177Lu-Dotatate
Significantly Improves Progression-Free
Survival in Patients with Midgut Neuroendocrine Tumours:
Results of the Phase III NETTER-1 Trial
Jonathan Strosberg1, Edward Wolin2, Beth Chasen3, Matthew Kulke4, David Bushnell5,
Martyn Caplin6, Richard P. Baum7, Erik Mittra8, Timothy Hobday9, Andrew Hendifar10,
Kjell Oberg11, Maribel Lopera Sierra12, Philippe Ruszniewski13, Dik Kwekkeboom14
on behalf of the NETTER-1 study group
1
Moffitt Cancer Center, Tampa, FL 33612, USA;2 Markey Cancer Center, University of Kentucky, Lexington,
KY 40536-0093, USA;3 University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA;4 DanaFarber Cancer Institute, Boston, MA 02215, USA;5 University of Iowa, Iowa City, IA 52242, USA;6 Royal Free
Hospital, London, United Kingdom;7 Zentralklinik, Bad Berka, Germany;8 Stanford University Medical Center,
Stanford, CA 94305, USA;9 Mayo Clinic College of Medicine, Rochester, MN 55905, USA;10 Cedars Sinai
Medical Center, Los Angeles, CA 90048, USA;11 University Hospital, Uppsala University, Uppsala, Sweden;12
Advanced Accelerator Applications, New York, NY 10118, USA;13 Hopital Beaujon, Clichy, France;14 Erasmus
Medical Center, Rotterdam, Netherlands
Presentation Presidential Session II of the 18th ECCO – 40th ESMO – European Cancer Congress 2015, 27 September 2015, abstract 6LBA, Vienna
1
Introduction
•
•
•
•
•
•
Neuro Endocrine Tumors, also known as NETs, are a group of tumors originating in the
neuroendocrine cells of many different organs. NETs can remain clinically silent for
years delaying the diagnosis in a large number of patients. These cancers are rare but
they are the second most common type of gastrointestinal malignancy and their
incidence is increasing.
The estimated incidence of NETs for the combined populations of the United States
and the European Union is approximately 47,3001.
NETs are classified as orphan diseases by European and U.S. regulatory authorities.
From 1973 to 2004, incidence of NETs has grown by almost 500% (from 1,09/100,000
to 5,25/100,000 respectively).2
There are limited therapeutic options for patients with advanced midgut neuroendocrine
tumours (20-45% of NETs) progressing on first-line somatostatin analogue therapy.
Thousands of patients have been treated with 177Lu-Dotatate peptide receptor
radionuclide therapy (PRRT) with promising results.
1. Lawrence B, et al. 2011, 2. JC Yao et al. 2008 - see abstract on 1st page. 2. Yao et al: One hundred years after « carcinoid »: epidemiology of and prognostic factors for NET in 35,825
cases in the US. J. Clinical Oncology 26:3063-3072
Presentation Presidential Session II of the 18th ECCO – 40th ESMO – European Cancer Congress 2015, 27 September 2015, abstract 6LBA, Vienna
2
NET Epidemiology
A growing population of patients
•
From 1973 to 2004, incidence of NETs has grown by almost 500% (from 1,09/100,000 to
5,25/100,000 respectively)1
Incidence of NETs vs all malignant neoplasms from 1973 to 20042.
1.Yao et al: One hundred years after « carcinoid »: epidemiology of and prognostic factors for NET in 35,825 cases in the US. J. Clinical Oncology 26:3063-3072; 2. SEER: National
Cancer Institute’s Surveillance, Epidemiology, and End Results
A brief presentation of 177Lu-DOTATATE
•177Lu-DOTATATE belongs to an innovative drug
category called PRRT (Peptide Receptor Radionuclide
Therapy). PRRT involves the systemic
administration of a specific radiopharmaceutical to
deliver cytotoxic radiation to a tumor1
Structure of a radiopharmaceutical2
•177Lu-DOTATATE is composed of a lutetium
radionuclide chelated to a peptide1. Lutetium emits
high energy electrons (therapy) and gamma rays
(imaging).
•The peptide is designed to target somatostatin
receptors1 which are overexpressed in
approximately 80% of NETs.
The affinity for SSTRs and the specificity of binding ensures a high level of
specificity in the delivery of radiation to the tumor
1. Zaknun et al. Eur J Nucl Med Mol Imaging 2013, 40: 800-16; 2. Bergsma et al. Best Practice & Res Clin Gastroenterol 2012, 26: 867-81 3. Reubi et al. Eur J Nucl Med Mol Imaging
4
2003, 30: 781-93
177Lu-DOTATATE
1.Injection
2.Concentration
into
neuroendocrine
tumor (NETs)
sites
3.The
radiopeptide
binds to
somatostatin
receptors type 2
(sstr2)
overexpressed
by NETs
4.The
radiopeptide is
internalized in
the NET cell
mode of action
5.The
radiopeptide
delivers radiation
within the cancer
cell
6.Radiation
induces DNA
strands break
causing tumor
cell death
Progression-Free Survival
177Lu-Dotatate
Median PFS: Not reached
N = 229 (ITT)
Number of events: 90
• 177Lu-Dotatate:
•
23
Oct 60 mg LAR: 67
Hazard Ratio [95% CI]
0.209 [0.129 – 0.338]
Risk reduction: 79.1
p < 0.0001
Octreotide LAR 60 mg
Median PFS: 8.4 months
All progressions centrally confirmed and independently reviewed for eligibility (SAP)
Presentation Presidential Session II of the 18th ECCO – 40th ESMO – European Cancer Congress 2015, 27 September 2015, abstract 6LBA, Vienna
6
Tumour Response Rate
(currently evaluable patients)
177Lu-Dotatate
(n=101)
Octreotide LAR 60mg
(n=100)
Complete Response (n)
1
0
Partial Response (n)
18
3
19 (11-26) %
3 (0-6) % *
5 (4%)
27 (24%)
77 (66%)
70 (62%)
Objective Response Rate
(CI 95%)
Progressive Disease (n, %)
Stable Disease (n, %)
*P<0.0004
Presentation Presidential Session II of the 18th ECCO – 40th ESMO – European Cancer Congress 2015, 27 September 2015, abstract 6LBA, Vienna
7
Overall Survival (interim analysis)
0.5
N = 229 (ITT)
Number of deaths:
• 177Lu-Dotatate:
• Octreotide 60 mg
35
13
LAR: 22
P < 0.0186
Presentation Presidential Session II of the 18th ECCO – 40th ESMO – European Cancer Congress 2015, 27 September 2015, abstract 6LBA, Vienna
8
177Lu-Dotatate
Safety - SAE
SAE (n)
Blood & lymphatic system
Lymphocytopenia
Thrombocytopenia
Neutropenia
Pancytopenia
Bicytopenia
7
3
1
1
1
1
Renal & urinary disorders
Acute kidney injury
Renal failure
3
2
1
Vascular disorders
Portal hypertension
1
1
Presentation Presidential Session II of the 18th ECCO – 40th ESMO – European Cancer Congress 2015, 27 September 2015, abstract 6LBA, Vienna
9
Summary and Conclusions
•
•
•
•
In this first prospective randomized study in patients with
progressive metastatic midgut NETs, 177Lu-Dotatate was
superior to Octreotide 60 mg in terms of PFS (NR vs 8.4
months, p<0.0001) and ORR (19% vs 3%, p<0.0004)
Interim analysis suggests increased overall survival (13 vs 22
deaths), to be confirmed by final analysis(
Currently available safety data confirm the results of Phase I-II
study, with favorable safety profile
While few treatment options were up to now available, 177LuDotatate appears as a major advance in this patient population
Presentation Presidential Session II of the 18th ECCO – 40th ESMO – European Cancer Congress 2015, 27 September 2015, abstract 6LBA, Vienna
10
177Lu-Dotatate
Significantly Improves Progression-Free
Survival in Patients with Midgut Neuroendocrine Tumours:
Results of the Phase III NETTER-1 Trial
Back-up Slides
Presentation Presidential Session II of the 18th ECCO – 40th ESMO – European Cancer Congress 2015, 27 September 2015, abstract 6LBA, Vienna
11
Introduction
•
•
There are limited therapeutic options for patients with advanced midgut
neuroendocrine tumours (20-45% of NETs) progressing on first-line
somatostatin analogue therapy.
Thousands of patients have been treated with 177Lu-Dotatate peptide
receptor radionuclide therapy (PRRT) with promising results.
Lutathera Phase I-II results
Disease related survival in 310
patients according to treatement
outcome.
Ref: Kwekkeboom D.J et coll., J Clin
Oncol, 2008, 26: 2124-2130.
Presentation Presidential Session II of the 18th ECCO – 40th ESMO – European Cancer Congress 2015, 27 September 2015, abstract 6LBA, Vienna
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Neuro Endocrine Tumors (NETs) Overview
What are NETs?
 Heterogeneous group of tumors originating from
the cells of the endocrine (hormonal) and nervous
systems
 They have different behavior depending on the site
of origin
NETs
~47,300 patients/year in the US & EU1
~288,000 patients in US & EU2
GEP-NETs* (GI NET** +
pNETs***)
Current Treatment Paradigm
 Many patients do not have symptoms => incidental
finding.
 When present, symptoms unspecific => delayed
diagnosis
 Diagnosis is made with radiolabeled somatostatin
analogs (SSA) such as Octreoscan
 There is a significant unmet medical need for
patients with inoperable GEPNETs who are
progressive under SSAs. Patients lack options for
antiproliferative treatment.
~30,000 patients/year in the US & EU1
~175,000 patients in US & EU2
 NETs are generally slow-growing tumors and
therefore prevalence is high compared to incidence
* Gastroenteropancreatic NETs
** Gastrointestinal NETs
*** Pancreatic NETs
1. Lawrence B, et al. 2011 (table3 page8), 2. JC Yao et al. 2008 - see abstract on 1st page
 ~80% of NETs overexpress somatostatin receptors
(particularly sstr2)
NETTER -1 Study Objectives and Design
Aim
Design
Evaluate the efficacy and safety of 177Lu-Dotatate plus Octreotide30 mg
compared to Novartis Octreotide LAR 60mg (off-label use)1 in patients with
inoperable, somatostatin receptor positive, midgut NET, progressive under
Octreotide LAR 30mg (label use)
International, multicenter, randomized, comparator-controlled, parallel-group
Phase III study conducted in 51 centers with 230 patients randomized
Treatment and Assessments
Progression free survival (Recist criteria) every 12 weeks
Dose 1 Dose 2 Dose 3 Dose 4
n = 115
4 administrations of 7.4 GBq of LUTATHERA every
8 weeks + Octreotide30 mg
n = 115
Octreotide LAR 60mg every 4 weeks
Baseline
and
Randomization
5
Years
follow
up
1. FDA and EMA recommendation
Presentation Presidential Session II of the 18th ECCO – 40th ESMO – European Cancer Congress 2015, 27 September 2015, abstract 6LBA, Vienna
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Participating Sites in 51 centers - 11 countries
Presentation Presidential Session II of the 18th ECCO – 40th ESMO – European Cancer Congress 2015, 27 September 2015, abstract 6LBA, Vienna
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Study Endpoints
Primary objective
Compare Progression Free Survival (PFS) after treatment with
177Lu-Dotatate plus 30 mg octreotide LAR vs treatment with high
dose (60 mg) octreotide LAR
Secondary objectives
▪
▪
▪
▪
▪
Compare the Objective Response Rate between study arms
Compare the Overall Survival between study arms
Compare the Time to Progression between study arms
Evaluate the safety and tolerability of 177Lu-Dotatate
Evaluate the health related quality of life (QoL) as measured by
the EORTC QLQ-G.I.NET21 questionnaire
Presentation Presidential Session II of the 18th ECCO – 40th ESMO – European Cancer Congress 2015, 27 September 2015, abstract 6LBA, Vienna
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177Lu-Dotatate
Patients who completed trt phase, N=102*
Exposure
Nb of Patients
Drug exposure, n (%)
800 mCi
400 – 800 mCi
200 – 400 mCi
200 mCi
No administration
Number of administrations, n (%)
4
3
2
1
0
81
5
9
3
4
(79%)
(5%)
(9%)
(3%)
(4%)
78 (76%)
5 (5%)
11 (11%)
4 (4%)
4 (4%)
Dose modifying toxicity, n (%)
All treated patients – N=111
No DMT
DMT
105 (95%)
6 (5%)
*14 pts still under treatment
Presentation Presidential Session II of the 18th ECCO – 40th ESMO – European Cancer Congress 2015, 27 September 2015, abstract 6LBA, Vienna
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Safety and Tolerability
(Nb of patients (%), Safety Set; n=221)
Any adverse event
Related to treatment
Serious adverse events
Related to treatment
Withdrawals due to adverse events
Related to treatment
177-Lu-Dotatate
(n=111)
Octreotide LAR
60mg (n=110)
106 (96%)
95 (86%)
95 (86%)
34 (31%)
29 (26%)
26 (24%)
10 (9%)
1 (1%)
7 (6%)
10 (9%)
5 (5%)
0 (0%)
Presentation Presidential Session II of the 18th ECCO – 40th ESMO – European Cancer Congress 2015, 27 September 2015, abstract 6LBA, Vienna
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Main Inclusion Criteria
•
•
•
•
•
•
•
Patients ≥18 years of age
Metastatic or locally advanced, inoperable, histologically
proven, midgut NET
Ki67 index ≤ 20% (Grade 1-2)
Progressive disease (RECIST Criteria 1.1 centrally
confirmed) on uninterrupted fixed dose of octreotide
LAR (20-30 mg every 3-4 weeks)
Somatostatin receptor positive disease
Karnofsky Performance Score ≥ 60
Including functioning and non-functioning
Presentation Presidential Session II of the 18th ECCO – 40th ESMO – European Cancer Congress 2015, 27 September 2015, abstract 6LBA, Vienna
19
Population Characteristics at Enrolment
(ITT population, N=229)
177Lu-Dotatate
(n=116)
Octreotide LAR 60mg
(n=113)
Male
Female
Age (years), mean (SD)
53 (46%)
63 (54%)
63 (±9)
60 (53%)
53 (47%)
64 (±10)
BMI (Kg/sqm), mean (SD)
25 (±5)
26 (±7)
6 (5%)
86 (74%)
1 (1%)
3 (3%)
20 (17%)
9 (8%)
82 (73%)
2 (2%)
1 (1%)
19 (17%)
97 (84%)
77 (66%)
13 (11%)
11 (10%)
40 (35%)
94 (83%)
65 (58%)
12 (11%)
5 (4%)
37 (33%)
Gender, n (%)
Primary tumour site, n (%)
Jejunum
Ileum
Appendix
Right colon
Other
Site of metastasis, n (%)
Liver
Lymph nodes
Bone
Lungs
Other
Presentation Presidential Session II of the 18th ECCO – 40th ESMO – European Cancer Congress 2015, 27 September 2015, abstract 6LBA, Vienna
20
Population Characteristics at Enrolment
(ITT population, N=229)
177Lu-Dotatate
(n=116)
Octreotide LAR 60mg
(n=113)
76/40 (66/34%)
81/32 (72/28%)
13 (11%)
34 (29%)
69 (60%)
14 (12%)
32 (28%)
67 (59%)
Chromogranin A (µg/L), mean (SD)
649 (420)
670 (422)
5-HIAA (mg/24h), mean (SD)*
100 (183)
77 (83)
Ki67, n (%)
ENETS G1/G2
SRS, Krenning scale, n (%)
Grade 2
Grade 3
Grade 4
*Only available in 98 patients
Presentation Presidential Session II of the 18th ECCO – 40th ESMO – European Cancer Congress 2015, 27 September 2015, abstract 6LBA, Vienna
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Main Exclusion Criteria
•
•
•
•
•
Serum creatinine >150 µmol/L, or creatinine clearance <50 mL/min
Hb concentration <5.0 mmol/L
WBC <2x109/L , Platelets <75x109/L
Treatment with >30 mg Octreotide LAR at 3-4 weeks intervals
within 12 weeks prior to randomization
Surgery, radioembolization, chemoembolization, chemotherapy and
RF ablation within 12 weeks prior to randomization
Presentation Presidential Session II of the 18th ECCO – 40th ESMO – European Cancer Congress 2015, 27 September 2015, abstract 6LBA, Vienna
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Assumptions Primary End-Point PFS
▪
▪
▪
▪
▪
▪
▪
177Lu-Dotatate:
median PFS of 30 months
(conservative vs data from Phase I/II)
Octreotide LAR: median PFS of 14 months (PROMID study)
Significance level 5% two-sided with 90% power
Pre-defined accrual period: 18 months
Follow-up period: 18 months (length of standard trt period)
Sample size: 124 patients (62 per trt group)
Number of events: 74 evaluable and centrally confirmed disease
progression (RECIST criteria assessed every 12±1 weeks)
Presentation Presidential Session II of the 18th ECCO – 40th ESMO – European Cancer Congress 2015, 27 September 2015, abstract 6LBA, Vienna
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Assumptions Secondary End-Point OS
▪
▪
▪
▪
▪
▪
▪
▪
177Lu-Dotatate:
median OS of 50 months
(data from Phase I/II confirmed with published studies)
Octreotide mg LAR: median OS of 32 months (RADIANT-2)
Significance level 5% two-sided with 80% power
Pre-defined accrual period: 18 months
Follow-up period: 5 years
Sample size: 230 patients (115 per trt group)
Number of events: 158 confirmed events
Interim analysis at the time of the PFS analysis: significance
level adjusted to 0.0085% (p<0.000085)
Presentation Presidential Session II of the 18th ECCO – 40th ESMO – European Cancer Congress 2015, 27 September 2015, abstract 6LBA, Vienna
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Current Status – Statistical Analysis
▪
▪
▪
▪
▪
▪
▪
▪
End of recruitment in Dec 2014
Substudy still ongoing (not randomized population)
DB cut-off date of July 24, 2015, with primary end-point analysis
Submission of first results (PFS) at ESMO and NANETS
Database complete lock on Sept 14, 2015
Statistical analysis ongoing; main results on Sept 18, 2015
Full Statistical Report expected end of October 2015
Aligned with FDA/EMA expectations for demonstrating
therapeutic benefit and acceptable safety profile to support
approval.
Presentation Presidential Session II of the 18th ECCO – 40th ESMO – European Cancer Congress 2015, 27 September 2015, abstract 6LBA, Vienna
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Population Characteristics at Enrolment
(ITT population, N=229)
177Lu-Dotatate
Synaptophysin, n (%)
0% positive cells
1-50% positive cells
> 50% positive cells
Not evaluable
Overall tumour burden, n (%)
Limited
Moderate
Extensive
Chromogranin A, n (%)
0% positive cells
1-50% positive cells
> 50% positive cells
Not evaluable
(n=116)
Octreotide LAR 60mg
(n=113)
1 (0.9%)
3 (2.6%)
111 (95.7%)
1 (0.9%)
0 (0.0%)
4 (3.5%)
108 (95.6%)
1 (0.9%)
99 (85.3%)
13 (11.2%)
4 (3.4%)
98 (86.7%)
13 (11.5%)
2 (1.8%)
2 (1.7%)
5 (4.3%)
107 (92.2%)
2 (1.7%)
1 (0.9%)
5 (4.4%)
106 (93.8%)
1 (0.9%)
Presentation Presidential Session II of the 18th ECCO – 40th ESMO – European Cancer Congress 2015, 27 September 2015, abstract 6LBA, Vienna
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Population Characteristics at Enrolment
(ITT population, N=229)
177Lu-Dotatate
(n=116)
Octreotide
LAR 60mg
(n=113)
Chromogranin A (µg/L), mean (SD)
N=207 (Lutate: 101 - Octreotide: 106)
648.9 (419.6)
670.4 (421.6)
5-HIAA (mg/24h), mean (SD)
N=98 (Lutate: 47 - Octreotide: 51)
100.1 (183.3)
76.9 (83.3)
Alkaline phosphatase (U/L), mean (SD)
N=209 (Lutate: 111 - Octreotide: 98)
173.8 (269.1)
155.8 (170.5)
Presentation Presidential Session II of the 18th ECCO – 40th ESMO – European Cancer Congress 2015, 27 September 2015, abstract 6LBA, Vienna
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Prior Cancer Treatments at Enrolment
(ITT population, N=229)
177Lu-Dotatate
(n=116)
Octreotide LAR 60mg
(n=113)
90 (78%)
93 (82%)
6 (5%)
11 (10%)
Chemo-embolization, n (%)
14 (12%)
11 (10%)
Time since last intervention, yrs (SD)
4.7 (±3.3)
5.7 (±3.6)
Type of previous treatment
Radiotherapy
PRRT
Chemotherapy
Other
7
1
47
48
8
0
51
40
Prior resection, n (%)
Prior ablation, n (%)
(4%)
(1%)
(27%)
(28%)
(5%)
(0%)
(30%)
(24%)
Presentation Presidential Session II of the 18th ECCO – 40th ESMO – European Cancer Congress 2015, 27 September 2015, abstract 6LBA, Vienna
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Patient Disposition
(ITT population, N=229)
177Lu-Dotatate
(n=116)
Reason for end of treatment phase
n (%)
Consent withdrawal
Best subject interest
Adverse event
Disease progression
9
10
7
19
(8%)
(9%)
(6%)
(16%)
Octreotide LAR
60mg (n=113)
9
9
7
58
(8%)
(8%)
(6%)
(51%)
Presentation Presidential Session II of the 18th ECCO – 40th ESMO – European Cancer Congress 2015, 27 September 2015, abstract 6LBA, Vienna
29
Population Characteristics at Enrolment
(ITT population, N=229)
177Lu-Dotatate
(n=116)
Octreotide
LAR 60mg
(n=113)
Statistical
Significance
Time since first diagnosis
(years)
5.13
5.93
NS (p=0.09)
Time since first disease
progression (years)
2.73
2.93
NS (p=0.42)
Time since diagnosis of
metastasis (years)
4.28
4.97
NS (p=0.30)
Presentation Presidential Session II of the 18th ECCO – 40th ESMO – European Cancer Congress 2015, 27 September 2015, abstract 6LBA, Vienna
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Treatment Time without Progression
(at the cut-off date for analysis)
177Lu-Dotatate
(n=99)
Octreotide LAR
60mg (n=55)
Mean
15.1
13.1
Maximum
32.2
33.6
Median
14.4
11.9
Minimum
1.6
1.7
Treatment Time (months)
Safety and Tolerability - All Grades
(Safety Set; n=221)
Maximal Severity,
number of episodes
177-Lu-Dotatate
(n=111)
Octreotide LAR
60mg (n=110)
Grade 1 (mild)
938
494
Grade 2 (moderate)
370
178
Grade 3 (severe)
98
56
Grade 4 (threatening / disabling)
5
6
Grade 5 (death)
5
8
Missing
19
2