Efficacy, Safety, and Pharmacokinetic of MSC2156119J in Asian Participants With Hepatocellular Carcinoma: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Efficacy, Safety, and Pharmacokinetic of MSC2156119J in Asian Participants With Hepatocellular Carcinoma (NCT01988493), a randomized phase 1, phase 2 study. The primary outcome is Phase 1b: Number of Participants Experiencing Dose Limiting Toxicity.

2. Clinical Question

3. Trial Design

The registry record describes an integrated, multicenter, randomized, open-label Phase Ib/II trial. Its stated purpose was to determine a recommended Phase 2 dose for tepotinib and evaluate efficacy, safety, and pharmacokinetics against sorafenib in Asian participants with MET+ advanced hepatocellular carcinoma and Child-Pugh class A liver function. The record lists 117 enrolled participants and a completed study status.

Phase 1b included three tepotinib dose groups: 300 mg, 500 mg, and 1000 mg. Each was taken orally once daily over a 21-day cycle. Phase 2 compared tepotinib at the recommended Phase 2 dose, selected from Phase 1b, with sorafenib 400 mg orally twice daily. The registry states that treatment continued until disease progression, intolerable toxicity, or participant withdrawal. The stated Phase 2 population had MET+ disease, Barcelona Clinic Liver Cancer Stage C, no prior systemic treatment, and Child-Pugh class A liver function.

The Phase 1b primary endpoint was the number of participants experiencing dose-limiting toxicity during the first cycle. The posted Phase 2 outcomes include progression-free survival assessed by an Independent Review Committee, overall survival, and time to progression assessed by the investigator. The record also lists pharmacokinetic measures for Phase 1b, including exposure and observed plasma concentrations.

Randomization is reported for the trial, but the allocation ratio and details of the randomization procedure are not reported in the registry record. The study was unmasked. The registry lists start and primary completion dates of 2014-01-06 and 2018-02-05, respectively.

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: A total of 27 participants were enrolled in Phase 1b part of the study and a total of 90 participants were enrolled in phase 2 part of the study. Participants enrolled in phase 1b were not eligible for randomization in phase 2.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Dose Limiting Toxicity (DLT) set included all participants who experienced a DLT during Cycle 1, or received at least 80 percent of all planned doses of treatment during Cycle.

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: The safety analysis set included all participants who had received any dose of the study medication.

6. Primary Endpoint

The registry lists the primary outcome as Phase 1b: Number of Participants Experiencing Dose Limiting Toxicity, measured over Day 1 to Day 21 of Cycle 1 (each cycle is 21 days).

The primary endpoint counts participants who experienced a dose-limiting toxicity during Day 1 to Day 21 of Cycle 1. The registry defines these toxicities as events judged related to study treatment by the investigator and/or sponsor, including specified severe blood-count abnormalities, febrile neutropenia, thrombocytopenia with bleeding, uncontrolled nausea, vomiting or diarrhea, and certain other severe non-hematological adverse events. The registry’s definition excludes the specified gastrointestinal events and alopecia from that last category.

The DLT population included participants who experienced a DLT during Cycle 1 or received at least 80 percent of all planned treatment doses during the cycle. This population definition matters when interpreting the counts: it describes who could be included in the endpoint set, rather than a general safety population covering all treatment exposure.

In general, early-cycle DLT counts are used in dose evaluation because they summarize treatment-related toxicities over a defined initial period. In this trial, dose evaluation was relevant to selecting the recommended Phase 2 dose. The reported counts are 0 participants for each Phase 1b dose group: tepotinib 300 mg (6.0 participants), 500 mg (12.0 participants), and 1000 mg (5.0 participants). These counts describe this endpoint and its stated population; they do not by themselves summarize all adverse events or establish the safety of a dose over longer exposure.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does a median time-to-event result describe?

For a time-to-event endpoint, the median is the time by which half of the observed group has had the event, under the analysis method used. It is not an average, and it does not mean that every participant experienced the event at that time. The Phase 2 record reports medians in months for progression-free survival, overall survival, and time to progression. The endpoints differ in what event is counted and, for progression outcomes, in who assessed tumor status.

The registry also reports 90% confidence intervals for the medians. In general, a confidence interval describes statistical uncertainty around an estimate under the analysis assumptions; it is not a range containing every participant’s outcome. A wider interval indicates less precision than a narrower interval. The registry reports intervals for these medians, but does not describe all details of the estimation method or handling of censoring.

How should hazard ratios and confidence intervals be read?

A hazard ratio compares event hazards over follow-up between groups, rather than comparing the medians directly. In general, a hazard ratio below 1 indicates a lower estimated event hazard in the numerator group relative to the reference group, while a value above 1 indicates a higher estimated hazard. The registry’s reported comparisons place tepotinib first and sorafenib second. A hazard ratio is not a ratio of median times, nor does it state the probability that an individual participant will experience an event.

The reported 90% confidence intervals indicate the range of values reasonably compatible with the estimate under the model and its assumptions. For progression-free survival and time to progression, the reported intervals lie below 1. For overall survival, the interval includes 1. In general, an interval including 1 leaves the data compatible with no relative hazard difference as well as with values in either direction. The registry labels the reported analyses as equivalence, but an equivalence conclusion requires a prespecified margin and an appropriate analysis; an equivalence margin is not reported in the registry record.

What does the log-rank method contribute?

The reported hazard-ratio comparisons used the log-rank method. In general, the log-rank test compares event-time patterns between groups over follow-up, taking account of the ordering of event times and censoring. The test’s p-value describes how unusual the observed test statistic would be under its null hypothesis and assumptions. It is not the probability that the null hypothesis is true, and it does not measure the size or clinical importance of an effect.

The registry reports p-values for each of the three Phase 2 comparisons. It does not report a statistical analysis plan, a prespecified significance threshold for these comparisons, or whether the analyses were confirmatory or exploratory. Therefore, the p-values should be read alongside the estimates and confidence intervals, not treated as a complete account of the evidence. The trial’s open-label design also means that masking did not protect participants or study personnel from knowledge of assigned treatment; independent review was specified for the progression-free survival assessment, but not for investigator-assessed time to progression.

What is the role of the Phase 1b count?

The primary endpoint is a count of participants with a DLT, rather than a mean or time-to-event measure. The reported count is zero in each listed dose group. A count is straightforward to interpret, but its meaning depends on the endpoint definition, the population included, and the observation period. Here, the period is the first 21-day cycle and the registry defines the DLT set using DLT occurrence or receipt of at least 80 percent of planned doses in that cycle. The record does not report a comparative statistical test for these dose groups, and the posted result should not be converted into a claim of no toxicity.

How should the planning illustrations be understood?

The sample-size illustrations use the observed effect as a starting point and show planning scenarios for detecting stated fractions of that effect. The record specifies a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation for these illustrations. For time-to-event endpoints, the figures represent total events using the Schoenfeld approach; other endpoint illustrations are expressed as participants per arm. These are planning calculations, not observed trial results, and they are not observed power.

In general, planning calculations depend on assumptions about the target effect, event accrual, allocation, and statistical method. The illustrations do not establish that the completed trial was designed with those assumptions, because the registry explicitly describes them as calculations from the observed effect rather than the trial’s own design. The trial’s sample-size justification is not reported in the registry record. Nor should the illustration totals be interpreted as the number of events or participants actually observed in this trial.

What remains uncertain about the analyses?

The registry reports arm sizes and effect estimates for the Phase 2 endpoints, but not the analysis populations in sufficient detail to establish how all randomized participants were handled. The missing-data approach, censoring rules, covariate adjustment, and any sensitivity analyses are not reported in the registry record. For the safety outcomes, exposure duration and the precise analysis population are not detailed in the material. Such omissions limit assessment of whether the results could be sensitive to analysis choices.

In general, these details matter because time-to-event methods rely on assumptions about censoring and comparison over follow-up, while safety counts depend on exposure and event definitions. Confidence intervals and p-values describe sampling uncertainty under a chosen analysis; they do not correct for missing analysis details, systematic bias, or multiple testing. Those issues should be kept distinct from the arithmetic of the reported estimates.

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("Phase 1b: Tepotinib 300 mg", "Phase 1b: Tepotinib 500 mg", "Phase 1b: Tepotinib 1000 mg")
n      <- c(6, 12, 5)
events <- c(0, 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  Phase 1b: Tepotinib 300 mg  6  0  0.0  0.0  45.9  0.0  39.0  0.4  41.0
ARM  Phase 1b: Tepotinib 500 mg  12  0  0.0  0.0  26.5  0.0  24.2  0.2  24.7
ARM  Phase 1b: Tepotinib 1000 mg  5  0  0.0  0.0  52.2  0.0  43.4  0.4  45.9

11. Multiplicity, Missing Data and Analysis Populations

The registry’s primary endpoint is the Phase 1b DLT count. The Phase 2 comparisons of progression-free survival, overall survival, and investigator-assessed time to progression are listed among secondary outcomes. The registry record does not report whether a formal testing hierarchy was specified, whether multiplicity adjustment was used, or how the reported secondary p-values were intended to be interpreted collectively. Without those details, the possibility of chance findings across multiple analyses cannot be evaluated from the reported results alone.

Analysis populations are also incompletely described. The DLT population has a specific definition based on DLT occurrence or receipt of at least 80 percent of planned doses in Cycle 1. The registry reports Phase 2 arm sizes for each efficacy endpoint, but does not provide enough detail to establish the full analysis population definition or how participants were handled if they lacked evaluable follow-up. The allocation ratio and the randomization procedures are not reported in the registry record.

Missing-data methods, censoring rules, and sensitivity analyses are not reported in the registry record. These details are relevant to interpreting time-to-event estimates because participants may have different follow-up and event status. The record also does not report whether interim analyses were conducted, the statistical analysis plan, or the sample-size justification for the trial. The planning illustrations are based on observed effects and are explicitly not the trial’s own design; they do not fill those gaps.

These omissions do not invalidate the posted estimates, but they limit independent assessment of prespecification, analysis choices, and robustness. Interpretation should distinguish what is directly reported—the endpoint definitions, estimates, intervals, and p-values—from what cannot be established because further analysis details are not reported in the registry record.

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: abdominal pain (16.7%), candida infection (16.7%), decreased appetite (16.7%), muscular weakness (16.7%), seizure (16.7%).

The safety record gives serious adverse event counts for participants at risk and affected, counts for other adverse events, and deaths by treatment group. These are separate summaries: a serious adverse event count is not the same as a count of all adverse events, and the deaths column should not be treated as an attribution of cause. The registry record does not provide additional detail about event duration, exposure-adjusted rates, or whether events were judged treatment-related.

In Phase 2, serious adverse events affected 23 of 45 participants at risk in the tepotinib group and 12 of 44 in the sorafenib group. Other adverse events affected 43 of 45 and 43 of 44, respectively. The death counts were 24 and 30, respectively. In Phase 1b, the record separately reports serious adverse events and deaths for the three dose groups; these counts are not interchangeable with the Cycle 1 DLT counts.

The registry lists abdominal pain, Candida infection, decreased appetite, muscular weakness, seizure, and disease progression among the top serious adverse event terms, with the reported percentages. These terms should be read as a list from the safety record, not as evidence of comparative risk or causation. Differences in exposure and follow-up may affect raw counts, and those details are not reported in the registry record.

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

The results describe observations in a completed, open-label Phase Ib/II trial of tepotinib and sorafenib in the specified population. The Phase 1b primary result is a count of DLTs during the first cycle, and the Phase 2 results are estimates of time-to-event outcomes. Each answers a limited question defined by its endpoint and analysis population.

The Phase 2 estimates provide comparisons of progression-free survival, overall survival, and investigator-assessed time to progression. Their point estimates and confidence intervals describe the direction and precision of the reported comparisons. They do not establish that every participant would have the same outcome, and the overall-survival interval is compatible with a range that includes no relative hazard difference. The record’s open-label design and unreported analysis details are relevant when judging how much weight to place on the findings.

These results do not establish that tepotinib is effective or ineffective for every person with hepatocellular carcinoma, nor do they establish results outside the trial population. The registry describes Asian participants with MET+ advanced disease and Child-Pugh class A liver function; the Phase 2 description further specifies Stage C and systemic-treatment-naive disease. Generalization to other populations, disease settings, or treatment histories is not established by these data.

The DLT counts do not mean that no adverse events occurred or that treatment was free of risk. The separate safety record reports serious adverse events, other adverse events, and deaths. Nor do the efficacy comparisons identify a mechanism or explain why outcomes differed. The registry record does not report enough information about missing data, multiplicity, or the analysis plan to resolve all uncertainties. The appropriate reading is therefore descriptive and statistical: estimates, intervals, counts, and their limitations, rather than a medical recommendation.

14. Why This Trial Matters Statistically

This trial is statistically notable because it combines early dose evaluation with a randomized Phase 2 comparison. Those phases address different inferential tasks. The first-cycle DLT count is intended to inform evaluation of dose, while the randomized Phase 2 endpoints compare time-to-event outcomes at the recommended Phase 2 dose with sorafenib. Keeping these questions separate prevents an early toxicity count from being mistaken for an efficacy result.

The Phase 2 record reports several kinds of uncertainty: median confidence intervals, hazard-ratio confidence intervals, and log-rank p-values. Reading these together is more informative than focusing on a single point estimate. The confidence intervals show that estimates vary in precision across outcomes; the overall-survival comparison in particular remains compatible with a range that includes 1. The progression outcomes use different assessment approaches, which also matters when comparing their patterns.

The record also illustrates why registry transparency matters. Randomization and open-label status are stated, and the endpoint definitions and reported estimates are available. However, the statistical analysis plan, missing-data procedures, multiplicity strategy, and trial sample-size justification are not reported in the registry record. Those items help readers judge prespecification and robustness, so their absence limits a full statistical appraisal.

Finally, planning illustrations based on observed effects are not evidence of observed power and do not reconstruct the trial’s design. Distinguishing planning assumptions from completed-trial results is essential when interpreting event-based sample-size scenarios. Together, these features make the trial a useful example of how design, endpoint choice, uncertainty, and reporting completeness shape interpretation.

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 registry describes a randomized, open-label design, but does not report the allocation ratio, randomization procedure, or allocation concealment. Lack of masking can matter for outcomes involving assessment or decisions, although the progression-free survival endpoint was assessed by an Independent Review Committee. Time to progression was assessed by the investigator, so its assessment process differs from the committee-reviewed progression-free survival endpoint.

The enrolled population was specific: Asian participants with MET+ advanced hepatocellular carcinoma and Child-Pugh class A liver function, with Phase 2 described as Stage C and systemic-treatment naive. The results do not directly establish outcomes in other clinical or demographic populations. The record does not describe the screening population or reasons for exclusion, limiting assessment of selection into the trial.

The Phase 1b DLT endpoint covers the first 21-day cycle only. It cannot summarize adverse events over the full treatment period. The registry’s DLT population definition also differs from the Phase 2 efficacy arm sizes, so the endpoint counts should not be used as a substitute for broader safety or efficacy analyses.

For the Phase 2 outcomes, the registry does not report missing-data procedures, censoring rules, sensitivity analyses, covariate adjustment, or full analysis-population definitions. It also does not report a multiplicity plan or the statistical analysis plan. The reported 90% confidence intervals and log-rank results are therefore interpretable as posted, but independent evaluation of all assumptions and prespecification is limited. Finally, the planning scenarios use observed effects and are not the trial’s own design; they cannot establish the adequacy of the original sample-size planning.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Efficacy, Safety, and Pharmacokinetic of MSC2156119J in Asian Participants With Hepatocellular Carcinoma — NCT01988493.
• Registry record last updated 2022-08-24; status last verified 2022-08.
• Results first posted 2019-07-24.
• 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

The registry record describes a completed, randomized, open-label Phase Ib/II trial of tepotinib in Asian participants with MET+ advanced hepatocellular carcinoma and Child-Pugh class A liver function, with sorafenib as the Phase 2 comparator. It lists enrollment of 117 and a start date of 2014-01-06, with primary completion on 2018-02-05.

The Phase 1b primary endpoint counted DLTs during the first treatment cycle. No DLTs were reported in the three dose groups. Phase 2 outcomes included committee-assessed progression-free survival, overall survival, and investigator-assessed time to progression. Their reported estimates favor tepotinib in direction for the two progression outcomes; the overall-survival confidence interval includes 1.

Safety counts include serious adverse events, other adverse events, and deaths. Important analysis details—including the statistical analysis plan, missing-data methods, and multiplicity approach—are not reported in the registry record.