Study of Seribantumab in Adult Patients With NRG1 Gene Fusion Positive Advanced Solid Tumors: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Study of Seribantumab in Adult Patients With NRG1 Gene Fusion Positive Advanced Solid Tumors (NCT04383210), a non-randomized phase 2 study. The primary outcome is Objective Response Rate.

2. Clinical Question

CRESTONE was a phase 2 study of seribantumab in adults with recurrent, locally advanced or metastatic solid tumors harboring an NRG1 gene fusion. The primary clinical question was whether seribantumab monotherapy, at 3,000 mg QW, produced an objective response in patients with centrally confirmed NRG1 fusion, as assessed by investigators using RECIST v1.1. Objective response was defined as a confirmed complete response or partial response.

The study divided participants among cohorts with different treatment-history or tumor-fusion characteristics. Cohort 1 was for patients who had received prior standard treatment, excluding prior ERBB-directed therapy. Cohort 2 allowed prior ERBB-directed therapy. Cohort 3 concerned NRG1 fusions lacking an EGF-like domain; prior ERBB-directed therapy may have been included. The registry describes these as non-randomized cohorts, not as comparable treatment arms.

The primary efficacy population was narrower than everyone enrolled in Cohort 1: 29 of 36 patients met the stated criteria of centrally confirmed NRG1 fusion status and receipt of 3,000 mg QW dosing, and were evaluable for investigator-assessed response. The registry record does not give the number of responders in that population, so it does not permit the primary response rate to be read from the posted outcome information.

3. Trial Design

CRESTONE was an open-label, international, multi-center phase 2 study. Its allocation was non-randomized, its masking was none, and its model was parallel. The intervention listed in the registry was the drug seribantumab. The study included adult patients with recurrent, locally advanced or metastatic solid tumors harboring an NRG1 gene fusion, with tumor types including pancreatic, lung, head and neck, breast, kidney, colorectal, bladder, ovarian, uterine, prostate and other solid tumors.

The registry describes three cohorts rather than a randomized treatment-versus-control comparison. Cohort 1 concerned patients who had received prior standard treatment but not prior ERBB-directed therapy. Cohort 2 allowed prior ERBB-directed therapy. Cohort 3 concerned patients with NRG1 fusions lacking an EGF-like domain, and prior ERBB-directed therapy may have been included. These eligibility distinctions matter: outcomes across cohorts could reflect different patient histories or fusion characteristics as well as treatment, so a contrast between cohorts would not isolate a treatment effect.

The arm descriptions specify seribantumab by intravenous infusion, with schedules involving once-weekly, every-2-weeks and every-3-weeks dosing during induction, consolidation and maintenance. The description is truncated in the registry record, and the complete dosing details are not reported there. The stated primary objective, however, focuses on seribantumab monotherapy at 3,000 mg QW in the primary efficacy population.

The registry lists enrollment as 54 and status as terminated. The recorded start date is 2020-09-29 and primary completion date is 2024-02-28. The reason for termination is not reported in the registry record. The record gives planned cohort descriptions that include a minimum of 55 for Cohort 1, while the reported enrollment and primary efficacy population figures describe different aspects of the study; the registry record does not explain this distinction.

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

Analysis population for the primary outcome, as defined in the registry: Among the 36 patients enrolled in Cohort 1, 29 of 36 patients met criteria (criteria includes centrally confirmed NRG1 fusion status and patient received 3,000 mg QW dosing) to be included in the primary efficacy population and were evaluable for investigator assessed response per RECIST v1.1. In Cohorts 2 and 3, one patient in each cohort was not evaluable for investigator assessed response per RECIST v1.1.

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 Objective Response Rate, measured over Up to 12 months.

The primary endpoint is Objective Response Rate (ORR), expressed as a count of participants in the outcome record. The study description defines an objective response as a confirmed complete response or partial response, assessed by investigators using RECIST v1.1. A complete response means disappearance of all target lesions. A partial response requires at least a 30% decrease in the sum of the longest diameter of target lesions. Tumor assessments were evaluated at baseline by computerized tomography or magnetic resonance imaging.

ORR is used in oncology studies to describe the proportion of an analyzed population whose tumors meet predefined response criteria. It focuses on shrinkage or disappearance meeting those criteria; it does not by itself describe how long a response lasts, whether disease progression is delayed, or how participants feel or function. Those are different outcomes and require their own definitions and analyses.

The registry specifies a timeframe of up to 12 months. It identifies the primary objective as assessing investigator-assessed response for seribantumab monotherapy at 3,000 mg QW among patients with centrally confirmed NRG1 fusion. It reports that 29 of 36 Cohort 1 patients met criteria for inclusion in the primary efficacy population and were evaluable for response. However, the number with complete or partial response is not reported in the registry record. Without that numerator, the primary ORR cannot be interpreted from the posted outcome information.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The statistical methods that can be described from the registry record are limited. It identifies a binary primary outcome: participants who meet the confirmed complete or partial response definition are counted as having an objective response. The registry does not report an inferential analysis for this outcome, and the response count is not reported there. The concepts below explain how such results are generally interpreted; they do not imply that any particular analysis was performed in CRESTONE.

What does an objective response count represent?

For a binary endpoint, each participant is classified according to whether the defined event occurred. For ORR, the event is a confirmed complete or partial response under the stated assessment rules. The response rate is generally the number meeting the definition divided by the number in the analysis population. Here, the record identifies 29 of 36 patients as evaluable for the primary efficacy assessment, but does not state how many met the response definition. A rate therefore cannot be recovered from the registry entry without inventing a numerator.

The outcome is based on investigator assessment per RECIST v1.1. Tumor assessment criteria make response classification more structured, but the registry entry does not provide participant-level measurements, confirmation dates, independent review results or the detailed assessment schedule. Whether those procedures were specified elsewhere is not reported in the registry record.

How should uncertainty be understood?

In general, a confidence interval describes the statistical uncertainty around an estimated effect or rate under an analysis model. It is not a guarantee that the true value lies within the interval, nor does it account automatically for every source of bias or measurement error. A response estimate based on a limited analysis population can have substantial uncertainty, but the registry record gives no interval for this endpoint. Without both the response count and its analysis denominator, readers cannot assess the estimate or its precision from the posted results.

A hypothesis test, when used, evaluates compatibility between data and a specified null model under stated assumptions. A p-value is not the probability that a treatment works, nor does it measure the size or clinical importance of an effect. The registry record reports no p-value or inferential analysis for the primary endpoint. The analysis plan, null hypothesis and any decision threshold are not reported in the registry record.

Why does the design matter?

Random allocation is a method for balancing measured and unmeasured baseline characteristics between treatment groups, on average. CRESTONE is listed as non-randomized and has no masking. Thus, the study record does not support a randomized treatment comparison. If outcomes are compared across its cohorts, cohort eligibility differences and other differences between participants could influence the contrast. A within-cohort response description would still be observational with respect to any comparison to an alternative treatment or to no treatment.

Open-label means that masking was none according to the record. In general, knowledge of treatment can affect care, reporting or assessment. The use of defined imaging criteria may standardize some response assessment, but it does not establish that assessment was blinded or independently reviewed. Those details are not reported in the registry record.

What is over-dispersion, and does it apply?

Over-dispersion is a general issue in count models: observed variability can exceed what a simple model assumes, often because observations are more heterogeneous or dependent than expected. It is relevant when an outcome and analysis use a count model with a variance assumption. CRESTONE's listed primary endpoint is a binary participant count, and no count-model analysis or dispersion parameter is reported. There is therefore no basis in this record to claim that over-dispersion was assessed or affected the primary result.

What do the planning illustrations mean?

Sample-size calculations are planning exercises, not observed trial outcomes. The stated illustration assumes a two-sided significance level of 0.05, equal allocation between two arms and a normal approximation, with the effect to detect set as a stated fraction of the observed effect. For time-to-event outcomes, the illustration uses a total number of events; other outcomes use participants per arm. These general assumptions do not turn CRESTONE into a randomized two-arm trial, and the illustrations are not observed power. Their output is not reported in the registry record. The sponsor's own analysis takes precedence if a recalculated value is marked as discrepant; no such recalculated primary analysis is reported.

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("Cohort 1", "Cohort 2", "Cohort 3")
n      <- c(29, 10, 6)
events <- c(10, 1, 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  Cohort 1  29  10  34.5  17.9  54.3  19.9  52.7  19.9  52.8
ARM  Cohort 2  10  1  10.0  0.3  44.5  1.8  40.4  2.3  41.3
ARM  Cohort 3  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 does not report how multiplicity was handled. Multiplicity arises when several outcomes, groups, time points or statistical tests are considered: the chance of at least one apparently notable result can increase as more tests are examined. General approaches include identifying a primary test in advance, adjusting significance thresholds, or describing other analyses as exploratory. The record identifies a primary objective, but it does not report a multiplicity strategy or the statistical analysis plan.

The record lists one outcome measure and no analyses. It does not provide a primary endpoint response count, an analysis denominator tied to a response result, an uncertainty interval, a p-value or details of any secondary efficacy analyses. It also does not report interim analyses or stopping rules. Their existence or absence beyond what is listed cannot be inferred; these details are not reported in the registry record.

The record gives 29 of 36 Cohort 1 patients as meeting the criteria for the primary efficacy population and being evaluable. It does not fully describe how participants who did not meet those criteria were handled in analyses, whether missing or unevaluable assessments occurred, or how any such cases were classified. Missing-data methods and sensitivity analyses are not reported in the registry record. In general, excluding participants with unavailable endpoint assessments can affect interpretation if missingness is related to prognosis or response; the record does not provide information to determine whether that concern applies.

The population is described using central NRG1 fusion confirmation and receipt of 3,000 mg QW dosing. The registry does not report a full analysis-population specification, including whether the principal analysis followed an intention-to-treat principle or another prespecified approach. It also does not explain how protocol deviations, treatment discontinuation or assessments outside the stated timeframe were addressed. These gaps limit reproducibility and make it difficult to determine how broadly any eventual result would apply.

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: malignant neoplasm progression (18.2%), pneumonia (14.3%), hepatic encephalopathy (14.3%), ascites (14.3%), vomiting (14.3%).

The safety record reports serious adverse event figures separately for Cohort 1, Cohort 2 and Cohort 3. The listed numbers of participants at risk are 36, 11 and 7, respectively; the corresponding numbers affected are 17, 6 and 4. The record also lists deaths as 21, 8 and 7 by cohort. These are cohort-level figures, not a randomized comparison, and no causal interpretation follows from comparing them.

The serious adverse event terms with the highest listed percentages are malignant neoplasm progression at 18.2%, pneumonia at 14.3%, hepatic encephalopathy at 14.3%, ascites at 14.3%, vomiting at 14.3% and abdominal pain at 9.1%. The registry record does not give the denominator or further event-level context for each listed percentage in this summary. These terms should not be read as an exhaustive safety profile or as proof that seribantumab caused each event.

In general, participant counts and event counts are not interchangeable: one participant can experience more than one event, and the registry summary may present affected participants separately from event occurrences. The record does not describe timing, duration, seriousness criteria, attribution, recurrence or resolution for each term. Small cohort sizes and the absence of randomization also limit comparative interpretation. The reason for termination is not reported in the registry record and should not be inferred from the safety figures.

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

The record establishes what the primary endpoint was intended to measure: confirmed complete or partial tumor response by investigator assessment using RECIST v1.1, in the specified seribantumab population. It also reports that 29 of 36 patients enrolled in Cohort 1 met the eligibility criteria for the primary efficacy population and were evaluable. Those details clarify the intended outcome and analysis population, but they are not the response result.

The registry record does not report how many evaluable patients had an objective response, the estimated ORR, or an uncertainty interval. It therefore does not support a quantitative conclusion about the observed response rate or its precision. The absence of a posted result in the registry record is not evidence that there were no responses, just as the endpoint definition and evaluability count are not evidence that responses occurred.

The design does not permit a randomized comparison with a control treatment. The cohorts were non-randomized and had differences in eligibility, including prior ERBB-directed therapy and fusion-domain status. Any comparison among cohorts would be vulnerable to differences in patient characteristics and treatment history. The record does not establish a causal treatment effect relative to another therapy or to no treatment.

Objective response is one dimension of tumor outcome. By itself, it does not establish response duration, survival, symptom change, quality of life or the balance of benefit and harm. The registry's safety figures provide some counts and listed serious event terms, but they are not a complete account of clinical context or causality. The study is recorded as terminated, but the reason is not reported. Taken together, the posted record allows a reader to understand the intended question and key design constraints, but not to judge the primary efficacy result or draw a comparative treatment conclusion.

14. Why This Trial Matters Statistically

This trial is statistically notable for the gap between a clearly specified response question and the limited outcome information in the registry record. The endpoint definition identifies what counted as an objective response, and the record identifies an evaluable primary efficacy population. Yet the actual response count and its statistical uncertainty are not reported. That distinction is central: a study objective and analysis population do not substitute for an estimate.

The design also makes the choice of interpretation important. Non-randomized cohorts can describe outcomes within defined groups, but they do not provide the balance created by random allocation. Because the cohorts differed in prior treatment eligibility and fusion-domain characteristics, cohort contrasts would not isolate the effect of seribantumab. This is a useful example of why trial labels and cohort structure should be read alongside the endpoint rather than treating any group difference as a treatment comparison.

The record further illustrates that an efficacy result requires more than a response definition. Readers need the outcome count, the denominator used for analysis, and a measure of uncertainty to understand both the estimated response and its precision. Missing-data rules, analysis populations and multiplicity handling also help establish how the result was produced and how much confidence to place in it. These details are not reported in the registry record.

Finally, planning illustrations must be kept distinct from evidence observed in a trial. A sample-size calculation under specified assumptions is not an observed outcome or observed power. In this case, the posted record gives assumptions for planning illustrations but not their numerical outputs. The statistical lesson is to separate design intent, observed data, analysis results and limitations rather than allowing one to stand in for another.

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.

Several limitations are specific to the information and design recorded for CRESTONE. The principal one is that the registry record does not report the primary response count, estimated ORR, confidence interval or inferential analysis. Although 29 of 36 patients in Cohort 1 are identified as evaluable for the primary efficacy assessment, this does not reveal how many met the response criteria. The primary endpoint therefore cannot be quantitatively interpreted from the posted outcome information.

The trial was non-randomized and unmasked, with no like-for-like control group described. Cohort eligibility differed according to prior ERBB-directed therapy and fusion-domain characteristics. As a result, comparisons across cohorts would be confounded by design and should not be treated as estimates of comparative efficacy.

The record's cohort descriptions and outcome details are incomplete. The arm descriptions are truncated, and the stated dosing schedules are not fully reproduced. The registry lists enrollment as 54, while the Cohort 1 description specifies a minimum of 55 and the primary efficacy population statement identifies 36 enrolled patients in Cohort 1. The record does not explain the relationship among those figures. The reason for termination is also not reported.

Analysis methods for missing assessments, participant exclusions, multiplicity, interim analyses and sensitivity analyses are not reported in the registry record. Safety reporting gives cohort-level counts and selected serious adverse event terms, but not the event-level detail needed to assess timing, attribution or clinical course. These limitations do not establish that unreported analyses or details do not exist; they mean they cannot be evaluated from the registry record.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Study of Seribantumab in Adult Patients With NRG1 Gene Fusion Positive Advanced Solid Tumors — NCT04383210.
• Registry record last updated 2025-04-03; status last verified 2025-03.
• Results first posted 2025-04-03.
• 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

CRESTONE, NCT04383210, is recorded as a phase 2, open-label, international, multi-center, non-randomized study of seribantumab in adults with NRG1 fusion-positive locally advanced or metastatic solid tumors. The registry lists enrollment as 54, status as terminated, a start date of 2020-09-29 and a primary completion date of 2024-02-28.

The primary endpoint was Objective Response Rate, defined as confirmed complete or partial response by investigator assessment per RECIST v1.1. For the primary efficacy population, 29 of 36 Cohort 1 patients met the stated criteria and were evaluable. The registry record does not report the response count, ORR estimate, confidence interval or inferential analysis. It also does not report the reason for termination, missing-data methods or multiplicity strategy.