T h e ne w e ngl a nd jou r na l o f m e dicine
`
`original article
`
`Targeting BTK with Ibrutinib in Relapsed
`or Refractory Mantle-Cell Lymphoma
`Michael L. Wang, M.D., Simon Rule, M.D., Peter Martin, M.D., Andre Goy, M.D.,
`Rebecca Auer, M.D., Ph.D., Brad S. Kahl, M.D., Wojciech Jurczak, M.D., Ph.D.,
`Ranjana H. Advani, M.D., Jorge E. Romaguera, M.D., Michael E. Williams, M.D.,
`Jacqueline C. Barrientos, M.D., Ewa Chmielowska, M.D., John Radford, M.D.,
`Stephan Stilgenbauer, M.D., Martin Dreyling, M.D., Wieslaw Wiktor Jedrzejczak, M.D.,
`Peter Johnson, M.D., Stephen E. Spurgeon, M.D., Lei Li, Ph.D.,
`Liang Zhang, M.D., Ph.D., Kate Newberry, Ph.D., Zhishuo Ou, M.D.,
`Nancy Cheng, M.S., Bingliang Fang, Ph.D., Jesse McGreivy, M.D., Fong Clow, Sc.D.,
`Joseph J. Buggy, Ph.D., Betty Y. Chang, Ph.D., Darrin M. Beaupre, M.D., Ph.D.,
`Lori A. Kunkel, M.D., and Kristie A. Blum, M.D.
`
`ABS TR ACT
`
`BACKGROUND
`Bruton’s tyrosine kinase (BTK) is a mediator of the B-cell–receptor signaling path-
`way implicated in the pathogenesis of B-cell cancers. In a phase 1 study, ibrutinib,
`a BTK inhibitor, showed antitumor activity in several types of non-Hodgkin’s lym-
`phoma, including mantle-cell lymphoma.
`METHODS
`In this phase 2 study, we investigated oral ibrutinib, at a daily dose of 560 mg, in
`111 patients with relapsed or refractory mantle-cell lymphoma. Patients were en-
`rolled into two groups: those who had previously received at least 2 cycles of bor-
`tezomib therapy and those who had received less than 2 complete cycles of bortezo-
`mib or had received no prior bortezomib therapy. The primary end point was the
`overall response rate. Secondary end points were duration of response, progression-
`free survival, overall survival, and safety.
`RESULTS
`The median age was 68 years, and 86% of patients had intermediate-risk or high-risk
`mantle-cell lymphoma according to clinical prognostic factors. Patients had received a
`median of three prior therapies. The most common treatment-related adverse events
`were mild or moderate diarrhea, fatigue, and nausea. Grade 3 or higher hematologic
`events were infrequent and included neutropenia (in 16% of patients), thrombocytope-
`nia (in 11%), and anemia (in 10%). A response rate of 68% (75 patients) was observed,
`with a complete response rate of 21% and a partial response rate of 47%; prior treat-
`ment with bortezomib had no effect on the response rate. With an estimated median
`follow-up of 15.3 months, the estimated median response duration was 17.5 months
`(95% confidence interval [CI], 15.8 to not reached), the estimated median progression-
`free survival was 13.9 months (95% CI, 7.0 to not reached), and the median overall
`survival was not reached. The estimated rate of overall survival was 58% at 18 months.
`CONCLUSIONS
`Ibrutinib shows durable single-agent efficacy in relapsed or refractory mantle-cell
`lymphoma. (Funded by Pharmacyclics and others; ClinicalTrials.gov number,
`NCT01236391.)
`
`The authors’ affiliations are listed in the
`Appendix. Address reprint requests to
`Dr. Wang at the University of Texas M.D.
`Anderson Cancer Center, 1515 Hol-
`combe Blvd., Unit 429, Houston, TX
`77030, or at miwang@mdanderson.org.
`
`This article was published on June 19, 2013,
`at NEJM.org.
`
`N Engl J Med 2013.
`DOI: 10.1056/NEJMoa1306220
`Copyright © 2013 Massachusetts Medical Society.
`
`n engl j med nejm.org
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`The New England Journal of Medicine
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` Copyright © 2013 Massachusetts Medical Society. All rights reserved.
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`Exhibit 2003 Page 001
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`Pharmacyclics LLC - Ex. 2003
`Coalition for Affordable Drugs IV LLC v. Pharmacyclics LLC
`Case IPR2015-01076
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`

`

`T h e ne w e ngl a nd jou r na l o f m e dicine
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`Mantle-cell lymphoma is a distinct
`
`subtype of non-Hodgkin’s lymphoma
`that has an aggressive clinical course
`and a poor prognosis.1 Current frontline combi-
`nation chemotherapies2 and intensive chemoim-
`munotherapy followed by stem-cell transplanta-
`tion have improved the outcome for patients with
`this disease.3,4 Although these regimens have
`high initial response rates, most patients eventu-
`ally have a relapse and die from mantle-cell lym-
`phoma. More effective agents are needed.
`Constitutive activation of B-cell receptor signal-
`ing appears to be essential for the survival and
`proliferation of malignant B cells, an observation
`that has led to the design of inhibitors of B-cell
`receptor–associated kinases.3-5 Bruton’s tyrosine
`kinase (BTK) has been identified as an essential
`component of the B-cell–receptor signaling path-
`way.6-9 An antigen-driven origin of mantle-cell
`lymphoma has been suggested,10 and genomic and
`expression profiling of samples from patients with
`mantle-cell lymphoma has identified proteins up-
`stream of BTK, such as the spleen tyrosine kinase
`Syk, as important contributors to the growth and
`survival of mantle-cell lymphoma cells.11
`Ibrutinib (PCI-32765) is an oral covalent inhibi-
`tor of BTK that significantly reduced the tumor
`burden in a rodent treatment and prevention
`model of mantle-cell lymphoma.12 In early-stage
`clinical trials, ibrutinib has shown antitumor
`activity in B-cell cancers.13-15 In a phase 1 study,
`ibrutinib induced a response in seven of nine
`patients with relapsed or refractory mantle-cell
`lymphoma; investigation of the side effects and
`efficacy at various doses in this study established
`560 mg as the phase 2 dose.14 On the basis of
`these results, we conducted a phase 2, open-label
`trial to assess the efficacy and safety of ibrutinib
`at a daily dose of 560 mg in patients with relapsed
`or refractory mantle-cell lymphoma.
`
`Methods
`
`PATIENTS
`Eligible patients had a confirmed diagnosis of
`mantle-cell lymphoma with cyclin D1 overex-
`pression or translocation breakpoints at t(11;14)
`and measurable disease (lymph-node diameter,
`≥2 cm). Patients had received at least one but no
`more than five previous lines of treatment, with
`no partial or better response to the most recent
`
`treatment regimen or with disease progression
`after the most recent regimen.
`Other eligibility criteria included an Eastern Co-
`operative Oncology Group (ECOG) performance
`status of 2 or less (scores range from 0 to 5, with
`0 indicating asymptomatic and higher numbers
`indicating increasing disability) and adequate or-
`gan function. An absolute neutrophil count of at
`least 0.75×109 per liter and a platelet count of at
`least 50×109 per liter were required unless the pa-
`tient had bone marrow involvement by lymphoma.
`
`STUDY DESIGN AND TREATMENT
`This international open-label, phase 2 study was
`conducted at 18 sites. Patients with mantle-cell
`lymphoma were enrolled without randomization
`and were classified as either having received treat-
`ment with bortezomib (≥2 cycles) or not having
`received such treatment (<2 complete cycles or no
`prior bortezomib therapy). Single-agent bortezo-
`mib is a treatment approved by the Food and
`Drug Administration for patients with mantle-
`cell lymphoma that has progressed after at least
`one initial treatment. Therefore, a defined cohort
`of patients with prior bortezomib treatment was
`included in this study, and the combination of the
`two cohorts was representative of a broad popu-
`lation of patients with relapsed or refractory man-
`tle-cell lymphoma. Patients received single-agent
`ibrutinib administered orally at a daily dose of
`560 mg until progression of disease or until un-
`acceptable levels of adverse events occurred. All
`the patients provided written informed consent.
`The institutional review board at each site ap-
`proved the study protocol, which was conducted
`according to the principles of the Declaration of
`Helsinki and the International Conference on Har-
`monisation Guidelines for Good Clinical Prac-
`tice. The protocol, including the statistical analy-
`sis plan, is available with the full text of this
`article at NEJM.org.
`
`STUDY OVERSIGHT
`The academic authors were responsible for design-
`ing the study protocol and statistical analysis
`plan together with the sponsor, Pharmacyclics.
`The investigators and their respective research
`teams collected all the data, and the sponsor con-
`firmed the accuracy of the data and compiled
`them for summation and analysis. Statistical anal-
`yses were performed by the biometrics group at
`
`2
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`The New England Journal of Medicine
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`Ibrutinib in Mantle-Cell Lymphoma
`
`Janssen Research and Development and were in-
`dependently confirmed and validated by a sepa-
`rate statistical group at Pharmacyclics. The inves-
`tigators had full access to the data and analyses
`for the compilation of this report. Manuscript
`drafts were prepared by all the authors, with edi-
`torial assistance from a professional medical
`writer paid by the sponsor. All the authors vouch
`for the accuracy and completeness of the data
`reported and for the adherence of the study to
`the protocol, and all the authors made the deci-
`sion to submit the manuscript for publication.
`
`ASSESSMENTS
`The primary end point was the rate of overall
`response, defined as either a partial response or
`a complete response according to the Revised In-
`ternational Working Group Criteria for non-
`Hodgkin’s lymphoma.16 In addition, a response
`evaluation based on computed tomographic (CT)
`and positron-emission tomographic (PET) scans,
`bone marrow–biopsy specimens, gastrointestinal
`biopsy specimens (if a gastrointestinal biopsy was
`performed), and clinical data was conducted by an
`independent central review vendor (BioClinica).
`Tumor assessment was performed during screen-
`ing with the use of CT scans of the chest, abdomen,
`pelvis, and any other disease sites (e.g., neck);
`PET scans; and bone marrow biopsy. CT scan-
`ning was repeated at cycles 3, 5, and 7 and then
`every three cycles until disease progression. A
`PET scan was mandatory for confirmation of a
`complete response.
`The secondary end points included response
`duration, measured from the time when the crite-
`ria for a response were met until the first date on
`which recurrent or progressive disease was objec-
`tively documented; progression-free survival, mea-
`sured as the time from the first administration
`of the study drug until lymphoma progression or
`death from any cause; overall survival, measured
`from the time of the first administration of the
`study drug until the date of death; and safety.
`Safety was assessed on the basis of the frequency
`and severity of adverse events. Adverse events
`were graded according to the National Cancer
`Institute’s Common Terminology Criteria for Ad-
`verse Events, version 4.0.17 The safety assessment
`was based on reported adverse events, clinical labo-
`ratory tests (hematologic testing, serum chemical
`testing, and urinalysis), measurements of weight
`
`and vital signs, physical examinations, and ECOG
`performance status.
`
`PERIPHERAL-BLOOD LYMPHOCYTE COUNTS
`In chronic lymphocytic leukemia, ibrutinib causes
`a transient increase in blood lymphocytes that is
`concurrent with a reduction in lymph-node size.15
`Whether a similar phenomenon occurs in patients
`with mantle-cell lymphoma was investigated by
`counting and characterizing peripheral-blood lym-
`phocytes after treatment with ibrutinib (see the
`Supplementary Appendix, available at NEJM.org).
`The effect of ibrutinib on cytokine expression was
`also evaluated in a subset of patients (see the Sup-
`plementary Appendix).
`
`STATISTICAL ANALYSIS
`The sample for this study was 115 patients; we
`planned to include 65 patients with no prior treat-
`ment with bortezomib and 50 with prior bort-
`ezomib treatment. With the use of Simon’s two-
`stage design18 (see the study protocol), the study
`was designed to check the efficacy of the drug in
`a small group of patients before enrolling the en-
`tire planned study population. If an appropriate
`number of patients had a response in the first
`stage (see below), then we would continue enroll-
`ment; if the level of response did not meet our
`success criteria for clinical benefit, the study
`would be terminated for that group.
`For the cohort of patients without prior treat-
`ment with bortezomib, a two-stage design was
`planned to test the null hypothesis that the
`response rate would be 20% or less (i.e., before
`the investigators could proceed to stage 2 of the
`study, at least 6 of 25 patients had to have a re-
`sponse). We calculated that a sample of 65 pa-
`tients would provide 91% power to test a differ-
`ence in the response rate of 20% versus 40% at
`a one-sided alpha level of 0.01. For the cohort of
`patients with prior bortezomib treatment, a two-
`stage design was planned to test the null hypoth-
`esis that the response rate would be 15% or less
`(i.e., before the investigators could proceed to
`stage 2 of the study, at least 5 of 25 patients had
`to have a response). We calculated that a sam-
`ple of 50 patients would provide 80% power to
`test a difference in the response rate of 15%
`versus 35% at a one-sided alpha level of 0.01.
`In each cohort, an interim analysis for futility
`was conducted on the basis of the stopping rules
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`T h e ne w e ngl a nd jou r na l o f m e dicine
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`for Simon’s two-stage design.18 On the basis of this
`interim analysis, enrollment in both study cohorts
`was allowed to continue, per protocol.
`The final analysis was planned to be performed
`approximately 8 months after the last patient was
`enrolled in the study. Frequency tables were used
`
`to summarize categorical variables. The distribu-
`tion of time-to-event end points, including re-
`sponse duration, progression-free survival, and
`overall survival, were estimated with the use of the
`Kaplan–Meier method.19 All statistical tests were
`based on a two-sided alpha level of 0.05.
`
`Table 1. Demographic and Baseline Clinical Characteristics.*
`
`Characteristic
`
`Age — yr
`Median
`Range
`Sex — no. (%)
`Male
`Female
`ECOG performance status — no. (%)‡
`0 or 1
`2
`>2
`No. of prior regimens
`Median
`Range
`≥3 — no. (%)
`Previous therapy — no. (%)
`Hyper-CVAD
`Stem-cell transplantation
`Lenalidomide
`Rituximab or rituximab-containing regimen
`Simplified MIPI — no. (%)§
`Low risk
`Intermediate risk
`High risk
`Bulky mass — no. (%)¶
`At least one node ≥5 cm — no. (%)
`Refractory disease — no. (%)‖
`Advanced disease — no. (%)**
`
`No Prior Treatment
`with Bortezomib
`(N = 63)
`
`Prior Treatment
`with Bortezomib
`(N = 48)
`
`All Patients
`(N = 111)†
`
`66
`46–83
`
`46 (73)
`17 (27)
`
`53 (84)
`9 (14)
`1 (2)
`
`2
`1–5
`31 (49)
`
`18 (29)
`8 (13)
`9 (14)
`56 (89)
`
`9 (14)
`24 (38)
`30 (48)
`6 (10)
`26 (41)
`27 (43)
`49 (78)
`
`69
`40–84
`
`39 (81)
`9 (19)
`
`46 (96)
`2 (4)
`0
`
`3
`1–5
`30 (62)
`
`15 (31)
`4 (8)
`18 (38)
`43 (90)
`
`6 (12)
`18 (38)
`24 (50)
`3 (6)
`17 (35)
`23 (48)
`31 (65)
`
`68
`40–84
`
`85 (77)
`26 (23)
`
`99 (89)
`11 (10)
`1 (1)
`
`3
`1–5
`61 (55)
`
`33 (30)
`12 (11)
`27 (24)
`99 (89)
`
`15 (14)
`42 (38)
`54 (49)
`9 (8)
`43 (39)
`50 (45)
`80 (72)
`
`* Percentages may not add up to 100% because of rounding. Hyper-CVAD denotes hyperfractionated cyclophospha-
`mide, vincristine, doxorubicin, and dexamethasone.
`† Four patients who were enrolled in the study did not receive ibrutinib treatment owing to the investigator’s decision.
`‡ Eastern Cooperative Oncology Group (ECOG) performance-status scores range from 0 to 5, with 0 indicating asymp-
`tomatic, 1 symptomatic but ambulatory, and 2 symptomatic and in bed less than half the day; a score of more than 2
`indicates only limited self-care and in bed more than half the day (3), completely disabled and confined to bed or chair
`(4), or dead (5).
`§ The simplified Mantle-Cell Lymphoma International Prognostic Index (MIPI) score was derived with the use of the four
`prognostic factors of age, ECOG score, lactate dehydrogenase level, and white-cell count at baseline, and its range de-
`pends on the range of these characteristics. The index classifies patients as having low-, intermediate-, or high-risk dis-
`ease, as defined by scores of 0 to 3, 4 or 5, and 6 to 11, respectively.
`¶ Bulky mass was defined as a tumor with a diameter of at least 10 cm.
`‖ Refractory disease was defined as a lack of at least a partial response to the last therapy before study entry.
`** Advanced disease was defined as involvement of bone marrow, extranodal sites, or both.
`
`4
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`The New England Journal of Medicine
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`Downloaded from nejm.org on June 19, 2013. For personal use only. No other uses without permission.
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` Copyright © 2013 Massachusetts Medical Society. All rights reserved.
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`Exhibit 2003 Page 004
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`Ibrutinib in Mantle-Cell Lymphoma
`
`R esults
`
`PATIENTS AND TREATMENT
`From February 15, 2011, through March 21,
`2012, a total of 115 patients with relapsed or re-
`fractory mantle-cell lymphoma were enrolled
`without randomization. We classified patients
`into two groups: patients with prior bortezomib
`treatment (50 patients) or no prior bortezomib
`treatment (65 patients, including 58 who had
`never received bortezomib and 7 who had re-
`ceived fewer than two cycles). The baseline char-
`acteristics of the patients in the two groups are
`provided in Table 1.
`Of the 115 enrolled patients, 3 (2 patients with
`prior bortezomib treatment and 1 without prior
`treatment) did not receive the study drug owing
`to rapid disease progression, and 1 was not treated
`for administrative reasons. A total of 111 patients
`received at least one dose of ibrutinib, and the
`median number of cycles administered in the
`overall study population was 9 (range, 1 to 24).
`
`With an estimated median follow-up of 15.3
`months (range, 1.9 to 22.3), 46 patients were still
`receiving treatment, and 65 had discontinued
`therapy. Reasons for treatment discontinuation
`included progression of disease in 50 patients
`(including 2 patients who discontinued treatment
`within 30 days after the first dose and 1 with un-
`confirmed progression of disease), patient or in-
`vestigator decision for 7 patients (including 1 pa-
`tient who proceeded to stem-cell transplantation),
`and adverse events in 8 patients (including 2 pa-
`tients with subdural hematomas, and 1 each with
`pneumonia, an elevated bilirubin level, sepsis,
`metastatic adenocarcinoma, respiratory failure,
`and cardiac arrest) (Table S1 in the Supplementary
`Appendix).
`
`SAFETY
`With continuous ibrutinib treatment, the major-
`ity of the adverse events observed were grade 1 or
`2. The most common nonhematologic adverse
`events occurring in more than 20% of patients
`
`Table 2. Adverse Events.*
`
`Event
`
`Grade 1
`
`Grade 2
`
`Grade 3
`
`Grade 4
`
`Grade 5
`
`Overall
`
`no. of patients with event (%)
`
`Hematologic event
`
`Neutropenia
`
`Thrombocytopenia
`
`Nonhematologic event
`
`Diarrhea
`
`Fatigue
`
`Nausea
`
`Peripheral edema
`
`Dyspnea
`
`1 (1)
`
`4 (4)
`
`36 (32)
`
`22 (20)
`
`26 (23)
`
`21 (19)
`
`14 (13)
`
`1 (1)
`
`4 (4)
`
`13 (12)
`
`19 (17)
`
`8 (7)
`
`8 (7)
`
`11 (10)
`
`7 (6)
`
`8 (7)
`
`7 (6)
`
`5 (5)
`
`0
`
`1 (1)
`
`4 (4)
`
`11 (10)
`
`4 (4)
`
`0
`
`0
`
`0
`
`1 (1)
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
`1 (1)
`
`20 (18)
`
`20 (18)
`
`56 (50)
`
`46 (41)
`
`34 (31)
`
`31 (28)
`
`30 (27)
`
`28 (25)
`
`Constipation
`
`20 (18)
`
`Upper respiratory tract infection
`
`6 (5)
`
`Vomiting
`
`Decreased appetite
`
`Cough
`
`Pyrexia
`
`Abdominal pain
`
`Contusion
`
`Rash
`
`19 (17)
`
`11 (10)
`
`13 (12)
`
`14 (13)
`
`10 (9)
`
`17 (15)
`
`11 (10)
`
`8 (7)
`
`20 (18)
`
`6 (5)
`
`10 (9)
`
`7 (6)
`
`5 (5)
`
`3 (3)
`
`2 (2)
`
`4 (4)
`
`0
`
`0
`
`0
`
`2 (2)
`
`0
`
`1 (1)
`
`6 (5)
`
`0
`
`2 (2)
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
`26 (23)
`
`25 (23)
`
`23 (21)
`
`20 (18)
`
`20 (18)
`
`19 (17)
`
`19 (17)
`
`17 (15)
`
`* Data are for adverse events reported during treatment in the 111 patients included in the study. Listed events occurred
`in at least 15% of patients on or before the data-cutoff date of December 26, 2012. For four events (one event each of
`diarrhea, depression, asthenia, and hypersomnia), the grade was not available; these four events are included in the
`grade 3 category.
`
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`T h e ne w e ngl a nd jou r na l o f m e dicine
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`were diarrhea (in 50% of patients), fatigue (in 41%),
`nausea (in 31%), peripheral edema (in 28%), dys-
`pnea (in 27%), constipation (in 25%), upper respi-
`ratory tract infection (in 23%), vomiting (in 23%),
`and decreased appetite (in 21%) (Table 2). The
`most common infection of grade 3, 4, or 5 was
`pneumonia (in 6% of patients) (Table S2 in the
`Supplementary Appendix). Serum IgM, IgG, and
`IgA levels did not change during treatment (data
`not shown). A decrease in neutrophils, platelets,
`or hemoglobin level was reported in less than
`19% of patients.
`Grade 3 and 4 hematologic adverse events in-
`cluded neutropenia (in 16% of patients), throm-
`bocytopenia (in 11%), and anemia (in 10%).
`Grade 3 bleeding events occurred in five patients,
`with no grade 4 or 5 hemorrhagic events (Table
`S2 in the Supplementary Appendix). Four patients
`had subdural hematomas (grade 1 in one patient,
`grade 2 in one, and grade 3 in two); all were as-
`sociated with falls, head trauma, or both. In ad-
`dition, all four patients were receiving either aspi-
`rin or warfarin within 2 days before or on the
`date of occurrence of these events.
`An adverse event leading to discontinuation
`
`Table 3. Best Response to Therapy.*
`
`Variable
`
`Response — no. (%)
`
`Overall
`
`Complete
`
`Partial
`
`None†
`
`Response duration — mo
`
`Median
`
`95% CI
`
`Progression-free survival
`— mo
`
`Median
`
`95% CI
`
`Overall survival — mo
`
`Median
`
`95% CI
`
`No Prior Treatment
`with Bortezomib
`(N = 63)
`
`Prior Treatment
`with Bortezomib
`(N = 48)
`
`All Patients
`(N = 111)
`
`43 (68)
`
`12 (19)
`
`31 (49)
`
`20 (32)
`
`15.8
`
`5.6–NR
`
`7.4
`
`5.3–19.2
`
`NR
`
`10.0–NR
`
`32 (67)
`
`11 (23)
`
`21 (44)
`
`15 (31)
`
`75 (68)
`
`23 (21)
`
`52 (47)
`
`35 (32)
`
`NR
`
`17.5
`
`NR–NR
`
`15.8–NR
`
`16.6
`
`8.3–NR
`
`13.9
`
`7.0–NR
`
`NR
`
`NR
`
`11.9–NR
`
`13.2–NR
`
`* Response data included only those patients who received ibrutinib and had at
`least one postbaseline efficacy assessment. CI denotes confidence interval,
`and NR not reached.
`† No response was defined as stable or progressive disease.
`
`of therapy occurred in 8 patients (7%) (Table S1
`in the Supplementary Appendix). A total of 16 pa-
`tients (14%) died during the trial, with 12 deaths
`due to disease progression and 4 due to an ad-
`verse event (2 deaths from pneumonia, 1 from
`sepsis, and 1 from a cardiac arrest that was
`deemed not to be drug-related).
`
`EFFICACY
`In the 111 patients who had received ibrutinib,
`the estimated median follow-up was 15.3 months
`(range, 1.9 to 22.3). The response rate for all pa-
`tients was 68%, with 47% of patients having a
`partial response and 21% having a complete re-
`sponse (Table 3). The response to ibrutinib did
`not vary on the basis of baseline characteristics
`or the presence of risk factors associated with
`treatment failure with chemotherapy (Fig. 1). Of
`43 patients with lymph nodes that were at least
`5 cm in diameter, 27 (63%) had a response to
`treatment (Fig. S1 in the Supplementary Appen-
`dix). Response rates were similar in the two co-
`horts, and 17 of 27 patients (63%) previously
`treated with lenalidomide had a response to ibru-
`tinib. The overall response rate and the complete
`response rate also improved over time with con-
`tinued therapy.
`For the 75 patients who had a response at the
`time of data analysis, the estimated median re-
`sponse duration was 17.5 months (range, 0.0 to
`19.6; 95% confidence interval [CI], 15.8 to not
`reached) (Fig. 2A and Table 3). The median time
`to a response was 1.9 months (range, 1.4 to 13.7),
`and the median time to a complete response was
`5.5 months (range, 1.7 to 11.5). The estimated
`median progression-free survival among all treat-
`ed patients was 13.9 months (range, 0.7 to 21.4;
`95% CI, 7.0 to not reached) (Fig. 2B and Table 3).
`The median progression-free survival for pa-
`tients who had a partial response as the best
`response was 17.5 months, and the median
`progression-free survival for those who had a
`complete response was not reached. The median
`overall survival for this study was also not
`reached (estimated overall survival rate of 58%
`at 18 months) (Fig. 2C and Table 3).
`The efficacy data, which were further evalu-
`ated by an independent review committee,
`showed a response rate of 69%, with a complete
`response rate of 21% and a partial response rate
`of 48%. For 95% of patients with an investiga-
`tor-assessed response, the response was con-
`
`6
`
`n engl j med nejm.org
`
`The New England Journal of Medicine
`
`Downloaded from nejm.org on June 19, 2013. For personal use only. No other uses without permission.
`
` Copyright © 2013 Massachusetts Medical Society. All rights reserved.
`
`Exhibit 2003 Page 006
`
`

`

`Ibrutinib in Mantle-Cell Lymphoma
`
`Subgroup
`
`No.ofPatients
`
`OverallResponseRate(95%CI)
`
`67.6 (58.9–76.3)
`
`68.3 (54.1–82.5)
`67.1 (56.1–78.2)
`
`68.3 (56.8–79.8)
`66.7 (53.3–80.0)
`
`70.6 (60.9–80.3)
`57.7 (38.7–76.7)
`
`66.7 (57.5–75.8)
`77.8 (50.6–100.0)
`
`76.0 (64.2–87.8)
`60.7 (48.4–72.9)
`
`73.3 (51.0–95.7)
`66.7 (52.4–80.9)
`66.7 (54.1–79.2)
`
`72.6 (60.3–84.8)
`64.6 (51.1–78.1)
`58.3 (30.4–86.2)
`
`65.0 (54.6–75.5)
`74.2 (58.8–89.6)
`
`62.8 (48.3–77.2)
`66.7 (35.9–97.5)
`
`70.6 (48.9–92.3)
`67.0 (57.5–76.5)
`
`64.0 (50.7–77.3)
`70.5 (59.1–81.9)
`
`76.9 (63.7–90.2)
`62.5 (51.3–73.7)
`
`63.0 (44.8–81.2)
`69.1 (59.2–78.9)
`
`111
`
`41
`70
`
`63
`48
`
`85
`26
`
`102
`9
`
`50
`61
`
`15
`42
`54
`
`51
`48
`12
`
`80
`31
`
`43
`9
`
`17
`94
`
`50
`61
`
`39
`72
`
`27
`84
`
`All patients
`Age
`<65 yr
`≥65 yr
`Bortezomib exposure
`No
`Yes
`Sex
`Male
`Female
`Race
`White
`Nonwhite
`No. of previous regimens
`<3
`≥3
`Simplified MIPI score
`Low risk (0–3)
`Intermediate risk (4 or 5)
`High risk (6–11)
`Baseline ECOG performance status
`
`0 1 ≥
`
`2
`Advanced disease
`Yes
`No
`Tumor bulk (largest diameter)
`≥5 cm
`≥10 cm
`History of blastoid
`Yes
`No
`Refractory disease
`Yes
`No
` Previous high-intensity therapy
`Yes
`No
`Previous lenalidomide therapy
`Yes
`No
`
`0
`
`20
`
`40
`
`60
`
`80
`
`100
`
`Percent
`
`Figure 1. Overall Response Rates According to Subgroup.
`This forest plot of data for all treated patients shows the overall response rate according to demographic and clini-
`cal characteristics and risk factors. The 95% confidence intervals (CIs) are based on normal approximation to the
`binomial distribution. The simplified Mantle-Cell Lymphoma International Prognostic Index (MIPI) score ranges
`from 0 to 11 and was derived with the use of the four prognostic factors of age, Eastern Cooperative Oncology
`Group (ECOG) performance-status score, lactate dehydrogenase level, and white-cell count at baseline. The index
`classifies patients as having low-, intermediate-, or high-risk disease, as defined by scores of 0 to 3, 4 or 5, and 6 to
`11, respectively. ECOG performance-status scores range from 0 to 5, with 0 indicating asymptomatic, 1 symptomat-
`ic but ambulatory, and 2 symptomatic and in bed less than half the day; a score of more than 2 indicates only limit-
`ed self-care and in bed more than half the day (3), completely disabled and confined to bed or chair (4), or dead (5).
`Advanced disease was defined as involvement of bone marrow, extranodal sites, or both; and refractory disease as
`a lack of at least a partial response to the last therapy before study entry. High-intensity therapy was defined as
`stem-cell transplantation; treatment with hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexa-
`methasone (hyper-CVAD); or treatment with a hyper-CVAD–like regimen.
`
`n engl j med nejm.org
`
`7
`
`The New England Journal of Medicine
`
`Downloaded from nejm.org on June 19, 2013. For personal use only. No other uses without permission.
`
` Copyright © 2013 Massachusetts Medical Society. All rights reserved.
`
`Exhibit 2003 Page 007
`
`

`

`T h e ne w e ngl a nd jou r na l o f m e dicine
`
`Figure 2. Duration of Response, Progression-free Sur-
`vival, and Overall Survival.
`Panel A shows the duration of the response (shown as
`the percentage of patients alive without progression of
`disease) for the 75 patients who had a response; the
`estimated median duration was 17.5 months. For the
`43 patients in the cohort without prior bortezomib
`treatment who had a response, the estimated median
`duration was 15.8 months. For the 32 patients in the
`cohort with prior bortezomib treatment who had a re-
`sponse, the median duration was not reached. Panel B
`shows progression-free survival for all 111 treated pa-
`tients, according to cohort. In this analysis, data from
`the 1 patient who received subsequent anticancer
`therapy before progression of disease were censored
`at the time of the start of that therapy. For all patients,
`the estimated median progression-free survival was
`13.9 months; for the 63 patients without prior borte z-
`omib treatment and for the 48 with prior bortezomib
`treatment, the estimated median progression-free sur-
`vival was 7.4 and 16.6 months, respectively. Panel C
`shows the results of the overall-survival analysis per-
`formed at the time of the primary analysis of progres-
`sion-free survival, when 70 patients (63%) were alive.
`The median overall survival was not reached.
`
`firmed by the independent review committee.
`The median response duration estimated by the
`independent review committee was 19.6 months.
`
`MANTLE-CELL LYMPHOMA CELLS IN PERIPHERAL
`BLOOD
`Ibrutinib has been shown to inhibit the adhesion
`of chronic lymphocytic leukemia cells20 and man-
`tle-cell lymphoma cells21 in vitro, suggesting the
`potential to mobilize cells from tissues to the
`peripheral blood. The findings in a mouse model
`bearing human mantle-cell lymphoma cells en-
`grafted in subcutaneously implanted human fetal
`bone22 were consistent with these observations,
`revealing a substantial increase in mantle-cell
`lymphoma cells in the peripheral blood 10 days
`after ibrutinib treatment, followed by a decrease
`to near baseline by day 28 (data not shown). A to-
`tal of 34% of patients had a transient increase in
`the absolute lymphocyte count (≥50% increase
`from baseline and >5000 cells per cubic millime-
`ter) during the course of ibrutinib treatment, with
`the peak count occurring at a median of 4 weeks
`after the initiation of treatment (Fig. S2 in the Sup-
`plementary Appendix). Toward the end of the sec-
`ond cycle, the elevated lymphocyte levels decreased
`substantially and tapered off during cycle 4 or 5.
`Peripheral-blood mononuclear cells obtained
`from patients before treatment and 1 week
`
`All
`Bortezomib exposure
`No bortezomib exposure
`Censored
`
`0
`4
`8
`12
`16
`20
`MonthssinceFirstDocumentationofResponse
`
`100
`90
`80
`70
`60
`50
`40
`30
`20
`10
`0
`
`PatientsAlivewithoutProgression(%)
`
`000
`
`336
`
`30
`26
`56
`
`23
`17
`40
`
`15
`9
`24
`
`No.atRisk
`No bortezomib exposure
`Bortezomib exposure
`All
`
`43
`32
`75
`
`All
`Bortezomib exposure
`No bortezomib exposure
`Censored
`
`0
`
`4
`
`8
`12
`16
`MonthssinceFirstDose
`
`20
`
`24
`
`100
`90
`80
`70
`60
`50
`40
`30
`20
`10
`0
`
`Progression-freeSurvival(%)
`
`000
`
`022
`
`63
`48
`111
`
`44
`37
`81
`
`28
`29
`57
`
`19
`14
`33
`
`12
`10
`22
`
`No.atRisk
`No bortezomib exposure
`Bortezomib exposure
`All
`
`All
`Bortezomib exposure
`No bortezomib exposure
`Censored
`
`0
`
`4
`
`8
`12
`16
`MonthssinceFirstDose
`
`20
`
`24
`
`100
`90
`80
`70
`60
`50
`40
`30
`20
`10
`0
`
`OverallSurvival(%)
`
`000
`
`145
`
`63
`48
`111
`
`55
`43
`98
`
`39
`37
`76
`
`30
`21
`51
`
`19
`13
`32
`
`No.atRisk
`No bortezomib exposure
`Bortezomib exposure
`All
`
`A
`
`B
`
`C
`
`8
`
`n engl j med nejm.org
`
`The New England Journal of Medicine
`
`Downloaded from nejm.org on June 19, 2013. For personal use only. No other uses without permission.
`
` Copyright © 2013 Massachusetts Medical Society. All rights reserved.
`
`Exhibit 2003 Page 008
`
`

`

`Ibrutinib in Mantle-Cell Lymphoma
`
` after treatment were subjected to triple stain-
`ing for CD19, CD5, and CD3 and analyzed by
`means of flow cytometry. The increase in pe-
`riph eral-blood lymphocytes included primarily
`CD19+CD5+CD3− lymphocytes (data not shown).
`The peripheral-blood CD19+CD5+CD3− cells
`showed a pattern of light-chain restriction,
`which was consistent with the presence of
`mantle-cell lymphoma cells in the peripheral
`blood, after 1 week of ibrutinib therapy. Ibruti-
`nib treatment also led to a decrease in the secre-
`tion of macrophage inflammatory proteins 1α
`(CCL3) and 1β (CCL4), macrophage-derived che-
`mokine (CCL22), and tumor necrosis factor α in
`most of the patients who were evaluated (Fig. S2
`in the Sup