# Presentation: 680396

## Cure Rate Models and Adjuvant Trial Design for ECOGMelanoma Studies in the Past, Present, and Future

**Joseph Ibrahim, PhD**
**Harvard School of Public Health,**
**Dana-Farber Cancer Institute,**
**and ECOG Statistical Center**

## Outline

**Rationale for cure rate models in trial design**
**What is a cure rate model**
**How to design trials using cure rate models**
**Statistical designs for E1684, E1690, E1697, and E1694**
**Noninferiority designs using cure rate models – E1601**
**Future designs for trials involving HDI**

## Cure Rate Models

**The cure rate model is useful for designing studies with time-to-event endpoints, such as RFS and OS**
**It is most useful when a plateau is reached in the survival curve after sufficient follow-up**
**For adjuvant melanoma studies, this plateau occurs after approximately 5 yr based on the ECOG experience**

## Plateau for E1684Relapse-Free Survival

**	****	****	****Time interval and no. events/no. at risk**
**Group ****	****0-2 ****	****2-4 ****	****4-6 ****	****6-8 ****	****8-10 ****	****10-12 ****	****12-14 ****	****14-16**
**Observation ****	****89/140 ****	****12/51 ****	****3/39 ****	****0/35 ****	****1/32 ****	****1/29 ****	****0/15 ****	****0/3**
**Interferon ****	****73/146 ****	****14/68 ****	****3/53 ****	****1/50 ****	****2/48 ****	****2/44 ****	****0/31 ****	****0/10**

**0**

**0.2**

**0.4**

**0.6**

**0.8**

**1.0**

**0**

**2**

**4**

**6**

**8**

**10**

**12**

**14**

**16**

**Time, yr**

**IFN vs Observation:**
***P*****2 ****= .02, *****P*****1 ****= .01, HR = 1.38**

**Proportion alive and**
**relapse free**

**Observation**

**Interferon**

## Plateau for E1684Overall Survival

**0**

**0.2**

**0.4**

**0.6**

**0.8**

**1.0**

**0**

**2**

**4**

**6**

**8**

**10**

**12**

**14**

**16**

**Time, yr**

**Proportion alive**

**IFN vs Observation:**
***P*****2 ****= .18, *****P*****1 ****= .09, HR = 1.22**

**	****	****	****Time interval, no. events/no. at risk**
**Group ****	****0-2 ****	****2-4 ****	****4-6 ****	****6-8 ****	****8-10 ****	****10-12 ****	****12-14 ****	****14-16**
**Observation ****	****60/140 ****	****22/80 ****	****10/57 ****	****1/46 ****	****2/43 ****	****0/38 ****	****0/21 ****	****0/6**
**Interferon ****	****54/146 ****	****19/90 ****	****10/70 ****	****3/60 ****	****2/56 ****	****5/52 ****	****0/35 ****	****0/10**

**Observation**

**Interferon**

## Plateau for E1690Relapse-Free Survival

**0**

**0.2**

**0.4**

**0.6**

**0.8**

**1.0**

**0**

**1**

**2**

**3**

**4**

**5**

**6**

**7**

**10**

**Time, yr**

**Proportion alive and**
**relapse free**

**IFN vs Observation:**
***P*****2 ****= .09, HR = 1.24**

**	****	****Time interval, no. events/no. at risk**
**Group ****	****0-2 ****	****2-4 ****	****4-6 ****	****6-8 ****	****8-10 **
**Observation ****	****105/212 ****	****16/94 ****	****5/72 ****	****2/44 ****	****0/13 **
**Interferon ****	****98/215 ****	****15/108 ****	****5/85 ****	****2/53 ****	****0/20 **

**Observation**

**Interferon**

**8**

**9**

## Assumptions for Cure Rate Model (1)

**The cure rate model assumes that study population consists of 2 subpopulations: cured and not cured**
****** ****= proportion of patients who are cured**
**1 – ******** = proportion of patients who are not cured**

## Assumptions for Cure Rate Model (2)

**The proportion of patients not cured experience events according to an exponential distribution with rate ******
**The probability of surviving beyond time *****t***** is given by S(*****t*****) = ******** + (1 - ********) exponential (–*********t*****)**
**S(*****t*****) is the vertical axis in a Kaplan-Meier plot**

## Properties of Cure Rate Model

****** ****= .26 means that 26% of the population are “cured” and 74% are “not cured”**
**If ******** = 0, then we obtain an exponential survival model**
**The cure rate model fits the data better than an exponential model when a plateau occurs in the right tail of the survival curve**
**For E1684, a cure rate model fit the data better than an exponential model**
**The log-rank test yields high statistical power when cure rate model is used in design**

## Statistical Design for E1684

**E1684: 2-arm study of HDI vs Obs**
**Survival assumed to follow an exponential model (no prior experience to guide design)**
**4 yr of accrual, 3 yr of follow-up**
**Sample size of 285 yields 83% power**
**Detect 50% improvement in median RFS from 1.5 to 2.25 yr**

## Statistical Design for E1690

**E1690: 3-arm study, HDI vs LDI vs Obs**
**Cure rate model was used in the statistical design based on E1684 experience**
**4 comparisons of interest**
**HDI vs Obs with respect to RFS and OS**
**LDI vs Obs with respect to RFS and OS**
**A 1-sided significance level of .025 was used for each comparison**

## Design Assumptions for E1690 (1)

**Based on the Obs arm of E1684, the estimate of the long-term cure rate (********) is 26.4% for relapse-free survival and 32.5% for overall survival**
**The estimate of median survival among noncured patients (log(2)/********) is 0.576 yr for RFS and 1.312 yr for OS**
**The estimate of the cure rate for RFS on the HDI arm of E1684 was 37.9% (an improvement of 12% over no therapy)**

## Design Assumptions for E1690 (2)

**4.5 yr of accrual, 2.5 yr of follow-up **
**Sample size of 625 yields **
**81% power for RFS to detect**
**10% increase in cure rate **
**50% increase in median RFS among noncured group**
**82% power for OS to detect **
**10% increase in cure rate **
**50% increase in median OS among noncured group**

## Design Assumptions for E1690 (3)

**Relapse-free survival**
**Null hypothesis: **
**	******** ****= 26.4%, median RFS time = 6.9 mo**
**Alternative hypothesis: **
**	******** ****= 36.4%, median RFS time = 10.4 mo**
**Overall survival**
**Null hypothesis:**
**	******** ****= 32.5%, median OS time = 15.7 mo**
**Alternative hypothesis:**
**	******** ****= 42.5%, median OS time = 23.6 mo**

## Sequential Monitoring for E1690

**Sequential monitoring is used in all phase III ECOG studies**
**4 interim analyses were planned at times corresponding to equal amounts of statistical information accrued on RFS**

## Sequential Monitoring Plan for E1690

**	****	****                         ****Relapse-free survival**
**	****	****HDI vs Obs ****	****	****	****LDI vs Obs**
**	****Information****	****Number of ****	****Nominal ****	****Information ****	****Number of ****	****Nominal**
**	****time ****	****recurrences ****	****significance ****	****time ****	****recurrences ****	****significance**
**	****0.258****	****  65****	****< 10****-5****	****  .310****	**** 78****	****      .0000145**
**	****0.517****	****130****	****  .00101****	****  .517****	****130****	****  .00101**
**	****0.756****	****190****	****  .00772****	****  .756****	****190****	****  .00772**
**	****1.000****	****252****	****.0223****	****1.000****	****252****	****.0223**
**	****	****                                ****Overall survival**
**	****	****HDI vs Obs ****	****	****	****LDI vs Obs**
**Information****	****Number of ****	****Nominal ****	****Information ****	****Number of ****	****Nominal**
**	****time ****	****recurrences ****	****significance ****	****time ****	****recurrences ****	****significance**** **
**	****.141****	****  28****	****< 10****-6****	****  .151****	****  30****	**** < 10****-6**
**	****.398****	****  79****	****    .000146****	****  .398****	****  79****	****   .000146**
**	****.623****	****124****	****  .00308****	****  .623****	****124****	**** .00308**
**	****1.000****	****199****	****.0239****	****1.000****	****199****	****.0239 ****	**** **

## Statistical Design for E1694

**E1694: 2-arm study of GMK vs HDI**
**First melanoma trial design using HDI as control arm**
**Designed as a superiority trial**
**Cure rate model used in the statistical design**

## E1694 Design Assumptions (1)

**1-sided significance level of .025**
**Cure rate and median time to event among noncured group for HDI were estimated from E1690 data**

## E1694 Design Assumptions (2)

**3.3 yr of accrual, 2 yr of follow-up**
**Total sample size of 851 patients yields**
**86% power for the RFS endpoint**
**80% power for the OS endpoint to detect**
**10% increase in cure rate**
**15% relative increase in median time to event among noncured group**

## E1694 Design Assumptions

**	****	****Median time ****	****Cure rate, % ****	**** to event, yr**

**	****HDI ****	****GMK ****	****HDI ****	****GMK**
**Relapse-free survival ****	****35.9 ****	****45.9 ****	****  .747 ****	****  .859**
**Overall survival ****	****38.4 ****	****48.4 ****	****1.658 ****	****1.907**

## E1694 Sequential Monitoring Plan for RFS

**	****	****	****	****	**
**	****	****	****	****Rejection ****	****Nominal**
**Real ****	****Information ****	****Relapses ****	****Upper ****	****probability ****	****significance**
**time, yr ****	****time ****	****under H****1**** ****	****bound ****	****under H****0**** ****	****level**
**2.01 ****	****0.35 ****	**** 149 ****	****3.6128 ****	****  <0.0001 ****	**** <.0001**
**2.82****	****0.61****	****260****	****2.6506****	****0.004****	**** .004**
**3.87****	****0.86 ****	****366 ****	****2.1894 ****	**** 0.012 ****	**** .014**
**5.30 ****	****1.00 ****	****426 ****	****2.0536 ****	****  0.009 ****	**** .020**
**	****	****	****	**** ****0.025**

**H****0**** = Null hypotheses.**
**H****1**** = Alternative hypothesis.**

## E1694 Sequential Monitoring Plan for OS

**	****	****	****	****	**
**	****	****	****	****Rejection ****	****Nominal**
**Real ****	****Information ****	****Deaths ****	****Upper ****	****probability ****	****significance**
**time, yr****	****time ****	****under H****1**** ****	****bound ****	****under H****0**** ****	****level**
**2.01 ****	****0.25 ****	****   81 ****	****4.3326 ****	****< 0.0001 ****	****< .0001**
**2.82****	****0.47****	****151****	****3.0738****	****0.001****	****  .001**
**3.87****	****0.74 ****	****238 ****	****2.3757 ****	**** 0.008 ****	****    .0109**
**5.30 ****	****1.00 ****	****322 ****	****2.0132 ****	**** 0.016 ****	****  .022**
**	****	****	****	****0.025**

**H****0**** = Null hypotheses.**
**H****1**** = Alternative hypothesis.**

## Statistical Design for E1697

**Patient population (ECOG/US): *****T*****3*****N*****0****(International NCI-Canada, Australia): ****T3N0, T4N0, Tany, N1a**
**First ECOG phase III trial for this patient population**
**2-arm trial of 1-mo HDI vs Obs**
**Designed as a superiority trial**

## E1697 Statistical Design Assumptions (1)

**Primary endpoints are RFS and OS**
**Cure rate model is used in the statistical design**
**1-sided significance level of 0.025**

## E1697 Statistical Design Assumptions (2)

**Sample size of 1,420 patients yields**
**3 yr of accrual, 3 yr of follow-up**
**88% power for both RFS and OS to detect**
**7.5% increase in cure rate**
**15% relative increase in median time to event among noncured group**

## E1697 Statistical Design Assumptions (3)

**	****	****Median time ****	****Cure rate, % ****	**** to event, yr**

**	****Obs ****	****HDI ****	****Obs ****	****HDI**
**Relapse-free survival ****	****65 ****	****72.5 ****	****1.5 ****	****1.725**
**Overall survival ****	****75 ****	****82.5 ****	****2.5 ****	****2.875**

## E1697 Sequential Monitoring Plan for RFS

**	****	****                   ****	****	**
**	****	****	****Upper bound ****	****Nominal**
**Real ****	****Information ****	****Relapses ****	****for early****	****significance**
**time, yr ****	****time ****	****under H****1**** ****	****stopping ****	****level**
**1.95****	****0.25****	****  85****	****4.3326****	**** <.0001**
**2.92****	****0.50****	****169****	****2.9680****	****  .0030**
**3.99****	****0.75****	****254****	****2.3617****	****  .0182**
**5.00****	****0.90****	****305****	****2.1681****	****  .0301**
**6.00****	****1.00****	****339****	****2.0774****	****  .0377**

**H****1**** = Alternative hypothesis.**

## E1697 Sequential Monitoring Plan for OS

**	****	****	****	**
**	****	****	****Upper bound ****	****Nominal**
**Real ****	****Information****	****Deaths ****	****for early****	****significance**
**time, yr ****	****time ****	****under H****1**** ****	****stopping ****	****level**
**2.15 ****	****0.25 ****	****  46 ****	****4.3326 ****	****< .0001**
**3.20 ****	****0.50 ****	****  93 ****	****2.9680 ****	****  .0030**
**4.33 ****	****0.75 ****	****139 ****	****2.3617 ****	****  .0182**
**5.25 ****	****0.90 ****	****167 ****	****2.1681 ****	****  .0301**
**6.00 ****	****1.00 ****	****186 ****	****2.0774 ****	****  .0377**

**H****1**** = Alternative hypothesis.**

## Conditional Power Considerations for E1697 (1)

**Conditional power **
**Probability of observing a significant result at full information, given the current data and the specified alternative under the statistical design**
**Conditional power allows us to stop the study early if experimental therapy not better than control**
**Timing of conditional power calculation is important**

## Conditional Power Considerations for E1697 (2)

**In most ECOG studies, we carry out conditional power calculations**
**Conditional power is very important in trials involving observation arms or trials investigating A vs A + B**
**Conditional power calculations are to be carried out at each interim analysis of E1697**

## Noninferiority Designs

**These designs will play a prominent role in future trials involving HDI**
**Especially relevant for future trials involving HDI and vaccine**
**Within the context of the cure rate model, these designs can be constructed by taking small differences in cure rates**
**Sample size increases dramatically with cure rate differences of ******** 5%**
**Use a higher significance level than the conventional 0.05 level**

## Statistical Design for E1601 (1)

**Patient population: *****T*****4*****N*****0, TANY, N1a, and *****N*****2a****§**
**2-arm, noninferiority trial of 1-mo HDI vs ****1-yr HDI**
**Primary endpoint is RFS **

**§Only one positive node.**

## Statistical Design for E1601 (2)

**Will declare 1-mo HDI arm noninferior if**
**There is < 25% absolute difference in median RFS for those not cured**
**And < 3% absolute difference in the cure rate between the 2 arms**
**With a noninferiority design, a high power ****(at least 90%) is desirable**
**E1601 designed with 95% power**
**Power based on 1-sided, log-rank test with significance level of 0.075**

## Statistical Design for E1601 (3)

**Assume 4 yr of accrual and 6 yr of follow-up**
**Sample size of 2,780 yields**
**95% power for RFS to detect**
**3% increase in cure rate**
**25% increase in median time to event in noncured group**

## Statistical Design for E1601 (4)

**	****	****Median time ****	****Cure rate, % ****	**** to event, yr**

**	****1-yr HDI ****	****1-mo HDI ****	****1-yr HDI ****	****1-mo HDI**
**Relapse-free survival ****	****63 ****	****60 ****	****0.90 ****	****0.65**

## Sequential Monitoring Plan for E1601 (1)

**	****	****                   ****	****	**
**	****	****	****	****Nominal**
**Real ****	****Information ****	****Relapses ****	****Upper ****	****significance**
**time, yr ****	****time ****	****under H****1**** ****	****bound****§**** ****	****level**
**1.95 ****	****.25 ****	****254 ****	****3.3747 ****	****  .0004**
**3.09 ****	****.50 ****	****507 ****	****2.2710 ****	****.012**
**4.15 ****	****.75 ****	****761 ****	****1.7990 ****	****.036**
**7.23 ****	****.90 ****	****913 ****	****1.6647 ****	****.048**
**10.0 ****	****1.00 ****	****1016 ****	****1.6041 ****	****.054**

**§Upper bound for rejecting noninferiority in favor of I year of HDI.**

## Sequential Monitoring Plan for E1601 (2)

**Conditional power will be computed to determine the noninferiority of 1 mo of HDI relative to 1 yr of HDI**
**Conditional power based on RFS endpoint**
**Conditional power computed at the 75% and 90% information times to allow for sufficient follow-up**
**Accrual goal is attained at 75% statistical information**

## Sample Sizes Under Several Design Scenarios to Achieve 95% Power

**	****Cure rate ****	****Difference in median ****	****Sample ****difference, % ****	**** time to event, % ****	****size ****	**
**	****  ****3 ****	****25 ****	****2640**
**	****  ****3 ****	****20 ****	****3300**
**	****  ****3****	****15 ****	****4400**
**	****  ****5****	****25 ****	****1520 ****	**** 5****	****20 ****	****1820**
**	****  ****5****	****15 ****	****2260**
**	****  ****7****	****25 ****	****1040**
**	****  ****7****	****20 ****	****1220**
**	****  ****7****	****15 ****	****1400**
**	****10****	****25 ****	****   600 **
**	****10****	****20 ****	****  680**
**	****10****	****15 ****	****   760 **

## Future Trial Designs

**Noninferiority designs of the type used for E1601 will be used for future phase III trials comparing investigational therapies to HDI**
**The definition of noninferiority is critical**
**Need small cure rate differences**

## Future Trial Designs

**Conditional power plays a key role in ****noninferiority designs**
**The next ECOG adjuvant phase III trial will ****be HDI vs**
**Best vaccine from E1696**
**Best vaccine from E2601**
**Other regimens**
**Next trial likely to be designed as noninferiority trial**

## Bayesian Design and Monitoring (1)

**Design and monitor trials using a cure rate model within a Bayesian framework**
**Bayesian approaches offer several advantages in design and monitoring**
**Incorporate historical data into the sample size calculation**
**Continuous monitoring**
**No significance level inflation**

## Bayesian Design and Monitoring (2)

**Abundance of historical data on HDI from E1684, E1690, and E1694**
**Construct appropriate prior distributions for the HDI effect using these data**
**Prior distributions can be incorporated in the sample size calculations and will often result in a smaller sample size than a traditional design**

## Bayesian Design and Monitoring (3)

**Bayesian interim monitoring rules can be easily developed**
**The Bayesian paradigm allows us to assess the posterior probability that a treatment works, given the current data**
**Posterior probabilities can be presented at every DMC meeting**
**No inflation of significance levels**