This page provides an independent statistical analysis and educational interpretation of publicly reported results. ClinicalTrials.gov provides the official trial registry record. Numerical trial results on this page are restricted to the results posted in the ClinicalTrials.gov record; calculations added by Clinical Biostats are labelled as such.
1. Trial at a Glance
This page covers the registry results for GSK3174998 Alone and With Pembrolizumab in Participants With Advanced Solid Tumors (ENGAGE-1) (NCT02528357), a non-randomized phase 1 study. The primary outcome is Part 1: Number of Participants With Any Serious Adverse Event (SAE) and Non-serious Adverse Event (Non-SAE).
| Feature | Registry value |
|---|---|
| ClinicalTrials.gov identifier | NCT02528357 |
| Phase | Phase 1 |
| Condition | Neoplasms |
| Allocation | Non-Randomized |
| Design model | Sequential |
| Masking | None (open label) |
| Enrollment | 141 |
| Arms in the primary outcome | n/a |
| Lead sponsor | GlaxoSmithKline |
| Results posted | Yes |
2. Clinical Question
Population
Participants had selected advanced or recurrent solid tumors. The registry lists Neoplasms as the condition and an enrollment of 141. The primary outcome population is described as all treated participants who received at least one dose of GSK3174998.
Intervention
The study evaluated intravenous GSK3174998 as monotherapy in Part 1 and with pembrolizumab in Part 2. Dose escalation was followed by cohort expansion. In the combination arms, pembrolizumab was given at 200 mg intravenously every 3 weeks.
Comparator
There was no randomized control group. The registry describes a non-randomized, sequential study, with different dose groups and disease-specific expansion cohorts. The arm counts therefore do not constitute a like-for-like comparison of treatments.
Primary question
The primary outcome asks how many participants in Part 1 experienced any serious adverse event or non-serious adverse event, up to a maximum of 39 weeks. It is a safety outcome, not a direct measure of tumor response or a test of comparative efficacy.
ENGAGE-1 was designed as a first-time-in-human study to evaluate safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary clinical activity. Its staged structure began with GSK3174998 dose escalation as monotherapy. Once a dose was identified as tolerable and showing pharmacodynamic activity, Part 2 could begin with escalating doses of GSK3174998 alongside fixed-dose pembrolizumab. The registry also describes cohort expansion, including melanoma, soft tissue sarcoma, and NSCLC cohorts. These features make the study useful for describing observed events within the tested treatment groups and for early investigation of activity. They do not create a randomized comparison between monotherapy and combination treatment, or between a treatment group and an untreated control.
3. Trial Design
ENGAGE-1 is registered as a phase I, open-label, non-randomized, multicenter study using a sequential model. The registry records enrollment of 141 and status as completed. The study start date is 2015-09-11 and the primary completion date is 2020-04-29. Participants had selected advanced or recurrent solid tumors.
The study had two parts. Part 1 evaluated GSK3174998 monotherapy through dose escalation, with doses described from 0.003 to 10.0 mg/kg intravenously every 3 weeks. Part 2 evaluated GSK3174998 with pembrolizumab 200 mg intravenously every 3 weeks. The combination dose-escalation groups used the same stated GSK3174998 range; the Part 2B expansion used a dose level considered tolerable in Part 2A. Both parts included dose escalation followed by cohort expansion in the study description.
The treatment duration could be up to approximately 2 years or 35 cycles, whichever came first. Safety follow-up was planned for a minimum of 3 months from the last dose, and post-treatment disease assessments were described every 12 weeks until documented progressive disease. These protocol descriptions are not outcome results.
Because allocation was non-randomized and the study proceeded sequentially through dose groups, treatment groups were not formed to ensure comparable baseline characteristics. Doses, study parts, and expansion cohorts also differ in purpose and composition. Thus, differences in event counts across groups should be read as descriptive observations, not as estimates of a causal treatment effect. The registry record does not report a randomized comparator or a masking procedure.
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 141 participants were enrolled in the study: 45 participants in Part 1 and 96 participants in Part 2 (74 in Part 2A+ 22 in Part 2B).
Only the first 6 of 19 groups are shown.
Part1:Monotherapy(Up to Maximum 39weeks)
| Stage | Part 1: GSK3174998 0.003 mg/kg | Part 1: GSK3174998 0.01 mg/kg | Part 1: GSK3174998 0.03 mg/kg | Part 1: GSK3174998 0.1 mg/kg | Part 1: GSK3174998 0.3 mg/kg | Part 1: GSK3174998 1.0 mg/kg |
|---|---|---|---|---|---|---|
| STARTED | 1 | 1 | 8 | 10 | 10 | 4 |
| COMPLETED | 1 | 0 | 6 | 9 | 6 | 2 |
| NOT COMPLETED | 0 | 1 | 2 | 1 | 4 | 2 |
Reasons for not completing this period:
| Reason | Part 1: GSK3174998 0.003 mg/kg | Part 1: GSK3174998 0.01 mg/kg | Part 1: GSK3174998 0.03 mg/kg | Part 1: GSK3174998 0.1 mg/kg | Part 1: GSK3174998 0.3 mg/kg | Part 1: GSK3174998 1.0 mg/kg |
|---|---|---|---|---|---|---|
| Lost to Follow-up | 0 | 1 | 0 | 0 | 0 | 0 |
| Physician Decision | 0 | 0 | 0 | 1 | 0 | 2 |
| Withdrawal by Subject | 0 | 0 | 2 | 0 | 3 | 0 |
| Follow-up assessments removed (Protocol Amendment 4) | 0 | 0 | 0 | 0 | 1 | 0 |
Part2A:Comb. Th. (Up to Maximum 105wks)
| Stage | Part 1: GSK3174998 0.003 mg/kg | Part 1: GSK3174998 0.01 mg/kg | Part 1: GSK3174998 0.03 mg/kg | Part 1: GSK3174998 0.1 mg/kg | Part 1: GSK3174998 0.3 mg/kg | Part 1: GSK3174998 1.0 mg/kg |
|---|---|---|---|---|---|---|
| STARTED | 0 | 0 | 0 | 0 | 0 | 0 |
| COMPLETED | 0 | 0 | 0 | 0 | 0 | 0 |
| NOT COMPLETED | 0 | 0 | 0 | 0 | 0 | 0 |
Reasons for not completing this period:
| Reason | Part 1: GSK3174998 0.003 mg/kg | Part 1: GSK3174998 0.01 mg/kg | Part 1: GSK3174998 0.03 mg/kg | Part 1: GSK3174998 0.1 mg/kg | Part 1: GSK3174998 0.3 mg/kg | Part 1: GSK3174998 1.0 mg/kg |
|---|---|---|---|---|---|---|
| Investigator site closed | 0 | 0 | 0 | 0 | 0 | 0 |
| Physician Decision | 0 | 0 | 0 | 0 | 0 | 0 |
| Withdrawal by Subject | 0 | 0 | 0 | 0 | 0 | 0 |
| Follow-up assessments removed (Protocol Amendment 4) | 0 | 0 | 0 | 0 | 0 | 0 |
Part2B:Expan. Coh.(Up to Maximum 33 Wks)
| Stage | Part 1: GSK3174998 0.003 mg/kg | Part 1: GSK3174998 0.01 mg/kg | Part 1: GSK3174998 0.03 mg/kg | Part 1: GSK3174998 0.1 mg/kg | Part 1: GSK3174998 0.3 mg/kg | Part 1: GSK3174998 1.0 mg/kg |
|---|---|---|---|---|---|---|
| STARTED | 0 | 0 | 0 | 0 | 0 | 0 |
| COMPLETED | 0 | 0 | 0 | 0 | 0 | 0 |
| NOT COMPLETED | 0 | 0 | 0 | 0 | 0 | 0 |
Reasons for not completing this period:
| Reason | Part 1: GSK3174998 0.003 mg/kg | Part 1: GSK3174998 0.01 mg/kg | Part 1: GSK3174998 0.03 mg/kg | Part 1: GSK3174998 0.1 mg/kg | Part 1: GSK3174998 0.3 mg/kg | Part 1: GSK3174998 1.0 mg/kg |
|---|---|---|---|---|---|---|
| Withdrawal by Subject | 0 | 0 | 0 | 0 | 0 | 0 |
| Follow-up assessments removed (Protocol Amendment 4) | 0 | 0 | 0 | 0 | 0 | 0 |
Analysis population for the primary outcome, as defined in the registry: All Treated Population consisted of all participants who received at least one dose of GSK3174998.
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 20 groups are shown.
| Characteristic | Unit | Part 1: GSK3174998 0.003 mg/kg | Part 1: GSK3174998 0.01 mg/kg | Part 1: GSK3174998 0.03 mg/kg | Part 1: GSK3174998 0.1 mg/kg | Part 1: GSK3174998 0.3 mg/kg | Part 1: GSK3174998 1.0 mg/kg |
|---|---|---|---|---|---|---|---|
| Participants analysed | 1 | 1 | 8 | 10 | 10 | 4 | |
| Age, Customized: 18 to 64 years | Participants | 1 | 0 | 5 | 8 | 4 | 2 |
| Age, Customized: 65 to 84 years | Participants | 0 | 1 | 3 | 2 | 6 | 2 |
| Age, Customized: >=85 years | Participants | 0 | 0 | 0 | 0 | 0 | 0 |
| Sex: Female, Male: Female | Participants | NA | NA | 6 | 6 | 5 | 1 |
| Sex: Female, Male: Male | Participants | NA | NA | 2 | 4 | 5 | 3 |
| Race/Ethnicity, Customized: Race – African American/African Heritage | Participants | NA | NA | 0 | 1 | 0 | 0 |
| Race/Ethnicity, Customized: Race – Asian - Central/South Asian Heritage | Participants | NA | NA | 0 | 1 | 0 | 0 |
| Race/Ethnicity, Customized: Race – Asian - East Asian Heritage | Participants | NA | NA | 0 | 0 | 0 | 0 |
| Race/Ethnicity, Customized: Race – Asian - South East Asian Heritage | Participants | NA | NA | 0 | 0 | 0 | 0 |
| Race/Ethnicity, Customized: Race – White - Arabic/North African Heritage | Participants | NA | NA | 1 | 1 | 0 | 0 |
| Race/Ethnicity, Customized: Race – White - White/Caucasian/European Heritage | Participants | NA | NA | 6 | 7 | 10 | 4 |
| Race/Ethnicity, Customized: Race – Missing | Participants | NA | NA | 1 | 0 | 0 | 0 |
6. Primary Endpoint
The registry lists the primary outcome as Part 1: Number of Participants With Any Serious Adverse Event (SAE) and Non-serious Adverse Event (Non-SAE), measured over Up to maximum 39 weeks.
| Element | Registry entry |
|---|---|
| Result type | Count Of Participants |
| Measure of spread | not applicable |
| Unit | Participants |
| Endpoint classification | Binary Endpoint |
The primary outcome is the number of participants in Part 1 with any serious adverse event (SAE) and non-serious adverse event (non-SAE), up to a maximum of 39 weeks. The registry defines an adverse event as an untoward medical occurrence temporally associated with use of a medicinal product, whether or not it is considered related to that product. An SAE includes an occurrence that results in death, is life threatening, requires or prolongs hospitalization, causes disability or incapacity, is a congenital anomaly or birth defect, or is otherwise judged serious on medical or scientific grounds.
The endpoint is a count of participants with events, rather than a measure of tumor response or a comparison of treatment benefit. Reporting both serious and non-serious events helps describe the range of observed safety experience during early dose evaluation. In a dose-escalation study, this kind of outcome is relevant to tolerability assessment and to the monitoring of participants receiving investigational treatment. It does not, by itself, establish that an event was caused by treatment: the registry definition explicitly includes events regardless of whether they are considered related to the medicinal product. The primary population is described as all treated participants who received at least one dose of GSK3174998.
7. Why No Re-analysis Is Shown
8. Statistical Interpretation
The posted results give arm-level counts of participants with serious adverse events, non-serious adverse events, and deaths. They are descriptive counts, not estimates from a randomized treatment comparison. The groups represent different GSK3174998 doses, treatment combinations, and expansion cohorts; their sizes and clinical contexts vary. A difference in counts between groups therefore cannot be attributed to a dose or to the addition of pembrolizumab on the basis of this design alone.
For example, the Part 1 group receiving 0.1 mg/kg lists 7 of 10 participants with an SAE, while the group receiving 0.3 mg/kg lists 2 of 10. These counts describe the posted groups; they do not show that one dose caused more or fewer serious events. Likewise, in Part 2A, the 0.03 mg/kg group lists 6 of 10 participants with an SAE, and the 3.0 mg/kg group lists 2 of 12. Differences in group composition, exposure, and chance may contribute, and the registry record does not supply adjusted comparative analyses for these counts.
Non-serious adverse events were listed for all participants in most dose groups. The Part 2A 0.3 mg/kg group lists 13 of 14, while the Part 2B NSCLC cohort lists 4 of 5. The registry also reports deaths within each group, including 9 in the Part 1 0.1 mg/kg group and 9 in the Part 2A 0.1 mg/kg group. The registry’s adverse-event definition does not make these deaths treatment-related, and the posted counts should not be read as attribution. A cause-specific breakdown or causal assessment is not reported in the registry record.
The secondary outcomes include objective response rate and disease control rate for Parts 1, 2A, and 2B, along with plasma concentrations of GSK3174998 at indicated time points for Parts 1 and 2A. Their results are not reported in the registry record. Consequently, these safety counts cannot answer whether tumor response differed between study parts or doses. The record lists 0 analyses, and does not report confidence intervals or a formal comparative analysis for the displayed safety counts. The scale of the groups also means the event counts should be interpreted as early-study descriptions rather than precise estimates of event frequency in a broader population.
Any sample-size material associated with the posted results is a planning illustration based on an observed effect, not a feature of this trial’s design and not observed power. It should not be used to turn these non-randomized safety observations into a confirmatory comparison.
9. Statistical Methods Explained
The primary outcome is binary at the participant level: a participant either appears among those with an event or does not, for the outcome definition and observation period. The registry reports counts and the number at risk for each treatment group. A count communicates how many participants had an event; the group size provides context for that count. The reported count is not the number of separate event episodes, because the endpoint is framed as participants with an event.
What does a confidence interval add?
In general, a confidence interval expresses the uncertainty around an estimate. For a proportion, it helps show how much the observed estimate may vary because it is based on a limited group of participants. A narrow interval indicates greater precision than a wide interval, but neither interval proves that an association is causal. In a non-randomized study, a confidence interval around an event proportion would describe sampling uncertainty and would not remove differences in participant characteristics, exposure, or follow-up between groups. The registry record does not report confidence intervals for the safety counts.
Why does the study structure matter?
Random allocation can help make treatment groups comparable on average. ENGAGE-1 is recorded as non-randomized and sequential, with dose escalation and expansion rather than randomized assignment to competing treatments. Participants in one dose group therefore cannot be treated as a control group for participants in another dose group. The groups also span monotherapy, combination treatment, and disease-specific cohorts. A raw contrast between counts could reflect factors other than treatment, and the registry record does not report an adjusted comparison to separate those possibilities.
What does the denominator mean?
The group-specific number at risk is the relevant context for a participant count. It should not be replaced by the total enrollment, because the registry reports separate groups and the primary outcome population is defined as treated participants. The registry does not provide a single common denominator that would make all groups directly comparable. Nor should a count be interpreted as an event rate over equal follow-up without information about participant time under observation. The primary outcome timeframe is stated as up to maximum 39 weeks, but a detailed account of each participant’s follow-up for this endpoint is not reported in the registry record.
Why can adverse-event categories overlap?
Serious and non-serious describe event classification, not whether an event is related to treatment. The registry defines an adverse event as temporally associated with medicinal-product use whether or not it is considered related. An SAE is classified by seriousness criteria, including death, life-threatening events, hospitalization, disability or incapacity, congenital anomaly or birth defect, or other medical or scientific judgment. A participant can experience more than one event, but the posted endpoint counts participants with events. The record does not provide enough detail to reconstruct event-level timing or the relationship between categories for each participant.
What do the planning calculations represent?
Any sample-size values associated with the posted results are planning illustrations, not the trial’s original design justification. Their stated assumptions are a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation; the effect to detect is a stated fraction of the observed effect. Such calculations illustrate the scale of a future comparison under those assumptions. They are not observed power, do not validate this study’s design, and do not change the descriptive nature of its non-randomized results. The sample-size justification used when ENGAGE-1 was planned is not reported in the registry record.
General statistical interpretation also depends on the analysis being matched to the question. A comparison of participant proportions would require a defined comparator, a specified analysis population, and an approach to uncertainty and missing observations. Those elements are not reported as a formal comparative plan for these safety counts. The registry lists 0 analyses. No recalculated or adjusted inferential result should therefore be substituted for the sponsor’s own analysis; the registry record does not provide such an analysis for this endpoint.
10. Multiplicity, Missing Data and Analysis Populations
The registry lists secondary outcomes for objective response rate and disease control rate in Parts 1, 2A, and 2B, as well as plasma concentrations of GSK3174998 at indicated time points in Parts 1 and 2A. These are distinct outcome families, and the registry lists 58 outcome measures. When many outcomes or time points are examined, the chance of seeing an apparently notable finding by chance can increase. Statistical methods can address this issue through prespecified testing strategies or adjustments, but a multiplicity approach for ENGAGE-1 is not reported in the registry record.
The record lists 0 analyses. It does not report whether interim analyses were planned or performed, how missing outcome data were handled, or whether any sensitivity analyses were conducted. These details should not be inferred from the sequential dose-escalation structure. The protocol description states that progression guided post-treatment disease assessments, but it does not specify a missing-data method for the primary safety outcome or the secondary outcomes.
The primary population is defined as all treated participants who received at least one dose of GSK3174998. That definition identifies the population intended for the primary safety outcome, but does not by itself explain how incomplete follow-up, withdrawal, or missing event assessments were handled. The primary timeframe is up to maximum 39 weeks. The registry does not report participant-level follow-up completeness or a statistical method for censoring or missingness for this endpoint.
Without a reported multiplicity plan, analysis population details beyond the stated primary population, and missing-data procedures, the registry record does not support a full assessment of the inferential framework for the outcome family. These omissions are limitations in interpreting any formal statistical claims, not evidence that a particular method was or was not used outside the registry record.
11. Safety Results
The registry reports serious adverse events as affected participants divided by participants at risk.
| Arm | Participants with serious adverse events | Participants at risk | Percentage |
|---|---|---|---|
| Part 1: GSK3174998 0.003 mg/kg | 1 | 1 | 100.0% |
| Part 1: GSK3174998 0.01 mg/kg | 0 | 1 | 0.0% |
| Part 1: GSK3174998 0.03 mg/kg | 3 | 8 | 37.5% |
| Part 1: GSK3174998 0.1 mg/kg | 7 | 10 | 70.0% |
| Part 1: GSK3174998 0.3 mg/kg | 2 | 10 | 20.0% |
| Part 1: GSK3174998 1.0 mg/kg | 1 | 4 | 25.0% |
| Part 1: GSK3174998 3.0 mg/kg | 2 | 7 | 28.6% |
| Part 1: GSK3174998 10.0 mg/kg | 1 | 4 | 25.0% |
| Part 2A: GSK3174998 0.003 mg/kg + Pembrolizumab 200 mg | 1 | 5 | 20.0% |
| Part 2A: GSK3174998 0.01 mg/kg + Pembrolizumab 200 mg | 1 | 5 | 20.0% |
| Part 2A: GSK3174998 0.03 mg/kg + Pembrolizumab 200 mg | 6 | 10 | 60.0% |
| Part 2A: GSK3174998 0.1 mg/kg + Pembrolizumab 200 mg | 4 | 12 | 33.3% |
| Part 2A: GSK3174998 0.3 mg/kg + Pembrolizumab 200 mg | 4 | 14 | 28.6% |
| Part 2A: GSK3174998 1.0 mg/kg + Pembrolizumab 200 mg | 4 | 12 | 33.3% |
| Part 2A: GSK3174998 3.0 mg/kg + Pembrolizumab 200 mg | 2 | 12 | 16.7% |
| Part 2A: GSK3174998 10.0 mg/kg + Pembrolizumab 200 mg | 2 | 4 | 50.0% |
| Part 2B: Melanoma Cohort | 1 | 9 | 11.1% |
| Part 2B: Soft Tissue Sarcoma Cohort | 2 | 8 | 25.0% |
| Part 2B: NSCLC Cohort | 1 | 5 | 20.0% |
Deaths
| Arm | Deaths (participants affected of at risk) |
|---|---|
| Part 1: GSK3174998 0.003 mg/kg | 1 of 1 |
| Part 1: GSK3174998 0.01 mg/kg | 0 of 1 |
| Part 1: GSK3174998 0.03 mg/kg | 6 of 8 |
| Part 1: GSK3174998 0.1 mg/kg | 9 of 10 |
| Part 1: GSK3174998 0.3 mg/kg | 6 of 10 |
| Part 1: GSK3174998 1.0 mg/kg | 2 of 4 |
Other (non-serious) adverse events
Participants with at least one non-serious event at or above the registry's 0% reporting threshold.
| Arm | Participants affected of at risk |
|---|---|
| Part 1: GSK3174998 0.003 mg/kg | 1 of 1 |
| Part 1: GSK3174998 0.01 mg/kg | 1 of 1 |
| Part 1: GSK3174998 0.03 mg/kg | 8 of 8 |
| Part 1: GSK3174998 0.1 mg/kg | 10 of 10 |
| Part 1: GSK3174998 0.3 mg/kg | 10 of 10 |
| Part 1: GSK3174998 1.0 mg/kg | 4 of 4 |
Most frequent serious adverse event terms
| Event term | Organ system | Part 1: GSK3174998 0.003 mg/kg | Part 1: GSK3174998 0.01 mg/kg | Part 1: GSK3174998 0.03 mg/kg | Part 1: GSK3174998 0.1 mg/kg | Part 1: GSK3174998 0.3 mg/kg | Part 1: GSK3174998 1.0 mg/kg |
|---|---|---|---|---|---|---|---|
| Infusion related reaction | Injury, poisoning and procedural complications | 0 of 1 | 0 of 1 | 1 of 8 | 0 of 10 | 0 of 10 | 1 of 4 |
| Anaemia | Blood and lymphatic system disorders | 0 of 1 | 0 of 1 | 0 of 8 | 0 of 10 | 1 of 10 | 0 of 4 |
| Large intestinal obstruction | Gastrointestinal disorders | 0 of 1 | 0 of 1 | 0 of 8 | 1 of 10 | 0 of 10 | 0 of 4 |
| Pyrexia | General disorders | 0 of 1 | 0 of 1 | 0 of 8 | 1 of 10 | 0 of 10 | 0 of 4 |
| Device related infection | Infections and infestations | 0 of 1 | 0 of 1 | 1 of 8 | 0 of 10 | 0 of 10 | 0 of 4 |
| Urinary tract infection | Infections and infestations | 0 of 1 | 0 of 1 | 0 of 8 | 1 of 10 | 0 of 10 | 0 of 4 |
| Urosepsis | Infections and infestations | 1 of 1 | 0 of 1 | 0 of 8 | 0 of 10 | 0 of 10 | 0 of 4 |
| Dislocation of vertebra | Injury, poisoning and procedural complications | 0 of 1 | 0 of 1 | 0 of 8 | 1 of 10 | 0 of 10 | 0 of 4 |
| Hip fracture | Injury, poisoning and procedural complications | 0 of 1 | 0 of 1 | 0 of 8 | 1 of 10 | 0 of 10 | 0 of 4 |
| Hyperglycaemia | Metabolism and nutrition disorders | 0 of 1 | 0 of 1 | 1 of 8 | 0 of 10 | 0 of 10 | 0 of 4 |
Most frequent non-serious adverse event terms
| Event term | Organ system | Part 1: GSK3174998 0.003 mg/kg | Part 1: GSK3174998 0.01 mg/kg | Part 1: GSK3174998 0.03 mg/kg | Part 1: GSK3174998 0.1 mg/kg | Part 1: GSK3174998 0.3 mg/kg | Part 1: GSK3174998 1.0 mg/kg |
|---|---|---|---|---|---|---|---|
| Fatigue | General disorders | 0 of 1 | 1 of 1 | 4 of 8 | 3 of 10 | 3 of 10 | 1 of 4 |
| Asthenia | General disorders | 0 of 1 | 1 of 1 | 2 of 8 | 3 of 10 | 0 of 10 | 2 of 4 |
| Anaemia | Blood and lymphatic system disorders | 1 of 1 | 0 of 1 | 1 of 8 | 2 of 10 | 2 of 10 | 1 of 4 |
| Diarrhoea | Gastrointestinal disorders | 0 of 1 | 1 of 1 | 1 of 8 | 3 of 10 | 1 of 10 | 1 of 4 |
| Nausea | Gastrointestinal disorders | 0 of 1 | 0 of 1 | 2 of 8 | 3 of 10 | 1 of 10 | 0 of 4 |
| Vomiting | Gastrointestinal disorders | 0 of 1 | 0 of 1 | 4 of 8 | 2 of 10 | 0 of 10 | 0 of 4 |
| Dyspnoea | Respiratory, thoracic and mediastinal disorders | 1 of 1 | 0 of 1 | 1 of 8 | 3 of 10 | 1 of 10 | 0 of 4 |
| Pyrexia | General disorders | 0 of 1 | 0 of 1 | 1 of 8 | 1 of 10 | 3 of 10 | 0 of 4 |
| Back pain | Musculoskeletal and connective tissue disorders | 0 of 1 | 0 of 1 | 0 of 8 | 3 of 10 | 2 of 10 | 0 of 4 |
| Arthralgia | Musculoskeletal and connective tissue disorders | 0 of 1 | 0 of 1 | 1 of 8 | 0 of 10 | 3 of 10 | 0 of 4 |
Serious events with the highest arm-level rate: urosepsis (100.0%), hydronephrosis (100.0%), myocarditis (25.0%), nausea (25.0%), vomiting (25.0%).
The safety results give, for each dose or cohort, the number of participants with at least one SAE, the number with a non-SAE, and the number of deaths. For instance, the Part 1 0.03 mg/kg group lists 3 of 8 participants with an SAE and 8 of 8 with a non-SAE; the Part 2B melanoma cohort lists 1 of 9 with an SAE and 9 of 9 with a non-SAE. These are participant counts, not counts of all event episodes.
The death counts are also descriptive. The record lists 6 deaths in the Part 1 0.03 mg/kg group and 4 in the Part 2A 0.003 mg/kg group. Because the adverse-event definition covers events whether or not they are considered related to the medicinal product, these numbers should not be interpreted as deaths caused by study treatment. The record does not report a cause-specific or treatment-attribution analysis for these counts.
The listed top serious terms include Urosepsis at 100.0%, Hydronephrosis at 100.0%, Myocarditis at 25.0%, Nausea at 25.0%, Vomiting at 25.0%, and Asthenia at 25.0%. The denominator and calculation details for these percentages are not reported in the registry record, so their scope should not be assumed.
12. What the Result Does, and Does Not, Mean
The posted safety counts show that adverse events were recorded across the monotherapy, combination dose-escalation, and expansion groups. They describe experience among the participants in those groups, using the registry’s distinction between serious and non-serious events. They do not, on their own, establish that an event was caused by GSK3174998 or pembrolizumab, or that the treatments differed in safety.
This distinction matters because an adverse event is defined by its temporal association with medicinal-product use, whether or not it is considered related. The endpoint is a count of participants with events over the stated timeframe, not an adjudication of treatment causation. The death counts likewise are not identified as treatment-related in the posted results. The registry’s counts should therefore be read as reported safety observations, with causal attribution not reported in the registry record.
The design also limits comparative conclusions. ENGAGE-1 was non-randomized and sequential; the dose groups and cohorts were not a like-for-like control comparison. Some groups received GSK3174998 alone, others received it with pembrolizumab, and the expansion cohorts represent named tumor groups. The recorded counts cannot isolate the effect of dose, combination therapy, or tumor type.
The record’s stated secondary outcomes include response and disease control, but results for those outcomes are not reported in the registry record. Thus these safety results do not establish whether tumor response occurred, whether one regimen had greater activity, or whether findings apply to patients outside the study groups. The data are informative as early clinical safety descriptions, but the record does not supply the comparative analyses, precision estimates, or missing-data details needed for stronger inferences.
13. Why This Trial Matters Statistically
ENGAGE-1 illustrates why early-phase clinical data need to be read in light of their design. A dose-escalation study can describe events observed at successive dose levels and support early assessment of tolerability. Here, the registry records GSK3174998 as monotherapy and in combination with pembrolizumab, with expansion cohorts for melanoma, soft tissue sarcoma, and NSCLC. The range of treatment settings makes the record clinically and statistically distinct from a randomized comparison of fixed regimens.
Its primary outcome is a participant count for serious and non-serious adverse events. This is a useful descriptive endpoint in an early study, but it does not answer every safety question. Counts do not show event timing, duration, recurrence, or treatment attribution, and group-level denominators do not describe differences in exposure or follow-up. The registry record also does not report confidence intervals or a formal comparative analysis for these safety results.
The study is a reminder that numerical differences among small, non-randomized dose groups are not automatically evidence of dose response or treatment effect. Sequential enrollment and varying cohort purposes make contextual interpretation essential. The registry’s secondary outcomes include response, disease control, and pharmacokinetic measures, but their results are not reported in the registry record. Keeping endpoint, design, and analysis in view prevents descriptive safety observations from being mistaken for comparative evidence.
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 main limitation for interpretation is the non-randomized, sequential design. The dose groups and cohorts are not randomized comparators, and the record does not report adjustment for differences between them. Monotherapy, combination dose escalation, and tumor-specific expansion cohorts differ in treatment and purpose, so their counts should not be compared as if they arose from equivalent groups.
The primary outcome population is described as all treated participants who received at least one dose of GSK3174998, and the timeframe is up to maximum 39 weeks. The registry record does not report individual follow-up completeness, event timing, missing-data handling, or a detailed account of how incomplete observations were treated. The stated SAE and non-SAE counts do not provide event-level descriptions or treatment attribution for each participant.
The record does not report confidence intervals, a formal comparative analysis, multiplicity procedures, or interim-analysis details. Although it lists secondary outcomes for objective response rate, disease control rate, and plasma concentrations, results for those outcomes are not reported in the registry record. The protocol’s sample-size justification is also not reported in the registry record. These gaps constrain assessment of precision, the broader outcome plan, and the strength of any comparative interpretation.
Finally, the findings describe a selected population with advanced or recurrent solid tumors in a phase I study. The registry record does not establish that these arm-level counts generalize to other populations or treatment settings. The observations should remain tied to the enrolled groups and the reported outcome definitions.
15. Related Tutorials
16. Related Statistical Calculators
17. Sources
- ClinicalTrials.gov: GSK3174998 Alone and With Pembrolizumab in Participants With Advanced Solid Tumors (ENGAGE-1) — NCT02528357.
- Registry record last updated 2021-05-18; status last verified 2021-04.
- Results first posted 2021-05-18.
- 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.
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18. Record Summary
ENGAGE-1 (NCT02528357) is a completed, phase I, open-label, non-randomized, multicenter study of GSK3174998 alone and with pembrolizumab in participants with selected advanced or recurrent solid tumors. The registry records enrollment of 141, a start date of 2015-09-11, and a primary completion date of 2020-04-29.
The primary outcome is the number of Part 1 participants with any SAE and non-SAE up to maximum 39 weeks. The record defines the primary population as all treated participants who received at least one dose of GSK3174998. Posted results provide group-level counts for serious events, non-serious events, and deaths. These are descriptive observations in non-randomized dose and cohort groups, not a like-for-like treatment comparison. Results for the listed response, disease-control, and pharmacokinetic secondary outcomes are not reported in the registry record.