T h e ne w e ngl a nd jou r na l o f m e dicine
`
`Original Article
`
`Phase 3 Trial of 177Lu-Dotatate for Midgut
`Neuroendocrine Tumors
`J. Strosberg, G. El-Haddad, E. Wolin, A. Hendifar, J. Yao, B. Chasen, E. Mittra,
`P.L. Kunz, M.H. Kulke, H. Jacene, D. Bushnell, T.M. O’Dorisio, R.P. Baum,
`H.R. Kulkarni, M. Caplin, R. Lebtahi, T. Hobday, E. Delpassand, E. Van Cutsem,
`A. Benson, R. Srirajaskanthan, M. Pavel, J. Mora, J. Berlin, E. Grande, N. Reed,
`E. Seregni, K. Öberg, M. Lopera Sierra, P. Santoro, T. Thevenet, J.L. Erion,
`P. Ruszniewski, D. Kwekkeboom, and E. Krenning, for the NETTER-1 Trial Investigators*
`
`ABSTR ACT
`
`BACKGROUND
`Patients with advanced midgut neuroendocrine tumors who have had disease progres-
`sion during first-line somatostatin analogue therapy have limited therapeutic options.
`This randomized, controlled trial evaluated the efficacy and safety of lutetium-177
`(177Lu)–Dotatate in patients with advanced, progressive, somatostatin-receptor–positive
`midgut neuroendocrine tumors.
`METHODS
`We randomly assigned 229 patients who had well-differentiated, metastatic midgut neu-
`roendocrine tumors to receive either 177Lu-Dotatate (116 patients) at a dose of 7.4 GBq
`every 8 weeks (four intravenous infusions, plus best supportive care including octreotide
`long-acting repeatable [LAR] administered intramuscularly at a dose of 30 mg) (177Lu-
`Dotatate group) or octreotide LAR alone (113 patients) administered intramuscularly at
`a dose of 60 mg every 4 weeks (control group). The primary end point was progression-
`free survival. Secondary end points included the objective response rate, overall survival,
`safety, and the side-effect profile. The final analysis of overall survival will be conducted
`in the future as specified in the protocol; a prespecified interim analysis of overall sur-
`vival was conducted and is reported here.
`RESULTS
`At the data-cutoff date for the primary analysis, the estimated rate of progression-free
`survival at month 20 was 65.2% (95% confidence interval [CI], 50.0 to 76.8) in the 177Lu-
`Dotatate group and 10.8% (95% CI, 3.5 to 23.0) in the control group. The response rate
`was 18% in the 177Lu-Dotatate group versus 3% in the control group (P<0.001). In the
`planned interim analysis of overall survival, 14 deaths occurred in the 177Lu-Dotatate
`group and 26 in the control group (P = 0.004). Grade 3 or 4 neutropenia, thrombocyto-
`penia, and lymphopenia occurred in 1%, 2%, and 9%, respectively, of patients in the
`177Lu-Dotatate group as compared with no patients in the control group, with no evidence
`of renal toxic effects during the observed time frame.
`CONCLUSIONS
`Treatment with 177Lu-Dotatate resulted in markedly longer progression-free survival and
`a significantly higher response rate than high-dose octreotide LAR among patients with
`advanced midgut neuroendocrine tumors. Preliminary evidence of an overall survival
`benefit was seen in an interim analysis; confirmation will be required in the planned
`final analysis. Clinically significant myelosuppression occurred in less than 10% of
`patients in the 177Lu-Dotatate group. (Funded by Advanced Accelerator Applications;
`NETTER-1 ClinicalTrials.gov number, NCT01578239; EudraCT number 2011-005049-11.)
`
`The authors’ full names, academic de-
`grees, and affiliations are listed in the
`Appendix. Address reprint requests to Dr.
`Strosberg at the Moffitt Cancer Center,
`12902 Magnolia Dr., Tampa, FL 33612, or
`at jonathan.strosberg@moffitt.org.
`
`* A complete list of investigators in the Neu-
`roendocrine Tumors Therapy (NETTER-1)
`trial is provided in the Supplementary
`Appendix, available at NEJM.org.
`
`N Engl J Med 2017;376:125-35.
`DOI: 10.1056/NEJMoa1607427
`Copyright © 2017 Massachusetts Medical Society.
`
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`January 12, 2017
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`Neuroendocrine tumors of the mid-
`
`gut (which is defined as the jejunoileum
`and the proximal colon) commonly metas-
`tasize to the mesentery, peritoneum, and liver and
`are frequently associated with the carcinoid syn-
`drome.1,2 Neuroendocrine tumors of the midgut
`represent the most common type of malignant
`gastrointestinal neuroendocrine tumors and are
`associated with 5-year survival rates of less than
`50% among persons with metastatic disease.3,4
`First-line systemic therapy usually consists of a
`somatostatin analogue for control of both hor-
`monal secretion and tumor growth.5-7 With the
`exception of everolimus for the treatment of
`nonfunctional neuroendocrine tumors,8 no stan-
`dard second-line systemic treatment options are
`currently available.8,9
`Since 1992,10-15 radiolabeled somatostatin ana-
`logue therapy (a form of treatment also known as
`peptide receptor radionuclide therapy) has shown
`considerable promise for the treatment of ad-
`vanced, well-differentiated neuroendocrine tumors,
`a majority of which express high levels of soma-
`tostatin receptors to which somatostatin analogues
`bind.16 This targeted form of systemic radiother-
`apy allows the delivery of radionuclides directly to
`tumor cells. Initial efficacy results were based on
`very high doses of 111In-DTPA0-octreotide,11 but
`more promising results were subsequently found
`with 90Y-DOTA0-Tyr3–octreotide (90Y-DOTATOC)17
`and with 177Lu-DOTA0-Tyr3–octreotate (177Lu-
`Dotatate).12 Lutetium-177 (177Lu) is a beta- and
`gamma-emitting radionuclide with a maximum
`particle range of 2 mm and a half-life of 160
`hours.18 In a single-group trial of 177Lu-Dotatate
`involving 310 patients who had gastroenteropan-
`creatic neuroendocrine tumors, complete tumor
`remissions occurred in 2% of the patients and
`partial tumor remissions in 28%.12 The median
`progression-free survival was 33 months.
`We report here results from the phase 3 Neuro-
`endocrine Tumors Therapy (NETTER-1) trial,
`which evaluated the efficacy and safety of 177Lu-
`Dotatate as compared with high-dose octreotide
`long-acting repeatable (LAR) in patients with
`advanced, progressive, somatostatin-receptor–
`positive midgut neuroendocrine tumors.
`
`Methods
`
`Patients
`This international, multicenter, phase 3 trial was
`conducted at 41 centers in 8 countries world-
`
`wide. Eligible patients were adults who had mid-
`gut neuroendocrine tumors that had metastasized
`or were locally advanced, that were inoperable,
`that were histologically confirmed and centrally
`verified, and that showed disease progression
`(according to Response Evaluation Criteria in
`Solid Tumors [RECIST], version 1.119) on either
`computed tomography (CT) or magnetic reso-
`nance imaging (MRI) over the course of a maxi-
`mum period of 3 years during treatment with
`octreotide LAR (20 to 30 mg every 3 to 4 weeks
`for at least 12 weeks before randomization). Pa-
`tients were required to have a Karnofsky perfor-
`mance-status score of at least 60 (on a scale
`from 0 to 100, with lower numbers indicating
`greater disability), a tumor with well-differenti-
`ated histologic features, and somatostatin recep-
`tors present on all target lesions (as confirmed
`by blinded, independent central review). Well-
`differentiated histologic features were defined
`as a Ki67 index (the percentage of cells that are
`positive for Ki67 as determined by immunos-
`taining of the primary tumor) of 20% or less;
`tumors were assessed as low-grade if they had a
`Ki67 index of 0 to 2%, intermediate-grade if they
`had a Ki67 index of 3 to 20%, or high-grade if
`they had a Ki67 index of greater than 20%, with
`a lower grade indicating a lower rate of prolifera-
`tive activity. Target lesions were selected from CT
`or MRI, and the degree of expression of soma-
`tostatin receptors was determined on the basis of
`the lesion that had the highest uptake of radio-
`tracer observed on planar somatostatin receptor
`scintigraphy within 24 weeks before randomiza-
`tion. All CT and MRI images were reviewed and
`evaluated for disease progression (according to
`RECIST criteria) and somatostatin receptor ex-
`pression by independent central reviewers who
`were unaware of the treatment assignments.
`Key exclusion criteria were a serum creatinine
`level of more than 150 μmol per liter (1.7 mg per
`deciliter) or a creatinine clearance of less than
`50 ml per minute; a hemoglobin level of less
`than 8.0 g per deciliter; a white-cell count of less
`than 2000 per cubic millimeter; a platelet count
`of less than 75,000 per cubic millimeter; a total
`bilirubin level of more than 3 times the upper
`limit of the normal range; a serum albumin
`level of more than 3.0 g per deciliter, unless the
`prothrombin time value was within the normal
`range; treatment with more than 30 mg of octreo-
`tide LAR within 12 weeks before randomization;
`peptide receptor radionuclide therapy at any time
`
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`January 12, 2017
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`Downloaded from nejm.org on April 13, 2020. For personal use only. No other uses without permission.
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`177Lu-Dotatate for Midgut Neuroendocrine Tumors
`
`before randomization; and any surgery, liver-
`directed transarterial therapy, or chemotherapy
`within 12 weeks before randomization.
`
`Trial Design
`In this open-label, phase 3 trial, we randomly
`assigned patients, in a 1:1 ratio, to receive 177Lu-
`Dotatate plus best supportive care, consisting of
`octreotide LAR at a dose of 30 mg every 4 weeks
`for symptom control (177Lu-Dotatate group) or to
`receive high-dose octreotide LAR, at a dose of
`60 mg every 4 weeks (control group). Random-
`ization was performed with the use of a central-
`ized permuted block (block size of 4) randomiza-
`tion scheme, with stratification according to the
`highest tumor uptake score on somatostatin re-
`ceptor scintigraphy (grade 2, 3, or 4 on a scale
`ranging from 0 [no uptake by tumor] to 4 [very
`intense uptake by tumor] with higher grades in-
`dicating a higher level of expression of soma-
`tostatin receptors)12 and according to the length
`of time that a patient had been receiving a con-
`stant dose of octreotide (≤6 months or >6 months).
`In the 177Lu-Dotatate group, 7.4 GBq (200 mCi)
`of 177Lu-Dotatate was infused intravenously over
`a period of 30 minutes. Patients received four
`infusions every 8 weeks (cumulative radioactivity,
`29.6 GBq [800 mCi]) unless unacceptable toxic
`effects occurred, centrally confirmed disease
`progression (according to RECIST) was present
`on imaging, the patient was unable or unwilling
`to adhere to trial procedures, the patient with-
`drew consent, or the patient died. For renal
`protection, an intravenous amino acid solution
`(Aminosyn II 10% [21.0 g of lysine and 20.4 g
`of arginine in 2 liters of solution] or VAMIN-18
`[18 g of lysine and 22.6 g of arginine in 2 liters
`of solution]) was administered concomitantly for
`at least 4 hours, starting 30 minutes before infu-
`sion of the radiopharmaceutical. In the 177Lu-
`Dotatate group, patients continued to receive
`supportive care with octreotide LAR, which was
`administered intramuscularly at a dose of 30 mg
`approximately 24 hours after each infusion of
`177Lu-Dotatate and then monthly after completion
`of all four treatments. In the control group,
`octreotide LAR at a dose of 60 mg was adminis-
`tered intramuscularly every 4 weeks. In both treat-
`ment groups, patients were allowed to receive
`subcutaneous rescue injections of octreotide in
`the event of hormonal symptoms (i.e., diarrhea
`or flushing) associated with their carcinoid syn-
`drome.
`
`Trial Oversight
`This trial was sponsored by Advanced Accelera-
`tor Applications and was designed by Advanced
`Accelerator Applications in collaboration with the
`last two authors. The trial protocol was approved
`by the investigational review board or independent
`ethics committee at each participating institu-
`tion. Contract research organizations monitored
`the trial and collected, compiled, maintained, and
`analyzed the data. The trial was performed in ac-
`cordance with the principles of the Declaration of
`Helsinki, International Conference on Harmoni-
`sation Good Clinical Practice guidelines, and all
`applicable regulations. All the patients provided
`written informed consent. An independent data
`and safety monitoring board oversaw the conduct
`of the trial. The first draft of the manuscript was
`prepared by the first author with assistance from
`a professional medical writer funded by the spon-
`sor. All the authors contributed to subsequent
`drafts and agreed to submit the manuscript for
`publication. All the authors vouch for the accu-
`racy and completeness of the data and the analy-
`sis and for the fidelity of the trial to the protocol.
`The protocol and statistical analysis plan are avail-
`able with the full text of this article at NEJM.org.
`
`End Points and Assessments
`The primary end point was progression-free sur-
`vival, which was defined as the time from ran-
`domization to documented disease progression
`(as evaluated by independent central review by
`radiologists who were unaware of the treatment
`assignments) or death from any cause. Secondary
`end points included the objective response rate,
`overall survival (defined as the time from ran-
`domization to death from any cause), safety, and
`the side-effect profile. An objective tumor assess-
`ment on CT or MRI was performed every 12 weeks
`after the date of randomization in both treatment
`groups. The treatment was considered to have
`failed if a patient had progressive disease on
`imaging, according to central assessment with the
`use of RECIST criteria, and patients with treat-
`ment failure proceeded directly to the long-term
`follow-up phase. We calculated the response rate
`as the percentage of patients who had a response
`according to RECIST (sum of partial responses
`and complete responses). Definitions of all re-
`sponse categories are provided in the protocol.
`Safety was assessed (at least every 2 to 12 weeks,
`depending on the phase of the trial [treatment
`phase or follow-up phase] and treatment group)
`
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`on the basis of adverse events (which were
`graded according to the National Cancer Insti-
`tute Common Terminology Criteria for Adverse
`Events, version 4.03), laboratory results (hemato-
`logic, chemical, and urologic), physical examina-
`tions, vital signs, electrocardiography, and Kar-
`nofsky performance status. Additional details
`are provided in the Supplementary Appendix,
`available at NEJM.org.
`
`means of the Kaplan–Meier method. Objective
`response rates and corresponding 95% confi-
`dence intervals were calculated for each treat-
`ment group and were compared with the use of
`Fisher’s exact test. Survival curves were com-
`pared with the use of an unstratified log-rank
`test and were tested against the null hypothesis.
`Hazard ratios were estimated with the use of an
`unstratified Cox proportional-hazards model.
`
`Statistical Analysis
`We calculated the required number of patients
`for the trial assuming that the median progres-
`sion-free survival would be 30 months in the
`177Lu-Dotatate group and 14 months in the con-
`trol group, the study would have 90% nominal
`power at an alpha level of 5%, and the prespeci-
`fied enrollment period and follow-up period for
`both groups would be 18 months. On the basis
`of those assumptions, we calculated that we
`needed a sample of 124 patients, and the analy-
`sis of the primary end point was planned to be
`conducted after at least 74 events of disease
`progression or death that were centrally con-
`firmed and could be evaluated had occurred.
`However, the sample size of the trial was ad-
`justed to 230 patients to enable us to detect a
`statistically significant and clinically relevant
`difference between the two treatment groups in
`overall survival as a secondary end point. This
`calculation was based on the assumption that
`the median overall survival would be 50 months
`in the 177Lu-Dotatate group and 32 months in the
`control group, with 80% nominal power at an
`alpha level of 5%, and a prespecified enrollment
`period of 18 months and a long-term follow-up
`period of 60 months. A prespecified interim
`analysis of overall survival was conducted at the
`time of the analysis of progression-free survival.
`The final analysis of overall survival is planned
`to be performed either after 158 deaths have oc-
`curred or 5 years after the last patient underwent
`randomization, whichever occurs first.
`All patients who underwent randomization
`were included in the analyses of efficacy, demo-
`graphics, and baseline characteristics. The safe-
`ty population, which comprised all patients who
`underwent randomization and received at least
`one dose of trial treatment, was used for all
`safety analyses. The median point estimate and
`95% confidence interval for progression-free
`survival and overall survival were estimated by
`
`R esults
`
`Patients
`From September 2012 through mid-January
`2016, a total of 229 patients underwent random-
`ization at 41 sites (27 sites in Europe and 14 in
`the United States); 221 of the 229 patients who
`underwent randomization received at least one
`dose of trial treatment, including 111 patients in
`the 177Lu-Dotatate group and 110 in the control
`group (safety population) (Fig. S1 in the Supple-
`mentary Appendix). The demographic and clini-
`cal characteristics of the patients were well bal-
`anced between the two treatment groups; the
`ileum was the primary tumor site in a majority
`of patients (73%), and most patients presented
`with metastases in the liver (83%), the lymph
`nodes (62%), or both, typically in the mesentery
`or retroperitoneum (Table 1, and Table S1 in the
`Supplementary Appendix). The treatment groups
`were well balanced with respect to tumor grade
`(low-grade [grade 1] Ki67 proliferation index in
`66% of patients in the 177Lu-Dotatate group and
`in 72% in the control group) and with respect to
`the highest uptake of tumor somatostatin radio-
`tracer (high-grade [grade 4] uptake in 61% of
`patients in the 177Lu-Dotatate group and in 59%
`of patients in the control group). Serum chromo-
`granin A levels and 5-hydroxyindoleacetic acid
`levels in a 24-hour urine specimen were similar
`in the two treatment groups. Approximately
`80% of the patients had undergone previous
`surgical resection (78% in the 177Lu-Dotatate
`group and 82% in the control group), and nearly
`half the patients had undergone a previous form
`of systemic therapy other than somatostatin
`analogue therapy (41% of patients in the 177Lu-
`Dotatate group and 45% in the control group).
`
`Efficacy
`At the time of the data cutoff for the primary
`analysis (July 24, 2015), 23 events of disease
`
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`177Lu-Dotatate for Midgut Neuroendocrine Tumors
`
`Table 1. Demographic and Baseline Clinical Characteristics of All Patients Who Underwent Randomization.*
`
`Characteristic
`
`Sex — no. (%)
`
`Male
`
`Female
`
`Age — yr
`
`Body-mass index†
`
`Median time since diagnosis — yr
`
`Primary tumor site — no. (%)
`
`Ileum
`
`Small intestine, not otherwise specified
`
`Midgut, not otherwise specified
`
`Jejunum
`
`Right colon
`
`Appendix
`
`Site of metastasis — no. (%)
`
`Liver
`
`Lymph nodes
`
`Mesentery
`
`Bone
`
`Other
`
`Peritoneum
`
`Lungs
`
`Ovaries
`
`Somatostatin receptor scintigraphy, Krenning scale
`— no. (%)‡
`
`Grade 2
`
`Grade 3
`
`Grade 4
`
`177Lu-Dotatate Group
`(N = 116)
`
`Control Group
`(N = 113)
`
`63 (54)
`
`53 (46)
`
`63±9
`
`25±5
`
`3.8
`
`86 (74)
`
`11 (9)
`
`9 (8)
`
`6 (5)
`
`3 (3)
`
`1 (1)
`
`97 (84)
`
`77 (66)
`
`17 (15)
`
`13 (11)
`
`15 (13)
`
`7 (6)
`
`11 (9)
`
`1 (1)
`
`11 (9)
`
`34 (29)
`
`71 (61)
`
`53 (47)
`
`60 (53)
`
`64±10
`
`26±7
`
`4.8
`
`82 (73)
`
`12 (11)
`
`7 (6)
`
`9 (8)
`
`1 (1)
`
`2 (2)
`
`94 (83)
`
`65 (58)
`
`8 (7)
`
`12 (11)
`
`10 (9)
`
`10 (9)
`
`5 (4)
`
`9 (8)
`
`12 (11)
`
`34 (30)
`
`67 (59)
`
`* Plus–minus values are means ±SD. Percentages may not sum to 100 because of rounding.
`† The body-mass index is the weight in kilograms divided by the square of the height in meters.
`‡ The Krenning scale ranges from grade 0 (no uptake by tumor) to grade 4 (very intense uptake by tumor), with higher
`grades indicating a higher level of expression of somatostatin receptors. The highest grade per patient was reported.
`
`progression or death had occurred in the 177Lu-
`Dotatate group and 68 such events had occurred
`in the control group. The estimated rate of pro-
`gression-free survival at month 20 was 65.2%
`(95% confidence interval [CI], 50.0 to 76.8) in
`the 177Lu-Dotatate group and 10.8% (95% CI, 3.5
`to 23.0) in the control group. The median pro-
`gression-free survival had not yet been reached
`in the 177Lu-Dotatate group and was 8.4 months
`(95% CI, 5.8 to 9.1) in the control group (hazard
`ratio for disease progression or death with 177Lu-
`Dotatate vs. control, 0.21; 95% CI, 0.13 to 0.33;
`
`P<0.001), which represented a 79% lower risk of
`disease progression or death in the 177Lu-Dot-
`atate group than in the control group (Fig. 1A).
`Consistent treatment benefits associated with
`177Lu-Dotatate were observed irrespective of
`stratification factors and prognostic factors,
`which included levels of radiotracer uptake on
`somatostatin receptor scintigraphy, tumor grade,
`age, sex, and tumor marker levels (Fig. 1C).
`In addition to the analysis of progression-free
`survival, we performed a planned interim analy-
`sis of overall survival. A total of 14 deaths in the
`
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`177Lu-DOTATATE
`
`P=0.004
`
`Control
`
`(% of patients)
`Overall Survival
`
`177Lu-DOTATATE
`
`P<0.001
`
`B Overall Survival (Interim Analysis)
`100
`90
`80
`70
`60
`50
`40
`30
`20
`10
`0
`
`A Progression-free Survival
`100
`90
`80
`70
`60
`50
`40
`30
`20
`10
`0
`
`(% of patients)
`
`Progression-free Survival
`
`0
`
`5
`
`Control
`
`10
`15
`20
` Months since Randomization
`
`25
`
`0
`
`5
`
`10
`15
`20
`Months since Randomization
`
`25
`
`30
`
`30
`
`0 0
`
`0 0
`
`3 0
`
`8 1
`
`116
`
`108
`
`113
`
`103
`
`96
`
`83
`
`79
`
`64
`
`64
`
`41
`
`47
`
`32
`
`31
`
`17
`
`21
`
`5
`
`No. at Risk
`177Lu-DOTATATE
`group
`Control group
`
`2 0
`
`3 1
`
`116
`
`97
`
`113
`
`80
`
`76
`
`47
`
`59
`
`28
`
`42
`
`17
`
`28
`
`10
`
`19
`
`12
`
`4
`
`3
`
`No. at Risk
`177Lu-DOTATATE
`group
`Control group
`
`0.20 (0.12–0.35)
`0.15 (0.04–0.50)
`
`0.21 (0.09–0.49)
`0.19 (0.11–0.35)
`
`0.23 (0.12–0.41)
`0.18 (0.08–0.39)
`
`0.15 (0.08–0.29)
`0.19 (0.06–0.55)
`
`0.19 (0.09–0.27)
`0.11 (0.01–0.87)
`
`0.15 (0.07–0.34)
`0.24 (0.13–0.44)
`
`0.24 (0.12–0.45)
`0.17 (0.08–0.35)
`
`0.24 (0.12–0.48)
`0.20 (0.10–0.38)
`0.21 (0.13–0.33)
`
`C Prespecified Subgroup Analysis of Progression-free Survival
`Subgroup
`
`Hazard Ratio (95% CI)
`
`tff ff ti jt tt Ii tf rr
`
` Extrahepatic metastases
`Yes
`No
`Alkaline phosphatase
`>ULN
`≤ULN
`Somatostatin receptor expression
`Grade <4
`Grade 4
`5-HIAA
`>2× ULN
`≤2× ULN
`Chromogranin A
`>2× ULN
`≤2× ULN
`Tumor grade
`ENETS Grade 2
`ENETS Grade 1
`Sex
`Male
`Female
`Age
`>65 yr
`≤65 yr
`Overall
`
`0.00
`
`0.25
`
`0.50
`
`0.75
`
`1.00
`
`1.25
`
`1.50
`
`177Lu-DOTATATE Better
`
`Control Better
`
`Figure 1. Progression-free Survival and Overall Survival.
`Panel A shows the results of the Kaplan–Meier analysis of progression-free survival as assessed by independent central reviewers who
`were unaware of the treatment assignments, and Panel B the results of the planned interim analysis of overall survival. Tick marks in
`Panel A represent data censored at the last time the patient was known to be alive and without disease progression and tick marks in
`Panel B represent data censored at the last time the patient was known to be alive. Panel C shows the effect of trial treatment on pro-
`gression-free survival in prespecified subgroups. European Neuroendocrine Tumor Society (ENETS) grade 1 indicates a low-grade tu-
`mor, and ENETS grade 2 indicates an intermediate-grade tumor. The 177Lu-Dotatate group received 177Lu-Dotatate at a dose of 7.4 GBq
`every 8 weeks (four intravenous infusions, plus best supportive care including octreotide long-acting repeatable [LAR] administered intra-
`muscularly at a dose of 30 mg). The control group received octreotide LAR alone administered intramuscularly at a dose of 60 mg every
`4 weeks. 5-HIAA denotes 5-hydroxyindoleacetic acid, CI confidence interval, and ULN upper limit of the normal range.
`
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`177Lu-Dotatate for Midgut Neuroendocrine Tumors
`
`Table 2. Objective Tumor Response.*
`
`Response Category
`
`Complete response — no. (%)
`
`Partial response — no. (%)
`
`Objective response
`
`No. with response
`
`Rate — % (95% CI)
`
`177Lu-Dotatate Group
`(N = 101)
`
`Control Group
`(N = 100)
`
`P Value†
`
`1 (1)
`
`17 (17)
`
`18
`
`18 (10–25)
`
`0
`
`3 (3)
`
`3
`
`3 (0–6)
`
`<0.001
`
`* The objective response rate was defined as the percentage of patients who had a response according to Response
`Evaluation Criteria in Solid Tumors (RECIST) (sum of partial responses and complete responses). Patients for whom
`no post-baseline computed tomography (CT) or magnetic resonance imaging (MRI) scans or central response data
`were available (15 patients in the 177Lu-Dotatate group and 13 patients in the control group) were excluded from this
`analysis (trial is still ongoing).
`† The P value was calculated with the use of Fisher’s exact text.
`
`Table 3. Overview of Adverse Events (Safety Population).*
`
`Event
`
`Adverse event
`
`Any
`
`Related to treatment
`
`Serious adverse event
`
`Any
`
`Related to treatment
`
`Withdrawal from trial because of adverse event
`
`Because of any adverse event
`
`Because of adverse event related to treatment
`
`177Lu-Dotatate Group
`(N = 111)
`
`Control Group
`(N = 110)
`
`P Value†
`
`number of patients (percent)
`
`106 (95)
`
`95 (86)
`
`29 (26)
`
`10 (9)
`
`7 (6)
`
`5 (5)
`
`95 (86)
`
`34 (31)
`
`26 (24)
`
`1 (1)
`
`10 (9)
`
`0
`
`0.02
`
`<0.001
`
`0.76
`
`0.01
`
`0.46
`
`0.06
`
`* The safety population included all patients who underwent randomization and received at least one dose of trial treatment.
`† P values were calculated with the use of Fisher’s exact text.
`
`177Lu-Dotatate group and 26 deaths in the con-
`trol group were observed, which represented
`an estimated risk of death that was 60% lower
`in the 177Lu-Dotatate group than in the control
`group (hazard ratio for death with 177Lu-Dotatate
`group vs. control, 0.40; P = 0.004) (Fig. 1B). The
`O’Brien–Fleming threshold for significance at
`the first interim analysis was 0.000085. Data were
`not sufficiently mature to provide an estimate of
`the median overall survival in either treatment
`group. Within the population of patients who
`could be evaluated for tumor response (201 pa-
`tients), the total number of complete and partial
`responses was 18 in the 177Lu-Dotatate group
`and 3 in the control group, which corresponded
`to response rates of 18% and 3%, respectively
`(P<0.001) (Table 2).
`
`Treatment Administration and Safety
`A majority of patients (77%) in the 177Lu-Dotatate
`group received all four infusions of 177Lu-Dotatate.
`A total of eight patients required dose reduction.
`Details regarding patient exposure to treatment
`are presented in Table S2 in the Supplementary
`Appendix.
`In total, 201 patients (95% of patients in the
`177Lu-Dotatate group and 86% of patients in the
`control group) had at least one adverse event dur-
`ing the trial. Adverse events that were considered
`by the investigator to be related to trial treatment
`occurred in 129 patients: 95 patients (86%) in the
`177Lu-Dotatate group and 34 patients (31%) in
`the control group (Table 3). Adverse events that
`occurred after the start of treatment and subse-
`quently led to premature withdrawal from the
`
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`T h e ne w e ngl a nd jou r na l o f m e dicine
`
`Table 4. Adverse Events (Safety Population).*
`
`Event
`
`177Lu-Dotatate Group
`(N = 111)
`
`Control Group
`(N = 110)
`
`P Value†
`
`Any Grade
`
`Grade 3 or 4
`
`Any Grade
`
`Grade 3 or 4
`
`Any Grade
`
`number of patients (percent)
`
`Any adverse event
`
`105 (95)
`
`46 (41)
`
`92 (84)
`
`36 (33)
`
`0.01
`
`Gastrointestinal disorders
`
`Nausea
`
`Vomiting
`
`Abdominal pain
`
`Diarrhea
`
`Distension
`
`General disorders
`
`Fatigue or asthenia
`
`Edema peripheral
`
`Blood disorders
`
`Thrombocytopenia
`
`Anemia
`
`65 (59)
`
`52 (47)
`
`29 (26)
`
`32 (29)
`
`14 (13)
`
`44 (40)
`
`16 (14)
`
`28 (25)
`
`16 (14)
`
`4 (4)
`
`8 (7)
`
`3 (3)
`
`3 (3)
`
`0
`
`2 (2)
`
`0
`
`2 (2)
`
`0
`
`13 (12)
`
`11 (10)
`
`29 (26)
`
`21 (19)
`
`15 (14)
`
`28 (25)
`
`8 (7)
`
`1 (1)
`
`6 (5)
`
`2 (2)
`
`1 (1)
`
`6 (5)
`
`2 (2)
`
`0
`
`2 (2)
`
`0
`
`0
`
`0
`
`<0.001
`
`<0.001
`
`1.00
`
`0.11
`
`0.84
`
`0.03
`
`0.13
`
`<0.001
`
`0.04
`
`Lymphopenia
`
`Leukopenia
`
`Neutropenia
`
`Musculoskeletal disorders
`
`20 (18)
`
`11 (10)
`
`6 (5)
`
`10 (9)
`
`1 (1)
`
`1 (1)
`
`2 (2)
`
`1 (1)
`
`1 (1)
`
`Musculoskeletal pain
`
`32 (29)
`
`2 (2)
`
`22 (20)
`
`Nutrition disorders
`
`Decreased appetite
`
`Nervous system disorders
`
`Headache
`
`Dizziness
`
`Vascular disorders
`
`Flushing
`
`Skin disorders
`
`Alopecia
`
`Respiratory disorders
`
`Cough
`
`20 (18)
`
`18 (16)
`
`12 (11)
`
`0
`
`0
`
`0
`
`9 (8)
`
`5 (5)
`
`6 (5)
`
`14 (13)
`
`1 (1)
`
`10 (9)
`
`12 (11)
`
`12 (11)
`
`0
`
`0
`
`2 (2)
`
`6 (5)
`
`0
`
`0
`
`0
`
`1 (1)
`
`3 (3)
`
`0
`
`0
`
`0
`
`0
`
`0
`
`<0.001
`
`0.005
`
`0.12
`
`0.16
`
`0.04
`
`0.007
`
`0.22
`
`0.52
`
`0.01
`
`0.22
`
`* Shown are all adverse events that were reported in at least 10% of the patients in the 177Lu-Dotatate group, with the
`exception of neutropenia, which was reported in less than 10% of the patients in the 177Lu-Dotatate group. For the indi-
`vidual events, the system organ classes in the Medical Dictionary for Regulatory Activities (MedDRA) hierarchy are shown
`in bold and are followed by the MedDRA preferred terms (not bold). The safety population included all patients who
`underwent randomization and received at least one dose of trial treatment.
`† P values were calculated with the use of Fisher’s exact text.
`
`trial occurred in 7 patients (6%) in the 177Lu-
`Dotatate group and in 10 patients (9%) in the
`control group. The most common adverse events
`
`among patients in the 177Lu-Dotatate group were
`nausea (65 patients [59%]) and vomiting (52 pa-
`tients [47%]). A majority of these cases (in 42 of
`
`132
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`
`The New England Journal of Medicine
`Downloaded from nejm.org on April 13, 2020. For personal use only. No other uses without permission.
` Copyright © 2017 Massachusetts Medical Society. All rights reserved.
`
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`177Lu-Dotatate for Midgut Neuroendocrine Tumors
`
`the 65 patients [65%] and in 38 of the 52 patients
`[73%], respectively) were attributable to amino
`acid infusions that were performed concurrently
`with administration of 177Lu-Dotatate, and the
`events resolved once the infusions were com-
`pleted. Other common adverse events in the
`177Lu-Dotatate group included fatigue or asthe-
`nia, abdominal pain, and diarrhea; however, a
`majority of the patients in whom these events
`were reported (≥97%) had events of grade 1 or 2
`(Table 4). Among patients in the control group,
`the most common adverse events were gastro-
`intestinal disorders and fatigue or asthenia. The
`rates of grade 3 or 4 adverse events were similar
`in the two groups; however, grade 3 or 4 neutro-
`penia, thrombocytopenia, and lymphopenia were
`reported in 1%, 2%, and 9% of patients, respec-
`tively, in the 177Lu-Dotatate group versus no pa-
`tients in the control group. These hematologic
`events were transient (Fig. S2 in the Supplemen-
`tary Appendix). No evidence of renal toxic effects
`was seen among patients in the 177Lu-Dotatate
`group (Fig. S3 in the Supplementary Appendix)
`during the observed time frame