Combination of Lanreotide Autogel 120mg and Temozolomide in Progressive GEP-NET: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Combination of Lanreotide Autogel 120mg and Temozolomide in Progressive GEP-NET (NCT02231762), a na phase 2 study. The primary outcome is Disease Control Rate (DCR) After 6 Months.

2. Clinical Question

The study was intended to evaluate efficacy and tolerability in patients whose GEP-NET had been classified as progressive. The primary question concerns disease status at a defined assessment point, not the duration of disease control over the full follow-up period. The registry names further outcomes, including disease control after 12 months and progression-free survival within 12 months, but their results are not reported in the registry record.

The comparison with 45% provides a reference for evaluating the observed disease control proportion. It is not a comparison with patients receiving a different treatment under the same study conditions. Since allocation is listed as not applicable and the model is single group, the record does not support interpreting any maintenance subgroup as a randomized control. The clinical question is therefore narrower than whether the combination is better than another treatment: it concerns the disease control proportion recorded after the combination phase and its uncertainty relative to the stated benchmark.

3. Trial Design

This is a Phase II, multicentre, open-label, single-group study. The registry records an enrollment of 57 and a completed study status. The listed study start is 2014-10 and the primary completion date is 2016-12. The sponsor is Ipsen. The record identifies the condition as gastroenteropancreatic neuroendocrine tumours and the study population as patients with progressive GEP-NET graded G1 or G2.

During the combination phase, participants received lanreotide Autogel 120 mg and temozolomide for the first 6 months. The record describes a subsequent maintenance phase in which participants either received lanreotide Autogel 120 mg for 6 months or received no treatment for 6 months. It also separates maintenance groups by functioning and non-functioning NET. How participants entered these maintenance groups is not reported in the registry record. The listed allocation field is not applicable, so these groups should not be treated as randomized arms or as like-for-like treatment comparisons.

The study was open label, with no masking. Tumour assessments used RECIST 1.1. CT scans or MRI could be used for tumour measurement, and the same measurement method was used throughout the study for each subject. The registry describes scans at screening or baseline, at weeks 12 and 24, and at early withdrawal or when clinical or biological signs of progression occurred.

The primary endpoint was disease control rate after 6 months, defined as the proportion with complete response, partial response, or stable disease. The planned statistical test compared that proportion with 45% using an exact binomial proportion test. The analysis population and missing-assessment approach are described in the endpoint record. A sample-size justification, the basis for the selected benchmark, and a more complete statistical analysis plan are not reported in the registry record.

4. Participant Flow and Accounting

The registry reports how participants moved through each stage of the study. All counts below are exactly as posted; missing counts are not inferred from other stages.

Before assignment: Overall, 64 subjects were screened, 7 were screening failures of which 5 subjects did not meet the entry criteria. 57 subjects were assigned to receive treatment in the baseline population.

Combination Phase

Reasons for not completing this period:

Maintenance Phase

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: The ITT population is all subjects that had at least one baseline and at least one post baseline assessment of the primary efficacy parameter.

5. Baseline Characteristics

The table reproduces the baseline characteristics posted in the registry, which describe the participants analysed at baseline and help show whether the randomized groups were comparable.

6. Primary Endpoint

The registry lists the primary outcome as Disease Control Rate (DCR) After 6 Months, measured over 6 months.

The primary endpoint is disease control rate after 6 months of combination treatment. It is the proportion of subjects whose tumour assessment shows complete response, partial response, or stable disease, according to RECIST 1.1. This combines response categories with stable disease into a single measure of disease control at the specified assessment point.

RECIST provides standardized criteria for classifying tumour changes. The registry states that CT or MRI could be used, with each subject assessed using the same measurement method throughout the study. Assessments were scheduled at baseline and at weeks 12 and 24, with additional assessment at early withdrawal or when signs of progression arose. These procedures define how tumour status was evaluated; they do not, by themselves, establish how consistently assessments were completed or reviewed.

A proportion is useful for describing how common a defined status was in the analyzed population at a particular time. The registry planned to report the disease control proportion with a 95% confidence interval and compare it with a 45% benchmark using an exact binomial proportion test. The endpoint therefore addresses the frequency of disease control at 6 months, while the confidence interval describes uncertainty around the estimated proportion.

The observed disease control proportion and its confidence interval are not reported in the registry record. As a result, the endpoint definition and planned comparison can be described, but the posted record does not permit a conclusion about the size or precision of the observed disease control rate.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The statistical methods described for this study center on a single-group estimate of a binary outcome. For each subject included in the primary efficacy population, the endpoint classifies disease status at 6 months as disease control or not disease control. Disease control comprises complete response, partial response, or stable disease under RECIST 1.1. A binary endpoint reduces a set of tumour-status categories to whether the stated criterion was met.

What does the disease control proportion describe?

A proportion describes the share of an analysis population meeting a defined condition. In this study, the condition is having complete response, partial response, or stable disease after 6 months of combination treatment. The proportion is intended as a summary of disease status at that assessment point. It is not a measure of the length of time a subject remains in a response category, and it is not equivalent to progression-free survival.

The registry says the disease control proportion would be described with a 95% confidence interval. In general, a confidence interval gives a range of values compatible with the observed data under the assumptions of the statistical method. Its width reflects statistical precision: wider intervals indicate less precise estimation, while narrower intervals indicate greater precision. A confidence interval does not remove uncertainty about the study design, assessment process, missing data, or the applicability of results to other patients. The actual estimate and interval are not reported in the registry record.

Why use an exact binomial proportion test?

The registry describes comparing the disease control proportion with 45% using an exact binomial proportion test. In general, a binomial test assesses whether an observed count of subjects meeting a binary criterion is compatible with a specified reference proportion, under a model in which each subject contributes a binary outcome. The exact method calculates the test probability from the binomial distribution rather than relying on a large-sample normal approximation. It can be useful when counts are limited or when an approximation may be less reliable. The test addresses compatibility with the stated reference; it does not estimate a treatment effect against a concurrent control group.

The benchmark is a fixed reference in the planned analysis. The registry record does not report why 45% was selected, how it was established, or whether the test was one- or two-sided. The description of the exact test is therefore not enough to reconstruct all details of the inferential procedure. The test result itself is not reported in the registry record.

How should the analysis population be understood?

The primary efficacy population is described as all subjects who had at least one baseline and at least one post-baseline assessment of the primary efficacy parameter. The record calls this the ITT population, but the stated inclusion rule is assessment-based. It does not say that every enrolled subject was included regardless of whether a post-baseline assessment was available. Readers should use the registry’s explicit population definition when interpreting the planned endpoint rather than assuming that the label alone resolves who was analyzed.

What does last observation carried forward do?

The registry says last observation carried forward was used to replace missing assessments at the end of the combination phase. In general, this approach substitutes a participant’s most recent available assessment for a missing assessment at the endpoint. It creates an endpoint value for analysis, but it does not recover an unobserved tumour status. Its appropriateness depends on the reasons assessments are missing and on whether the earlier status remains informative at the endpoint. The registry record does not report the amount or pattern of missing data, the timing of carried-forward assessments, or sensitivity analyses using alternative assumptions.

For a clinical outcome that can change over time, carrying an earlier assessment forward may fail to represent the participant’s status at the later assessment. This is a general limitation of the method, not a claim about what happened to any participant in this study. Without details about missingness and the actual analysis, the robustness of the primary result to this choice cannot be assessed.

What can safety counts establish?

Safety counts describe how many participants in a stated phase group were recorded as affected by serious or other adverse events. They are descriptive and depend on the period and group definition used. The registry lists these counts separately for the combination phase and maintenance groups. Maintenance group sizes differ, and the record does not describe these groups as randomized comparisons. Comparing their counts directly would not establish that one phase or treatment caused more harm.

General statistical interpretation also requires distinguishing counts from rates over time. The record gives numbers at risk and affected, but the exposure time and a comparative analysis are not reported in the registry record. The event counts therefore should not be read as exposure-adjusted rates. A serious event’s appearance in the record does not by itself establish causation by a study drug.

What is not available for assessment?

The registry lists 17 outcome measures and no posted analyses. The primary endpoint description gives the planned test and confidence interval, but the actual result is absent. Details of multiplicity control, interim analyses, a complete statistical analysis plan, and a sample-size justification are not reported in the registry record. In general, multiplicity methods address the increased chance of false-positive findings when several hypotheses are tested; their relevance depends on which outcomes and tests were formally analyzed. No conclusion about such adjustments can be drawn from the outcome list alone.

The separate planning illustrations use stated assumptions: a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation, with the effect to detect expressed as a fraction of the observed effect. These are planning assumptions, not a report of the trial’s design or observed power. The study itself is a single-group design, so an equal-allocation two-arm illustration should not be mistaken for its actual allocation or a randomized comparison. No calculated planning values are.

10. Exact Estimates for Each Arm

No two-arm comparison is shown for this trial, but each arm's result can still be summarized with exact interval estimates computed from the posted counts. The Clopper-Pearson interval is exact and conservative; the Wilson interval is a common closer-to-nominal alternative; the Bayesian credible interval uses a uniform Beta(1, 1) prior. For small groups the three can differ noticeably.

R code and output

arm    <- c("Combination Phase")
n      <- c(49)
events <- c(36)
for (i in seq_along(n)) {
  ci <- binom.test(events[i], n[i])$conf.int          # Clopper-Pearson exact interval
  cr <- qbeta(c(0.025, 0.975), 1 + events[i], 1 + n[i] - events[i])   # Bayesian, uniform Beta(1,1) prior
  wi <- (function(x, n) { p <- x / n; z <- qnorm(0.975); d <- 1 + z^2 / n
    c((p + z^2 / (2 * n) - z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d, (p + z^2 / (2 * n) + z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d) })(events[i], n[i])
  cat(sprintf("ARM|%s|%d|%d|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f\n", arm[i], n[i], events[i], 100 * events[i] / n[i],
              100 * ci[1], 100 * ci[2], 100 * wi[1], 100 * wi[2], 100 * cr[1], 100 * cr[2]))
}

ARM  Combination Phase  49  36  73.5  58.9  85.1  59.7  83.8  59.7  83.8

11. Multiplicity, Missing Data and Analysis Populations

The registry lists 17 outcome measures, including the primary disease control rate after 6 months and secondary outcomes concerning disease control, progression-free survival, response timing and duration, and biochemical response. The existence of multiple outcomes raises a general statistical question about multiplicity: when several outcomes or hypotheses are tested, the chance of at least one apparently notable result can increase. Whether adjustment is appropriate depends on the analysis plan and the role assigned to each outcome. A multiplicity strategy is not reported in the registry record, so it is not possible to determine whether or how the study addressed this issue.

The primary endpoint description identifies an exact binomial proportion test against 45% and a 95% confidence interval. It does not report the test result, the confidence interval, or a full account of prespecified analyses. The registry reports no analyses. Interim analyses and the detailed statistical analysis plan are not reported in the registry record. It would therefore be inappropriate to infer that a particular adjustment, monitoring plan, or analysis hierarchy was used.

For the primary endpoint, the stated analysis population includes subjects with at least one baseline and at least one post-baseline assessment. The registry also says missing assessments at the end of the combination phase were replaced using last observation carried forward. It does not report how many assessments were missing, why they were missing, or whether results were checked under alternative missing-data assumptions. Consequently, the effect of missing-data handling on the endpoint estimate cannot be evaluated from the record.

The enrollment of 57 is reported, but a sample-size justification is not reported in the registry record. Planning illustrations based on observed effects are not evidence of the study’s original design rationale and are not observed power. The record does not report whether the planned enrollment was based on a target precision, a hypothesis-testing objective, feasibility, or another consideration.

12. Safety Results

The registry reports serious adverse events as affected participants divided by participants at risk.

Deaths

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 5% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: ocular vascular disorder (9.1%), pneumonia (9.1%), back pain (9.1%), abdominal pain (8.3%), ascites (8.3%).

The registry reports serious and other adverse-event counts by study phase or maintenance group. During the combination phase, 17 of 57 participants were recorded as affected by serious adverse events and 52 of 57 by other adverse events; 1 death is listed. The maintenance group for functioning NET with lanreotide records 3 of 11 affected by serious adverse events and 9 of 11 by other adverse events, with 1 death. The non-functioning NET maintenance group with lanreotide records 4 of 14 affected by serious adverse events and 13 of 14 by other adverse events, with 1 death. The non-functioning NET group with no treatment records 4 of 12 affected by serious adverse events and 11 of 12 by other adverse events, with 1 death.

These are phase-specific counts, not results from randomized, like-for-like treatment arms. The record does not state how participants were assigned to maintenance groups, and the groups have different numbers at risk. Counts should not be added across phases, since the record does not establish that each phase entry represents a different participant. Nor do the figures account for differences in exposure time.

The listed serious-event terms include ocular vascular disorder, pneumonia, back pain, abdominal pain, ascites, and cholangitis, with percentages reported for each term. The registry record does not provide the corresponding event counts or enough detail to interpret those percentages as comparative risks. Adverse events recorded during a treatment period are not necessarily caused by that treatment. The figures describe reported safety events, not proof of causation or a comparison with another therapy.

13. What the Result Does, and Does Not, Mean

The registry record establishes that a Phase II, open-label, single-group study evaluated lanreotide Autogel 120 mg with temozolomide in progressive GEP-NET G1/G2. It defines the primary endpoint as disease control after 6 months, using complete response, partial response, or stable disease under RECIST 1.1. It also describes an exact binomial comparison with a 45% benchmark and a 95% confidence interval.

Those details explain what the study set out to measure, but the primary numerical result is not reported in the registry record. The observed disease control proportion, its confidence interval, and the test result are absent. Thus, the record does not establish whether the observed proportion was above or below the benchmark, how large it was, or how precise it was. It also does not show whether the primary comparison met any specified criterion for statistical significance.

The design does not provide a randomized concurrent control group. A benchmark comparison is not equivalent to a head-to-head comparison, and the maintenance groups cannot be treated as randomized arms. The record does not report how participants entered those groups. It therefore cannot establish that the combination performed better or worse than another treatment, or that differences between maintenance groups were caused by their listed regimens.

The registry lists several secondary outcomes, but their results are not reported in the registry record. The endpoint description cannot answer questions about response duration, progression-free survival, or biochemical changes. The safety counts can describe reported events during the stated phases, but they do not establish that a drug caused an event or allow a fair comparative safety judgment.

The most defensible interpretation is limited to the protocol-level information and the reported safety counts: the study had a defined disease-control endpoint, a stated reference value, a specified missing-assessment method, and a single-group design. The absent efficacy results prevent interpretation of the observed primary outcome. This absence should not be read as evidence of either benefit or lack of benefit.

14. Why This Trial Matters Statistically

This trial is statistically informative as an example of how a single-group study can frame a clinical question around a binary endpoint and a prespecified reference proportion. Disease control after 6 months is defined in terms of RECIST categories, and the planned exact binomial test directly addresses whether the observed proportion is compatible with the 45% benchmark. The confidence interval was intended to communicate precision as well as the point estimate.

The design also illustrates why the choice of comparator matters. A single-group benchmark comparison can answer a different question from a randomized trial. It can describe an outcome proportion in the study population and compare it with a fixed reference, but it cannot control through random allocation for differences between study participants and an external population. The registry does not report the basis for the benchmark, leaving an important part of that comparison’s interpretation uncertain.

The endpoint and population definitions matter as well. The analysis population requires baseline and post-baseline assessment, while missing endpoint assessments were to be handled with last observation carried forward. These choices influence which observations contribute to the primary estimate and how missing endpoint status is represented. The record does not report missingness details or sensitivity analyses, so the impact of these choices cannot be assessed.

Finally, a registry record can document a planned analysis without reporting its result. Here, the design and methods are described, but the primary efficacy estimate and test result are not reported in the registry record. This distinction is central to evidence appraisal: a clearly specified endpoint is not itself an outcome finding. The record supports careful discussion of the planned statistical question and its limitations, but not a numerical conclusion about the study’s efficacy.

15. Limitations

• The posted summary statistics are the only data these results rest on; patient-level data, full protocols and statistical analysis plans are not available.
• Recalculated results are simple, unadjusted calculations from posted summaries. They do not replace the sponsor's prespecified analysis.

The primary limitation for interpreting efficacy is that the disease control rate after 6 months, its 95% confidence interval, and the exact binomial test result are not reported in the registry record. The endpoint definition and analysis plan do not substitute for the observed result. The record also does not report results for the listed secondary outcomes, including disease control after 12 months, progression-free survival, time to response, duration of response, or biochemical response.

The single-group, open-label design has no randomized concurrent control. The primary comparison is against a fixed 45% benchmark, whose rationale and source are not reported in the registry record. The record does not report masking or independent central review of tumour assessments. These omissions limit assessment of potential differences in outcome assessment and of how well the benchmark supports an external comparison.

The maintenance groups should not be interpreted as comparable treatment arms. The record identifies groups by functioning status and maintenance regimen, but does not report how participants were assigned to them. It does not provide a randomized comparison or analysis that would address differences between the groups. Their safety counts are also reported over different group sizes, with no exposure-adjusted comparative analysis in the registry record.

For the primary endpoint, subjects needed baseline and post-baseline assessments to enter the stated analysis population, and missing end-of-phase assessments were handled using last observation carried forward. The amount and pattern of missing data, reasons for missingness, and sensitivity analyses are not reported. The record also does not report a sample-size justification, a complete statistical analysis plan, multiplicity handling, or interim analyses. These limits leave uncertainty about planning assumptions and the robustness of any unreported efficacy findings.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Combination of Lanreotide Autogel 120mg and Temozolomide in Progressive GEP-NET — NCT02231762.
• Registry record last updated 2019-05-06; status last verified 2019-02.
• Results first posted 2019-05-06.
• Data retrieved from ClinicalTrials.gov on 2026-11-09.
• Group sizes, means, event counts and sponsor-reported p-values are reproduced as posted. Effect estimates, confidence intervals and p-values not attributed to the sponsor are independently calculated from the posted summary statistics.

19. Record Summary

NCT02231762 is a completed Phase II, multicentre, open-label, single-group study sponsored by Ipsen. It enrolled 57 participants with progressive GEP-NET graded G1 or G2. The combination phase used lanreotide Autogel 120 mg and temozolomide for the first 6 months, followed by a described maintenance period of lanreotide or no treatment. The record does not describe maintenance allocation as randomized.

The primary endpoint was disease control rate after 6 months, defined as complete response, partial response, or stable disease under RECIST 1.1. The planned analysis used an exact binomial proportion test against 45%, with a 95% confidence interval, and last observation carried forward for missing end-of-phase assessments. The primary efficacy estimate and test result are not reported in the registry record.

Safety counts are recorded for the combination and maintenance phases. They are descriptive and do not establish causation or comparative safety. The registry lists 17 outcome measures and reports no analyses. A sample-size justification, multiplicity approach, and detailed statistical analysis plan are not reported in the registry record.