A Study of Pertuzumab With Erlotinib in Patients With Locally Advanced or Metastatic Non-Small Cell Lung Cancer (NSCLC): Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Study of Pertuzumab With Erlotinib in Patients With Locally Advanced or Metastatic Non-Small Cell Lung Cancer (NSCLC) (NCT02507375), a non-randomized phase 1 study. The primary outcome is Percentage of Participants With Dose Limiting Toxicities (DLTs).

2. Clinical Question

The study's stated purpose was to assess the safety and tolerability of the combination and make a preliminary assessment of activity. Secondary outcomes included responder status, complete or partial response at specified cycle ends, and pharmacokinetic measures for pertuzumab in the presence of erlotinib. The registry record lists these outcomes but does not report their numerical results. The central statistical question is consequently what the prespecified safety endpoint was intended to capture, and what conclusions can be drawn when its result is absent. The record supports a description of the design and outcome definitions; it does not support a quantitative estimate of DLT frequency or a comparison of efficacy between the cohorts.

3. Trial Design

This was a Phase Ib, open-label, multicenter study with nonrandomized allocation and a parallel model. The registry lists 17 participants enrolled and describes two cohorts with different erlotinib dose levels. Cohort 1 received daily oral erlotinib at 100 mg, while Cohort 2 received it at 150 mg. Both cohorts received the same pertuzumab schedule: an 840 mg loading dose on Day 1, then 420 mg every 3 weeks by intravenous infusion.

The intended population had locally advanced or metastatic NSCLC after failure of at least one prior chemotherapy regimen. The official title gives the disease stage as IIIb/IV. The brief summary describes treatment as continuing until disease progression or unacceptable toxicity and gives an anticipated target sample size of less than 100 individuals. The actual registry enrollment was 17. Further details about eligibility criteria, cohort assignment, dose escalation, or the rationale for the selected dose levels are not reported in the registry record.

The trial began in 2006-09, had primary completion in 2008-12, and is listed as completed. The primary outcome was the percentage of participants with DLTs from baseline through the end of the study, up to 42 weeks. Secondary outcomes addressed response classifications and pertuzumab pharmacokinetics in the presence of erlotinib. The registry lists nine outcome measures in total.

Because allocation was nonrandomized and there was no masking, differences between cohorts could reflect factors other than erlotinib dose. The registry record does not describe a concurrent randomized control group, so the two dose cohorts should not be treated as equivalent treatment groups differing only by chance. The design is suited to describing what was observed in the study cohorts, but causal claims about dose effects or treatment benefit would require evidence beyond these cohort descriptions. No protocol rationale for the design or detailed analysis plan is 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: Two participants in cohort 2 did not begin experimental study drug treatment in Cycle 1, so were not included in the analysis set.The resulting participant flow includes only participants who received pertuzumab.

Overall Study

Reasons for not completing this period:

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: All recruited participants who received at least 1 dose of both pertuzumab and erlotinib.

6. Primary Endpoint

The registry lists the primary outcome as Percentage of Participants With Dose Limiting Toxicities (DLTs), measured over From baseline to end of the study (up to 42 weeks).

The primary endpoint is the percentage of participants classified as having dose-limiting toxicities (DLTs). It covers the period from baseline to the end of the study, up to 42 weeks. The registry defines a DLT as a qualifying toxicity attributed to the study compounds under the stated criteria. The definition includes non-hematological toxicity at Grade 3 or higher according to Common Terminology Criteria for Adverse Events, version 3.0, with exceptions for fever, chills, and flu-like symptoms despite adequate management.

The definition also specifies exemptions for certain Grade 1-3 skin or epithelial toxicities consistent with erlotinib single-agent therapy, unless they did not respond to treatment or dose reduction or interruption. Grade 4 skin or epithelial toxicities counted as DLTs. Other specified criteria include Grade 4 neutropenia lasting > 7 days, febrile neutropenia despite adequate management, Grade 4 thrombocytopenia or thrombocytopenia requiring platelet transfusion, and toxicity judged subjectively intolerable by the investigator and related to either compound.

In general, a DLT endpoint is used in early-phase research to summarize treatment-limiting toxicity under defined rules. Its interpretation depends on the operational definition, observation period, number assessed, and completeness of follow-up. Here, the registry record provides the definition and timeframe but does not report the DLT count, percentage, denominator used for the analysis, or uncertainty interval. The endpoint's intended safety meaning can be described, but its observed frequency cannot be assessed from the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does a percentage endpoint represent?

The primary outcome is a binary participant-level classification: each participant either met the stated DLT definition during the observation period or did not. A percentage summarizes the proportion classified as having the event among a specified analysis population. Its interpretation depends on knowing both the numerator and the denominator, as well as how participants with incomplete follow-up or missing assessments were handled. The registry record defines the event but does not report the count, percentage, or analysis population for this endpoint.

As a general statistical concept, a confidence interval expresses uncertainty around an estimate under a specified method and its assumptions. For a percentage based on a small group, the interval can be wide because relatively few observations contribute information. The width and meaning of any interval depend on the denominator, the observed event count, and the method used. No primary endpoint interval or method for calculating one is reported in the registry record, so the precision of the DLT estimate cannot be evaluated.

Why does allocation matter?

Random allocation, when used, aims to balance measured and unmeasured participant characteristics across treatment groups on average. This study is listed as nonrandomized, and the cohorts are not described as a like-for-like control comparison. A contrast between the 100 mg and 150 mg daily erlotinib cohorts would therefore be descriptive unless supported by additional design or analysis information. Differences could arise from cohort composition or other aspects of care, rather than the dose distinction alone. The registry record does not report an adjusted comparison or a method intended to address confounding.

Open-label status means the record does not describe masking of treatment. This matters because knowledge of treatment can influence subjective assessments, reporting, treatment decisions, or the timing of assessments. The primary endpoint has defined toxicity criteria, which help specify classification, but they do not by themselves establish that assessment was unaffected by knowledge of cohort. Blinding procedures for particular assessments are not reported in the registry record.

What do the planning illustrations mean?

General sample-size planning asks how many participants or events might be needed to detect a prespecified difference under assumptions about variability, significance level, allocation, and statistical model. The planning illustrations associated with this trial use a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. They are calculated from the observed effect, with the target effect stated as a fraction of that observed effect. These are planning assumptions, not a description of the trial's original design.

For time-to-event outcomes, the stated planning convention is a total number of events using the Schoenfeld method; for other outcomes, the convention is participants per arm. These calculations should be interpreted as hypothetical planning quantities rather than as evidence about the trial's probability of success. They are not observed power. The registry record does not report the original sample-size justification, and the trial's own design assumptions should not be inferred from retrospective planning illustrations.

In general, over-dispersion matters when outcome variability is greater than assumed by a model. If it is ignored, standard errors may be too small and interval estimates may appear more precise than warranted. A binary percentage endpoint is not automatically over-dispersed, but clustering, repeated measures, or unmodeled differences among participants can alter variability. The registry record does not report a model for the primary endpoint, an over-dispersion assessment, or a method for handling clustering or repeated observations. Such methods cannot be attributed to this analysis.

What information is needed to judge an estimate?

A complete interpretation would ordinarily consider the event count, denominator, follow-up, handling of incomplete observation, point estimate, and uncertainty interval. For a DLT endpoint, the operational definition and assessment window are also important because changing either can change which events qualify. The record supplies the definition and follow-up window but does not report the endpoint result or the analysis details needed to assess precision. The missing result is not evidence that no DLTs occurred; it means the outcome is not reported in the registry record.

Analysis populations also affect interpretation. An enrolled population, a treated population, and a population with adequate follow-up can differ. A percentage based on one population may not match a percentage based on another. The registry record does not identify the primary endpoint analysis population or explain how participants with missing assessments were handled. Accordingly, the enrollment figure and adverse-event group counts should not be substituted for a missing primary endpoint denominator.

Finally, the number of outcomes and comparisons can affect how results are interpreted. The record lists multiple secondary outcomes, but does not report an analysis plan, a hierarchy of confirmatory tests, or adjustment for multiple testing. In general, examining many outcomes can increase the chance of finding an apparently notable result by chance, especially when results are selected after inspection. Since numerical secondary results and testing procedures are not reported in the registry record, this general concern cannot be quantified for this study.

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("Erlotinib 100 mg + Pertuzumab 420 mg", "Erlotinib 150 mg + Pertuzumab 420 mg")
n      <- c(6, 6)
events <- c(0, 0)
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  Erlotinib 100 mg + Pertuzumab 420 mg  6  0  0.0  0.0  45.9  0.0  39.0  0.4  41.0
ARM  Erlotinib 150 mg + Pertuzumab 420 mg  6  0  0.0  0.0  45.9  0.0  39.0  0.4  41.0

11. Multiplicity, Missing Data and Analysis Populations

The registry record lists nine outcome measures: the primary DLT percentage, response-related outcomes, and pharmacokinetic outcomes for pertuzumab in the presence of erlotinib. It does not report an analysis plan, a hierarchy among secondary outcomes, or a method for controlling multiplicity. In general, multiple outcome assessments or repeated comparisons create more opportunities for chance findings. A prespecified hierarchy or adjustment can clarify how such results should be interpreted, but whether either was used is not reported in the registry record.

The registry lists 0 analyses. The primary endpoint estimate, its denominator, and an uncertainty measure are not reported in the registry record. Numerical results for the listed secondary outcomes are also not reported. This absence prevents assessment of which planned outcomes were analyzed, whether all were reported, or how any statistical tests were conducted. It also means no claim about statistical significance or about a multiplicity adjustment can be made.

Missing-data procedures and analysis populations are not reported in the registry record. In general, missing outcome assessments can affect a percentage if the people without assessments differ from those assessed, or if their event status is not handled consistently. Interpretation would require knowing who was included, how incomplete follow-up was treated, and whether participants were classified using all available observations or a defined assessment window. These details are not reported.

Although the study enrolled 17 participants, that figure does not establish the denominator for the primary endpoint. The adverse-event summaries give separate at-risk counts by cohort, but the registry record does not explain how these relate to the endpoint analysis population. No protocol-based sample-size justification, interim-analysis plan, or statistical analysis plan is reported in the registry record.

12. 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 5% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: myocardial infarction (11.1%), diarrhea (11.1%), lung cancer malignant (11.1%), renal failure acute (11.1%), thrombosis (11.1%).

The adverse-event summary gives separate cohort counts. For Cohort 1, 6 participants were at risk and 0 were reported as affected by a serious adverse event. For Cohort 2, 9 were at risk and 4 were reported as affected. These are descriptive counts; the nonrandomized design does not support treating the difference as a causal comparison between erlotinib dose levels.

The record also lists Myocardial Infarction, Diarrhea, Lung Cancer Malignant, Renal Failure Acute, and Thrombosis among the top serious terms, each with a reported frequency of 11.1%. The record does not give further detail in this summary about event timing, severity grades, relatedness, recurrence, or how the term frequencies map to cohort-specific participant counts. A participant can experience more than one event, so event-term listings should not automatically be read as mutually exclusive groups of people.

Deaths are recorded as null in the adverse-event summaries. This means death information is not reported in those summaries; it should not be interpreted as a confirmed count of zero. The safety figures are limited to the registry summaries and do not establish the complete safety profile or comparative risk. The DLT endpoint has a specific definition and observation period, while serious adverse-event reporting is a separate summary; the two should not be treated as interchangeable measures.

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

The registry record establishes the study question, treatment schedules, cohort structure, and primary endpoint definition. It reports a completed Phase Ib study with 17 participants enrolled, conducted in patients with locally advanced or metastatic NSCLC after failure of at least one prior chemotherapy regimen. Both cohorts received pertuzumab; the erlotinib dose level differed between them. The primary endpoint was the percentage of participants with DLTs over a period of up to 42 weeks.

What the record does not establish is the observed DLT percentage. The primary endpoint result, its denominator, and an uncertainty estimate are not reported in the registry record. Without those details, the amount and precision of observed DLTs cannot be quantified. This should not be interpreted as evidence that the endpoint had no events or that it was not assessed; the outcome result is simply not reported in the registry record.

The nonrandomized allocation limits any comparison of the two cohorts. A difference in outcome, if one were reported, could not automatically be attributed to the erlotinib dose because the cohorts were not randomized. The record also does not report adjusted analyses that might address differences between groups. Consequently, the cohort descriptions do not establish a causal dose effect.

Likewise, the study's listed response and pharmacokinetic outcomes do not establish treatment activity or pharmacokinetic findings without their numerical results. No efficacy conclusion follows from the presence of outcome names alone. The serious adverse-event counts are descriptive, and the record does not report deaths in those summaries. They do not constitute a complete account of safety or a randomized safety comparison.

In general, early-phase studies can describe tolerability and generate information for further research, but interpretation depends on the observed outcomes, follow-up, and analysis methods. Here, the available registry information supports a description of the intended safety question and the two dose cohorts. It does not support a claim that the combination is effective or ineffective, or a conclusion that one cohort is safer than the other.

14. Why This Trial Matters Statistically

This trial is statistically informative as an example of how early-phase safety questions are framed. Its primary endpoint was not a broad, undefined tally of adverse events: the registry specifies a DLT classification, detailed exceptions, and an observation window extending from baseline to the end of study, up to 42 weeks. Those definitions matter because an event's classification depends on criteria and timing, and the resulting percentage is meaningful only in relation to the participants assessed.

The study also illustrates why design labels matter. Its two cohorts differed in daily erlotinib dose, but allocation was nonrandomized and treatment was open-label. A dose-group contrast in such a design can be useful descriptively, but it is not automatically a causal estimate. Clear interpretation requires separating the observed cohort descriptions from claims that would need a controlled comparison.

The record lists a modest enrollment of 17 alongside adverse-event summaries with cohort-specific at-risk counts. Without the primary endpoint denominator and analysis population, those different counts cannot be treated as interchangeable. The missing DLT result is especially important: an outcome definition is not an outcome estimate, and a safety question cannot be answered quantitatively from the definition alone.

Finally, the trial has multiple listed response and pharmacokinetic outcomes, but no numerical analyses are reported. This emphasizes the distinction between registering outcomes and reporting results. For biostatisticians and clinical researchers, the record highlights the need for transparent denominators, analysis populations, missing-data methods, uncertainty estimates, and plans for interpreting multiple outcomes. Those details are not reported in the registry record, limiting what can be learned from its posted results.

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 main limitation for interpretation is that the registry record does not report the primary DLT result. It gives the endpoint definition and follow-up window but not the number affected, percentage, denominator, or uncertainty interval. Without these, neither the observed frequency nor its precision can be evaluated. The record also does not identify the endpoint analysis population or explain how incomplete follow-up was handled.

Enrollment is reported as 17, while the adverse-event summaries identify 6 participants at risk in Cohort 1 and 9 in Cohort 2. The record does not explain the relationship between these counts. They should not be used to reconstruct a primary endpoint denominator or infer that particular participants were excluded.

The design is nonrandomized and open-label, with cohorts differentiated by erlotinib dose. There is no like-for-like randomized control comparison described. Accordingly, cohort differences would be vulnerable to confounding and should not be interpreted as an isolated effect of dose. The registry record does not report an adjusted comparison or detailed methods for accounting for differences between cohorts.

Response and pharmacokinetic outcomes are listed but their numerical results are not reported in the registry record. The record also does not report a statistical analysis plan, multiplicity handling, missing-data procedures, interim analyses, or a sample-size justification for the original study. The study's stated target was less than 100 individuals, but no additional protocol rationale is reported. Serious adverse-event summaries give selected counts and terms; the death fields are null, and the record does not provide enough detail in these summaries to interpret null as no deaths. These limitations restrict both quantitative interpretation and assessment of how fully outcomes were reported.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: A Study of Pertuzumab With Erlotinib in Patients With Locally Advanced or Metastatic Non-Small Cell Lung Cancer (NSCLC) — NCT02507375.
• Registry record last updated 2015-10-16; status last verified 2015-09.
• Results first posted 2015-10-16.
• 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

NCT02507375 is a completed Phase Ib, open-label, multicenter, nonrandomized study of pertuzumab with erlotinib in locally advanced or metastatic NSCLC after failure of at least one prior chemotherapy regimen. The record lists 17 participants enrolled. Cohort 1 received daily oral erlotinib at 100 mg, and Cohort 2 received 150 mg; both received pertuzumab with an 840 mg loading dose on Day 1 followed by 420 mg every 3 weeks.

The primary endpoint was the percentage of participants with DLTs from baseline to the end of the study, up to 42 weeks. The registry record defines DLTs but does not report the primary endpoint result or its analysis denominator. Response and pharmacokinetic outcomes are listed without numerical results. The serious adverse-event summaries report 0 affected among 6 at risk in Cohort 1 and 4 among 9 at risk in Cohort 2; death information is not reported in those summaries. The study began in 2006-09 and reached primary completion in 2008-12.