Study of Efficacy and Safety of LEE011 in Postmenopausal Women With Advanced Breast Cancer: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Study of Efficacy and Safety of LEE011 in Postmenopausal Women With Advanced Breast Cancer (NCT01958021), a randomized phase 3 study. The primary outcome is Progression Free Survival (PFS) by Investigator Assessment.

2. Clinical Question

The comparison addresses the incremental contribution of ribociclib within a treatment regimen that included letrozole in both groups. It does not compare either regimen with no treatment, nor does it directly answer whether the findings apply to other populations or treatment settings. The registry lists overall survival, response, clinical benefit, performance status, and quality-of-life outcomes as secondary outcomes.

3. Trial Design

This was a randomized, quadruple-masked, parallel-group phase 3 study sponsored by Novartis Pharmaceuticals. The registry lists 668 participants enrolled. Each of the two primary comparison groups included 334 participants in the primary outcome record: ribociclib plus letrozole and placebo plus letrozole. The trial is marked completed.

The treatment groups differed by assignment to ribociclib or placebo, while both included letrozole. In the ribociclib group, the registry describes oral ribociclib 600 mg daily for 3 weeks on and 1 week off, alongside oral letrozole 2.5 mg daily. The comparator received daily oral placebo on the same on/off schedule alongside daily oral letrozole 2.5 mg.

The stated primary purpose was to assess ribociclib efficacy using progression-free survival in postmenopausal women with hormone receptor-positive, HER2-negative advanced breast cancer who had received no prior treatment for advanced disease. The primary outcome was assessed by investigators according to RECIST 1.1, with follow-up described as up to 23 months. The registry record gives a start date of 2013-12-17 and a primary completion date of 2016-01-29.

The record also notes that participants were unblinded after completion of the final overall survival analysis and implementation of a protocol amendment, and that participants in the placebo group were given an option to cross over to ribociclib plus letrozole. The date and amendment details are not needed to interpret the randomized primary comparison, but crossover is relevant when considering later survival follow-up. Further details of the trial’s original sample-size justification and full statistical analysis plan are not reported in the registry record.

4. Participant Flow and Accounting

The registry reports how participants moved through each stage of the study. All counts below are exactly as posted; missing counts are not inferred from other stages.

Before assignment: Screening assessments were conducted up to 21 days prior to the randomization

Treatment

Reasons for not completing this period:

Post-treatment Efficacy Follow-up

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Full Analysis Set (FAS) including all randomized participants

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 Progression Free Survival (PFS) by Investigator Assessment, measured over Up to 23 months.

Progression-free survival measures the time from randomization until the first documented disease progression or death from any cause. For a participant without a recorded event, the registry says the time was censored at the last adequate tumor assessment. Clinical deterioration without objective radiological evidence was not counted as documented progression. Investigators assessed progression according to RECIST 1.1.

This time-to-event endpoint is used to capture both how long participants remain alive without documented progression and the timing of events across follow-up. Unlike a simple count of events at one fixed visit, the analysis can incorporate different lengths of observation, while censoring records the last point at which a participant was adequately assessed without a known event. Censoring does not establish what happened after that assessment; the method relies on assumptions about the relationship between censoring and future event risk.

The registry states that Kaplan–Meier methods were used to estimate the survival curves and medians, and a stratified Cox regression model was used to estimate the hazard ratio with a 95% confidence interval. A median is the estimated time by which half of the group has had an event under the analysis; it does not describe every participant’s experience. The primary outcome timeframe is listed as up to 23 months. The registry reports the placebo-plus-letrozole median as 14.7 months, but the ribociclib-plus-letrozole median itself is not reported in the registry record.

7. Results Posted in the Registry

• Ribociclib + Letrozole vs Placebo + Letrozole: hazard ratio 0.56 (95% CI 0.43–0.72), reported p < 0.001 (as reported in the registry).

8. Secondary Efficacy Endpoints

The registry also posts results for secondary outcomes. For each outcome below, the endpoint type, the test applied to the posted summary statistics, the result and its interpretation are given in turn. Secondary endpoints are usually not adjusted for multiple testing, so they support rather than confirm the primary finding.

Overall Survival (OS)

• Endpoint type: Time to event: compared as a hazard ratio.
• Test: Hazard ratio as reported by the sponsor (Log Rank); it was not recalculated.
• Result:
  • Ribociclib + Letrozole vs Placebo + Letrozole: hazard ratio 0.77 (95% CI 0.63–0.93), reported p = 0.004 (as reported in the registry).
• Interpretation:
  • The 95% confidence interval excludes no difference (a ratio of 1), so the hazard of the event is statistically lower for Ribociclib + Letrozole vs Placebo + Letrozole than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.

Overall Response Rate (ORR) by Investigator Assessment

• Endpoint type: Binary: the percentage of participants with the event (counts rebuilt from the posted percentages and group sizes).
• Test: Unadjusted two-proportion z-test, with a Wald 95% confidence interval for the risk difference.
• Result:
  • Ribociclib + Letrozole: 40.7% (136/334) versus 27.5% (92/334) on control; risk difference 13.2 percentage points (95% CI 6.1 to 20.3), risk ratio 1.48 (1.19–1.84); unadjusted two-proportion z-test p = <0.001.
• Interpretation:
  • The 95% confidence interval excludes no difference, so the proportion with the event is statistically higher for Ribociclib + Letrozole than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.

Clinical Benefit Rate (CBR) by Investigator Assessment

• Endpoint type: Binary: the percentage of participants with the event (counts rebuilt from the posted percentages and group sizes).
• Test: Unadjusted two-proportion z-test, with a Wald 95% confidence interval for the risk difference.
• Result:
  • Ribociclib + Letrozole: 79.6% (266/334) versus 72.8% (243/334) on control; risk difference 6.9 percentage points (95% CI 0.4 to 13.3), risk ratio 1.09 (1.01–1.19); unadjusted two-proportion z-test p = 0.037.
• Interpretation:
  • The 95% confidence interval excludes no difference, so the proportion with the event is statistically higher for Ribociclib + Letrozole than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.

The secondary outcomes cover survival, tumor response, clinical benefit, performance status, and quality of life. The posted overall survival estimate points in the same direction as the primary time-to-event result: the reported hazard ratio is below 1 for ribociclib plus letrozole versus placebo plus letrozole. The response and clinical benefit percentages are also higher in the ribociclib group in the posted results. Taken together, the reported secondary outcomes broadly align with the primary comparison, although they measure different aspects of outcome and are not interchangeable.

The registry lists overall response and clinical benefit by investigator assessment, as well as time to worsening of performance status and quality of life and change in quality-of-life score. The posted outcome record includes only some of the listed secondary results; further numerical results for the other secondary outcomes are not reported in the registry record. The registry lists six secondary outcomes, while the posted results contain fewer numerical secondary endpoint records.

Secondary outcomes generally carry less weight than a prespecified primary endpoint because they may be numerous, may be evaluated at different times, and can involve different statistical methods. When many hypotheses are tested, some can appear statistically persuasive by chance even if no true effect exists. The reported secondary p-values should therefore be interpreted in the context of the full set of outcomes and any planned multiplicity strategy. Whether the trial adjusted these tests for multiplicity is not reported in the registry record.

There is also a distinction between supportive consistency and independent confirmation. Findings on overall survival and response can add context to the primary progression-free survival result, but they do not erase uncertainty about analysis choices, missing outcome reporting, or the effects of crossover on longer-term follow-up. Each endpoint answers a separate question, and the strength of evidence depends on its design, analysis, precision, and place in the trial’s testing plan.

Secondary outcomes registered for this trial, for reference (only those above were recalculated):

• Overall Survival (OS)
• Overall Response Rate (ORR) by Investigator Assessment
• Clinical Benefit Rate (CBR) by Investigator Assessment
• Time to Definitive Deterioration of Eastern Cooperative Oncology Group Performance Status (ECOG PS) by at Least One Category of the Score
• Time to Definitive 10% Deterioration in the Global Health Status/Quality of Life (GHS/QoL) Scale Score of the European Organization for Research and Treatment of Cancer's Core Quality of Life Questionnaire (EORTC QLQ-C30)
• Change From Baseline in the GHS/QoL Scale Score of the EORTC QLQ-C30

9. Statistical Interpretation

10. Statistical Methods Explained

Progression-free survival and overall survival are time-to-event outcomes. The relevant event for progression-free survival was documented progression or death from any cause. For overall survival, the event is death. These analyses use the timing of events, rather than only comparing the proportion of participants with an event at a single time point.

How Kaplan–Meier estimates work

Kaplan–Meier estimation builds an estimated event-free survival curve over follow-up. Participants contribute information while they are observed and have not yet had an event. If their event status is not known beyond their last adequate assessment, their follow-up is censored at that point. Censoring allows their observed time to contribute without treating them as if they had an event or remained event-free indefinitely.

The method depends on adequate follow-up and assumptions about censoring. In general, the estimate is most straightforward to interpret when censoring does not systematically select participants with a different future event risk. The registry record specifies the progression-free survival censoring rule but does not report further detail about censoring patterns or checks of these assumptions.

What the median and hazard ratio describe

The median is a point on the estimated curve: the time by which the estimated event-free proportion reaches one half. It is an absolute time measure, but it does not usefully summarize every feature of the curve, and it can be unavailable if the curve does not reach that point within the observed follow-up. For the primary outcome, the comparator median is 14.7 months; the intervention-group median is not reported in the registry record.

The hazard ratio compares the estimated event hazards between groups over follow-up. A value below 1 for ribociclib plus letrozole versus placebo plus letrozole indicates a lower estimated hazard in the ribociclib group. The hazard ratio is not the ratio of medians, nor does it directly state an absolute risk reduction. A Cox model estimates this comparative measure; the registry describes the primary analysis as using a stratified Cox regression model. The reported analysis also identifies a log-rank method. The stratification factors and further model details are not reported in the registry record.

A hazard ratio is often interpreted as a single relative comparison across follow-up. If the relative hazards change over time, a single estimate may not capture that changing pattern. The registry record does not report a proportional-hazards diagnostic or a time-varying analysis, so no conclusion about those checks can be drawn from the record.

How to read the confidence interval and p-value

A confidence interval expresses uncertainty about an estimated effect under the analysis method. For the primary hazard ratio, the 95% interval runs from 0.429 to 0.720. The range lies below 1, which is consistent with a lower estimated hazard in the ribociclib group. The interval does not describe the range of individual participant outcomes, and it does not account automatically for every design or analysis limitation.

The reported p-value is evidence against a statistical null hypothesis under the specified analysis 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 primary reported p-value is < 0.001. The registry reports p-values for several secondary outcomes as well, but a set of separate tests raises a multiplicity question: the more outcomes and analyses considered, the greater the opportunity for chance findings unless the analysis plan accounts for that. Whether and how the trial adjusted for multiplicity is not reported in the registry record.

What the recalculations add

For binary outcomes, a simple unadjusted recalculation can use the posted group percentages and participant counts to estimate an absolute difference and its uncertainty. It is a descriptive comparison based on summary data, not a replacement for a sponsor analysis that may account for stratification or other prespecified features. For overall response and clinical benefit, the registry reports Cochran–Mantel–Haenszel analyses, while unadjusted recalculations use the posted outcome summaries. These approaches can yield different p-values because they do not necessarily use the same information or assumptions.

Such recalculations are useful as a transparent check on the scale and precision of the posted group results. They do not reconstruct participant-level data, establish the exact trial analysis plan, or account for unreported covariates. For time-to-event outcomes, the posted sponsor hazard ratios are used rather than attempting a new estimate from medians, because medians alone are insufficient to reproduce the trial’s time-to-event analysis.

11. Confidence Intervals and Precision

The primary hazard ratio is 0.556, with a 95% confidence interval from 0.429 to 0.720. The interval is entirely below 1, indicating that the estimate is compatible with a lower event hazard in the ribociclib group under the reported model. Its width shows that the estimated relative effect is not known with unlimited precision; plausible values under the model extend from a more pronounced relative reduction to a less pronounced one.

Confidence intervals are not guarantees that the true value lies within the displayed range, nor do they show the distribution of outcomes among individual participants. They quantify statistical uncertainty associated with the estimate and method. They do not automatically incorporate uncertainties from outcome measurement, model choice, missing data, crossover, or other limitations.

The comparator median progression-free survival is 14.7 months, with a 95% confidence interval from 13.0 to 16.5 months. For ribociclib plus letrozole, the registry record lists a lower confidence bound of 19.3 months but does not report the median estimate or upper bound. This incomplete reporting prevents a full comparison of the groups’ median estimates and their precision using the registry record alone.

For overall survival, the reported hazard ratio is 0.765, with a 95% confidence interval from 0.628 to 0.932. The medians are 63.9 months and 51.4 months for ribociclib plus letrozole and placebo plus letrozole, respectively, with their corresponding confidence intervals reported in the outcome results. For the secondary binary outcomes, the group percentages also have confidence intervals, reflecting uncertainty in each estimated proportion. Precision should be judged from the intervals as well as the point estimates; a point estimate alone can make an uncertain result look more definite than it is.

12. Planning a Similar Trial: Sample Size

This is a planning illustration, not a re-evaluation of the original trial. It asks: if a new study wanted to detect a difference like the one observed, or a smaller one, how large would it need to be? It is deliberately not “observed power” of the finished trial, which is not a meaningful quantity.

The planning figures are illustrations based on the observed effect, not a report of the trial’s original design calculations. For the time-to-event outcomes, the figures refer to the total number of events needed, not participants per arm. For the binary outcomes, they refer to participants per arm. The calculations assume a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. The effect to detect is set at the stated fraction of the observed effect.

The 80% power column describes a planning scenario in which a study with the listed event or participant count would have an 80% chance of detecting the specified effect at the assumed significance level, if the assumptions hold. The 90% power column uses a higher target chance of detection and therefore generally calls for more information. These are planning illustrations, not observed power.

The rows that plan for 100% of the observed effect use the full observed effect as the target; rows for 75% and 50% plan for smaller effects. Smaller effects are harder to distinguish from chance variation, so more participants or events are generally needed to detect them with the same target power. For example, the primary time-to-event planning figures list 92 total events for 80% power and 122 for 90% power when planning for 100% of the observed effect. When planning for 50% of that effect, the listed totals are 365 and 488. These totals are events across the comparison, not a per-arm enrollment target.

For overall response, the corresponding per-arm figures are 203 participants for 80% power and 271 for 90% power at 100% of the observed effect; at 50% of the observed effect, they are 771 and 1,031 per arm. These are not the trial’s original sample-size justification. The trial’s own planning assumptions and original power calculation are not reported in the registry record.

13. How the Sample Size Is Derived

Power is the probability that a study of a given size rejects the null hypothesis when a specific true effect exists. It depends on four things: the effect to detect, the variability of the outcome, the significance level (here a two-sided α of 0.05, so z_1−α/2 = 1.960) and the desired power (z_1−β = 0.842 for 80% and 1.282 for 90%).

Formula

d is the total number of events needed (Schoenfeld's formula) with 1:1 allocation and proportional hazards.

Worked calculation for this trial

1. Hazard ratio HR = 0.556, so ln(HR) = -0.5870.
2. d = 4 × (1.96 + 0.842)² / [ln(0.556)]² = 91.1, rounded up to 92 events in total for 80% power.

The smaller-effect rows in the table above repeat the same calculation with the effect multiplied by 0.75 and 0.5 (for ratios, applied to the logarithm of the ratio).

R code

alpha <- 0.05
z_a   <- qnorm(1 - alpha / 2)          # two-sided
hr <- 0.556                              # observed hazard ratio
events_needed <- function(power, frac = 1) ceiling(round(4 * (z_a + qnorm(power))^2 / log(hr^frac)^2, 6))   # Schoenfeld, 1:1 allocation
for (f in c(1, 0.75, 0.5))
  cat(sprintf("%3.0f%% of observed effect: events = %s (80%% power), %s (90%% power)\n", 100 * f,
              format(events_needed(0.80, f), big.mark = ","), format(events_needed(0.90, f), big.mark = ",")))

# Simulation: given d total events under proportional hazards, events in the treatment arm are Binomial(d, hr / (1 + hr)).
# The score (log-rank type) statistic is (D1 - d / 2) / sqrt(d / 4).
set.seed(1958021)
d    <- events_needed(0.80)
reps <- 20000
D1 <- rbinom(reps, d, hr / (1 + hr))
z  <- (D1 - d / 2) / sqrt(d / 4)
cat(sprintf("Simulated power with %s events: %.3f (%d replicates)\n", format(d, big.mark = ","), mean(abs(z) > z_a), reps))

Output from running the code

100% of observed effect: events = 92 (80% power), 122 (90% power)
 75% of observed effect: events = 162 (80% power), 217 (90% power)
 50% of observed effect: events = 365 (80% power), 488 (90% power)
Simulated power with 92 events: 0.784 (20000 replicates)

The simulation uses the fact that, with d events in total and proportional hazards, the number of events in the treatment arm is binomial. It is an approximation that conditions on the total number of events, and it should land close to the target power.

14. Analyses Reported by the Sponsor

The sponsor-reported primary analysis gives a hazard ratio of 0.556, a 95% confidence interval from 0.429 to 0.720, and a p-value of < 0.001. The statistical presentation relies on that reported time-to-event analysis. No simple recalculation from the medians is used, because the medians do not contain enough information to reproduce a hazard ratio or its uncertainty.

For the secondary binary outcomes, the sponsor reports Cochran–Mantel–Haenszel tests. The overall response test has a reported p-value of < 0.001, while the unadjusted recalculation from the posted group summaries is reported as p < 0.001. For clinical benefit, the sponsor-reported p-value is 0.018, while the unadjusted recalculation is 0.037. The recalculations are simple comparisons of the posted summaries and do not reproduce the sponsor’s method or any stratification used in it.

The registry record does not flag a discrepancy between the sponsor analysis and recalculations. For interpretation, the sponsor’s own analysis takes precedence where it is reported, particularly when it reflects a trial-specific method. The unadjusted calculations can still help readers understand the group-level data, but they should not be presented as the trial’s primary inferential analysis or as evidence that the sponsor’s analysis used the same assumptions.

15. Multiplicity, Missing Data and Analysis Populations

The registry lists one primary endpoint and several secondary outcomes, with further analyses reported for overall survival, response, and clinical benefit. Testing multiple outcomes creates a multiplicity issue: without an adjustment or a clearly ordered testing strategy, the chance of at least one false-positive result across a collection of tests can be higher than the chance for a single test. This is a general statistical concern, not evidence that any particular result is false. The multiplicity procedure, if any, is not reported in the registry record.

The primary outcome population is identified as the Full Analysis Set, including all randomized participants. The record gives 334 participants in each primary comparison group. For the safety results, the risk sets differ: serious adverse events are reported among 334 participants in the ribociclib group and 330 in the placebo group, with a separate crossover group of 4. The reason the safety denominators differ from the randomized group sizes is not reported in the registry record, so the counts should be read using the specific risk sets attached to those results.

For progression-free survival, participants without an event were censored at their last adequate tumor assessment. The record does not provide further numerical detail about missing tumor assessments, censoring patterns, or sensitivity analyses for missing data. It also does not report a detailed missing-data approach for the secondary response, quality-of-life, or performance-status outcomes. Those absences make it difficult to assess whether incomplete follow-up could have influenced the estimates.

The registry describes the primary endpoint analysis as Kaplan–Meier estimation and a stratified Cox regression model, but does not report the stratification factors, a complete statistical analysis plan, or the original sample-size assumptions. It also does not report whether interim analyses were conducted. These items should not be inferred from the final results or from general practice in clinical trials.

Finally, the record notes unblinding after the final overall survival analysis and an option for crossover from placebo to ribociclib plus letrozole. Crossover may complicate interpretation of later comparisons of treatment assignment and overall survival, since some participants originally assigned to placebo could subsequently receive ribociclib. The registry information does not quantify the impact of crossover on the overall survival estimate.

16. 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: anxiety (25.0%), pneumonia (2.4%), dyspnoea (2.1%), abdominal pain (1.8%), nausea (1.5%).

The registry reports serious adverse events for the ribociclib-plus-letrozole group among 334 participants at risk, with 108 affected. For the placebo-plus-letrozole group, it reports 62 affected among 330 at risk. A separate crossover group has 1 affected participant among 4 at risk. These are counts of participants reported as affected in the registry’s safety results; they should be interpreted with their stated risk sets rather than assumed to have identical denominators.

The registry also lists serious adverse event terms and percentages, including Anxiety at 25.0%, Pneumonia at 2.4%, Dyspnoea at 2.1%, Abdominal pain at 1.8%, Nausea at 1.5%, and Vomiting at 1.5%. The record does not give additional detail in this summary about event timing, duration, severity beyond the serious-event classification, or the basis for the listed percentages. The Anxiety percentage is reproduced as reported and should not be treated as a rate calculated from the group-level affected counts.

These figures describe reported safety events in the registry, but do not alone establish comparative causation or provide a complete account of the benefits and risks of treatment. The record also lists deaths in several treatment and follow-up groups; those follow-up categories should not be added together or interpreted as an arm-level comparison without further details of their definitions and observation periods.

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

The primary result is evidence of a difference in investigator-assessed progression-free survival between the randomized treatment groups under the analysis reported in the registry. The hazard ratio of 0.556 is below 1, and its 95% confidence interval, 0.429 to 0.720, remains below 1. The result is statistically persuasive under the reported model, but it is still an estimate with uncertainty and depends on the analysis assumptions.

The finding does not mean that every participant in the ribociclib group avoided progression or lived longer than every participant in the comparator group. A hazard ratio summarizes relative event hazards across follow-up; it does not predict an individual’s outcome, provide a direct measure of time gained, or identify what would happen to a particular person. The placebo-group median of 14.7 months is a group-level estimate, and the ribociclib-group median is not reported in the registry record.

Overall survival and investigator-assessed response provide additional context, with reported results in the same general direction as the primary outcome. They remain secondary outcomes and should be interpreted with attention to multiplicity and the limitations of registry reporting. The later survival comparison also needs to be read alongside the record’s crossover information.

The study applies to its enrolled population and regimen: postmenopausal women with hormone receptor-positive, HER2-negative advanced breast cancer, no prior therapy for advanced disease, and treatment with letrozole in both groups. The results do not directly establish outcomes for populations or regimens not represented in this comparison.

Statistical evidence is not a recommendation to use or avoid a treatment. Treatment decisions require clinical context and a broader assessment than the registry’s reported endpoint estimates. The results describe the observed randomized comparison; they do not settle questions of individual benefit, patient preferences, or applicability to every clinical circumstance.

18. Why This Trial Matters Statistically

This trial illustrates why randomized comparisons and time-to-event methods are important in clinical research. Random assignment provides a structured comparison between ribociclib plus letrozole and placebo plus letrozole, while the progression-free survival analysis uses both the timing of progression or death and the information available before censoring. The hazard ratio offers a comparative summary, and the confidence interval makes its statistical uncertainty visible.

It also shows why different outcome summaries answer different questions. A median is an absolute time point on an estimated survival curve; a hazard ratio compares event hazards over follow-up. Response percentages describe the proportion with a specified response classification, while overall survival concerns death. These measures can support a coherent interpretation without being interchangeable.

The registry record further demonstrates the importance of distinguishing sponsor-reported analyses from simple recalculations using summary results. The sponsor’s stratified methods for binary outcomes are not the same as unadjusted comparisons of percentages. Recognizing that difference prevents a recalculation from being mistaken for the trial’s official inferential result.

Finally, multiplicity, incomplete reporting, safety denominators, and crossover all affect how confidently results can be interpreted. Statistical significance is only one part of evidence assessment. Precision, endpoint relevance, analysis methods, follow-up, and the population studied also matter. This is why a careful reading considers both the estimated effects and the limits of what the registry record documents.

19. 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 record does not report the median progression-free survival estimate or upper confidence bound for the ribociclib-plus-letrozole group, although it lists a lower confidence bound of 19.3 months. This limits direct comparison of the two groups’ median estimates. The primary comparative hazard ratio and its confidence interval are reported, but the missing median information remains a reporting limitation.

Further details needed to fully evaluate the primary model are not reported, including the Cox model’s stratification factors, diagnostics, and the full statistical analysis plan. The original sample-size justification and whether interim analyses were conducted are also not reported in the registry record. The planning illustrations based on observed effects cannot fill those gaps.

The record identifies crossover from placebo to ribociclib plus letrozole after unblinding and completion of the final overall survival analysis. It does not quantify how crossover affected the overall survival comparison. The safety summaries include different risk sets across randomized and crossover groups, and the reasons for the differing denominators are not reported in the registry record.

Although multiple secondary outcomes are listed, numerical results are not posted for all of them in the record. The multiplicity strategy and detailed missing-data methods for secondary outcomes are not reported. These omissions constrain assessment of the full pattern of outcomes and the robustness of secondary findings. The reported investigator assessments and the stated follow-up windows should also be kept in view when considering how widely the estimates apply.

20. Related Tutorials

21. Related Statistical Calculators

22. Sources

• ClinicalTrials.gov: Study of Efficacy and Safety of LEE011 in Postmenopausal Women With Advanced Breast Cancer — NCT01958021.
• Registry record last updated 2025-03-07; status last verified 2025-02.
• Results first posted 2017-05-12.
• 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.

23. Record Summary

NCT01958021 is a completed randomized, quadruple-masked, parallel-group phase 3 study sponsored by Novartis Pharmaceuticals. It enrolled 668 participants and compared ribociclib plus letrozole with placebo plus letrozole in postmenopausal women with hormone receptor-positive, HER2-negative advanced breast cancer who had received no prior therapy for advanced disease.

The primary outcome was investigator-assessed progression-free survival. The reported hazard ratio was 0.556, with a 95% confidence interval from 0.429 to 0.720 and p < 0.001. The placebo-plus-letrozole median was 14.7 months; the ribociclib-plus-letrozole median is not reported in the registry record. Overall survival and investigator-assessed response and clinical benefit were also posted as secondary outcomes.

The registry record does not report the original sample-size justification, a complete statistical analysis plan, the multiplicity strategy, or detailed missing-data methods. Crossover was permitted after unblinding, and its effect on the later survival comparison is not quantified in the record.