Study of Patritumab in Combination With Erlotinib in Subjects With Locally Advanced or Metastatic Non-Small-Cell Lung Cancer (NSCLC). (HER3-Lung): Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Study of Patritumab in Combination With Erlotinib in Subjects With Locally Advanced or Metastatic Non-Small-Cell Lung Cancer (NSCLC). (HER3-Lung) (NCT02134015), a randomized phase 3 study. The primary outcome is Part A: Progression Free Survival (PFS) in Heregulin-high Participants.

2. Clinical Question

The central question is whether progression-free survival differed between patritumab plus erlotinib and placebo plus erlotinib among Part A participants whose tumors had high heregulin. The registry describes adults with EGFR wild-type, locally advanced or metastatic non-small-cell lung cancer that had progressed after at least one prior systemic anti-cancer therapy. Participants also needed an available recent or archival tumor specimen and could not have received prior EGFR-targeted, anti-HER2, anti-HER3, or anti-HER4 therapy.

The primary endpoint was progression-free survival, defined from randomization to the earlier of documented radiographic progression or death from any cause. The registry also describes a separate Part B, in which only participants with high heregulin were eligible and overall survival was the primary outcome. The posted primary result analysed is specifically Part A progression-free survival; a Part B primary outcome result is not reported in the registry record.

3. Trial Design

HER3-Lung, registered as NCT02134015, was a Phase 3 randomized, placebo-controlled, double-blind, multicenter, parallel-group study sponsored by Daiichi Sankyo. The registry lists an enrollment of 145 and a status of terminated. The study began in 2014-03, and primary completion is recorded as 2016-11-11.

The registry describes two parts. In Part A, participants with high or low heregulin were eligible, and progression-free survival in the high-heregulin group was the primary outcome. In Part B, only participants with high heregulin were to be enrolled, and overall survival was the primary outcome. Both parts compared patritumab plus erlotinib with placebo plus erlotinib. The reported primary outcome is for Part A’s high-heregulin population, not a combined result across the two parts.

The patritumab group received an infusion described as a loading dose of 18 mg/kg followed by 9 mg/kg every 3 weeks, together with oral erlotinib 150 mg/day. The comparator group received placebo infusion every 3 weeks with oral erlotinib 150 mg/day. Randomization and double masking are recorded, but the registry does not report the allocation ratio, sequence-generation procedure, concealment details, or how masking was maintained.

The primary endpoint timeframe is described as by trial termination (at 20 months). This wording identifies the registry’s stated reporting timeframe; it does not establish that every participant had the same follow-up duration. The protocol’s reasons for termination, detailed conduct of each study part, and the number enrolled in each part 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: Of 537 patients screened, a total of 145 patients were randomized into this trial in 9 countries: United States (26 at 12 sites), Spain (19 at 5 sites), Hungary (18 at 4 sites), Italy (20 at 6 sites), Great Britain (11 at 5 sites), Poland (30 at 3 sites), Germany (16 at 6 sites), Canada (2 at 1 site) and Belgium (3 at 1 site).

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.

6. Primary Endpoint

The registry lists the primary outcome as Part A: Progression Free Survival (PFS) in Heregulin-high Participants, measured over by trial termination (at 20 months).

Progression-free survival (PFS) measures the time from randomization until the first of radiographic disease progression or death from any cause. The registry specifies radiographic progression according to RECIST Version 1.1, assessed by the investigator. Including death means that a participant who dies before documented progression has an event for this endpoint rather than being treated as progression-free indefinitely.

PFS is a time-to-event outcome. It can describe how long participants remain alive without documented progression while accounting for the fact that some participants may not have experienced an event by the time observation ends. In general, this is useful when the clinical question concerns disease control over follow-up and an endpoint based on a later event, such as overall survival, is not the primary measure. That general rationale does not establish why this trial selected PFS; the registry does not report the endpoint-selection rationale.

The posted outcome is a Kaplan-Meier estimate of median PFS in Part A participants with high heregulin. The median is the estimated time by which half the population has experienced progression or death. The registry reports an 80% confidence interval for each median, calculated using the Brookmeyer-Crowley method. These intervals describe uncertainty in the estimated medians; they are not ranges containing all individual participants’ PFS times.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The primary outcome is analysed as time to an event, not simply as a count of participants with progression. The registry states that the Kaplan-Meier method was used to estimate PFS and that the median confidence interval was calculated with the Brookmeyer-Crowley method. It reports 80% confidence intervals. A sponsor-reported test or model comparing the randomized groups is not reported in the registry record.

What does a Kaplan-Meier estimate represent?

In general, Kaplan-Meier estimation uses the observed event times while accounting for participants whose event time is not observed during their available follow-up. Such participants are censored at the last time they are known to be event-free, rather than being counted as if they had an event at that time. This interpretation relies on assumptions about censoring, including that censoring does not systematically select participants with different future event prospects after accounting for relevant information. The registry does not report censoring counts, reasons, or an assessment of those assumptions.

The Kaplan-Meier curve estimates the probability of remaining free of progression or death over time. Its median is the time at which the estimated event-free probability reaches one half. A median therefore condenses the curve to one point and does not describe its entire shape. Two groups could have similar medians but different curves at other times, or different medians without the same difference applying throughout follow-up. The registry’s posted primary result gives medians and intervals, but it does not provide a reported hazard ratio or other full-curve comparison in the record summarized by these results.

How should the confidence intervals be read?

In general, a confidence interval expresses uncertainty in an estimate under the method’s assumptions. The reported 80% intervals are specifically intervals for the group medians. They are not individual ranges for participant outcomes, and they are not a direct interval for the difference between groups. The Brookmeyer-Crowley method is a recognized method for forming a confidence interval for a median from time-to-event data. The registry reports that method but does not provide further details of its implementation.

An 80% confidence interval is less stringent in coverage than a 95% confidence interval. That statement is a general statistical explanation, not a claim about the trial’s design rationale. The registry does not explain why this confidence level was selected. Interval width reflects uncertainty, but interpretation also depends on the event and censoring information supporting the estimate. Those details are not reported in the registry record.

Why is a group comparison not obtained by comparing medians alone?

In general, comparing two separately estimated medians is not equivalent to conducting a formal test of the difference between groups. The uncertainty in each median does not directly give the uncertainty in their difference. Formal time-to-event comparisons may use methods that incorporate event timing across follow-up, but the registry record does not state which comparative method was planned or used for the primary endpoint. The record also does not report a primary PFS P-value or sponsor-reported treatment-effect estimate. Therefore, the medians support a descriptive account of each group, rather than a complete inferential comparison.

Overlap or non-overlap of separate confidence intervals should not be treated as a substitute for a direct comparison. In general, the relationship between separate intervals and a test of a contrast depends on the uncertainty structure and the comparison method. The correct reading is that the reported intervals quantify uncertainty in each median, while the registry does not provide the corresponding formal contrast.

What do the binary secondary comparisons add?

The registry also posts counts for overall survival and objective response outcomes, with unadjusted risk-difference comparisons and unadjusted P-values. In general, a risk difference expresses the difference in observed proportions between groups, and its confidence interval describes uncertainty in that contrast. A wide interval can be compatible with more than one underlying effect. The binary outcomes have limited numbers of observed events, and the record does not list sponsor-reported analyses for these outcomes. Their unadjusted comparisons should be read as exploratory descriptions rather than as definitive evidence.

The record’s planning illustrations use the observed effect as a reference and describe participants per arm for specified power targets and effect fractions. These are illustrations under stated assumptions: a two-sided significance level of 0.05, equal allocation, and a normal approximation. They are not the trial’s original design justification, are not observed power, and do not show what power the completed trial had. The registry does not report the original sample-size justification or whether the original planning assumptions were met.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists multiple outcomes across two study parts and more than one heregulin subgroup. It does not report a multiplicity strategy, such as a testing hierarchy or adjustment for multiple comparisons. This matters because repeatedly testing several outcomes or subgroups can increase the chance of a nominally notable finding by chance. The unadjusted secondary P-values should therefore not be interpreted as if they arose from a single prespecified test. Whether the study protocol specified a particular testing procedure is not reported in the registry record.

Missing-data and censoring methods for the primary PFS outcome are not reported in the registry record. The Kaplan-Meier method generally uses censoring for participants whose event is not observed during available follow-up, but the registry does not give the censoring rules, censoring counts, reasons for censoring, or sensitivity analyses. The handling of incomplete outcome assessments and missing tumor measurements is also not reported. For the binary secondary outcomes, the record does not explain how participants with unavailable endpoint information were handled.

The analysis populations are not described in sufficient detail to determine whether the outcome summaries use an intention-to-treat population, a modified intention-to-treat population, or another defined set. Although the study was randomized, that fact alone does not specify which participants were included in each reported analysis or how protocol deviations were treated. The registry does not report exclusions from the analyses or the reasons for them.

These omissions do not prove that the trial lacked planned procedures; they mean those procedures are not reported in the registry record. As a result, readers cannot assess from the record whether the posted outcomes followed the original multiplicity plan, how missingness might have influenced the results, or how closely the analysed populations preserve the randomized comparison.

11. 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: dyspnoea (6.8%), pneumonia (4.2%), general physical health deterioration (2.7%), haemoptysis (2.7%), respiratory failure (2.7%).

The adverse-event record lists serious adverse events for groups of 71 participants at risk in the placebo-plus-erlotinib group and 74 in the patritumab-plus-erlotinib group. Serious adverse events affected 29 and 27 participants, respectively. Other adverse events affected 66 and 68 participants, and the recorded death counts were 5 in each group. These are registry counts; the record does not establish that an event or death was caused by a study treatment.

The most frequently listed serious-event terms include dyspnoea, pneumonia, general physical health deterioration, haemoptysis, respiratory failure, and diarrhoea. The registry reports percentages for these terms, but does not provide additional context in this record about event timing, recurrence, severity grading, relatedness, or the basis for the listed percentages. These terms should therefore be read as reported event categories, not as comparative estimates of treatment risk.

The adverse-event group sizes differ from the primary outcome group sizes. The registry does not explain the relationship between these denominators and the analysis populations. Counts alone do not account for follow-up duration or exposure, and they do not establish a comparative safety profile. A fuller interpretation would require event definitions, exposure and follow-up information, and attribution details, which are not reported in the registry record.

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

The posted primary result describes median PFS in Part A participants with high heregulin: 2.7 months with placebo plus erlotinib and 1.9 months with patritumab plus erlotinib. The reported 80% confidence intervals show uncertainty around each group’s median. The numerical ordering is descriptive; the registry record does not report a formal sponsor comparison of PFS between groups.

These estimates do not show what would happen to every participant, nor do they describe the full distribution of time to progression or death. A group median is a summary, and confidence intervals are not predictions for individuals. The registry also does not provide enough information to assess the effects of censoring, missing outcomes, or analysis-population choices on the estimates.

The secondary results add information about other outcomes, but they are unadjusted and do not form a consistent, decisive pattern. Their presence does not establish a treatment effect, and their interpretation is limited by the absence of reported multiplicity procedures and sponsor-reported analyses. The safety counts likewise describe recorded events but do not establish causation or a comparative safety conclusion.

The registry records a terminated study, but the reason for termination is not reported in the registry record. The posted results should not be used to infer that termination was caused by efficacy, safety, or another factor. Nor do the posted figures establish why the observed group medians differ numerically. The appropriate conclusion is limited: the record contains group-level outcome summaries with uncertainty, but not the complete comparative analysis needed for a firm statistical conclusion about PFS.

13. Why This Trial Matters Statistically

This trial illustrates why time-to-event outcomes need careful interpretation. A median PFS is a useful summary of when the estimated event-free proportion reaches one half, but it does not replace a comparison of the full event-time experience between randomized groups. The record gives separate medians and confidence intervals without a reported primary comparative estimate, leaving a central inferential question unanswered in the registry record.

It also shows the importance of distinguishing outcome estimates from confirmatory evidence. The secondary outcomes span different endpoints and subgroups, and their unadjusted comparisons cannot be treated as independent confirmation of the primary result. Multiplicity, missing-data handling, censoring, and analysis-population definitions all affect how confidently results can be interpreted, yet these methods are not reported in the registry record.

The study is also a useful example of how a multi-part trial can have different primary outcomes in different parts. The posted primary result concerns Part A and high-heregulin participants, while the registry describes overall survival as the Part B primary outcome. Keeping these populations and questions separate avoids treating results from one part as if they answered the other part’s question.

Finally, safety counts and efficacy summaries use different reported group sizes. Without an explanation of their analysis populations and follow-up, counts should not be compared as if they necessarily share the same denominator or observation period. The record’s limitations are not evidence that methods were absent; they define what can be assessed from the registry reporting.

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 primary result is confined to Part A participants with high heregulin. It should not be generalized from this record to the low-heregulin subgroup, Part B, or all participants with non-small-cell lung cancer. The registry’s eligibility description also limits the population to EGFR wild-type disease with prior progression after systemic therapy and specified prior-treatment exclusions.

The record reports separate PFS medians and 80% confidence intervals, but does not report a formal sponsor comparison, hazard ratio, or P-value for this endpoint. The reason for trial termination is not reported in the registry record, and the stated timeframe does not establish equal follow-up for all participants. Censoring and missing-data details, analysis-population definitions, and the original sample-size justification are also not reported.

There is a distinction between the overall registry enrollment and the group counts attached to particular outcomes. The registry does not explain how the outcome denominators relate to the randomized population or why the adverse-event denominators differ from the primary endpoint group sizes. The extent and reasons for any exclusions or unavailable observations cannot be determined from the record.

The secondary comparisons are unadjusted, and no multiplicity strategy or sponsor-reported analyses are listed. Their estimates are therefore uncertain and should not be treated as confirmatory. Safety information is limited to counts and listed serious-event terms; event timing, relatedness, exposure-adjusted rates, and detailed severity information are not reported in the registry record. These trial-specific reporting gaps restrict the conclusions that can be drawn from the posted results.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Study of Patritumab in Combination With Erlotinib in Subjects With Locally Advanced or Metastatic Non-Small-Cell Lung Cancer (NSCLC). (HER3-Lung) — NCT02134015.
• Registry record last updated 2018-01-23; status last verified 2017-12.
• Results first posted 2018-01-23.
• 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

NCT02134015, HER3-Lung, was a Phase 3 randomized, double-blind, placebo-controlled parallel-group study of patritumab plus erlotinib versus placebo plus erlotinib in EGFR wild-type, locally advanced or metastatic non-small-cell lung cancer after prior systemic therapy. The registry lists enrollment of 145, status as terminated, a start of 2014-03, and primary completion on 2016-11-11.

The posted primary outcome is Part A PFS among high-heregulin participants, reported as Kaplan-Meier medians with 80% confidence intervals. Secondary outcomes include overall survival and objective response measures. The registry does not report a sponsor comparison for the primary PFS result, and key details about multiplicity, missing data, analysis populations, and the reason for termination are not reported in the registry record.