Pemetrexed Plus Cetuximab in Patients With Recurrent Non Small Cell Lung Cancer: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Pemetrexed Plus Cetuximab in Patients With Recurrent Non Small Cell Lung Cancer (NCT00216203), a na phase 1, phase 2 study. The primary outcome is Maximum Tolerated Dose (MTD) of Pemetrexed in Combination With Cetuximab.

2. Clinical Question

The study’s stated aims also included assessing feasibility and toxicity, and evaluating activity in an expanded phase II setting. These aims are not equivalent to a randomized test of the combination against either drug alone. The registry record describes only the combination treatment and does not provide a like-for-like control group.

The primary endpoint is a dose-finding question, not a comparison of clinical outcomes between treatment groups. The registry record specifies a measurement unit of mg/m^2 every 21 days and a timeframe of 12 months. It does not report the dose identified as the maximum tolerated dose or a numerical estimate of treatment activity. Secondary outcomes listed in the record are median survival time, toxicity and safety profile, and clinical benefit rate; numerical results for these outcomes are not reported in the registry record.

3. Trial Design

This is a completed phase I-IIa study of pemetrexed plus cetuximab in patients with recurrent non-small cell lung cancer. The registry record classifies the study as single-group, with no masking and allocation listed as not applicable. Its investigational treatment is the combination of pemetrexed and cetuximab. No separate control treatment is described.

The stated purpose was to examine whether the drugs could be combined, assess the toxicity profile, determine the maximum tolerated dose, and evaluate activity in an expanded phase II setting. The primary objective belongs to the phase I portion and is to define the maximum tolerated dose of the combination. The record says that 12 participants participated in that portion. It reports enrollment of 36 for the study overall.

The registry record lists a start date of 2005-05, primary completion of 2008-12, and status of completed. The primary endpoint timeframe is 12 months. Those registry dates describe the recorded study timeline; they do not supply information about participant-level follow-up or the timing of individual outcome assessments.

Because this is a single-group study, its design does not support a direct randomized comparison with pemetrexed alone, cetuximab alone, or another treatment. The record itself notes that the arms are not a like-for-like control comparison. The registry record does not describe the dose-escalation procedure, the number or size of dose levels, eligibility criteria beyond the recurrent disease population, or the statistical plan. These details 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.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: 12 participants participated in the phase I portion of the trial.

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.

Population: 33 of 36 consented participants received treatment.

6. Primary Endpoint

The registry lists the primary outcome as Maximum Tolerated Dose (MTD) of Pemetrexed in Combination With Cetuximab, measured over 12 months.

The primary endpoint is the maximum tolerated dose of pemetrexed in combination with cetuximab. It is expressed in mg/m^2 every 21 days, with a timeframe of 12 months. The phase I objective is to define the dose at which the combination can be administered within the study’s tolerability criteria. The registry record does not state those criteria or report the dose identified.

In general, dose-finding studies use tolerability information to guide selection of a dose for further study. The maximum tolerated dose is therefore a dose-selection endpoint, rather than a direct measure of how much a treatment changes survival or disease symptoms. Its interpretation depends on the dose levels studied, the toxicity definitions, the observation window, and the decision rules used to move between doses. Those procedural and analytic details are not reported in the registry record.

The record states that 12 participants took part in the phase I portion, but it gives no numerical primary endpoint result. It also does not report a confidence interval, a dose-specific toxicity summary, or the criteria by which the maximum tolerated dose was determined. Consequently, the stated endpoint and unit can be described, but the result cannot be reconstructed from the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry record identifies a phase I-IIa, single-group study with no masking. In a single-group design, participants receive the investigational treatment without a separate concurrent control group. This structure is consistent with a dose-finding objective, where the central question is which dose can be taken forward under specified tolerability rules. It does not, by itself, provide a randomized estimate of the combination’s effect relative to another treatment.

What does maximum tolerated dose mean?

In general, the maximum tolerated dose is a dose-selection concept based on observed toxicity under a study’s definitions and monitoring rules. Its meaning depends on which adverse events count, how the observation period is defined, and how dose decisions are made. A dose selected under one protocol’s rules cannot be interpreted independently of those rules. The registry record states the objective and the unit, mg/m^2 every 21 days, but does not report dose levels, toxicity thresholds, escalation rules, or a numerical dose result. Those details are not reported in the registry record.

Why does the single-group design matter?

Without a comparator group, observed events and outcomes describe participants who received the combination, but they do not show what would have happened to a comparable group receiving another treatment. General differences between groups cannot be estimated from this design because there is no separate group in the registry record to serve as a control. This matters especially for clinical activity: the record’s stated aim to evaluate activity is not a comparative efficacy estimate. The registry record also flags that there is no like-for-like control comparison.

What can the adverse-event counts tell us?

The serious adverse-event summary reports 11 affected participants among 36 at risk in the combination group. The other adverse-event summary reports 32 affected among 36 at risk. These counts describe the entries in the posted safety data; the record does not report whether events were judged related to treatment, how many events each participant experienced, or the timing and duration of events. In general, participant counts and event counts answer different questions: a participant may experience more than one event, while a count of affected participants records whether participants had an event in the specified category. The registry record does not provide enough detail to reconstruct event-level patterns.

The listed serious-event terms have associated percentages in the record. They are descriptions of reported terms, not estimates from a comparison between treatments. Some terms may represent different clinical experiences, and a term’s presence in a list does not establish causation. The recorded death count is not reported in the registry record, so the serious-event term referring to death should not be substituted for a separate death outcome count.

What do statistical estimates usually add?

In general, an estimate gives a numerical summary of an outcome, while a confidence interval describes uncertainty around that estimate under the analysis assumptions. A p-value summarizes how compatible the observed data are with a specified null model; it is not a measure of clinical importance or the probability that a treatment works. For a dose-finding result, the analysis may instead focus on selecting a dose using protocol-defined toxicity criteria. The registry record does not report estimates, confidence intervals, p-values, or the decision procedure for the primary endpoint. It records zero analyses.

Over-dispersion is a general statistical issue that arises when variability in count data exceeds what a simple model assumes. If present, it can make a model understate uncertainty unless the analysis accommodates the extra variation. The registry record does not identify a count-data model or report analyses from which over-dispersion could be assessed. This is a general consideration, not a finding about this study.

How should planning calculations be understood?

In general, a sample-size calculation asks how much information a future study might need under stated assumptions about an effect, significance level, allocation, and statistical model. It is a planning illustration, not a result observed in the trial. The planning assumptions associated with this record describe a two-sided significance level of 0.05, equal allocation between two hypothetical arms, and a normal approximation; the effect to detect is defined as a stated fraction of the observed effect. These assumptions do not change the single-group design recorded for the trial. Any sample-size illustrations are not observed power and do not establish that the study had a particular probability of detecting an effect.

The sample-size assumptions also distinguish calculations for time-to-event outcomes from calculations for other outcomes: the former are expressed as a total number of events, while the latter are expressed as participants per arm. These are general planning conventions in the stated illustration, not observed trial outcomes. The registry record does not report the trial’s own sample-size justification, statistical plan, or interim analyses. Those details are not reported in the registry record.

10. Multiplicity, Missing Data and Analysis Populations

The registry record lists one primary outcome: maximum tolerated dose of pemetrexed in combination with cetuximab. It also lists secondary outcomes of median survival time, toxicity and safety profile, and clinical benefit rate. The record states that there are five outcome measures, but it does not give numerical results for the primary endpoint or the listed secondary outcomes. It records zero analyses.

Multiplicity arises in general when several outcomes, time points, subgroups, or statistical tests are examined. If many tests are performed, the chance of at least one apparently unusual result can increase unless the analysis plan accounts for that. The registry record does not report whether any multiplicity adjustment or outcome hierarchy was prespecified. The statistical plan, including any adjustment approach, is not reported in the registry record.

Information about missing data is also not reported in the registry record. The record does not state whether any participants discontinued, how missing outcome measurements were handled, or whether any imputation or sensitivity analyses were used. The analysis populations are not reported in the registry record, including whether the primary endpoint was assessed in all enrolled participants or in a defined phase I population. The record does state that 12 participants participated in the phase I portion and that enrollment was 36, but these descriptions do not establish the number included in any particular analysis.

Without outcome estimates, analysis populations, and missing-data methods, readers cannot assess how incomplete observations may have affected the results. These omissions limit interpretation; they do not show that data were missing or that any particular analysis was performed.

11. Safety Results

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

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 0% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: death not associated with ctcae term / disease progression nos (5.6%), dizziness (5.6%), cns cerebrovascular ischemia (2.8%), dehydration (2.8%), dyspnea (shortness of breath) (2.8%).

The serious adverse-event summary for Pemetrexed + Cetuximab reports 11 affected among 36 at risk. The other adverse-event summary reports 32 affected among 36 at risk. These are separate categories in the registry record. They should not be added together: the record does not establish that the groups of affected participants are mutually exclusive.

The serious-event terms listed include “DEATH NOT ASSOCIATED WITH CTCAE TERM / DISEASE PROGRESSION NOS” and “DIZZINESS,” each at 5.6%. The record also lists “CNS CEREBROVASCULAR ISCHEMIA,” “DEHYDRATION,” “DYSPNEA (SHORTNESS OF BREATH),” and “HEMORRHAGE, PULMONARY/UPPER RESPIRATORY / LUNG,” each at 2.8%. These percentages are the registry’s reported figures and should be read as entries for specific event terms, not as a comparison between treatments.

The death count is not reported in the registry record. The term referring to death in the serious-event list is not a substitute for a separate death count. The record does not provide event timing, seriousness criteria, attribution to treatment, or detail on repeated events. These figures therefore describe the recorded safety summaries without establishing causation or comparative risk.

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

The registry record describes a study designed to assess the feasibility and tolerability of combining pemetrexed and cetuximab, with a phase I objective of defining the maximum tolerated dose. It also states an intention to evaluate activity in an expanded phase II setting. The primary endpoint is specified in mg/m^2 every 21 days and has a timeframe of 12 months. These details define the research question, but they do not provide the result.

The numerical maximum tolerated dose is not reported in the registry record. Numerical results for median survival time and clinical benefit rate are also not reported in the registry record. Consequently, the record does not permit a quantitative assessment of the combination’s clinical activity or the precision of an activity estimate. The absence of a reported result is not evidence that the endpoint was negative; it means the registry record does not contain the result needed to evaluate it.

The posted safety counts indicate that 11 of 36 participants were affected by serious adverse events and 32 of 36 by other adverse events. These counts describe the combination group and do not establish that the treatment caused the events. With no separate control group, the study design does not allow a direct comparison of adverse-event frequency or clinical outcomes against another treatment.

In general, a single-group study can describe outcomes among treated participants and can contribute to dose selection under its protocol’s rules. A controlled comparative study is needed to estimate how outcomes differ between treatments, subject to its design and analysis. The registry record does not report the protocol details or statistical analyses needed to characterize the dose-selection procedure, and it does not report a comparative treatment effect. The conclusions warranted by this record are therefore limited to its stated design, objective, and posted safety summaries.

13. Why This Trial Matters Statistically

This trial is statistically notable for the distinction between dose finding and comparative evaluation. The registry record describes a phase I-IIa, single-group study of pemetrexed plus cetuximab. Its primary objective is to define the maximum tolerated dose, while its broader aims include assessing toxicity and evaluating activity. These objectives require different kinds of interpretation: a selected dose is not itself an estimate of comparative clinical benefit.

The single-group design is important because it places a limit on what can be inferred. Outcomes observed among participants receiving the combination do not show how those outcomes compare with a separate treatment group. The registry record explicitly indicates that there is no like-for-like control comparison. This is relevant when reading any safety summaries or considering the stated interest in activity.

The record also illustrates why a defined endpoint is not the same as a reported result. It names the maximum tolerated dose, specifies mg/m^2 every 21 days, and gives a 12 months timeframe, but does not report the numerical dose. It lists secondary outcomes, yet provides no numerical results for them. Without estimates or analyses, readers cannot assess the precision of outcomes or determine how the planned statistical methods were applied.

Finally, planning calculations should remain separate from trial findings. General sample-size illustrations based on assumptions are not observed power and do not supply missing outcome evidence. The registry record does not report its own statistical plan or sample-size justification. Keeping design, planned aims, safety summaries, and numerical results distinct is essential for an accurate statistical reading of this study.

14. 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 registry record leaves important design and analysis details unreported. It does not describe the dose-escalation rules, dose levels, toxicity thresholds, or the decision procedure used to identify the maximum tolerated dose. These details are central to interpreting a dose-finding endpoint, because the selected dose depends on how tolerability is defined and evaluated.

The record does not report a numerical result for the primary endpoint, or numerical results for the listed secondary outcomes. It also records zero analyses, so there are no statistical estimates, confidence intervals, or tests to interpret. The statistical plan, including any prespecified multiplicity approach or interim analyses, is not reported in the registry record.

For safety, the record gives affected-participant counts and selected serious-event terms, but does not report event timing, attribution, duration, recurrence, or the criteria used to classify events. The death count is not reported in the registry record. These limits prevent a detailed account of the safety pattern and do not support causal comparisons.

The record does not report participant flow, the analysis populations, or missing-data methods. While it reports enrollment of 36 and says 12 participants participated in the phase I portion, it does not state how many participants contributed to each outcome analysis. Because there is no separate control group, the study also cannot directly estimate comparative effects. These are limitations of what the registry record documents; they do not establish that a particular protocol feature or analysis was absent from the study itself.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Pemetrexed Plus Cetuximab in Patients With Recurrent Non Small Cell Lung Cancer — NCT00216203.
• Registry record last updated 2016-09-29; status last verified 2016-08.
• Results first posted 2016-06-02.
• 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.

18. Record Summary

The registry record describes a completed phase I-IIa, single-group study of pemetrexed plus cetuximab in patients with recurrent non-small cell lung cancer. It reports enrollment of 36, with 12 participants in the phase I portion. The primary objective was to define the combination’s maximum tolerated dose, expressed in mg/m^2 every 21 days, over a timeframe of 12 months.

The record lists median survival time, toxicity and safety profile, and clinical benefit rate as secondary outcomes. It reports 11 of 36 participants affected by serious adverse events and 32 of 36 affected by other adverse events. The numerical primary endpoint result and numerical results for secondary outcomes are not reported in the registry record. The record contains no analyses and does not describe the statistical plan, analysis populations, or missing-data methods.