Safety and Efficacy of LAG525 Single Agent and in Combination With PDR001 in Patients With Advanced Malignancies.: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Safety and Efficacy of LAG525 Single Agent and in Combination With PDR001 in Patients With Advanced Malignancies. (NCT02460224), a non-randomized phase 1, phase 2 study. The primary outcome is Phase 1: Number of Participants With Dose-Limiting Toxicities (DLTs).

2. Clinical Question

The study was designed in two stages. Dose escalation examined LAG525 alone and with PDR001, with the stated purpose of determining a maximum tolerated dose or recommended Phase 2 dose. Dose expansion then characterized the combination at the selected dose or schedule. That structure focuses the early stage on dose and tolerability questions, followed by examination of treatment in disease-specific groups.

The registry record lists 490 enrolled participants overall, but the groups differed in treatment, dose, schedule, cancer type, and prior treatment history. Because assignment was non-randomized, observed differences between groups would not by themselves establish that one regimen caused a better or worse outcome. The record does not report a control-based comparison or a single comparative efficacy question. Results for the primary dose-limiting toxicity endpoint are not reported in the registry record.

3. Trial Design

This was a Phase I/II, open-label, multicenter study with non-randomized allocation and a parallel model. The registry lists an enrollment of 490 and a completed status. The study start is recorded as 2015-06-17 and primary completion as 2020-12-31. Novartis Pharmaceuticals is listed as the sponsor.

In phase 1, dose escalation included single-agent LAG525 groups and combination groups receiving LAG525 with PDR001. The registry describes a range of doses and schedules, including treatment every two, three, or four weeks. The stated aim was to determine the maximum tolerated dose or recommended Phase 2 dose for LAG525 alone and in combination with PDR001. In phase 2, the study characterized the combination at selected doses and schedules in groups defined by cancer type and prior anti-PD-1/PD-L1 treatment.

Because the study was open label, participants and study teams were not masked to treatment assignment. Because allocation was not randomized, the treatment groups should not be treated as balanced comparison arms. Differences in disease mix, prior treatment, dose, schedule, and other characteristics could contribute to differences in outcomes. No adjustment method or randomized comparison is reported in the registry record.

The registry lists 43 outcome measures, including phase-specific adverse-event measures, dose changes, relative dose intensity, and LAG525 maximum observed serum concentration. It lists no analyses. The detailed phase 1 primary outcome is the number of participants with dose-limiting toxicities. The registry does not report the observed values for that endpoint in the record, nor does it report a statistical analysis plan or a sample-size justification.

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: The screening period began once patients had signed the study informed consent. All screening/baseline evaluations were performed ≤ 21 days before Cycle 1 Day 1, except for baseline radiological evaluations which had to be done within 28 days.

Only the first 6 of 29 groups are shown.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: All patients in phase 1 who received at least one full or partial dose of LAG525 or PDR001, and who either completed a minimum exposure requirement or who had a DLT during the first 15 days of treatment (1 cycle) for single-agent LAG525 arms or the first 30 days (2 cycles) for the LAG525 + PDR001 arms. Japanese patients were analyzed together with the rest of the world (ROW) patients as per protocol.

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.

Only the first 6 of 30 groups are shown.

6. Primary Endpoint

The registry lists the primary outcome as Phase 1: Number of Participants With Dose-Limiting Toxicities (DLTs), measured over 15 days for single-agent LAG525 arms and 30 days for the combination LAG525 + PDR001 arms.

The phase 1 primary endpoint counts participants with dose-limiting toxicities, or DLTs. The registry defines a DLT as an adverse event or abnormal laboratory value of CTCAE grade 3 or higher, assessed as suspected to be related to study drug and not attributable to disease, disease progression, inter-current illness, or concomitant medications. Other clinically significant toxicities could also be considered DLTs even if they did not meet that grade threshold.

The observation window differed by treatment: 15 days for single-agent LAG525 arms and 30 days for combination LAG525 and PDR001 arms. The definition refers to the first cycle for single-agent treatment and the first two cycles for combination treatment. The endpoint population included phase 1 patients who received at least a full or partial dose and met a minimum exposure requirement, or who experienced a DLT within the specified early period.

General statistical context: dose-limiting toxicity counts are used in early dose-escalation research because they summarize acute, clinically important tolerability events within a defined exposure window. Their interpretation depends on the DLT definition, observation period, and number of evaluable participants in each dose group. The registry record does not report the observed phase 1 DLT counts, the dose-escalation decision rules, or the final dose-selection rationale. It therefore does not support a quantitative reading of this endpoint or a conclusion about which dose was selected from the DLT results.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The design combines dose escalation and dose expansion. In phase 1, groups received different LAG525 doses and schedules, either alone or with PDR001. In phase 2, combination treatment was characterized in groups defined by cancer type and prior anti-PD-1/PD-L1 treatment. This is a descriptive design rather than a randomized comparison: assignment was non-randomized, and the registry does not identify a concurrent control arm.

What the primary endpoint counts

The primary endpoint is a participant count, not a continuous measurement or a time-to-event outcome. It classifies a participant as having a DLT if the registry’s clinical and timing criteria are met. The criteria include a suspected relationship to study drug, specified alternative explanations to exclude, and the first 15 days of single-agent treatment or first 30 days of combination treatment. The definition also allows other clinically significant toxicities to be considered DLTs. Applying that definition requires clinical assessment; the registry record does not provide participant-level event data or observed DLT counts.

General statistical context: a count is often easier to interpret alongside its denominator, because the same count can mean different things in groups of different sizes. Even when group counts and denominators are available, comparisons across non-randomized dose groups are vulnerable to differences in participant characteristics, follow-up, treatment exposure, and reasons for assignment. The registry record does not report an adjusted comparison for DLTs.

How to read the adverse-event counts

The adverse-event listings present counts of participants at risk and counts affected, separated into serious adverse events, other adverse events, and deaths. The overall group records 490 participants at risk, with 208 affected by serious adverse events, 481 affected by other adverse events, and 33 deaths. These categories are reported descriptively. The record does not specify in these summaries whether a death was caused by an adverse event or related to study treatment. Nor do the overall counts indicate how many events each participant had; the unit is participants affected.

The arm-level figures should be read within their specific dose and disease groups. A group with fewer participants may have a count that is small simply because its denominator is small. Conversely, larger groups have more opportunity to include affected participants. General statistical context: comparing raw counts without accounting for group size and exposure duration can mislead. Comparing rates would also require a clearly defined time-at-risk measure, which is not reported in these adverse-event summaries.

What inferential statistics would add

General statistical context: an estimate describes the observed quantity, while an uncertainty interval communicates how imprecise that estimate may be. A hypothesis test addresses compatibility with a specified null model under stated assumptions. Neither a confidence interval nor a test can remove bias caused by non-random treatment assignment. No inferential analyses are listed for this study in the registry record, and the primary DLT outcome results are not reported there. As a result, no effect estimate or uncertainty measure for the primary endpoint can be interpreted.

Over-dispersion is a general concern when count data vary more than a chosen statistical model expects; if ignored, uncertainty may be understated. It is not possible to assess over-dispersion from the registry’s summary counts alone, and no count model is reported in the registry record. The primary outcome is specifically a count of participants with an event, rather than a count of every event occurrence, which is an important distinction when choosing or interpreting an analysis.

Planning illustrations are not trial results

General statistical context: sample-size calculations can illustrate how many participants per arm might be needed under explicit assumptions about a target effect, significance level, allocation, and model. The posted planning illustration is based on a fraction of an observed effect and states a two-sided significance level of 0.05, equal allocation, and a normal approximation. Such planning values are not observed outcomes and are not observed power. They do not establish the study’s original design rationale; that rationale is not reported in the registry record. The illustration also cannot transform these non-randomized groups into a valid randomized comparison.

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 1: LAG525 1 mg/kg Q2W", "Phase 1: LAG525 3 mg/kg Q2W", "Phase 1: LAG525 5 mg/kg Q2W", "Phase 1: LAG525 10 mg/kg Q2W", "Phase 1: LAG525 15 mg/kg Q2W", "Phase 1: LAG525 240 mg Q2W")
n      <- c(16, 12, 6, 5, 6, 28)
events <- c(1, 0, 2, 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 1: LAG525 1 mg/kg Q2W  16  1  6.2  0.2  30.2  1.1  28.3  1.5  28.7
ARM  Phase 1: LAG525 3 mg/kg Q2W  12  0  0.0  0.0  26.5  0.0  24.2  0.2  24.7
ARM  Phase 1: LAG525 5 mg/kg Q2W  6  2  33.3  4.3  77.7  9.7  70.0  9.9  71.0
ARM  Phase 1: LAG525 10 mg/kg Q2W  5  0  0.0  0.0  52.2  0.0  43.4  0.4  45.9
ARM  Phase 1: LAG525 15 mg/kg Q2W  6  0  0.0  0.0  45.9  0.0  39.0  0.4  41.0
ARM  Phase 1: LAG525 240 mg Q2W  28  0  0.0  0.0  12.3  0.0  12.1  0.1  11.9

11. Multiplicity, Missing Data and Analysis Populations

The study contains many treatment groups, doses, schedules, cancer types, and outcome measures. It lists 43 outcome measures, including phase-specific safety measures, dose reductions and interruptions, relative dose intensity, and maximum observed serum concentration of LAG525. With many outcomes or subgroup comparisons, the chance of highlighting an apparently unusual result can increase if analyses are selected after looking at the data. General statistical context: multiplicity procedures can address the increased false-positive risk created by multiple formal tests, but the appropriate approach depends on the prespecified hypotheses and analysis plan.

Multiplicity handling is not reported in the registry record. The record lists no analyses and does not report which outcomes, comparisons, or subgroups were prespecified for inferential testing. It also does not report a statistical analysis plan or interim-analysis approach. No assumptions about testing hierarchy, adjustment, or interim monitoring can therefore be made.

Missing-data methods and analysis populations are also not described in enough detail to assess how incomplete follow-up or missing outcome assessments were handled. For the phase 1 primary endpoint, the registry gives an exposure-based population definition, but the observed DLT results and the number meeting that definition are not reported in the registry record. For the adverse-event summaries, the record gives at-risk and affected counts, but does not explain the handling of missing records, exposure duration, or participants who discontinued early.

These gaps matter because a participant who is not observed for the full DLT window may have a different opportunity for an event to be recorded than a participant completing that window. General statistical context: transparent reporting of analysis populations, missingness, and outcome-specific denominators helps readers distinguish lack of an event from lack of observation. The registry record does not supply those details for the primary outcome.

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: small intestinal obstruction (40.0%), diarrhoea (33.3%), pyrexia (33.3%), cancer pain (33.3%), dyspnoea (33.3%).

The registry reports serious adverse events and other adverse events as counts of affected participants, with the number at risk shown for each group. In the overall group, 208 of 490 participants were recorded as affected by serious adverse events, and 481 of 490 by other adverse events. The record lists 33 deaths. These are participant counts; they do not state the total number of separate events.

Across the serious-event terms listed most frequently, small intestinal obstruction is recorded at 40.0%; diarrhoea, pyrexia, cancer pain, and dyspnoea at 33.3% each; and fatigue at 20.0%. The registry excerpt does not specify the denominator for these term percentages, so they should be treated as displayed term-level figures rather than assumed to represent all participants.

The arm-specific counts vary across dose schedules and disease groups. They are descriptive because treatment assignment was non-randomized and the groups differ in size and clinical composition. The registry does not say that the listed serious events or deaths were caused by study treatment. Such attribution is not reported in the registry record. These counts therefore describe what was recorded, not a treatment-versus-control risk estimate or evidence of causation.

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

The record describes a large, multi-group Phase I/II study that examined LAG525 alone and with PDR001 in people with advanced malignancies. Its phase 1 primary endpoint was designed to count early dose-limiting toxicities, with different observation windows for single-agent and combination treatment. The overall adverse-event summaries provide descriptive participant counts, including serious adverse events, other adverse events, and deaths.

Those descriptions do not answer whether one dose or schedule is safer than another. Assignment was non-randomized, and the groups differ in dose, schedule, cancer type, and prior treatment. The record does not provide a control-based estimate, an adjusted comparison, or inferential analyses. In addition, the observed primary DLT results are not reported in the registry record. The safety counts do not establish that treatment caused any event or death; the relationship is not reported in these summaries.

The record’s stated study aims include pharmacokinetics, pharmacodynamics, tolerability, and anti-tumor activity. However, the available details do not report numerical results for the primary DLT outcome or anti-tumor activity. The study’s completion status and total enrollment are not substitutes for outcome results. A planning illustration, if consulted alongside the posted material, is a hypothetical calculation under stated assumptions, not observed trial evidence and not a measure of observed power.

General statistical context: a study can be informative about the range of doses investigated and the structure of its safety evaluation even when its registry entry does not provide the outcome analysis needed for a comparative conclusion. Interpretation should distinguish study purpose, descriptive counts, and tested treatment effects. For this record, the strongest supported reading is that many regimens were studied and adverse events were recorded; the record does not report the primary endpoint results or establish comparative efficacy or safety.

14. Why This Trial Matters Statistically

This trial is statistically notable for its combination of dose escalation and disease-specific expansion without random allocation. Dose-escalation studies ask how tolerability varies across dose levels and schedules, while expansion groups can characterize outcomes in selected clinical subgroups. Here, those questions span single-agent LAG525 and combinations with PDR001, multiple schedules, and several phase 2 disease and prior-treatment groups.

That breadth creates an important interpretive challenge. Many groups may help describe the range of regimens and populations studied, but small or unequal groups provide different amounts of information. Non-randomized assignment also means apparent differences may reflect population and treatment-history differences rather than regimen effects. The registry does not report an adjustment strategy that would address these issues.

The primary endpoint is a clinically defined count of participants with DLTs during early exposure, with separate windows for single-agent and combination treatment. This makes the endpoint relevant to dose escalation, but interpretation requires the observed counts, evaluable denominators, and dose-selection rules. Those primary outcome results and decision rules are not reported in the registry record.

The record also illustrates why descriptive safety counts should not be mistaken for comparative risk estimates. Serious-event counts and death counts are reported across groups, but treatment attribution and inferential analyses are not. The registry’s aims include anti-tumor activity, yet the results needed to quantify that activity are not reported in the available record. Statistically, the study structure and outcome definitions are informative; a treatment-effect conclusion is not supported by the reported analyses.

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 central limitation for interpreting the primary endpoint is that the registry record defines phase 1 DLTs but does not report the observed DLT counts or the number of participants included in the endpoint analysis. The dose-escalation rules and the rationale for selecting the dose or schedule used in phase 2 are also not reported in the registry record. Without those details, the primary safety question cannot be assessed from the available outcome information.

The study was open label and non-randomized. There is no like-for-like randomized control comparison, and the groups vary by dose, schedule, disease, and prior anti-PD-1/PD-L1 treatment. This limits direct comparisons between arms and makes causal interpretation inappropriate without additional design and analysis information. No adjusted analyses are listed.

The safety summaries provide counts, but do not explain exposure duration, follow-up completeness, event attribution, or missing-data handling. The basis for the serious-event term percentages is not specified in the available record. The 33 deaths are listed as a count, but their causes and relationship to study treatment are not reported in the registry record.

The record lists 43 outcome measures but no analyses. Multiplicity methods, prespecified subgroup hypotheses, interim analyses, and statistical analysis details are not reported in the registry record. Although the study’s stated aims include anti-tumor activity, relevant numerical outcome results are not included in the registry entries. These limitations mean that the design and descriptive safety data can be characterized, but comparative efficacy and safety conclusions cannot be drawn from the reported information.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Safety and Efficacy of LAG525 Single Agent and in Combination With PDR001 in Patients With Advanced Malignancies. — NCT02460224.
• Registry record last updated 2022-02-10; status last verified 2022-01.
• Results first posted 2022-02-10.
• 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

NCT02460224 is a completed, open-label, non-randomized Phase I/II multicenter study sponsored by Novartis Pharmaceuticals. It enrolled 490 participants with advanced solid tumors and evaluated LAG525 as a single agent and in combination with PDR001. Phase 1 used dose escalation; phase 2 characterized combination treatment in groups defined by cancer type and prior anti-PD-1/PD-L1 treatment.

The primary phase 1 outcome was the number of participants with DLTs during an early treatment window. The registry record defines that endpoint but does not report its observed results. It lists 43 outcome measures and no analyses. Overall adverse-event summaries record 208 participants with serious adverse events, 481 with other adverse events, and 33 deaths among 490 participants. These are descriptive counts, and treatment attribution is not reported in the registry record.