Study of Efficacy and Safety of PDR001 in Patients With Advanced or Metastatic, Well-differentiated, Non-functional Neuroendocrine Tumors of Pancreatic, Gastrointestinal (GI), or Thoracic Origin or Poorly-differentiated Gastroenteropancreatic Neuroendocrine Carcinoma (GEP-NEC)

• Sponsor: Novartis Pharmaceuticals (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02955069
• Collaborator: (none)
• Enrollment: 116
• Locations: 35
• Arm: 1
• Actual Duration (Months): 38.9
• Patients Per Site: 3.3
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

This study aimed to investigate the efficacy and safety of PDR001 in patients with advanced or metastatic, well-differentiated, non-functional neuroendocrine tumors of pancreatic, gastrointestinal (GI), or thoracic origin or poorly-differentiated gastroenteropancreatic neuroendocrine carcinoma (GEP-NEC) that progressed on prior treatment.

Condition or Disease	Intervention/Treatment	Phase
Well-differentiated Non-functional NET of Thoracic Origin; Well-differentiated Non-functional NET of Gastrointestinal Origin; Well-differentiated Non-functional NET of Pancreatic Origin; Poorly-differentiated Gastroenteropancreatic Neuroendocrine Carcinoma	Drug: PDR001	Phase 2

Detailed Description

Two groups of adult patients with advanced (unresectable or metastatic) were included in this study:

• Well-differentiated (G1/2), non-functional, neuroendocrine tumor of GI, pancreatic or thoracic (lung/thymus) origin who have progressed on prior treatment

• Poorly-differentiated GEP-NEC who have progressed on or after one prior chemotherapy regimen.

The study was comprised of the following periods: screening, treatment, end of treatment (EOT), safety follow-up (30-Days, 60-Days, 90-Days, 120-Days, and 150-Days after the last dose of PDR001) and post-treatment efficacy follow-up. Subjects were treated with PDR001 as an infusion at a flat dose of 400 mg every 4 weeks (Q4W). Subjects were to continue study treatment beyond disease progression by RECIST 1.1 until disease progression as per irRECIST, as per BIRC, unacceptable toxicity, start of new antineoplastic therapy, withdrawal of consent, physician's decision, lost to follow-up, death, or study termination by the Sponsor.

Study Design

• Study Type: Interventional
• Actual Enrollment: 116 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: An Open Label Phase II Study to Evaluate the Efficacy and Safety of PDR001 in Patients With Advanced or Metastatic, Well-differentiated, Non-functional Neuroendocrine Tumors of Pancreatic, Gastrointestinal (GI), or Thoracic Origin or Poorly-differentiated Gastroenteropancreatic Neuroendocrine Carcinoma (GEP-NEC), That Have Progressed on Prior Treatment.
• Actual Study Start Date: Feb 14, 2017
• Actual Primary Completion Date: Aug 10, 2018
• Actual Study Completion Date: May 13, 2020

Arms and Interventions

Arm	Intervention/Treatment
Experimental: PDR001 Subjects with advanced or metastatic, well-differentiated, NET of pancreatic, GI, or thoracic origin or poorly-differentiated GEP-NEC, that have progressed on prior treatment were treated with 400mg PDR001 administered via intravenous infusion once every 4 weeks.	Drug: PDR001; PDR001 was administered at a dose of 400 mg via intravenous infusion once every 4 weeks (Q4W). PDR001 was administered on Day 1 of every cycle. Each cycle was 28 days.; Other Names: Spartalizumab

Outcome Measures

Primary Outcome Measures

1. Overall Response Rate (ORR) by RECIST 1.1 and as Per Blinded Independent Central Review (BIRC). [From baseline up to approximately 1.5 years]

   ORR is defined as the proportion of patients with best overall response (BOR) of complete response (CR) or partial response (PR), according to BIRC radiological assessment by RECIST 1.1. CR: disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to < 10 mm. PR: at least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters.

Secondary Outcome Measures

1. Duration of Response (DOR) by RECIST 1.1 and as Per BIRC [From the date of first documented response (CR or PR) until the first documented disease progression or death, whichever comes first, assessed up to approximately 1.5 years]

   DOR is defined as the time between the date of first documented response (CR or PR) and the date of first documented disease progression by RECIST 1.1 and as per BIRC or death due to underlying cancer. For DOR analysis, participants continuing without progression or death due to underlying cancer were censored at the date of their last adequate tumor assessment. An adequate tumour assessment is a tumour assessment with an overall response other than unknown. CR: disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to < 10 mm. PR: at least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters.

2. Disease Control Rate by RECIST 1.1 and as Per BIRC [From baseline up to approximately 1.5 years]

   Disease control rate is defined as the proportion of patients with best overall response of CR, PR or stable disease (SD) according to RECIST 1.1 criteria and as per BIRC. CR: disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to < 10 mm. PR: at least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters. SD: neither sufficient shrinkage to qualify for PR or CR nor an increase in lesions which would qualify for progressive disease.

3. Time to Response (TTR) by RECIST 1.1 and as Per BIRC [From baseline to the first documented response, assessed up to approximately 1.5 years]

   TTR is defined as the time from the date of start of treatment to the first documented response of either CR or PR, which must be subsequently confirmed. TTR was evaluated according to RECIST 1.1 and as per BIRC. CR: disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to < 10 mm. PR: at least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters.

4. Progression-free Survival (PFS) by RECIST 1.1 and as Per BIRC [From baseline until the date of the first documented radiological progression or death due to any cause, whichever comes first, assessed up to approximately 1.5 years]

   PFS is defined as the time from the date of first dose to the date of the first documented radiological progression or death due to any cause. PFS was evaluated according to RECIST 1.1 and as per BIRC. For participants who had not progressed or died at the analysis cut-off date, PFS was censored at the date of the last adequate tumor evaluation date. An adequate tumour assessment is a tumour assessment with an overall response other than unknown.

5. Immune Related Overall Response Rate (irORR) by irRECIST and as Per BIRC [From baseline up to approximately 1.5 years]

   irORR is the proportion of patients with a best overall response of immune related Complete Response (irCR) or immune related partial response (irPR), according to BIRC assessment by irRECIST. irCR: Complete disappearance of all measurable and non-measurable lesions. In addition, any pathological lymph nodes must have a reduction in short axis to < 10 mm. irPR: At least 30% decrease in the total measurable tumor burden (TMTB) compared to baseline and not qualifying for irCR or immune related progressive disease (irPD).

6. Immune Related Duration of Response (irDoR) by irRECIST and as Per BIRC. [From the date of first documented confirmed response (irCR or irPR) until the first documented progression, assessed up to approximately 1.5 years]

   irDOR is defined as the time from first documentation of irCR or irPR until the time of first documentation of progression per irRECIST based on BIRC assessment. Participants continuing without progression or death due to underlying cancer were censored at the date of their last adequate tumor assessment. An adequate tumour assessment is a tumour assessment with an overall response other than unknown for irRECIST. irCR: Complete disappearance of all measurable and non-measurable lesions. In addition, any pathological lymph nodes must have a reduction in short axis to < 10 mm. irPR: At least 30% decrease in the TMTB compared to baseline and not qualifying for irPD or irCR

7. Immune Related Time to Response (irTTR) by irRECIST and as Per BIRC [From baseline to the first documented response, assessed up to approximately 1.5 years]

   irTTR is defined as the time between date of start of treatment until first documented response (confirmed irCR or irPR) by irRECIST and as per BIRC. irCR: Complete disappearance of all measurable and non-measurable lesions. In addition, any pathological lymph nodes must have a reduction in short axis to < 10 mm. irPR: At least 30% decrease in the TMTB compared to baseline and not qualifying for irPD or irCR.

8. Immune Related Disease Control Rate (irDCR) by irRECIST and as Per BIRC [From baseline up to approximately 1.5 years]

   irDCR is defined as the proportion of patients with a best overall response of irCR or irPR or immune related stable disease (irSD) according to irRECIST and as per BIRC. irCR: Complete disappearance of all measurable and non-measurable lesions. In addition, any pathological lymph nodes must have a reduction in short axis to < 10 mm. irPR: At least 30% decrease in the TMTB compared to baseline and not qualifying for irPD or irCR. irSD: Neither a sufficient shrinkage to qualify for irPR or irCR, nor an increase in lesions, or a clear and unequivocal progression of existing nontarget or new non-measurable lesions that would qualify for irPD.

9. Immune Related Progression Free Survival (irPFS) by irRECIST and as Per BIRC [From baseline until the date of the first documented immune related progression or death due to any cause, whichever comes first, assessed up to approximately 1.5 years]

   irPFS is defined as the time from date of start of treatment to the date of event defined as the first documented assessment of immune related progression that is confirmed or death due to any cause. If a patient has not had an event, immune related progression-free survival was censored at the date of last adequate tumor assessment. An adequate tumor assessment is a tumor assessment with overall response other than unknown for irRECIST.

10. Overall Survival (OS) [From baseline until death due to any cause, assessed up to approx. 3 years]

    OS is defined as the time from the start of treatment date to the date of death, due to any cause. If a patient was not known to have died, then OS was censored at the latest date the patient was known to be alive.

11. Changes From Baseline in Chromogranin A (CgA) Levels [Baseline, day 1 of each cycle from Cycle 2 to end of treatment, assessed up to approx. 1.5 years. Cycle=28 days.]

    Blood samples were collected for assessment of CgA level. Change from Baseline at a particular visit was calculated as the CgA level at that visit minus Baseline.

12. Change From Baseline in Neuron Specific Enolase (NSE) Levels [Baseline, day 1 of each cycle from Cycle 2 to end of treatment, assessed up to approx. 1.5 years. Cycle= 28days]

    Blood samples were collected for assessment of NSE level. Change from Baseline at a particular visit was calculated as the NSE level at that visit minus Baseline.

13. PDR001 Plasma Concentration [Cycle(C)1 Day(D)1 pre-dose and 30min post-infusion,C2D1 Pre-dose,C3D1 Pre-dose and 30min post-infusion,D1 pre-dose from C4 to C13, assessed up to approx. 1.5 years.Cycle=28 days]

    Blood samples will be taken to evaluate the pharmacokinetics by assessing plasma concentration of PDR001 at selected time points

14. Change From Baseline in European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30) Global Health Status/Quality of Life Score [Baseline, every 8 weeks from Cycle 3 Day 1 for the first 13 cycles and every 12 weeks from Cycle 13 Day 1 thereafter and end of treatment, assessed up to approx. 1.5 years. Cycle=28 days]

    The EORTC QLQ-C30 is a patient completed 30 item questionnaire that is composed of both multi-item scales and single-item measures. These include five functional scales, three symptom scales, six single items and a global health status/QoL scale. Global health status/QoL response options are 1 to 4. Scores were averaged and transformed to 0 to 100. Higher scores indicate better functioning. Change from Baseline was calculated by subtracting Baseline value from the selected visit value. A positive change from Baseline indicates improvement.

15. Change From Baseline in EQ-5D-5L Index Score [Baseline, every 8 weeks from Cycle 3 Day 1 for the first 13 cycles and every 12 weeks from Cycle 13 Day 1 thereafter, and end of treatment, assessed up to approx.1.5 year. Cycle=28 days]

    The EQ-5D-5L descriptive system provides a profile of the participant's health state in 5 dimensions (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression). For each of these dimensions, the participant self-assigned a score: from 1 (no problems) to 5 (extreme problems). The 5 digit health states obtained for each dimension was converted into a single mean index value based on the EQ-5D crosswalk value set for the UK using the time trade-off method. This index ranges from -0.594 (worst health) to 1.0 (best health). Change from Baseline was calculated by subtracting Baseline value from the selected visit value. A positive change from baseline indicates improvement.

16. PDR001 Anti-drug Antibodies (ADA) Prevalence at Baseline [Baseline]

    ADA prevalence at baseline was calculated as the proportion of participants who had an ADA positive result at baseline

17. PDR001 ADA Incidence On-treatment [Cycle(C)1 Day(D)1 pre-dose and 30min post-infusion,C2D1 Pre-dose,C3D1 Pre-dose and 30min post-infusion,D1 pre-dose from C4 to C13 and every 6 cycles until C25, and end of treatment, assessed up to approx. 1.5 years. Cycle=28 days]

    ADA incidence on treatment was calculated as the proportion of participants who were treatment-induced ADA positive (post-baseline ADA positive with ADA-negative sample at baseline) and treatment-boosted ADA positive (post-baseline ADA positive with titer that is at least the fold titer change greater than the ADA-positive baseline titer)

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Pathologically confirmed, advanced (unresectable or metastatic):

• Well-differentiated (G1 or G2) based on local pathology report, non-functional neuroendocrine tumor of GI, pancreatic or thoracic (including lung and thymus) origin.

• Poorly-differentiated GEP-NEC based on local pathology report

• No active symptoms related to carcinoid syndrome during the last 3 months prior to start of study treatment.

• Patients must have been pretreated for advanced disease - the number of prior systemic therapy/regimen depended on which origin for NET and for GEP-NEC

• Tumor biopsy material must be provided for all patients for the purpose of biomarker analysis

• Radiological documentation of disease progression:

• Well-differentiated NET group: Disease progression while on/or after the last treatment, and this progression must have been observed within 6 months prior to start of study treatment (i.e. maximum of 24 weeks from documentation of progression until study entry). Disease must show evidence of radiological disease progression based on scans performed not more than 12 months apart.

• Poorly-differentiated GEP-NEC group: Disease progression while on or after prior treatment.

Exclusion Criteria:

• Well-differentiated grade 3 neuroendocrine tumors; poorly-differentiated neuroendocrine carcinoma of any origin (other than GEP-NEC); including NEC of unknown origin, adenocarcinoid, and goblet cell carcinoid

• Pretreatment with interferon as last treatment prior to start of study treatment.

• Prior treatment for study indication with:

• Antibodies or immunotherapy within 6 weeks before the first dose of study treatment.

• Peptide Radionuclide Receptor Therapy (PRRT) administered within 6 months of the first dose.

• Systemic antineoplastic therapy

• Tyrosine kinase inhibitors within 14 days or 5 half-lives, whichever is longer, before the first dose of study treatment.

• Prior Programmed Death-1 (PD-1) or Programmed Death-Ligand 1 (PD-L1) directed therapy.

• Cryoablation, radiofrequency ablation, or trans-arterial embolization of hepatic metastases

• History of severe hypersensitivity reactions to other monoclonal antibodies which in the opinion of the investigator may pose an increased risk of a serious infusion reaction.

Other inclusion/exclusion criteria might apply

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	City of Hope National Medical Center	Duarte	California	United States	91010
2	Rocky Mountain Cancer Centers SC-2	Denver	Colorado	United States	80218
3	H Lee Moffitt Cancer Center and Research Institute	Tampa	Florida	United States	33612
4	Mayo Clinic - Rochester	Rochester	Minnesota	United States	55905
5	Montefiore Medical Center	Bronx	New York	United States	10461
6	Memorial Sloan Kettering Cancer Center	New York	New York	United States	10065
7	University of TX MD Anderson Cancer Center	Houston	Texas	United States	77030
8	Novartis Investigative Site	St Leonards	New South Wales	Australia	2065
9	Novartis Investigative Site	Wien		Austria	A-1090
10	Novartis Investigative Site	Brussels		Belgium	BE-B-1200
11	Novartis Investigative Site	Leuven		Belgium	3000
12	Novartis Investigative Site	Toronto	Ontario	Canada	M4N 3M5
13	Novartis Investigative Site	Montreal	Quebec	Canada	H3T 1E2
14	Novartis Investigative Site	Lyon		France	69437
15	Novartis Investigative Site	Marseille		France	13273
16	Novartis Investigative Site	Toulouse Cedex 4		France	31054
17	Novartis Investigative Site	Erlangen		Germany	91054
18	Novartis Investigative Site	Essen		Germany	45147
19	Novartis Investigative Site	Mainz		Germany	55131
20	Novartis Investigative Site	Marburg		Germany	35039
21	Novartis Investigative Site	Bologna	BO	Italy	40138
22	Novartis Investigative Site	Meldola	FC	Italy	47014
23	Novartis Investigative Site	Milano	MI	Italy	20133
24	Novartis Investigative Site	Milano	MI	Italy	20141
25	Novartis Investigative Site	Roma	RM	Italy	00189
26	Novartis Investigative Site	Napoli		Italy	80131
27	Novartis Investigative Site	Nagoya	Aichi	Japan	464 8681
28	Novartis Investigative Site	Kashiwa	Chiba	Japan	277 8577
29	Novartis Investigative Site	Fukuoka city	Fukuoka	Japan	812-8582
30	Novartis Investigative Site	Chuo ku	Tokyo	Japan	104 0045
31	Novartis Investigative Site	Amsterdam		Netherlands	1066 CX
32	Novartis Investigative Site	Hospitalet de LLobregat	Catalunya	Spain	08907
33	Novartis Investigative Site	Madrid		Spain	28034
34	Novartis Investigative Site	Madrid		Spain	28041
35	Novartis Investigative Site	London		United Kingdom	NW3 2PR

Sponsors and Collaborators

• Novartis Pharmaceuticals

Investigators

• Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Study Documents (Full-Text)

• Statistical Analysis Plan - Sep 18, 2018
• Study Protocol - May 24, 2018

More Information

Publications

None provided.

• Responsible Party: Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT02955069
• Other Study ID Numbers: CPDR001E2201; 2016-002522-36
• First Posted: Nov 4, 2016
• Last Update Posted: Apr 12, 2021
• Last Verified: Mar 1, 2021

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Novartis Pharmaceuticals: Advanced or metastatic; NET; pNET; GI NET; thoracic NET; GEP-NEC
• Additional relevant MeSH terms: Carcinoma; Neuroendocrine Tumors; Carcinoma, Neuroendocrine; Spartalizumab

Study Results

Participant Flow

Recruitment Details	Recruitment took place in 35 investigative sites in 12 countries from 14 Feb 2017 to 04 Apr 2018
Pre-assignment Detail	A total of 149 participants were screened. Those participants who met the eligibility criteria entered the treatment period.

Arm/Group Title	Well-differentiated NET	Poorly-differentiated GEP-NEC
Arm/Group Description	Subjects with advanced or metastatic, well-differentiated non-functional NET of GI, pancreatic or thoracic origin that progressed on or after prior available treatments.	Subjects with advanced or metastatic poorly-differentiated GEP-NEC that progressed on or after prior available treatments.
Period Title: Overall Study
STARTED	95	21
Full Analysis Set (FAS)	95	21
Safety Set	95	21
Pharmacokinetic Analysis Set (PAS)	94	18
Immunogenicity (IG) Prevalence Set	94	21
IG Incidence Set	84	17
COMPLETED	0	0
NOT COMPLETED	95	21

Baseline Characteristics

Arm/Group Title	Well-differentiated NET	Poorly-differentiated GEP-NEC	Total
Arm/Group Description	Subjects with advanced or metastatic, well-differentiated non-functional NET of GI, pancreatic or thoracic origin that progressed on or after prior available treatments.	Subjects with advanced or metastatic poorly-differentiated GEP-NEC that progressed on or after prior available treatments.	Total of all reporting groups
Overall Participants	95	21	116
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	59.4 (11.21)	57.4 (8.56)	59.0 (10.77)
Sex: Female, Male (Count of Participants)
Female	43 45.3%	4 19%	47 40.5%
Male	52 54.7%	17 81%	69 59.5%
Race/Ethnicity, Customized (Count of Participants)
Caucasian	59 62.1%	16 76.2%	75 64.7%
Black	4 4.2%	0 0%	4 3.4%
Asian	7 7.4%	3 14.3%	10 8.6%
Native American	1 1.1%	0 0%	1 0.9%
Black or African American	2 2.1%	0 0%	2 1.7%
White	15 15.8%	1 4.8%	16 13.8%
Unknown	3 3.2%	1 4.8%	4 3.4%
Other	3 3.2%	0 0%	3 2.6%
Missing	1 1.1%	0 0%	1 0.9%

Outcome Measures

1. Primary Outcome

Title	Overall Response Rate (ORR) by RECIST 1.1 and as Per Blinded Independent Central Review (BIRC).
Description	ORR is defined as the proportion of patients with best overall response (BOR) of complete response (CR) or partial response (PR), according to BIRC radiological assessment by RECIST 1.1. CR: disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to < 10 mm. PR: at least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters.
Time Frame	From baseline up to approximately 1.5 years

Outcome Measure Data

Analysis Population Description

The FAS comprised of all subjects to whom study treatment had been assigned and who received at least one dose of PDR001 (including incomplete infusion).

Arm/Group Title	Well-differentiated NET	Poorly-differentiated GEP-NEC
Arm/Group Description	Subjects with advanced or metastatic, well-differentiated non-functional NET of GI, pancreatic or thoracic origin that progressed on or after prior available treatments.	Subjects with advanced or metastatic poorly-differentiated GEP-NEC that progressed on or after prior available treatments.
Measure Participants	95	21
Number (95% Confidence Interval) [Percentage of participants]	7.4 7.8%	4.8 22.9%

2. Secondary Outcome

Title	Duration of Response (DOR) by RECIST 1.1 and as Per BIRC
Description	DOR is defined as the time between the date of first documented response (CR or PR) and the date of first documented disease progression by RECIST 1.1 and as per BIRC or death due to underlying cancer. For DOR analysis, participants continuing without progression or death due to underlying cancer were censored at the date of their last adequate tumor assessment. An adequate tumour assessment is a tumour assessment with an overall response other than unknown. CR: disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to < 10 mm. PR: at least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters.
Time Frame	From the date of first documented response (CR or PR) until the first documented disease progression or death, whichever comes first, assessed up to approximately 1.5 years

Outcome Measure Data

Analysis Population Description

Participants in the FAS with confirmed CR or PR

Arm/Group Title	Well-differentiated NET	Poorly Differentiated GEP-NEC
Arm/Group Description	Subjects with advanced or metastatic, well-differentiated non-functional NET of GI, pancreatic or thoracic origin that progressed on or after prior available treatments.	Subjects with advanced or metastatic poorly-differentiated GEP-NEC that progressed on or after prior available treatments.
Measure Participants	7	1
Median (Full Range) [Days]	250	270

3. Secondary Outcome

Title	Disease Control Rate by RECIST 1.1 and as Per BIRC
Description	Disease control rate is defined as the proportion of patients with best overall response of CR, PR or stable disease (SD) according to RECIST 1.1 criteria and as per BIRC. CR: disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to < 10 mm. PR: at least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters. SD: neither sufficient shrinkage to qualify for PR or CR nor an increase in lesions which would qualify for progressive disease.
Time Frame	From baseline up to approximately 1.5 years

Outcome Measure Data

Analysis Population Description

The FAS comprised of all subjects to whom study treatment had been assigned and who received at least one dose of PDR001 (including incomplete infusion).

Arm/Group Title	Well-differentiated NET	Poorly-differentiated GEP-NEC
Arm/Group Description	Subjects with advanced or metastatic, well-differentiated non-functional NET of GI, pancreatic or thoracic origin that progressed on or after prior available treatments.	Subjects with advanced or metastatic poorly-differentiated GEP-NEC that progressed on or after prior available treatments.
Measure Participants	95	21
Number (95% Confidence Interval) [Percentage of participants]	64.2 67.6%	19.0 90.5%

4. Secondary Outcome

Title	Time to Response (TTR) by RECIST 1.1 and as Per BIRC
Description	TTR is defined as the time from the date of start of treatment to the first documented response of either CR or PR, which must be subsequently confirmed. TTR was evaluated according to RECIST 1.1 and as per BIRC. CR: disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to < 10 mm. PR: at least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters.
Time Frame	From baseline to the first documented response, assessed up to approximately 1.5 years

Outcome Measure Data

Analysis Population Description

Participants in the FAS with confirmed CR or PR.

Arm/Group Title	Well-differentiated NET	Poorly-differentiated GEP-NEC
Arm/Group Description	Subjects with advanced or metastatic, well-differentiated non-functional NET of GI, pancreatic or thoracic origin that progressed on or after prior available treatments.	Subjects with advanced or metastatic poorly-differentiated GEP-NEC that progressed on or after prior available treatments.
Measure Participants	7	1
Median (Full Range) [Days]	110	53

5. Secondary Outcome

Title	Progression-free Survival (PFS) by RECIST 1.1 and as Per BIRC
Description	PFS is defined as the time from the date of first dose to the date of the first documented radiological progression or death due to any cause. PFS was evaluated according to RECIST 1.1 and as per BIRC. For participants who had not progressed or died at the analysis cut-off date, PFS was censored at the date of the last adequate tumor evaluation date. An adequate tumour assessment is a tumour assessment with an overall response other than unknown.
Time Frame	From baseline until the date of the first documented radiological progression or death due to any cause, whichever comes first, assessed up to approximately 1.5 years

Outcome Measure Data

Analysis Population Description

The FAS comprised of all subjects to whom study treatment had been assigned and who received at least one dose of PDR001 (including incomplete infusion).

Arm/Group Title	Well-differentiated NET	Poorly-differentiated GEP-NEC
Arm/Group Description	Subjects with advanced or metastatic, well-differentiated non-functional NET of GI, pancreatic or thoracic origin that progressed on or after prior available treatments.	Subjects with advanced or metastatic poorly-differentiated GEP-NEC that progressed on or after prior available treatments.
Measure Participants	95	21
Median (95% Confidence Interval) [Months]	3.8	1.8

6. Secondary Outcome

Title	Immune Related Overall Response Rate (irORR) by irRECIST and as Per BIRC
Description	irORR is the proportion of patients with a best overall response of immune related Complete Response (irCR) or immune related partial response (irPR), according to BIRC assessment by irRECIST. irCR: Complete disappearance of all measurable and non-measurable lesions. In addition, any pathological lymph nodes must have a reduction in short axis to < 10 mm. irPR: At least 30% decrease in the total measurable tumor burden (TMTB) compared to baseline and not qualifying for irCR or immune related progressive disease (irPD).
Time Frame	From baseline up to approximately 1.5 years

Outcome Measure Data

Analysis Population Description

The FAS comprised of all subjects to whom study treatment had been assigned and who received at least one dose of PDR001 (including incomplete infusion).

Arm/Group Title	Well-differentiated NET	Poorly-differentiated GEP-NEC
Arm/Group Description	Subjects with advanced or metastatic, well-differentiated non-functional NET of GI, pancreatic or thoracic origin that progressed on or after prior available treatments.	Subjects with advanced or metastatic poorly-differentiated GEP-NEC that progressed on or after prior available treatments.
Measure Participants	95	21
Number (95% Confidence Interval) [Percentage of participants]	7.4 7.8%	4.8 22.9%

7. Secondary Outcome

Title	Immune Related Duration of Response (irDoR) by irRECIST and as Per BIRC.
Description	irDOR is defined as the time from first documentation of irCR or irPR until the time of first documentation of progression per irRECIST based on BIRC assessment. Participants continuing without progression or death due to underlying cancer were censored at the date of their last adequate tumor assessment. An adequate tumour assessment is a tumour assessment with an overall response other than unknown for irRECIST. irCR: Complete disappearance of all measurable and non-measurable lesions. In addition, any pathological lymph nodes must have a reduction in short axis to < 10 mm. irPR: At least 30% decrease in the TMTB compared to baseline and not qualifying for irPD or irCR
Time Frame	From the date of first documented confirmed response (irCR or irPR) until the first documented progression, assessed up to approximately 1.5 years

Outcome Measure Data

Analysis Population Description

Participants in the FAS with confirmed irCR or irPR

Arm/Group Title	Well-differentiated NET	Poorly-differentiated GEP-NEC
Arm/Group Description	Subjects with advanced or metastatic, well-differentiated non-functional NET of GI, pancreatic or thoracic origin that progressed on or after prior available treatments.	Subjects with advanced or metastatic poorly-differentiated GEP-NEC that progressed on or after prior available treatments.
Measure Participants	7	1
Median (Full Range) [Days]	228	270

8. Secondary Outcome

Title	Immune Related Time to Response (irTTR) by irRECIST and as Per BIRC
Description	irTTR is defined as the time between date of start of treatment until first documented response (confirmed irCR or irPR) by irRECIST and as per BIRC. irCR: Complete disappearance of all measurable and non-measurable lesions. In addition, any pathological lymph nodes must have a reduction in short axis to < 10 mm. irPR: At least 30% decrease in the TMTB compared to baseline and not qualifying for irPD or irCR.
Time Frame	From baseline to the first documented response, assessed up to approximately 1.5 years

Outcome Measure Data

Analysis Population Description

Participants in the FAS with confirmed irCR or irPR

Arm/Group Title	Well-differentiated NET	Poorly-differentiated GEP-NEC
Arm/Group Description	Subjects with advanced or metastatic, well-differentiated non-functional NET of GI, pancreatic or thoracic origin that progressed on or after prior available treatments.	Subjects with advanced or metastatic poorly-differentiated GEP-NEC that progressed on or after prior available treatments.
Measure Participants	7	1
Median (Full Range) [Days]	110	53

9. Secondary Outcome

Title	Immune Related Disease Control Rate (irDCR) by irRECIST and as Per BIRC
Description	irDCR is defined as the proportion of patients with a best overall response of irCR or irPR or immune related stable disease (irSD) according to irRECIST and as per BIRC. irCR: Complete disappearance of all measurable and non-measurable lesions. In addition, any pathological lymph nodes must have a reduction in short axis to < 10 mm. irPR: At least 30% decrease in the TMTB compared to baseline and not qualifying for irPD or irCR. irSD: Neither a sufficient shrinkage to qualify for irPR or irCR, nor an increase in lesions, or a clear and unequivocal progression of existing nontarget or new non-measurable lesions that would qualify for irPD.
Time Frame	From baseline up to approximately 1.5 years

Outcome Measure Data

Analysis Population Description

The FAS comprised of all subjects to whom study treatment had been assigned and who received at least one dose of PDR001 (including incomplete infusion).

Arm/Group Title	Well-differentiated NET	Poorly-differentiated GEP-NEC
Arm/Group Description	Subjects with advanced or metastatic, well-differentiated non-functional NET of GI, pancreatic or thoracic origin that progressed on or after prior available treatments.	Subjects with advanced or metastatic poorly-differentiated GEP-NEC that progressed on or after prior available treatments.
Measure Participants	95	21
Number (95% Confidence Interval) [Percentage of participants]	66.3 69.8%	19.0 90.5%

10. Secondary Outcome

Title	Immune Related Progression Free Survival (irPFS) by irRECIST and as Per BIRC
Description	irPFS is defined as the time from date of start of treatment to the date of event defined as the first documented assessment of immune related progression that is confirmed or death due to any cause. If a patient has not had an event, immune related progression-free survival was censored at the date of last adequate tumor assessment. An adequate tumor assessment is a tumor assessment with overall response other than unknown for irRECIST.
Time Frame	From baseline until the date of the first documented immune related progression or death due to any cause, whichever comes first, assessed up to approximately 1.5 years

Outcome Measure Data

Analysis Population Description

The FAS comprised of all subjects to whom study treatment had been assigned and who received at least one dose of PDR001 (including incomplete infusion).

Arm/Group Title	Well-differentiated NET	Poorly-differentiated GEP-NEC
Arm/Group Description	Subjects with advanced or metastatic, well-differentiated non-functional NET of GI, pancreatic or thoracic origin that progressed on or after prior available treatments.	Subjects with advanced or metastatic poorly-differentiated GEP-NEC that progressed on or after prior available treatments.
Measure Participants	95	21
Median (95% Confidence Interval) [Months]	3.8	1.8

11. Secondary Outcome

Title	Overall Survival (OS)
Description	OS is defined as the time from the start of treatment date to the date of death, due to any cause. If a patient was not known to have died, then OS was censored at the latest date the patient was known to be alive.
Time Frame	From baseline until death due to any cause, assessed up to approx. 3 years

Outcome Measure Data

Analysis Population Description

The FAS comprised of all subjects to whom study treatment had been assigned and who received at least one dose of PDR001 (including incomplete infusion).

Arm/Group Title	Well-differentiated NET	Poorly-differentiated GEP-NEC
Arm/Group Description	Subjects with advanced or metastatic, well-differentiated non-functional NET of GI, pancreatic or thoracic origin that progressed on or after prior available treatments.	Subjects with advanced or metastatic poorly-differentiated GEP-NEC that progressed on or after prior available treatments.
Measure Participants	95	21
Median (95% Confidence Interval) [Months]	23.4	6.8

12. Secondary Outcome

Title	Changes From Baseline in Chromogranin A (CgA) Levels
Description	Blood samples were collected for assessment of CgA level. Change from Baseline at a particular visit was calculated as the CgA level at that visit minus Baseline.
Time Frame	Baseline, day 1 of each cycle from Cycle 2 to end of treatment, assessed up to approx. 1.5 years. Cycle=28 days.

Outcome Measure Data

Analysis Population Description

The FAS comprised of all subjects to whom study treatment had been assigned and who received at least one dose of PDR001 (including incomplete infusion). Number analyzed signified number of participants with available data for this outcome measure at specified timepoints.

Arm/Group Title	Well-differentiated NET	Poorly-differentiated GEP-NEC
Arm/Group Description	Subjects with advanced or metastatic, well-differentiated non-functional NET of GI, pancreatic or thoracic origin that progressed on or after prior available treatments.	Subjects with advanced or metastatic poorly-differentiated GEP-NEC that progressed on or after prior available treatments.
Measure Participants	95	21
Cycle 2 Day 1	874.6 (6694.64)	6466.9 (23760.13)
Cycle 3 Day 1	-1811.7 (21413.11)	706.5 (2294.87)
Cycle 4 Day 1	579.9 (13437.06)	1544.5 (2712.23)
Cycle 5 Day 1	598.2 (11724.93)	1306.6 (3125.84)
Cycle 6 Day 1	1337.6 (7106.32)	4531.7 (8694.65)
Cycle 7 Day 1	-564.5 (12643.71)	11089.5 (17551.10)
Cycle 8 Day 1	3726.0 (18813.63)	9103.5 (14759.44)
Cycle 9 Day 1	22522.2 (94054.85)	-1342.0 (NA)
Cycle 10 Day 1	54301.5 (250229.27)	-1376.0 (NA)
Cycle 11 Day 1	84634.7 (344244.60)	-1393.0 (NA)
Cycle 12 Day 1	8177.6 (36820.47)	-1362.0 (NA)
Cycle 13 Day 1	-379.8 (1509.95)	-1377.0 (NA)
Cycle 14 Day 1	398.3 (1866.56)
Cycle 15 Day 1	13.1 (1120.60)
Cycle 16 Day 1	-81.0 (1583.99)
Cycle 17 Day 1	-176.0 (NA)
Cycle 18 Day 1	42.0 (NA)
End of treatment	30115.3 (131958.16)	3899.6 (7991.40)

13. Secondary Outcome

Title	Change From Baseline in Neuron Specific Enolase (NSE) Levels
Description	Blood samples were collected for assessment of NSE level. Change from Baseline at a particular visit was calculated as the NSE level at that visit minus Baseline.
Time Frame	Baseline, day 1 of each cycle from Cycle 2 to end of treatment, assessed up to approx. 1.5 years. Cycle= 28days

Outcome Measure Data

Analysis Population Description

The FAS comprised of all subjects to whom study treatment had been assigned and who received at least one dose of PDR001 (including incomplete infusion). Number analyzed signified number of participants with available data for this outcome measure at specified timepoints.

Arm/Group Title	Well-differentiated NET	Poorly-differentiated GEP-NEC
Arm/Group Description	Subjects with advanced or metastatic, well-differentiated non-functional NET of GI, pancreatic or thoracic origin that progressed on or after prior available treatments.	Subjects with advanced or metastatic poorly-differentiated GEP-NEC that progressed on or after prior available treatments.
Measure Participants	95	21
Cycle 2 Day 1	0.8 (29.71)	27.9 (40.77)
Cycle 3 Day 1	2.5 (29.33)	32.6 (56.87)
Cycle 4 Day 1	-0.1 (14.98)	21.9 (21.64)
Cycle 5 Day 1	4.8 (30.34)	31.8 (56.39)
Cycle 6 Day 1	-3.6 (19.18)	151.6 (204.21)
Cycle 7 Day 1	7.6 (39.44)	-3.0 (17.75)
Cycle 8 Day 1	1.0 (22.19)	40.4 (NA)
Cycle 9 Day 1	2.6 (8.64)	-12.7 (NA)
Cycle 10 Day 1	10.3 (33.74)	-15.0 (NA)
Cycle 11 Day 1	2.3 (8.89)
Cycle 12 Day 1	-2.4 (23.04)	-12.3 (NA)
Cycle 13 Day 1	-3.9 (24.22)	-17.8 (NA)
Cycle 14 Day 1	-4.5 (22.71)
Cycle 15 Day 1	-3.4 (29.73)
Cycle 16 Day 1	26.5 (35.38)
Cycle 17 Day 1	15.1 (NA)
Cycle 18 Day 1	13.8 (NA)
End of treatment	47.7 (136.78)	44.3 (66.73)

14. Secondary Outcome

Title	PDR001 Plasma Concentration
Description	Blood samples will be taken to evaluate the pharmacokinetics by assessing plasma concentration of PDR001 at selected time points
Time Frame	Cycle(C)1 Day(D)1 pre-dose and 30min post-infusion,C2D1 Pre-dose,C3D1 Pre-dose and 30min post-infusion,D1 pre-dose from C4 to C13, assessed up to approx. 1.5 years.Cycle=28 days

Outcome Measure Data

Analysis Population Description

The PAS comprised of all subjects who provide at least one evaluable PDR001 PK concentration. Number analyzed signified number of participants with available data for this outcome measure at specified timepoints.

Arm/Group Title	Well-differentiated NET	Poorly-differentiated GEP-NEC
Arm/Group Description	Subjects with advanced or metastatic, well-differentiated non-functional NET of GI, pancreatic or thoracic origin that progressed on or after prior available treatments.	Subjects with advanced or metastatic poorly-differentiated GEP-NEC that progressed on or after prior available treatments.
Measure Participants	94	18
Cycle 1 Day 1 pre-dose	0 (0)	0 (0)
Cycle 1 Day 1 30 min post-dose	106 (32.9)	100 (52.2)
Cycle 2 Day 1 Pre-dose	26.8 (9.76)	25.8 (9.30)
Cycle 3 Day 1 pre-dose	43.7 (18.9)	42.3 (19.6)
Cycle 3 Day 1 30 min post-dose	140 (46.7)	142 (44.3)
Cycle 4 Day 1 pre-dose	52.8 (25.1)	40.7 (17.2)
Cycle 5 Day 1 pre-dose	52.0 (32.3)	41.8 (8.88)
Cycle 6 Day 1 pre-dose	58.2 (31.6)	49.9 (NA)
Cycle 7 Day 1 pre-dose	64.3 (37.6)	66.9 (30.1)
Cycle 8 Day 1 pre-dose	59.6 (38.2)	64.7 (31.4)
Cycle 9 Day 1 pre-dose	65.1 (38.1)	93.7 (NA)
Cycle 10 Day 1 pre-dose	70.2 (40.2)
Cycle 11 Day 1 pre-dose	69.2 (39.1)	99.0 (NA)
Cycle 12 Day 1 pre-dose	71.7 (38.1)	111 (NA)
Cycle 13 Day 1 pre-dose	91.8 (46.0)

15. Secondary Outcome

Title	Change From Baseline in European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30) Global Health Status/Quality of Life Score
Description	The EORTC QLQ-C30 is a patient completed 30 item questionnaire that is composed of both multi-item scales and single-item measures. These include five functional scales, three symptom scales, six single items and a global health status/QoL scale. Global health status/QoL response options are 1 to 4. Scores were averaged and transformed to 0 to 100. Higher scores indicate better functioning. Change from Baseline was calculated by subtracting Baseline value from the selected visit value. A positive change from Baseline indicates improvement.
Time Frame	Baseline, every 8 weeks from Cycle 3 Day 1 for the first 13 cycles and every 12 weeks from Cycle 13 Day 1 thereafter and end of treatment, assessed up to approx. 1.5 years. Cycle=28 days

Outcome Measure Data

Analysis Population Description

The FAS comprised of all subjects to whom study treatment had been assigned and who received at least one dose of PDR001 (including incomplete infusion). Number analyzed signified number of participants with available data for this outcome measure at specified timepoints.

Arm/Group Title	Well-differentiated NET	Poorly-differentiated GEP-NEC
Arm/Group Description	Subjects with advanced or metastatic, well-differentiated non-functional NET of GI, pancreatic or thoracic origin that progressed on or after prior available treatments.	Subjects with advanced or metastatic poorly-differentiated GEP-NEC that progressed on or after prior available treatments.
Measure Participants	95	21
Cycle 3 Day 1	-1.00 (19.491)	-11.11 (27.003)
Cycle 5 Day 1	-1.91 (27.838)	-4.17 (17.347)
Cycle 7 Day 1	1.96 (29.945)	25.00 (35.355)
Cycle 9 Day 1	1.67 (31.823)	33.33 (NA)
Cycle 11 Day 1	-1.19 (28.048)
Cycle 13 Day 1	1.96 (27.088)	41.67 (NA)
Cycle 16 Day 1	-16.67 (16.667)
End of Treatment	-6.46 (23.607)	-22.92 (23.465)

16. Secondary Outcome

Title	Change From Baseline in EQ-5D-5L Index Score
Description	The EQ-5D-5L descriptive system provides a profile of the participant's health state in 5 dimensions (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression). For each of these dimensions, the participant self-assigned a score: from 1 (no problems) to 5 (extreme problems). The 5 digit health states obtained for each dimension was converted into a single mean index value based on the EQ-5D crosswalk value set for the UK using the time trade-off method. This index ranges from -0.594 (worst health) to 1.0 (best health). Change from Baseline was calculated by subtracting Baseline value from the selected visit value. A positive change from baseline indicates improvement.
Time Frame	Baseline, every 8 weeks from Cycle 3 Day 1 for the first 13 cycles and every 12 weeks from Cycle 13 Day 1 thereafter, and end of treatment, assessed up to approx.1.5 year. Cycle=28 days

Outcome Measure Data

Analysis Population Description

The FAS comprised of all subjects to whom study treatment had been assigned and who received at least one dose of PDR001 (including incomplete infusion). Number analyzed signified number of participants with available data for this outcome measure at specified timepoints.

Arm/Group Title	Well-differentiated NET	Poorly-differentiated GEP-NEC
Arm/Group Description	Subjects with advanced or metastatic, well-differentiated non-functional NET of GI, pancreatic or thoracic origin that progressed on or after prior available treatments.	Subjects with advanced or metastatic poorly-differentiated GEP-NEC that progressed on or after prior available treatments.
Measure Participants	95	21
Cycle 3 Day 1	0.03 (0.169)	-0.09 (0.157)
Cycle 5 Day 1	-0.02 (0.247)	0.02 (0.111)
Cycle 7 Day 1	-0.04 (0.241)	0.16 (0.135)
Cycle 9 Day 1	0.02 (0.247)	0.02 (NA)
Cycle 11 Day 1	0.02 (0.262)
Cycle 13 Day 1	-0.03 (0.299)	0.03 (NA)
Cycle 16 Day 1	-0.17 (0.085)
End of treatment	-0.10 (0.209)	-0.30 (0.263)

17. Secondary Outcome

Title	PDR001 Anti-drug Antibodies (ADA) Prevalence at Baseline
Description	ADA prevalence at baseline was calculated as the proportion of participants who had an ADA positive result at baseline
Time Frame	Baseline

Outcome Measure Data

Analysis Population Description

Participants in the Immunogenicity (IG) set with at least one determinant sample (sample that is neither ADA-inconclusive nor unevaluable) at baseline.

Arm/Group Title	Well-differentiated NET	Poorly-differentiated GEP-NEC
Arm/Group Description	Subjects with advanced or metastatic, well-differentiated non-functional NET of GI, pancreatic or thoracic origin that progressed on or after prior available treatments.	Subjects with advanced or metastatic poorly-differentiated GEP-NEC that progressed on or after prior available treatments.
Measure Participants	88	17
Count of Participants [Participants]	1 1.1%	0 0%

18. Secondary Outcome

Title	PDR001 ADA Incidence On-treatment
Description	ADA incidence on treatment was calculated as the proportion of participants who were treatment-induced ADA positive (post-baseline ADA positive with ADA-negative sample at baseline) and treatment-boosted ADA positive (post-baseline ADA positive with titer that is at least the fold titer change greater than the ADA-positive baseline titer)
Time Frame	Cycle(C)1 Day(D)1 pre-dose and 30min post-infusion,C2D1 Pre-dose,C3D1 Pre-dose and 30min post-infusion,D1 pre-dose from C4 to C13 and every 6 cycles until C25, and end of treatment, assessed up to approx. 1.5 years. Cycle=28 days

Outcome Measure Data

Analysis Population Description

The IG incidence set comprised of all subjects in the IG prevalence set with a determinant baseline IG sample and at least one determinant post-baseline IG sample. Determinant sample: sample that is neither ADA-inconclusive nor unevaluable.

Arm/Group Title	Well-differentiated NET	Poorly-differentiated GEP-NEC
Arm/Group Description	Subjects with advanced or metastatic, well-differentiated non-functional NET of GI, pancreatic or thoracic origin that progressed on or after prior available treatments.	Subjects with advanced or metastatic poorly-differentiated GEP-NEC that progressed on or after prior available treatments.
Measure Participants	84	17
Count of Participants [Participants]	10 10.5%	2 9.5%

19. Post-Hoc Outcome

Title	All Collected Deaths
Description	Deaths on-treatment are collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approximately 3 years. Total Deaths are collected from first dose of study treatment until end of post-treatment efficacy or survival follow, up to maximum duration of approximately 3 years.
Time Frame	up to 3 years

Outcome Measure Data

Analysis Population Description

The Safety Set comprised all subjects who received at least one dose of PDR001

Arm/Group Title	Well-differentiated NET	Poorly-differentiated GEP-NEC
Arm/Group Description	Subjects with advanced or metastatic, well-differentiated non-functional NET of GI, pancreatic or thoracic origin that progressed on or after prior available treatments.	Subjects with advanced or metastatic poorly-differentiated GEP-NEC that progressed on or after prior available treatments.
Measure Participants	95	21
Total Deaths	47 49.5%	16 76.2%
Deaths on-treatment	1 1.1%	1 4.8%

Adverse Events

Time Frame	Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approximately 3 years.
Adverse Event Reporting Description	Any sign or symptom that occurs during the study treatment plus 30 days post treatment
Arm/Group Title	Well-differentiated NET		Poorly-differentiated GEP-NEC		All Subjects
Arm/Group Description	Subjects with advanced or metastatic, well-differentiated non-functional NET of GI, pancreatic or thoracic origin that progressed on or after prior available treatments.		Subjects with advanced or metastatic poorly-differentiated GEP-NEC that progressed on or after prior available treatments		All subjects
All Cause Mortality
	Well-differentiated NET		Poorly-differentiated GEP-NEC		All Subjects
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/95 (1.1%)		1/21 (4.8%)		2/116 (1.7%)
Serious Adverse Events
	Well-differentiated NET		Poorly-differentiated GEP-NEC		All Subjects
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	29/95 (30.5%)		6/21 (28.6%)		35/116 (30.2%)
Blood and lymphatic system disorders
Anaemia	1/95 (1.1%)		0/21 (0%)		1/116 (0.9%)
Thrombocytopenia	1/95 (1.1%)		0/21 (0%)		1/116 (0.9%)
Cardiac disorders
Torsade de pointes	1/95 (1.1%)		0/21 (0%)		1/116 (0.9%)
Gastrointestinal disorders
Abdominal pain	6/95 (6.3%)		1/21 (4.8%)		7/116 (6%)
Abdominal pain upper	1/95 (1.1%)		0/21 (0%)		1/116 (0.9%)
Constipation	2/95 (2.1%)		0/21 (0%)		2/116 (1.7%)
Diarrhoea	1/95 (1.1%)		0/21 (0%)		1/116 (0.9%)
Gastric haemorrhage	0/95 (0%)		1/21 (4.8%)		1/116 (0.9%)
Vomiting	1/95 (1.1%)		1/21 (4.8%)		2/116 (1.7%)
General disorders
Generalised oedema	1/95 (1.1%)		0/21 (0%)		1/116 (0.9%)
Malaise	1/95 (1.1%)		0/21 (0%)		1/116 (0.9%)
Pyrexia	3/95 (3.2%)		0/21 (0%)		3/116 (2.6%)
Hepatobiliary disorders
Cholestasis	0/95 (0%)		1/21 (4.8%)		1/116 (0.9%)
Hepatorenal syndrome	0/95 (0%)		1/21 (4.8%)		1/116 (0.9%)
Immune system disorders
Insulin autoimmune syndrome	1/95 (1.1%)		0/21 (0%)		1/116 (0.9%)
Infections and infestations
Candida infection	1/95 (1.1%)		0/21 (0%)		1/116 (0.9%)
Febrile infection	1/95 (1.1%)		0/21 (0%)		1/116 (0.9%)
Gastroenteritis	0/95 (0%)		1/21 (4.8%)		1/116 (0.9%)
Influenza	1/95 (1.1%)		0/21 (0%)		1/116 (0.9%)
Pneumonia	1/95 (1.1%)		0/21 (0%)		1/116 (0.9%)
Respiratory tract infection	1/95 (1.1%)		0/21 (0%)		1/116 (0.9%)
Septic shock	1/95 (1.1%)		0/21 (0%)		1/116 (0.9%)
Systemic infection	0/95 (0%)		1/21 (4.8%)		1/116 (0.9%)
Injury, poisoning and procedural complications
Fall	1/95 (1.1%)		0/21 (0%)		1/116 (0.9%)
Femur fracture	1/95 (1.1%)		0/21 (0%)		1/116 (0.9%)
Post procedural haemorrhage	0/95 (0%)		1/21 (4.8%)		1/116 (0.9%)
Skin laceration	1/95 (1.1%)		0/21 (0%)		1/116 (0.9%)
Metabolism and nutrition disorders
Hypercalcaemia	1/95 (1.1%)		1/21 (4.8%)		2/116 (1.7%)
Hypoglycaemia	1/95 (1.1%)		0/21 (0%)		1/116 (0.9%)
Hyponatraemia	1/95 (1.1%)		0/21 (0%)		1/116 (0.9%)
Musculoskeletal and connective tissue disorders
Arthralgia	1/95 (1.1%)		0/21 (0%)		1/116 (0.9%)
Back pain	2/95 (2.1%)		0/21 (0%)		2/116 (1.7%)
Bone pain	1/95 (1.1%)		0/21 (0%)		1/116 (0.9%)
Muscular weakness	1/95 (1.1%)		0/21 (0%)		1/116 (0.9%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Tumour necrosis	1/95 (1.1%)		0/21 (0%)		1/116 (0.9%)
Nervous system disorders
Dizziness	1/95 (1.1%)		0/21 (0%)		1/116 (0.9%)
Hepatic encephalopathy	1/95 (1.1%)		0/21 (0%)		1/116 (0.9%)
Neuropathy peripheral	1/95 (1.1%)		0/21 (0%)		1/116 (0.9%)
Post herpetic neuralgia	1/95 (1.1%)		0/21 (0%)		1/116 (0.9%)
Seizure	0/95 (0%)		1/21 (4.8%)		1/116 (0.9%)
Product Issues
Device occlusion	0/95 (0%)		1/21 (4.8%)		1/116 (0.9%)
Renal and urinary disorders
Acute kidney injury	0/95 (0%)		1/21 (4.8%)		1/116 (0.9%)
Respiratory, thoracic and mediastinal disorders
Bronchial obstruction	1/95 (1.1%)		0/21 (0%)		1/116 (0.9%)
Dyspnoea	2/95 (2.1%)		0/21 (0%)		2/116 (1.7%)
Haemoptysis	1/95 (1.1%)		0/21 (0%)		1/116 (0.9%)
Pneumonia aspiration	0/95 (0%)		1/21 (4.8%)		1/116 (0.9%)
Pneumonitis	2/95 (2.1%)		0/21 (0%)		2/116 (1.7%)
Pulmonary haemorrhage	1/95 (1.1%)		0/21 (0%)		1/116 (0.9%)
Vascular disorders
Peripheral ischaemia	1/95 (1.1%)		0/21 (0%)		1/116 (0.9%)
Other (Not Including Serious) Adverse Events
	Well-differentiated NET		Poorly-differentiated GEP-NEC		All Subjects
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	86/95 (90.5%)		18/21 (85.7%)		104/116 (89.7%)
Blood and lymphatic system disorders
Anaemia	18/95 (18.9%)		3/21 (14.3%)		21/116 (18.1%)
Endocrine disorders
Hypothyroidism	7/95 (7.4%)		0/21 (0%)		7/116 (6%)
Gastrointestinal disorders
Abdominal distension	5/95 (5.3%)		2/21 (9.5%)		7/116 (6%)
Abdominal pain	17/95 (17.9%)		1/21 (4.8%)		18/116 (15.5%)
Abdominal pain upper	7/95 (7.4%)		0/21 (0%)		7/116 (6%)
Constipation	19/95 (20%)		3/21 (14.3%)		22/116 (19%)
Diarrhoea	26/95 (27.4%)		4/21 (19%)		30/116 (25.9%)
Dry mouth	5/95 (5.3%)		0/21 (0%)		5/116 (4.3%)
Gastrooesophageal reflux disease	2/95 (2.1%)		2/21 (9.5%)		4/116 (3.4%)
Nausea	20/95 (21.1%)		5/21 (23.8%)		25/116 (21.6%)
Vomiting	11/95 (11.6%)		3/21 (14.3%)		14/116 (12.1%)
General disorders
Asthenia	12/95 (12.6%)		2/21 (9.5%)		14/116 (12.1%)
Fatigue	36/95 (37.9%)		3/21 (14.3%)		39/116 (33.6%)
Oedema peripheral	14/95 (14.7%)		3/21 (14.3%)		17/116 (14.7%)
Pain	2/95 (2.1%)		2/21 (9.5%)		4/116 (3.4%)
Pyrexia	24/95 (25.3%)		2/21 (9.5%)		26/116 (22.4%)
Infections and infestations
Infection	0/95 (0%)		2/21 (9.5%)		2/116 (1.7%)
Investigations
Alanine aminotransferase increased	3/95 (3.2%)		3/21 (14.3%)		6/116 (5.2%)
Amylase increased	5/95 (5.3%)		1/21 (4.8%)		6/116 (5.2%)
Aspartate aminotransferase increased	1/95 (1.1%)		4/21 (19%)		5/116 (4.3%)
Blood alkaline phosphatase increased	3/95 (3.2%)		3/21 (14.3%)		6/116 (5.2%)
Gamma-glutamyltransferase increased	6/95 (6.3%)		3/21 (14.3%)		9/116 (7.8%)
Lipase increased	6/95 (6.3%)		1/21 (4.8%)		7/116 (6%)
Weight decreased	9/95 (9.5%)		1/21 (4.8%)		10/116 (8.6%)
Weight increased	4/95 (4.2%)		2/21 (9.5%)		6/116 (5.2%)
Metabolism and nutrition disorders
Decreased appetite	15/95 (15.8%)		3/21 (14.3%)		18/116 (15.5%)
Hyperglycaemia	7/95 (7.4%)		1/21 (4.8%)		8/116 (6.9%)
Hypoalbuminaemia	8/95 (8.4%)		0/21 (0%)		8/116 (6.9%)
Hypoglycaemia	5/95 (5.3%)		0/21 (0%)		5/116 (4.3%)
Hyponatraemia	5/95 (5.3%)		0/21 (0%)		5/116 (4.3%)
Musculoskeletal and connective tissue disorders
Arthralgia	8/95 (8.4%)		0/21 (0%)		8/116 (6.9%)
Back pain	12/95 (12.6%)		2/21 (9.5%)		14/116 (12.1%)
Muscular weakness	6/95 (6.3%)		0/21 (0%)		6/116 (5.2%)
Pain in extremity	7/95 (7.4%)		0/21 (0%)		7/116 (6%)
Nervous system disorders
Headache	8/95 (8.4%)		1/21 (4.8%)		9/116 (7.8%)
Psychiatric disorders
Anxiety	7/95 (7.4%)		0/21 (0%)		7/116 (6%)
Insomnia	3/95 (3.2%)		2/21 (9.5%)		5/116 (4.3%)
Renal and urinary disorders
Proteinuria	6/95 (6.3%)		1/21 (4.8%)		7/116 (6%)
Respiratory, thoracic and mediastinal disorders
Cough	14/95 (14.7%)		2/21 (9.5%)		16/116 (13.8%)
Dyspnoea	9/95 (9.5%)		6/21 (28.6%)		15/116 (12.9%)
Skin and subcutaneous tissue disorders
Pruritus	8/95 (8.4%)		1/21 (4.8%)		9/116 (7.8%)
Rash	10/95 (10.5%)		2/21 (9.5%)		12/116 (10.3%)
Vascular disorders
Hypertension	12/95 (12.6%)		0/21 (0%)		12/116 (10.3%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The terms and conditions of Novartis' agreements with its investigators may vary. However, Novartis does not prohibit any investigator from publishing. Any publications from a single-site are postponed until the publication of the pooled data (ie, data from all sites) in the clinical trial.