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`© 2013 by American Society of Clinical Oncology
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`Goy et al
`
`exact 95% CIs, with a requirement of ⬎ 15% responders to validate efficacy.
`Waterfall plots were evaluated for patients with baseline and postbaseline
`lesion assessments for a maximum percentage change from baseline in tumor
`burden for target lesions. DOR was calculated from the day of first response (of
`PR or better) to PD or last tumor assessment. The Kaplan-Meier product limit
`method estimated the survivorship function for all time-to-event end points
`(eg, DOR, PFS, OS) with median estimates and two-sided 95% CIs. Censoring
`rules followed regulatory guidance and were prespecified before database lock.
`AEs were assessed according to the National Cancer Institute’s Common
`Terminology Criteria for Adverse Events (CTCAE), version 3.0.
`Exploratory subgroup analyses included ORR and DOR assessments per
`baseline demographics and prior therapies. Multivariate logistic regression
`models evaluated possible baseline and prognostic factors predictive of re-
`sponse. Results were reported with a cutoff date of July 2, 2012, with continued
`follow-up until 70% patients had died or to a maximum of 4 years from last
`patient enrollment. All P values reported were two-sided.
`
`RESULTS
`
`Patient Characteristics
`From January 2009 to July 2012, 134 patients at 45 study sites
`worldwide received one or more doses of lenalidomide. Median age
`was 67 years and 63% of patients were age 65 years or older (Table 1).
`Almost all patients (93%) had stage III to IV MCL, 57% had high
`tumor burden, 33% had bulky disease, and one-third had prior HDT-
`ASCT. In addition to study-required prior therapies, other prior
`treatments included vincristine (96%), glucocorticoids (92%), cytar-
`abine (44%), etoposide (40%), bendamustine (25%), and platinum
`compounds (25%).
`
`Efficacy
`ORR by central review was 28% (95% CI, 20% to 36%; Table 2).
`The CR/CRu rate was 7.5% (95% CI, 4% to 13%). Responders showed
`a median DOR of 16.6 months (95% CI, 7.7 to 26.7 months; Fig 1),
`and median duration of CR/CRu of 16.6 months (95% CI, 16.6
`months to not reached). At data cutoff, 18 patients had a DOR ⱖ 6
`months and 10 patients had a DOR ⱖ 12 months (maximum DOR,
`29.2⫹ months). Eleven of 39 patients maintained stable disease for ⱖ
`6 months, including four patients with stable disease for ⱖ 12 months.
`Of note, efficacy results were similar for investigator assessments.
`The median TTR was 2.2 months (3.7 months for CR/CRu), with
`16 (43%) of 37 responders achieving at least PR by the first assessment
`(56 ⫾ 7 days). Most responses were reported after two to four cycles of
`lenalidomide, although in some patients, up to 13 months of treat-
`ment was required to achieve best response. Reduction in tumor
`burden was based on maximum percentage change from baseline for
`target lesions by central review (Appendix Fig A1, online only). For
`111 patients with baseline and postbaseline data available, 77 (69%)
`experienced a reduction, including 46 (41%) with a ⱖ 50% reduction
`in tumor burden. Efficacy assessments using the waterfall plot calcu-
`lated reductions in tumor burden that may not have met the stringent
`criteria for response even though there was a ⱖ 50% reduction of all
`target lesions.
`Median PFS was 4.0 months (95% CI, 3.6 to 5.6 months; Table
`2 and Fig 1); median TTP and TTF were 5.4 months (95% CI, 3.7 to
`7.5 months) and 3.8 months (95% CI, 2.3 to 4.5 months), respec-
`tively. With a median follow-up of 9.9 months, median OS was
`19.0 months (95% CI, 12.5 to 23.9 months; Fig 1).
`
`Table 1. Patient Demographics, Baseline Disease Characteristics at Time of
`Study Entry, and Prior Antilymphoma Treatment (N ⫽ 134)
`
`Characteristic
`
`Age, years
`ⱖ 65
`Male
`Stage III to IV
`ECOG PS
`0-1
`2
`Moderate-severe renal insufficiencyⴱ
`Time from original MCL diagnosis to
`enrollment, years
`⬍ 3
`ⱖ 3
`MIPI score group at enrollment
`Intermediate
`High
`Positive bone marrow involvement†
`High tumor burden‡
`Bulky disease§
`No. of prior treatment regimens
`No. of prior systemic antilymphoma
`therapies
`
`2
`3
`ⱖ 4
`Received prior bortezomib
`Refractory to prior bortezomib
`Refractory to last therapy
`Received prior high-dose or dose-
`intensive therapy㛳
`Received prior bone marrow or
`autologous stem cell
`transplantation
`Time from last prior systemic
`antilymphoma therapy, months
`⬍ 6
`ⱖ 6
`
`No. of
`Patients % Median
`
`67
`
`Range
`
`43-83
`
`85
`108
`124
`
`116
`18
`29
`
`52
`82
`
`51
`39
`55
`77
`44
`
`29
`34
`71
`134
`81
`74
`
`44
`
`39
`
`96
`38
`
`63
`81
`93
`
`87
`13
`22
`
`39
`61
`
`38
`29
`41
`57
`33
`
`22
`25
`53
`100
`60
`55
`
`33
`
`29
`
`72
`28
`
`4
`
`2-10
`
`3.1
`
`0.3-37.7
`
`Abbreviations: ECOG PS, Eastern Cooperative Oncology Group performance status;
`MCL, mantle cell lymphoma; MIPI, MCL International Prognostic Index.
`ⴱModerate renal
`insufficiency defined as creatinine clearance (CrCl) ⱖ 30
`and ⬍ 60 mL/min; severe renal insufficiency defined as CrCl ⬍ 30 mL/min.
`†Bone marrow involvement was not required per protocol; prior data for
`bone marrow biopsy and aspirate were collected in 115 evaluable patients.
`‡Defined as at least one lesion ⱖ 5 cm in diameter or three or more lesions that
`were ⱖ 3 cm in diameter by central radiology review.
`§Defined as at least one lesion ⱖ 7 cm in diameter by central radio-
`logy review.
`㛳Includes stem cell transplantation, hyper-CVAD (fractionated cyclophospha-
`mide, vincristine, doxorubicine, dexamethasone), or R-hyper-CVAD (rituximab
`plus hyper-CVAD).
`
`At data cutoff, 112 patients (84%) were off treatment and 22
`(16%) continued treatment. Sixty-two patients (46%) received subse-
`quent antilymphoma therapy following lenalidomide, with 13% ORR
`(eight of 62 patients) reported to date. The most common antilym-
`phoma treatment following lenalidomide included rituximab alone
`(n ⫽ 5), rituximab/bendamustine (rituximab/bendamustine ⫾ pred-
`nisone; n ⫽ 11), rituximab/bendamustine plus other chemotherapy/
`steroids (n ⫽ 12), and radiotherapy (n ⫽ 8). Four patients received
`lenalidomide following study completion (including one patient who
`discontinued therapy because of lack of PD postbortezomib, one with
`prolonged treatment delay in lenalidomide due to cytopenia, and two
`
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`Downloaded from ascopubs.org by 12.236.90.2 on March 16, 2018 from 012.236.090.002
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`Copyright © 2018 American Society of Clinical Oncology. All rights reserved.
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`

`

`Lenalidomide in Relapsed/Refractory MCL Postbortezomib (MCL-001)
`
`1.0
`
`0.8
`
`0.6
`
`0.4
`
`0.2
`
`Duration of Response
`
`(probability)
`
`Table 2. Efficacy Outcomes With Lenalidomide in Patients With
`Relapsed/Refractory MCL (N ⫽ 134)
`
`A
`
`Efficacy Parameter
`
`No. %
`
`95% CI
`
`No. %
`
`95% CI
`
`Central Review
`
`Investigator Review
`
`37
`10
`27
`39
`35
`
`23
`
`28
`7.5
`20
`29
`26
`
`17
`16.6
`
`7.7 to 26.7
`
`43
`22
`21
`36
`43
`
`32
`16
`16
`27
`32
`
`9
`
`12
`18.5
`
`12.8 to 26.7
`
`Median DOR (central) = 16.6 months (95% CI, 7.7 to 26.7)
`
`16.6
`
`16.6 to N/R
`
`26.7
`
`26.7 to N/R
`
`0
`
`5
`
`10
`15
`20
`Time (months)
`
`25
`
`30
`
`9.2
`
`5.7 to 20.5
`
`7.7
`
`3.7 to 21.4
`
`2.2
`1.7-13.1
`
`2.0
`1.7-15.9
`
`No. at risk
`(central review) 37
`B
`
`1.0
`
`25
`
`11
`
`8
`
`5
`
`4
`
`0
`
`Median PFS (central) = 4.0 months (95% CI, 3.6 to 5.6)
`
`0.8
`
`0.6
`
`0.4
`
`0.2
`
`Progression-Free Survival
`
`(probability)
`
`0
`
`5
`
`10
`
`15
`20
`Time (months)
`
`25
`
`30
`
`35
`
`47
`
`23
`
`15
`
`7
`
`4
`
`4
`
`0
`
`No. at risk
`(central review) 134
`C
`
`1.0
`
`0.8
`
`0.6
`
`0.4
`
`0.2
`
`Overall Survival
`
`(probability)
`
`Median OS = 19.0 months (95% CI, 12.5 to 23.9)
`
`0
`
`5
`
`10
`
`No. at risk
`
`134
`
`95
`
`66
`
`15
`20
`25
`30
`Time (months)
`44
`32
`16
`10
`
`35
`
`40
`
`45
`
`3
`
`1
`
`0
`
`Fig 1. Duration of (A) response (DOR), (B) progression-free survival (PFS), and
`(C) overall survival
`(OS) after lenalidomide in relapsed/refractory mantle-cell
`lymphoma (by central review).
`
`days (ie, after two cycles). Twenty-six patients (19%) discontinued
`lenalidomide due to AEs. The most common AEs leading to dose
`reductions,
`interruptions, or discontinuations were neutropenia
`and thrombocytopenia.
`Ninety-nine percent of patients experienced at least one AE,
`including 66% grade ⱖ 3 (Table 4). The most common grade ⱖ 3 AEs
`
`ORR
`CR/CRu
`PR
`SD
`PD
`Missing response
`assessmentⴱ
`Median DOR, months
`Median duration of
`CR/CRu, months
`Median duration of
`PR, months
`TTR, months
`Median
`Range
`Time to CR/CRu,
`months
`Median
`Range
`Median PFS, months
`Median TTP, months
`Median TTF months
`Median OS, months
`
`3.7
`1.9-29.5
`4.0
`5.4
`3.8
`19.0
`
`5.6
`1.8-24.2
`3.8
`4.0
`3.8
`19.0
`
`3.6 to 5.6
`3.7 to 7.5
`2.3 to 4.5
`12.5 to 23.9
`
`3.5 to 6.8
`3.6 to 7.5
`2.3 to 4.5
`12.5 to 23.9
`
`Abbreviations: CR, complete response; CRu, unconfirmed complete re-
`sponse; DOR, duration of response; MCL, mantle cell lymphoma; ORR, overall
`response rate; OS, overall survival; N/R, not reached; PD, progressive disease;
`PFS, progression-free survival; PR, partial response; SD, stable disease; TTF,
`time to treatment failure; TTP, time to progression; TTR, time to response.
`ⴱIncludes patients without or with incomplete postbaseline response assess-
`ment. For these 23 patients, the investigator’s assessment for best ORR
`included 12 with progressive disease, 10 not assessable, and one CR (no
`identifiable target lesions by the central radiology reviewer who reported this
`patient as not evaluable, although a single GI 关colon兴 lesion was reported by
`investigator readings). All 23 patients were included in the centrally reviewed
`response assessments as nonresponders.
`
`patients who were given lenalidomide as subsequent therapy follow-
`ing PD).
`
`Response by Subgroup Analysis
`Lenalidomide showed consistent ORR and DOR across sub-
`groups (Table 3). Multivariate logistic regression analysis (central
`review) evaluated factors including demographic characteristics, base-
`line disease characteristics, number of and response to prior therapies,
`and the starting dose of lenalidomide. The only factor that was signif-
`icant in both the univariate and multivariate models was high lactate
`dehydrogenase at baseline.
`
`Safety
`The average daily dose of lenalidomide was 20 mg per day (⫾ 6.5
`mg per day [standard deviation]) received for a median duration of 95
`days (range, 1 to 1,002 days). Fifty-eight percent of patients received
`three or more cycles of lenalidomide, 40% received six or more cycles,
`and 19% received 12 or more cycles. Dose interruptions were present
`in 57% of patients; median time to first dose interruption was 29 days
`(ie, after one cycle) with a median time to resume lenalidomide of 7
`days (range, 1 to 59 days). Dose reductions due to AEs were reported
`in 51 patients (38%), with a median time to first dose reduction of 57
`
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`

`Goy et al
`
`Table 3. Summary of Subgroup Analyses of ORR and DOR by Baseline Demographics and Patient Characteristics With Lenalidomide in Evaluable Patients With
`Relapsed/Refractory MCL (central review)
`
`ORR
`
`DOR
`
`Characteristic
`
`Total No. of Patients
`
`No.
`
`49
`85
`
`108
`26
`
`116
`18
`
`99
`28
`
`52
`82
`
`10
`124
`
`39
`51
`39
`
`84
`47
`
`15
`22
`
`28
`9
`
`31
`6
`
`28
`7
`
`12
`25
`
`1
`36
`
`14
`12
`10
`
`32
`5
`
`%
`
`31
`26
`
`26
`35
`
`27
`33
`
`28
`25
`
`23
`31
`
`10
`29
`
`36
`23
`26
`
`38
`11
`
`95% CI
`
`No.
`
`Median
`
`95% CI
`
`18 to 45
`17 to 37
`
`18 to 35
`17 to 56
`
`19 to 36
`13 to 59
`
`20 to 38
`11 to 45
`
`13 to 37
`21 to 42
`
`0.3 to 45
`21 to 38
`
`21 to 53
`13 to 38
`13 to 42
`
`28 to 49
`4 to 23
`
`22 to 45
`7 to 32
`30 to 93
`0.2 to 39
`
`15
`22
`
`28
`9
`
`31
`6
`
`28
`7
`
`12
`25
`
`1
`36
`
`14
`12
`10
`
`32
`5
`
`22
`7
`6
`1
`
`20.5
`9.2
`
`16.7
`7.7
`
`16.7
`7.7
`
`20.5
`9.2
`
`16.6
`14.8
`
`7.7
`16.6
`
`20.5
`16.7
`7.7
`
`16.7
`5.8
`
`14.8
`26.7
`N/A
`N/A
`
`5.6 to N/A
`5.8 to 16.7
`
`9.2 to N/A
`2.1 to 20.5
`
`14.8 to N/A
`1.7 to 9.2
`
`5.7 to N/A
`7.7 to 16.6
`
`5.1 to N/A
`5.8 to 20.5
`
`N/A
`9.2 to 26.7
`
`5.6 to N/A
`5.7 to 26.7
`3.6 to N/A
`
`14.8 to N/A
`1.7 to 7.7
`
`5.6 to 20.5
`7.7 to N/A
`3.6 to N/A
`N/A to N/A
`
`Median age, years
`⬍ 65
`ⱖ 65
`Sex
`Male
`Female
`ECOG PS
`0-1
`2-4
`Renal function
`Normal
`Moderate insufficiency
`Time from MCL diagnosis to first dose, years
`⬍ 3
`ⱖ 3
`MCL (Ann Arbor) stage
`I or II
`III or IV
`MIPI score at enrollment
`Low
`Intermediate
`High
`LDH
`Normal
`High
`WBC count (⫻ 109/L)
`⬍ 6.7
`6.7 to ⬍ 10
`10 to ⬍ 15
`ⱖ 15
`Tumor burden
`Highⴱ
`Low
`Bulky disease
`Yes†
`No
`Prior bone marrow involvement‡
`Positive
`Negative
`Indeterminate
`No. of prior systemic antilymphoma therapies
`⬍ 3
`ⱖ 3
`Received prior stem cell transplantation
`Yes
`No
`Received prior high-intensity therapy
`Yes
`No
`Time from last prior systemic antilymphoma therapy, months
`⬍ 6
`ⱖ 6
`Relapsed/refractory to prior bortezomib
`Refractory
`Relapsed/progressed
`Relapsed/refractory to last prior therapy
`Refractory
`Relapsed/progressed
`
`67
`41
`9
`12
`
`77
`54
`
`44
`87
`
`55
`52
`8
`
`29
`105
`
`39
`95
`
`44
`90
`
`96
`38
`
`81
`51
`
`74
`53
`
`22
`7
`6
`1
`
`22
`15
`
`13
`24
`
`13
`13
`4
`
`9
`28
`
`12
`25
`
`12
`25
`
`23
`14
`
`22
`15
`
`20
`16
`
`33
`17
`67
`8
`
`29
`28
`
`30
`28
`
`24
`25
`50
`
`31
`27
`
`31
`26
`
`27
`28
`
`24
`37
`
`27
`29
`
`27
`30
`
`19 to 40
`17 to 42
`
`17 to 45
`19 to 38
`
`13 to 37
`14 to 39
`16 to 84
`
`15 to 51
`19 to 36
`
`17 to 48
`18 to 36
`
`15 to 43
`19 to 38
`
`16 to 34
`22 to 54
`
`18 to 38
`18 to 44
`
`17 to 39
`18 to 44
`
`22
`15
`
`13
`24
`
`13
`13
`4
`
`9
`28
`
`12
`25
`
`12
`25
`
`23
`14
`
`22
`15
`
`20
`16
`
`14.8
`16.6
`
`14.8
`16.6
`
`9.2
`16.7
`14.8
`
`16.6
`16.7
`
`16.7
`14.8
`
`16.7
`14.8
`
`7.7
`16.7
`
`20.5
`16.6
`
`26.7
`14.8
`
`5.8 to 26.7
`5.6 to 16.6
`
`5.7 to N/A
`5.8 to N/A
`
`3.6 to N/A
`5.1 to N/A
`N/A to N/A
`
`7.7 to N/A
`5.7 to 26.7
`
`3.6 to 16.7
`5.8 to 26.7
`
`3.6 to 16.7
`5.8 to 26.7
`
`3.6 to 26.7
`14.8 to N/A
`
`7.7 to N/A
`5.1 to 16.7
`
`5.6 to N/A
`5.7 to 20.5
`
`(continued on following page)
`
`3692
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`

`

`Lenalidomide in Relapsed/Refractory MCL Postbortezomib (MCL-001)
`
`Table 3. Summary of Subgroup Analyses of ORR and DOR by Baseline Demographics and Patient Characteristics With Lenalidomide in Evaluable Patients With
`Relapsed/Refractory MCL (central review) (continued)
`
`Characteristic
`
`Total No. of Patients
`
`No.
`
`Starting dose of lenalidomide, mg
`10
`25
`
`29
`104
`
`6
`31
`
`ORR
`
`%
`
`21
`30
`
`95% CI
`
`No.
`
`Median
`
`95% CI
`
`DOR
`
`8 to 40
`21 to 40
`
`6
`31
`
`9.2
`16.7
`
`7.7 to 14.8
`5.7 to N/A
`
`Abbreviations: DOR, duration of response; ECOG PS, Eastern Cooperative Oncology Group performance status; LDH, lactate dehydrogenase; MCL, mantle-cell
`lymphoma; MIPI, MCL International Prognostic Index; N/A, not applicable; ORR, overall response rate.
`ⴱDefined as at least one lesion ⱖ 5 cm in diameter or three or more lesions that were ⱖ 3 cm in diameter by central radiology review.
`†Defined as at least one lesion ⱖ 7 cm in diameter by central radiology review.
`‡Bone marrow involvement was assessable in 115 evaluable patients.
`
`were neutropenia (43%), thrombocytopenia (27%), and anemia
`(11%). Growth factors were administered to 35 patients (26%) to treat
`neutropenia. Platelet transfusions were reported in 15 patients (11%)
`for thrombocytopenia. Six patients were identified with bleeding
`events (including GI hemorrhage), none related to lenalidomide and
`one concurrently with thrombocytopenia.
`Rash was observed in 30 patients (22%), mainly grade 1 to 2
`(grade 3 in two patients), and was primarily managed with antihista-
`mines or low-dose steroids. Thirteen patients (10%) experienced
`grade 1 to 2 TFRs, all occurring in cycle 1 with one additional event in
`
`Table 4. All Treatment-Emergent AEs After Lenalidomide (regardless of
`attribution) in ⱖ 10% of Patients With Relapsed/Refractory MCL (N ⫽ 134)
`
`Any
`Grade
`
`Grade 3
`
`Grade 4
`
`AE
`
`No. % No. % No. %
`
`Patients with one or more AEs
`Hematologic
`Neutropenia
`Thrombocytopenia
`Anemia
`Leukopenia
`Nonhematologic
`Fatigue
`Diarrhea
`Nausea
`Cough
`Pyrexiaⴱ
`Rash
`Dyspneaⴱ
`Pruritus
`Constipation
`Peripheral edema
`Pneumonia†
`Astheniaⴱ
`Decreased appetite
`Back pain
`Hypokalemia
`Muscle spasms
`Upper respiratory tract infection
`Decreased weight
`Vomiting
`
`132
`
`65
`48
`41
`20
`
`45
`42
`40
`38
`31
`30
`24
`23
`21
`21
`19
`19
`19
`18
`17
`17
`17
`17
`16
`
`99
`
`49
`36
`31
`15
`
`34
`31
`30
`28
`23
`22
`18
`17
`16
`16
`14
`14
`14
`13
`13
`13
`13
`13
`12
`
`47
`
`26
`23
`11
`7
`
`9
`8
`0
`1
`1
`2
`6
`1
`1
`0
`10
`2
`1
`2
`2
`1
`0
`0
`0
`
`35
`
`19
`17
`8
`5
`
`7
`6
`0
`⬍ 1
`⬍ 1
`1
`5
`⬍ 1
`⬍ 1
`0
`8
`1
`⬍ 1
`1
`1
`⬍ 1
`0
`0
`0
`
`41
`
`32
`14
`4
`2
`
`0
`0
`1
`0
`1
`0
`1
`0
`0
`0
`0
`1
`0
`0
`1
`0
`0
`0
`1
`
`31
`
`24
`10
`3
`1
`
`0
`0
`⬍ 1
`0
`⬍ 1
`0
`⬍ 1
`0
`0
`0
`0
`⬍ 1
`0
`0
`⬍ 1
`0
`0
`0
`⬍ 1
`
`Abbreviations: AE, adverse event; MCL, mantle-cell lymphoma.
`ⴱDenotes one grade 5 event per AE.
`†Two grade 5 pneumonia events.
`
`cycle 11. TFRs were managed with steroids, analgesics, or nonsteroidal
`anti-inflammatory agents without interruption or modification of
`lenalidomide dosing. There were no reports of TLS. Ten patients (7%)
`reported venous TEEs (seven grade 3 to 4), including five grade 3 to 4
`deep vein thrombosis, three pulmonary embolisms (one grade 2; two
`grade ⱖ 3), and one each with grade 2 thrombophlebitis and grade 2
`venous thrombosis. Further analysis indicated that 35 patients (26%)
`in this study received no prophylaxis; two (6%) of whom developed
`TEEs. Of the 99 patients who received prophylaxis, eight (8%) of 99
`developed TEEs. Of these 99 patients, 81% received aspirin, eight
`received LMWH, and nine received warfarin. Treatment-related seri-
`ous AEs were reported in 26 patients (19%); pneumonia was the most
`common in nine patients (7%), and all others were reported in less
`than 5% of patients.
`At a median 13.4-month follow-up, six SPMs (4.5%) were re-
`ported, including three invasive SPMs consisting of one MDS in a
`patient with prior ASCT and two solid tumors (one metastatic colon
`cancer; one squamous cell carcinoma of skin metastasized to cervical
`lymph node) for an overall incidence rate of 2.21 per 100 person-years.
`Median time to SPM diagnosis from initiation of lenalidomide was 7.3
`months (range, 3.1 to 9.7 months). Time to onset was 3.1 months for
`MDS, 7.3 months for metastatic squamous cell carcinoma, and 9.7
`months for colon cancer. Four patients showed noninvasive nonmela-
`noma skin cancer, including one patient with noninvasive skin carci-
`noma that progressed to metastatic squamous cell carcinoma. There
`were no reports of acute lymphocytic leukemia, Hodgkin lymphoma,
`or diffuse large B-cell lymphoma. Four of six patients with SPMs were
`alive at data cutoff; two died as a result of PD from MCL.
`Eighteen patients (13%) died within 30 days of the last dose of
`lenalidomide, 14 of 18 as a result of MCL progression. Other causes
`included one possibly treatment-related toxicity (Pseudomonas
`aeruginosa and neutropenic sepsis) and one unknown cause of death;
`deaths unrelated to lenalidomide were one PD/pneumonia and one
`non-neutropenic sepsis. Of 18 patients who died, nine were ⱖ 70 years
`of age and eight had received one or fewer cycles of lenalidomide
`(including two of four patients with other causes of death).
`
`DISCUSSION
`
`The MCL-001 trial results demonstrate the efficacy of lenalidomide in a
`large series of 134 patients with heavily pretreated relapsed/
`refractory MCL (median of four prior therapies; range, two to 10
`
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