Efficacy and Safety Study in Pancreatic or Midgut Neuroendocrine Tumours Having Progressed Radiologically While Previously Treated With Lanreotide Autogel® 120 mg

Time to Progression was defined as time from first injection of lanreotide Autogel® 120 mg every 14 days to progression. Disease progression was assessed by tumour response evaluation according to RECIST v1.0, every 12 weeks, measured by independent central review using the same imaging technique (CT scan or MRI) for each subject throughout the study. Median time to progression was estimated using the Kaplan Meier method for each cohort.

The percentage of subjects alive and progression-free was assessed throughout the study up to Week 60 for the panNET cohort and Week 96 for the midgut cohort. Disease progression was assessed by tumour response evaluation according to RECIST v1.0, every 12 weeks measured by independent central review using the same imaging technique (CT scan or MRI) for each subject throughout the study. The percentage of subjects alive and progression free was estimated using the Kaplan Meier method for each cohort.

Overall survival was defined as the time in months from the first injection of lanreotide Autogel® 120 mg every 14 days to death due to any cause. Median overall survival was estimated using the Kaplan Meier method for each cohort.

The ORR was defined as the percentage of subjects who achieve either complete response (CR) or partial response (PR) according to RECIST v1.0 criteria. ORR was evaluated every 12 weeks and results are presented for each cohort.

The DCR was defined as the percentage of subjects who achieved CR plus PR plus Stable Disease (SD), evaluated according to RECIST v1.0 criteria. The DCR at Weeks 24 and 48 is presented for each cohort.

Best overall response was defined as the best response recorded from the initiation of treatment until disease progression, according to RECIST v1.0 evaluation. The percentage of subjects in each response category and those who were non-evaluable (i.e. with no tumour assessment after the start of study treatment) throughout the study are presented for each cohort.

Median duration of SD was the time from first injection of lanreotide Autogel® 120 mg every 14 days until the first occurrence of PD by central assessment. Disease progression was assessed by tumour response evaluation according to RECIST v1.0, every 12 weeks, measured using the same imaging technique (CT scan or MRI) for each subject throughout the study. Median duration of stable disease was estimated using the Kaplan Meier method for each cohort.

A univariate cox proportional hazards model was used to assess whether the following factors were associated with PFS:

• Hepatic tumour load: >25% versus reference ≤25%
• Tumour Grade: Grade 2 versus reference Grade 1,
• Previous surgery of the primary tumour: No versus reference Yes,
• Proliferation index Ki67: ≥10% versus reference <10%
• Duration of treatment with lanreotide Autogel® 120 mg every 28 days by category: ≥median value versus reference <median value,
• Age by category: ≥65 years versus reference <65 years,
• Time from diagnosis to study entry by category: ≥3 years versus reference <3 years,
• Time interval between the two CT scans (pre-screening/screening): ≥12 months versus reference <12 months and
• Symptoms (diarrhoea or flushing at baseline): No versus reference Yes.

Each factor was assessed for its importance in the Cox model for PFS in a univariate fashion.

Symptom control was measured by the total number of stools (diarrhoea) and flushing episodes during the 7 days prior to the visit, reported orally by the subject to the investigator. The mean change from baseline in number of stools and flushing episodes reported at each visit is presented for each cohort.

Subjects were instructed to complete the 30 questions in the EORTC-QLQ-C30 v3.0 questionnaire at baseline and every 12 weeks throughout the study.

The global health status sub-score was assessed using the last 2 questions which represented subject's assessment of overall health \& QoL. Each question was coded on a 7-point scale (1=very poor to 7=excellent). The sub-score was transformed to range from 0-100, with a high score for global health status representing a high QoL. The mean change from baseline in the transformed global health status are presented for the end of study/early withdrawal visit, with a positive change indicating an improvement in QoL.

Subjects were instructed to complete the EQ-5D-5L descriptive system at baseline and every 12 weeks throughout the study.

The EQ-5D-5L descriptive system comprised the following 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension had 5 levels: no problems, slight problems, moderate problems, severe problems, extreme problems. The EQ-5D-5L health states, defined by the EQ-5D-5L descriptive system, was converted into a single index value with scores ranging from 0 (no problems) to 1 (extreme problems). The mean change from baseline at the end of study/early withdrawal visit is presented with a positive change from baseline in the index values indicating a worsening of symptoms.

Subjects were instructed to complete the EQ-5D-5L VAS at baseline and every 12 weeks throughout the study. The EQ-5D-5L VAS recorded the subject's self-rated health on a vertical VAS which is numbered from 0 (worst health state) to 100 (best health state). The mean change from baseline at the end of study/early withdrawal visit is presented with a positive change in the VAS indicating an improvement in symptoms.

Subjects were asked to complete the EORTC QLQ-GI.NET21 module which comprised 21 questions that used a 4-point scale (1 = Not at all, 2 = A little, 3 = Quite a bit, 4 = Very much) to evaluate 3 defined multi-item symptom scales (endocrine, gastrointestinal and treatment related side effects), 2 single item symptoms (bone/muscle pain and concern about weight loss), 2 psychosocial scales (social function and disease-related worries) and 2 other single items (sexuality and communication). Answers were converted into grading scale, with values between 0 and 100. Each individual sub-score was transformed to range from 0 to 100. The mean change from baseline at the end of study/early withdrawal visit is presented with a higher score representing more or worse problems.

Nonspecific tumour peptide biomarkers (chromogranin A [CgA], neuron specific enolase [NSE] and plasma/urinary 5-hydroxyindoleacetic acid [5-HIAA]) were evaluated in both pancreas and midgut subjects at baseline and Week 12 and every 12 weeks thereafter. At all scheduled visits, except baseline, plasma/urinary 5-HIAA was only performed in subjects with symptoms of carcinoid syndrome (diarrhoea and/or flushing) or if urinary 5-HIAA was elevated (above upper limit of normal [ULN]) at baseline. Mean change from baseline values were normalised by the ULN (xULN) and are presented for each cohort.

PanNET specific tumour peptide biomarkers were evaluated in pancreas subjects at baseline. Only the tumour biomarkers that were above normal range at baseline were evaluated every 12 weeks thereafter and at the end of study visit. The mean change from baseline values in picomole/liter (pmol/L) are presented for the end of study visit.

PanNET specific tumour peptide biomarkers were evaluated in pancreas subjects at baseline. Only the tumour biomarkers that were above normal range at baseline were evaluated every 12 weeks thereafter and at the end of study visit. The mean change from baseline values in nanograms (ng)/L are presented for the end of study visit.