# Presentation: 701184

## Efficacy and Safety of High-Dose IFN-2b in Patients With High-Risk Resected Cutaneous Melanoma

**John M. Kirkwood, MD**
**Professor and Vice Chair**
**Department of Medicine**
**University of Pittsburgh Cancer Institute**
**Chairman, ECOG Melanoma Committee**

**C**

**Notes:**
The Eastern Cooperative Oncology Group, and the Intergroup consisting of the Southwest and Cancer/Leukemia Group B Cooperative Groups have tested the potential benefit of high-dose IFN alfa-2b (HDI) in a series of 4 multicenter prospective randomized trials.  ECOG trial 1684 has shown a significant overall and relapse-free survival benefit, while the E1690 Intergroup Study showed an impact upon relapse-free, but not overall survival. E1694 has shown an overall  and relapse free survival benefit of IFN compared to the ganglioside GM2 vaccine GMK, and E2696 showed additive benefit of HDI and the GMK vaccine without loss of the immunologic benefit of the GMK.   

## Agenda

**John M. Kirkwood, MD****University of Pittsburgh Medical Center**
**	****Efficacy and Safety of Adjuvant High-Dose Interferon ****	****	****for Melanoma from ECOG and Intergroup Trials**
**Joseph G. Ibrahim, PhD****Harvard School of Public Health**
**	****Cure Rate Model Trial Design**

**C**

## Stage IIB and III Melanoma are at High Risk of Recurrence

**Adapted with permission Ketcham AS and Balch CM. In: *****Cutaneous Melanoma:  Clinical Management and Treatment Results Worldwide*****. 1985:55-62.**

**% Patients surviving**

**Survival, yr**

**Stage I**

**Stage II**

**Stage III**

**Stage IV**

**C**

## High-Risk Subgroups According to AJCC (2002) Stage Groupings (N = 17,600)

**	****TNM ****	****	****5-year**
**Stage****	****classification****	****                      Definition****	****survival rate, % ± SE**** **
**IIB****	****T3b N0 M0****	****2.01 to 4 mm with ulceration****	**** 63.0 ± 1.5**
**	****T4a N0 M0****	****> 4 mm; no ulceration****	**** 67.4 ± 2.4**
**IIC****	****T4b N0 M0****	****> 4 mm with ulceration****	**** 45.1 ± 1.9**
**IIIA****	****T1-4a N1a M0****	****Single micro node; no ulceration****	**** 69.5 ± 3.7**
**	****T1-4a N2a M0****	****2 to 3 micro nodes; no ulceration****	**** 63.3 ± 5.6**
**IIIB****	****T1-4a N1b-2c M0****	****1 to 3 macro nodes or in-transit mets; no ulcer****	****40 - 60****	****T1-4b N1a-2a M0****	****1 to 3 micro nodes; ulceration****	****40 - 55**
**IIIC****	****T1-4b N1b-2b M0****	****1 to 3 macro nodes; ulceration****	****20 - 35**
**	****AnyT N3 M0****	******** 4 nodes, matted, or nodes + in-transit mets****	**** 26.7 ± 2.5**

**Adapted with permission from Balch CM, et al. Final version of the American Joint Committee ****on Cancer staging system for cutaneous melanoma. *****J Clin Oncol.***** 2001;19:3635-3648.**

**C**

## Prognostic Significance of Sentinel Lymph Node Status

**1.0**
**0.8**
**0.6**
**0.4**
**0.2**
**0.0**

**	****0****	****12****	****24****	****36****	****48****	****60****	****72****	****84****	****90**
**Time, mo**

**+**

**+**

**+**

**+**

**+**

**+**

**+**

**Proportion disease-free**

***P***** < .001**

**Node-negative (n = 495)**

**Node-positive (n = 85)**

**Data from Gershenwald JE, et al. *****J Clin Oncol*****. 1999;17:976-983.**

**C**

## ECOG and Intergroup Adjuvant Trials in Stage IIB/III Melanoma

**Study****	****N****	****Comparison****	****Enroll dates**
**E1684****	****287****	****HDI vs Obs****	****1984 to 1990**
**E1690****	****642****	****HDI vs Obs****	****1991 to 1995**
**	****	****	****LDI vs Obs**
**E1694****	****880****	****HDI vs GMK****	****1996 to 1999**

**C**

## Inclusion Criteria

**Stage IIB (T4 Breslow depth > 4 mm) **
**Pathologically node negative by **
**Elective lymph node dissection* or**
**Selective sentinel lymph node dissection****	**
**Clinically node negative**
**Stage III (node positive) resected, without extracapsular extension, satellites, or clinically apparent in-transit metastases**
**Regional nodal recurrence**

***All patients in E1684 required to have complete lymph node dissection.**

**C**

## Comparative Demographics

**Disease status**
**	****cN0****	****31****	****(11)****	****163****	****(25)****	****202****	****(23)**
**	****pN1****	****34****	****(12)****	****68****	****(11)****	**
**	****cN1****	****41****	****(15)****	****83****	****(13)**
**	****Recurrent N (+)****	****174****	****(62)****	****326****	****(51)****	****314****	****(36)**
**Ulceration****	****46****	****(16)****	****231****	****(36)****	****288****	****(33)**
**Age > 50 yr****	****125****	****(45)****	****270****	****(42)****	****455****	****(52)**

**	****	****Patients, n (%)**
**	****E1684****	****E1690****	****E1694****Characteristic ****	****n = 280****	****n = 642****	****n = 774**

**258 (41)**

**C**

## E1684: Study Design

**Kirkwood JM, et al. *****J Clin Oncol.***** 1996;14:7-17.**

**Randomization****N = 287****(within 56 days)**

**Observation**

**Maintenance**

**Induction**

**52 wk**

**48 wk**

**4 wk**

**IFN-********2b**

**Induction:****	****20 MIU/m****2**** IV 5× weekly × 4 wk**
**Maintenance:****	****10 MIU/m****2**** SC TIW × 48 wk**
**Design: ****	****Exponential model**
**Stratification: ****	****AJCC stage groupings**

**S**
**U**
**R****G**
**E**
**R**
**Y**

**(with ELND)**

**C**

## E1684: Summary of ResultsIntent-to-Treat Analysis

**Impact of HDI versus Observation at 6.9 yr median follow-up**

**Kirkwood JM, et al. *****J Clin Oncol.***** 1996;14:7-17.**

**Median RFS significantly improved (*****P*****1**** = .0023) **
**Median OS significantly improved (*****P*****1**** = .0237)**
**Estimated 5-yr RFS:****	****37% versus 26%**
**Estimated 5-yr OS:****	****	****46% versus 37%**

**C**

## E1684: Relapse-Free Survival (Eligible Cases) at 6.9 yr Median Follow-up

**	****No.****	****No.****	****Median****	****	****5-yr****	****patients****	****relapsed****	****yr****	**** *****P***** value ****	****RFS**
**IFN-********2b****	****143****	****90****	****1.72****	****	****37%**
**Observation****	****137****	****103****	****0.98****	****	****26%**

**0**

**1**

**2**

**3**

**4**

**5**

**6**

**7**

**8**

**1.0**

**0.9**

**0.8**

**0.7**

**0.6**

**0.5**

**0.4**

**0.3**

**0.2**

**0.1**

**Time, yr**

**Probability of relapse-free survival**

**Kirkwood JM, et al. *****J Clin Oncol.***** 1996;14:7-17.**

**< .01**

**Treatment groups (n = 280)**

**IFN-********2b         Observation**

**C - **

**C**

## E1684: Overall Survival (Eligible Cases) at 6.9 yr Median Follow-up

**a**

**Kirkwood JM, et al. *****J Clin Oncol.***** 1996;14:7-17.**

**Time, yr**

**1.0**

**0.9**

**0.8**

**0.7**

**0.6**

**0.5**

**0.4**

**0.3**

**0.2**

**0.1**

**0**

**1**

**2**

**3**

**4**

**5**

**6**

**7**

**8**

**Probability of survival**

**	****No.****	****No.****	****Median****	****	****5-yr****	****patients****	****dead****	****yr****	**** *****P***** value ****	****survival**
**IFN-********2b****	****143****	****81****	****3.82****	****	****46%**
**Observation****	****137****	****90****	****2.78****	****	****37%**

**< .047**

**Treatment groups (n = 280)**

**IFN-********2b         Observation**

**C - **

**C**

## E1684: Conclusions

**Both RFS and OS significantly prolonged ****with HDI**
**After surgery alone, 50% of patients in observation arm had recurrence within 1 year**
**High-dose IFN-********2b approved as adjuvant therapy for high-risk melanoma in 1995**

**C**

## Impact of Adjuvant IFN Therapy for Melanoma Relative to Other Approved Adjuvant Therapies

**	****	****	****5-yr absolute****	****	****	****improvement****	****	****	****vs Obs**

**Cancer****	****Trial****	****Regimen****	****RFS, %****	****OS, %**
**Melanoma****	****E1684****	****HDI × 1 yr ****	****11****	****9**
**Colorectal****	****NSABP (93)****	****5-FU/lcv × 48 wk ****	****9****	****7**
**Rectal****	****NCCTG (91)****	****RT + 5-FU × 5 mo****	****21****	****11**
**Breast****	****Bonadonna (95)****	****CMF × 1 yr****	****9****	****9**

## Intergroup E1690 Phase III Trial of High or Low Dose IFN-2b Versus Observation

**Goal: Determine if low-dose IFN-********2b for 2 yr is effective as high-dose IFN-********2b for 1 yr**
**Design: Cure rate model**
**Stratification: AJCC stage groupings and number of positive nodes**

**High-dose IFN-********2b × 1 yr**

**Low-dose IFN-********2b × 2 yr**

**Observation**

**Randomization**
**N = 642**
**(within 70 days)**

**Kirkwood JM, et al. *****J Clin Oncol*****. 2000;18:2444-2458.**

**S**
**U**
**R****G**
**E**
**R**
**Y**

**C**

**Notes:**
The intergroup trial E1690/S9111/C9190 tested  High dose IFN for 1 year vs Low dose IFN as also tested by the WHO, in a 2 year regimen that corroborated an impact upon RFS, but not survival.

## E1690: Summary of Results Intent-to-Treat Analysis

**	****	****	****Hazard ****	****	****Log-rank**
**Intervention****	****ratio****	****95% CI****	*****P******2***** value**
**RFS**
**	****HDI****	****1.28****	****  (1.0 - 1.65)****	****.05**
**	****LDI****	****1.19****	****(0.93 - 1.53)****	****.17**
**OS**
**	****HDI****	****1.00****	****(0.75 - 1.33)****	****.99**
**	****LDI****	****1.04****	****(0.78 - 1.38)****	****.81**

**Kirkwood JM, et al. *****J Clin Oncol.***** 2000;18:2444-2458.**

**Impact of treatment versus observation at 4.3 yr median follow-up**

**C**

## E1690: Relapse-Free Survival (Eligible Cases)

**1.00**

**0.85**

**0.70**

**0.55**

**0.40**

**0.25**

**0**

**1**

**2**

**3**

**4**

**5**

**6**

**7**

**Probability**

**Time, yr**

**Time interval and no. events/no. at risk**

**Group**

**0-1**
**70/203****69/203****78/202**

**1-2**
**24/127****22/132****24/112**

**2-3**
**9/100****12/110****10/87**

**3-4**
**6/77****5/86****6/71**

**4-5**
**0/53****3/56****1/45**

**5-6**
**0/28****2/21****2/22**

**6-7**
**0/9****0/5****0/3**

**HDI****LDI****Obs**

**E1690: Relapse-Free Survival (Eligible Cases)**

**High-dose IFN**
**Low-dose IFN**
**Observation**

**Treatment groups  (n = 608)**

**C**

**C - **

## E1690: Overall Survival (Eligible Cases)

**Group**

**HDI****LDI****Obs**

**0-1**
**21/203****15/203****31/202**

**1-2**
**37/182****32/188****31/170**

**2-3**
**20/143 26/155****12/137**

**3-4**
**10/109****11/118****11/115**

**4-5**
**3/71****4/77****1/75**

**5-6**
**3/36****0/30****1/37**

**6-7**
**0/11****0/9****0/8**

**7-8**
**0/1****0/1****0/0**

**Probability**

**Time, yr**

**1.00**

**0.85**

**0.70**

**0.55**

**0.40**

**0.25**

**0**

**1**

**2**

**3**

**4**

**5**

**6**

**7**

**8**

**E1690: Overall Survival (Eligible Cases)**

**High-dose IFN**
**Low-dose IFN**
**Observation**

**Treatment groups  (n = 608)**

**C**

**Time interval and no. events/no. at risk**

**C - **

## Comparison of E1684 and E1690

**1**

**2**

**3**

**4**

**5**

**6**

**Time since randomization, yr**

**E1690**

**E1684**

**Obs**

**HDI**

**Obs**

**HDI**

**OS**

**RFS**

**0**

**Comparison of E1684 and E1690**

**C**

## Differing Outcome for Observation Arms of E1684 and E1690 (Overall Survival)

**Time interval, no. events/no. at risk**

**Group**

**0-2**

**2-4**

**4-6**

**6-8**

**8-10**

**10-12**

**12-14**

**14-16**

**E1684**

**60/140**

**22/80**

**10/57**

**1/46**

**2/43**

**0/38**

**0/21**

**0/6**

**E1690**

**66/212**

**26/145**

**6/116**

**5/79**

**0/22**

**0/0**

**0/0**

**0/0**

**Time, yr**

**0.0**

**0.2**

**0.4**

**0.6**

**0.8**

**1.0**

**0**

** ****2**

** ****4**

** ****6**

** ****8**

**10**

**12**

**14**

**16**

**Proportion alive**

**E1684**

**E1690**

## Comparison of E1690 and E1684: RFS for Observation Patients with 1 Node+ 

- 2

**C - **

## E1690: Conclusions 

**Consistent RFS benefit of HDI observed in E1684 and E1690**
**No significant benefit associated with LDI**
**No survival benefit associated with HDI or LDI**
**Post-trial crossover use of IFN-******** for regional recurrences may have confounded OS analysis**

**C**

## Intergroup E1694 Phase III Study of Ganglioside GM2 Vaccine (GMK) Versus High-Dose IFN-2b

**Goal: Determine if GMK is superior to HDI **
**Design: Cure rate model**
**Stratification: Number of involved nodes**

**GMK SC Days 1, 8, 15, 22, and **
**Weeks 12, 24, 36 48, 60, 72, 84, 96,**
** **
***	******versus***** **
**HDI 20 MIU/m****2**** IV 5× weekly × 4 wk**
**10 MIU/m****2**** SC TIW × 48 wk**

**Randomization**
**N = 880**
**(within 70 days)**** **

**Kirkwood JM, et al. *****J Clin Oncol.***** 2001;19:2370-2380.**

**S**
**U**
**R****G**
**E**
**R**
**Y**

**C**

## E1694: Summary of ResultsIntent-to-Treat and Eligible Populations

**Treatment benefit compared with GMK vaccine at ****16 months median follow-up****§**
**Clinical endpoint/****	****Hazard ****	****   Log-rank****	**** Cox****||**
**patient population****	****ratio ****	****   *****P******1***** value****	**** *****P******2***** value****	**
**RFS****	****	****	****	**
**  ****Eligible****	****	****1.47****	****  .0015****	****  .0027****	**
**  ****ITT****	****	****1.49****	****    .00045****	****  .0007****	**
**OS****	****	****	****	**
**  ****Eligible****	****	****1.52****	****.009****	****  .0147****	**
**  ****ITT****	****	****1.38****	****.023****	****.035**

**§As unblinded by decision of data safety monitoring board.**
**||Cox regression analysis adjusting for gender, performance status, nodal category,     ****  and age.**

**C**

## E1694: Relapse-Free Survival (Eligible Cases)

**19/178**

**3/84**

**2/25**

**0/1**

**110/389**

**32/188**

**7/90**

**2/23**

**0/1**

**E1694: Relapse-Free Survival (Eligible Cases)**

**Group**

**IFN-********2b**

**GMK**

**0-10**

**10-20**

**20-30**

**30-40**

**40-50**

**Months and no. events/no. at risk**

**1.0**

**0.8**

**0.6**

**0.4**

**0.2**

**0.0**

**0**

**5**

**10**

**15**

**20**

**25**

**30**

**35**

**40**

**Probability**

**45**

**Time interval, mo**

**IFN-********2b**

**GMK**

**Treatment groups (n = 774)**

**C**

## E1694: Overall Survival (Eligible Cases)

**1.0**

**0.8**

**0.6**

**0.4**

**0.2**

**0.0**

**0**

**5**

**10**

**15**

**20**

**25**

**30**

**35**

**40**

**45**

**Probability**

**Time interval, mo**

**Group**

**IFN-********2b**

**GMK**

**0-10**

**10-20**

**20-30**

**30-40**

**40-50**

**11/385**

**29/258**

**11/125**

**1/38**

**0/1**

**23/389**

**42/264**

**14/132**

**2/38**

**0/2**

**E1694: Overall Survival (Eligible Cases)**

**IFN-********2b**

**GMK**

**Treatment groups (n = 774)**

**C**

**Months and no. events/no. at risk**

## E1694: Subgroup Analysis of RFS by Nodal Involvement (Eligible Cases)

**HR = 2.07**
***P*****2**** = .015**

**1.0**

**0.8**

**0.6**

**0.4**

**0.2**

**0.0**

**0**

**5**

**10**

**15**

**20**

**25**

**30**

**35**

**40**

**45**

**Time, mo**

**Probability**

**E1694: Subgroup Analysis of RFS by Nodal Involvement (Eligible Cases)**

**1 Node**

**1.0**

**0.8**

**0.6**

**0.4**

**0.2**

**0.0**

**0**

**5**

**10**

**15**

**20**

**25**

**30**

**35**

**40**

**45**

**Time, mo**

**Probability**

**2-3 Nodes**

**1.0**

**0.8**

**0.6**

**0.4**

**0.2**

**0.0**

**0**

**5**

**10**

**15**

**20**

**25**

**30**

**35**

**40**

**Time, mo**

**Probability**

**4+ Nodes**

**1.0**

**0.8**

**0.6**

**0.4**

**0.2**

**0.0**

**0**

**5**

**10**

**15**

**20**

**25**

**30**

**35**

**40**

**Time, mo**

**Probability**

**HR = 1.44**
***P*****2**** =.091**

**HR = 1.16**
***P*****2**** = .563**

**HR = 1.47**
***P*****2**** =.18**

**C**

## E1694: Summary Conclusions

**Largest trial of HDI to date**
**Highly significant RFS and OS benefits for HDI versus GMK vaccine**
**Confirms RFS and OS benefits of HDI observed in E1684**
**No evidence for adverse impact of GMK on RFS or OS (******** observation in E1690)**
**Benefit of HDI consistent across stratification subgroups based on number of positive nodes**

**C**

## Relapse-Free Survival Benefit of HDIHazard Ratio by Number of Nodes Positive

**	****Number of****	****E1684 ****	****E1690 ****	****E1694 ****	****	****nodes positive****	****(ITT)****	****(eligible)****	****(eligible)**
**	****0****	****0.53****	****1.46****	**** 2.07****¶**
**	****1****	****  2.29****§****	****1.00****	****1.44**
**	****2 – 3****	****1.24****	**** 1.92****||****	****1.16**
**	******** ****4****	****1.18****	****1.15****	****1.47**

***Hazard ratios for E1684 are based on intent-to-treat, whereas the hazard ratios****given for E1690 and E1694 are based on eligible cases.**
**§*****P***** = .0015; ||*****P***** = .02; ¶*****P***** = .01.**

## Efficacy Summary of Adjuvant Trials in High-Risk Melanoma

**Highest level of evidence based on analysis of primary endpoints of randomized trials **
**High-dose IFN-********2b is the only regimen that has demonstrated consistent RFS and OS benefits compared with observation or GMK**
**Benefit of high-dose IFN-********2b consistent across nodal subsets**

**C**

## Common Grade 3/4 Adverse Events in Patients Treated With High-Dose IFN-2b

**§Based on data in the prescribing information from 143 patients treated with ****high-dose IFN-********2b in Trial E1684.**
**||Category includes neurologic manifestations characterized as depression, ****neuropsychiatric, or neuropsychological toxicity. **

**	****	****      ****Percent of patients**
**	****All grades****§****	****	****Grade 3/4**
**Adverse event ****	****(N = 143)****	****E1684****	****E1690****	****E1694**
**Fatigue****	****96****	****23****	****24****	****21**
**Fever****	****81****	****18****	****–****	****–**
**Myalgia****	****75****	****17****	****17****	****  4**
**Nausea****	****66****	****–****	****9****	****  5**
**Vomiting****	****66****	****–****	****5****	****  5**
**Anorexia****	****69****	****–****	****–****	****–**
**Myelosuppression****	****92****	****26****	****58****	****60**
**Liver (increased SGOT)****	****63****	****14****	****29****	****27**
**Depression****||**** ****	****40****	****  2****	****  9****	****10**

**C**

## Safety Summary for High-Dose IFN-2b

**All patients receiving HDI therapy experienced ****mild-to-moderate side effects**
**Some patients experienced more severe side effects, including fatigue and flu-like symptoms, neutropenia, abnormal liver function, and neuropsych/depression**
**Discontinuations due to adverse events**
**24% of patients in E1684 **
**13% of patients in E1690**
**10% of patients in E1694 **
**With appropriate supportive measures and dose modifications, the majority of patients tolerate a full course of therapy (ie, 52 wk or until progression)**

**C**

## A Updated and Pooled Analysis of ECOG and Intergroup Trials of High-Dose IFN-2b

**JM Kirkwood, J Manola, J Ibrahim, ****V Sondak, and M Ernstoff for **
**ECOG, SWOG and CALGB**

**C**

**Notes:**
The Eastern Cooperative Oncology Group, and the Intergroup consisting of the Southwest and Cancer/Leukemia Group B Cooperative Groups have tested the potential benefit of high-dose IFN alfa-2b (HDI) in a series of 4 multicenter prospective randomized trials.  ECOG trial 1684 has shown a significant overall and relapse-free survival benefit, while the E1690 Intergroup Study showed an impact upon relapse-free, but not overall survival. E1694 has shown an overall  and relapse free survival benefit of IFN compared to the ganglioside GM2 vaccine GMK, and E2696 showed additive benefit of HDI and the GMK vaccine without loss of the immunologic benefit of the GMK.   

## Studies Included in Updated and Pooled Analysis

**Studies Included in Updated and Pooled Analysis**

**Phase III randomized ECOG/Intergroup trials**
**	****E1684:****	****High-dose IFN versus Obs**
**	****E1690:****	****High-dose IFN versus Obs ****	****Low-dose IFN versus Obs **
**	****E1694:****	****HDI versus GM2 vaccine (GMK)**
**Phase II randomized ECOG trial**
**	****E2696:****	****GMK + HDI versus GMK alone**

**C**

**Notes:**
The trials for which endpoints were updated and factors of prognostic significance analyzed included the pivotal trial E1684, the Intergroup trials  E1690 and E1694  and the randomized ECOG phase II trial E2696.

## Objectives

**Update the results of ECOG and Intergroup ****phase III trials E1684, E1690, and E1694**
**Identify factors of prognostic importance in relation to RFS and OS**
**Analyze treatment effects of HDI versus Obs, adjusting for important prognostic factors**

**C**

**Notes:**
We decided to examine the effect of HDI upon OS and RFS in relation to observation or vaccines in these 4 trials for which the primary data were accessible, and possible to update for follow-up to April 2001.

The study was also designed to evaluate factors of prognostic significance in relation to the endpoints of overall and relapse-free survival.

## Methods

**Survival and disease status updated to April 2001 **
**RFS and OS by treatment analyzed using 2-sided univariate and log-rank statistics (ITT population)**
**Prognostic covariates treated as dichotomous (mostly) or continuous variables**
**Log-rank statistics used for dichotomous variables**
**Cox proportional hazards models developed**
**Models selected via forward selection algorithm**

**C**

**Notes:**
The data were collected from these 4 ECOG coordinated studies, including 2 intergroup studies. The factors judged to be important were available for >90% of the patients, and these were analyzed either as dichotomous or continuous variables.

## Patient Outcome (N = 1,912)

**136**

**  ****9**

**127**

**Died**

**222**

**20**

**202**

**Failed/died**

**474**

**35**

**439**

**Patients**

**GMK **

**303**

**102**

**108**

**  ****93**

**Died**

**372**

**157**

**120**

**  ****95**

**Failed/died**

**799**

**438**

**215**

**146**

**Patients**

**IFN**

**198**

**103**

**  ****95**

**Died**

**234**

**128**

**106**

**Failed/died **

**352**

**212**

**140**

**Patients**

**OBS**

**3.5**

**2.8**

**2.1**

**6.6**

**12.6**

**Median follow-up, yr**

**Total**

**E2696**

**E1694**

**E1690**

**E1684**

**C**

**Notes:**
In overview, the updated trials E1684 and 1690 now have achieved 6.6 to 12.6 years median followup, and an overall followup of 3.5 years exists for the patients studied in these 4 trials.  A total of 352 patients have been observed at median intervals of follow-up of more than 7 years, and 799 have received HDI at a median follow-up of 2.8 years, while 474 have received GMK vaccine, where the follow-up is still most limited at 2.1 years

## Patient Characteristics

**Median age = 49 yr ****(range, 17 to 85 yr)**
**63% male**
**98% white**
**31% had ulceration**
**48% had recurrent disease at study entry**
**Most common site = trunk (43%)**
**83% had ECOG PS = 0; ****17% had ECOG PS = 1**

**C**

**Notes:**
The demographics of these patients are consistent with the experience of other groups, demonstrating a median age of 49 years, with more than 60% male, 83% PS 0, and 98% Caucasian.

## E1684: Relapse-Free Survival (ITT at 12.6 yr Median Follow-up)

**Observation**

**140**

**106**

**34**

**1.0**

**High-dose IFN**

**146**

**95**

**51**

**1.7**

**Median**

**Alive or****relapsed-free**

**Dead or****relapsed**

**Total**

**E1684: Relapse-Free Survival ****(ITT at 12.6 yr Median Follow-up)**

**Log-rank test: *****P*****2 ****= .02; *****P*****1 ****= .01**

**0.0**

**0.1**

**0.2**

**0.3**

**0.4**

**0.5**

**0.6**

**0.7**

**0.8**

**0.9**

**1.0**

**Time, yr**

**0**

**1**

**2**

**3**

**4**

**5**

**6**

**7**

**8**

**9**

**10**

**11**

**12**

**13**

**14**

**15**

**16**

**Proportion alive and relapse-free**

**C - **

**Observation**

**High-dose IFN**

**Treatment groups (N = 286)**

**C**

**Notes:**
For E1684 RFS the differences to 16 years persist, and the increment at 10 years in continuous RFS is no less than at 7 years when reported in the literature.

## E1684: Overall Survival (ITT at 12.6 yr Median Follow-up)

**Median**

**Alive**

**Dead**

**Total**

**Observation**

**140**

**95**

**45**

**2.7**

**High-dose IFN**

**146**

**93**

**53**

**3.8**

**Log-rank test: *****P*****2 ****= .18; *****P*****1 ****= .09**

**0.0**

**0.1**

**0.2**

**0.3**

**0.4**

**0.5**

**0.6**

**0.7**

**0.8**

**0.9**

**1.0**

**Time, yr**

**Proportion alive**

**E1684: Overall Survival ****(ITT at 12.6 yr Median Follow-up)**

**C - **

**High-dose IFN**

**Treatment groups (N = 286)**

**C**

**Notes:**
For E1684, the long term data for survival are consistent with the original report, and with median followup of 12 years show median survival advantage of 1 .1 years for HDI

## E1690: Relapse-Free Survival (ITT at 6.6 yr)

**215**

**120**

**95**

**2.7**

**Low-dose IFN**

**215**

**129**

**86**

**2.4**

**Observation**

**212**

**128**

**84**

**1.6**

**Median**

**Alive or****relapse-free**

**Dead or****relapsed**

**Total**

**E1690: Relapse-Free Survival (ITT at 6.6 yr)**

**High-dose IFN vs Obs: *****P*****2 ****=.09; *****P*****1 ****= .05**
**Low-dose IFN vs Obs: *****P*****2 ****= .31; *****P*****1 ****= .16**

**0.0**

**0.1**

**0.2**

**0.3**

**0.4**

**0.5**

**0.6**

**0.7**

**0.8**

**0.9**

**1.0**

**Time, yr**

**Proportion alive and relapse-free**

**C - **

**Observation**

**Treatment groups (N = 642)**

**High-dose IFN**

**Low-dose IFN**

**C**

**Notes:**
For E1690 the RFS differences observed at 4.3 years are the same as noted at 6.6 years.

## E1690: Overall Survival (ITT at 6.6 yr)

**Alive**

**Dead**

**Total**

**High-dose IFN**

**215**

**108**

**107**

**6.0**

**Low dose IFN**

**215**

**104**

**111**

**7.7**

**Observation**

**212**

**103**

**109**

**6.8**

**E1690: Overall Survival (ITT at 6.6 yr)**

**1.0**

**High-dose IFN vs Obs: *****P*****2 ****= .98; *****P*****1 ****= .49**
**Low-dose IFN vs Obs: *****P*****2 ****= .78; *****P*****1 ****= .39**

**0.0**

**0.1**

**0.2**

**0.3**

**0.4**

**0.5**

**0.6**

**0.7**

**0.8**

**0.9**

**Time, yr**

**0**

**Proportion alive**

**C - **

**Observation**

**Treatment groups (N = 642)**

**High-dose IFN**

**Low-dose IFN**

**C**

## E1694: Relapse-Free Survival (ITT at 2.1 years Median Follow-up)

**439**

**202**

**237**

**2.3**

**High-dose IFN**

**438**

**159**

**279**

**3.9**

**Median**

**Alive or****relapse-free**

**Dead or****relapsed**

**Total**

**E1694: Relapse-Free Survival ****(ITT at 2.1 years Median Follow-up)**

**Log-rank test: *****P*****2 ****=.007; *****P*****1****= .0035**

**0.0**

**0.1**

**0.2**

**0.3**

**0.4**

**0.5**

**0.6**

**0.7**

**0.8**

**0.9**

**1.0**

**Time, yr**

**0**

**1**

**2**

**3**

**4**

**5**

**Proportion alive and relapse-free**

**C - **

**GMK**

**High-dose IFN**

**Treatment groups (n = 743)**

**C**

**Notes:**
RFS differences are consistent over GMK for HDI

## E1694: Overall Survival (ITT at 2.1 years Median Follow-up)

**Alive**

**Dead**

**Total**

**GMK**

**439**

**127**

**312**

**3.8**

**High-dose IFN**

**438**

**102**

**336**

**NR**

**E1694: Overall Survival ****(ITT at 2.1 years Median Follow-up)**

**Log-rank test: *****P*****2 ****= .04; *****P*****1 ****= .02**

**0.0**

**0.1**

**0.2**

**0.3**

**0.4**

**0.5**

**0.6**

**0.7**

**0.8**

**0.9**

**1.0**

**Time, yr**

**0**

**1**

**2**

**3**

**4**

**5**

**Proportion alive**

**C - **

**GMK**

**High-dose IFN**

**Treatment groups (n = 743)**

**C**

**Notes:**
For E1694 OS the differences at 1.3 y ears are identical to those observed at 2.1 years presently.

## Relapse-Free Survival by Treatment E1684 and E1690 (Pooled)

**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**

**194/352**

**28/145**

**8/111**

**2/79**

**1/45**

**1/29**

**0/15**

**0/3**

- 0.0

- 0.2

- 0.4

- 0.6

- 0.8

- 1.0

-  0

-  2

-  4

-  6

-  8

- 10

- 12

- 14

- 16

- Time, yr

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

**Interferon**

**171/361**

**29/176**

**8/138**

**3/103**

**2/68**

**2/44**

**0/31**

**0/10**

- IFN vs observation: *P**2* = .006, HR = 1.30

**Observation**

**Interferon**

**C - **

## Overall Survival by Treatment E1684 and E1690 (Pooled)

**0.0**

**0.2**

**0.4**

**0.6**

**0.8**

**1.0**

** ****0**

** ****2**

** ****4**

** ****6**

** ****8**

**10**

**12**

**14**

**16**

**Time, yr**

**Time interval, no. events/no. at risk**

**Group**

**0-2**

**2-4**

**4-6**

**6-8**

**8-10**

**10-12**

**12-14**

**14-16**

**Proportion alive**

**Observation**

**126/352**

**48/225**

**16/173**

**6/125**

**2/65**

**0/38**

**0/21**

**0/6**

**Interferon**

**115/361**

**51/243**

**22/186**

**6/134**

**2/80**

**5/52**

**0/35**

**0/10**

**IFN vs observation: *****P*****2 ****= .42, HR = 1.07**

**Observation**

**Interferon**

**C - **

## Proportional Hazards Multivariate Model of Prognostic Factors—Relapse-Free Survival

**Variable****	**** HR****	****95% CI****	*****P***** value**
**Recurrent disease****	****1.57****	****1.33 - 1.84****	****< .0001**
**Ulceration****	****1.54****	****1.32 - 1.79****	****< .0001**
**Protocol E1684****	****1.34****	****1.10 - 1.62****	****   .004**
**Abnormal LDH****	****1.26****	****1.04 - 1.53****	****   .02**
**Thickness ******** 3 mm****	****1.23****	****1.04 - 1.46****	****   .02**
**Age > 49 yr****	****1.20****	****1.04 - 1.39****	****   .01**
**Site upper limb****	****0.73****	****0.59 - 0.91****	****   .005**

**C**

## Proportional Hazards Multivariate Model of Prognostic Factors—Overall Survival

**Variable****	**** HR****	****95% CI****	*****P***** value**
**Ulceration****	****1.73****	****1.45 - 2.05****	****< .0001**
**Protocol E1684****	****1.71****	****1.39 - 2.11****	****< .0001**
**Recurrent disease****	****1.48****	****1.25 - 1.76****	****< .0001**
**Age > 49 yr****	****1.28****	****1.09 - 1.51****	****   .003**

**C**

## Treatment Effect: Multivariate Cox Model for Relapse-Free Survival (E1684 and E1690)

**Variable****	**** HR****	****95% CI****	*****P***** value**
**Observation ****	****1.28****	****1.05 - 1.54****	****  .01**
**Ulceration****	****1.44****	****1.17 - 1.78****	****  .0006**
**Protocol E1684****	****1.37****	****1.12 - 1.67****	****  .003**
**Recurrent disease****	****1.25****	****1.03 - 1.53****	****  .03**

**C**

## Treatment Effect: Multivariate Cox Model for Overall Survival (E1684 and E1690)

**Variable****	**** HR****	****95% CI****	*****P***** value**
**Observation****	****1.07****	****0.87 - 1.31****	****   .52**
**Protocol E1684****	****1.68****	****1.34 - 2.09****	****< .0001**
**Ulceration****	****1.64****	****1.31 - 2.05****	****< .0001**
**Age > 49 yr****	****1.32****	****1.08 - 1.62****	****   .007**
**Recurrent disease****	****1.22****	****0.99 - 1.50****	****   .07**

**C**

## ConclusionsUpdated Analysis of Individual Studies

**E1684:**** significant RFS benefit of high-dose IFN versus Obs still evident at median follow-up ****of 12.6 yr**
**OS benefit significance diminished, probably due to deaths from other competing causes  **
**E1690:**** no RFS or OS benefit associated with ****high-dose IFN at median follow-up of 6.6 yr**
**E1694:**** high-dose IFN significantly superior to GMK for RFS and OS at median follow-up of 2.1 yr**

**C**

**Notes:**
We conclude that HDI exhibits a significant advantage for OS and RFS compared to OBS in the pooled analysis at 3.5 years aggregate median followup.
It is superior to GMK in terms of both RFS and OS as a single trial at 2.1 years median followup, to April 2001

## ConclusionsPooled Analysis

**Based on 2-sided, univariate log-rank analysis, high-dose IFN-********2b significantly improves RFS compared with Obs **
**Factors predictive of decreased RFS and OS include ulceration, recurrent disease at entry, treatment on E1684, and age > 49 yr**
**Adjusting for important prognostic factors**
**RFS benefit of high-dose IFN-********2b vs Obs confirmed**
**Overall survival benefit of high-dose IFN vs ****Obs is not confirmed**

**C**

**Notes:**
HDI is superior to GMK in terms of RFS in the pooled analysis, but survival differences require longer followup for final conclusions

## Overall Conclusions—Role of HDI

**Highest level of evidence based on analysis of primary endpoints of randomized trials (E1684, E1690, E1694)**
**High-dose IFN-********2b has demonstrated consistent RFS and OS benefits compared with Obs and GMK**
**Pooled analysis of E1684 and E1690 shows significant improvement in RFS for HDI vs Obs**
**Meta-analysis of 10 adjuvant trials demonstrates a significant RFS benefit for interferon therapy ****(HR = 0.84, 95% CI = 0.77 to 0.92; *****P***** = .0001)**

**C**

**Wheatley K, et al. *****Proc Am Soc Clin Oncol*****. 2001;20:349a. ****Abstract 1394.**

## Current ECOG/Intergroup Studies of Adjuvant Therapy 

**Evaluate more aggressive combinations vs HDI **
**S0008: Chemobiotherapy × 3 month vs 1 yr HDI ****(stage III B/C)**
**Improve therapeutic index of HDI**
**	****Is 1 month IV HDI necessary and sufficient?**
**Intergroup E1697: 1 month IV HDI vs Obs for intermediate risk (stage IIA)**
**E1601: Equivalence trial comparing 1 month vs ****1 year HDI**
**Introduce new cytokines and peptide vaccines for IFN failures**
**Intergroup E4697: Adjuvant evaluation of GM-CSF and multi-epitope peptide vaccine**

- 4

## Strategies for Developing New Adjuvant Therapies in Stage IV Disease

**Introduce peptide vaccines with IFN and other cytokines**
**E1696: Multi-epitope peptide ± IFN ± GM-CSF**
**E1602: Multi-epitope lineage and cancer-testis vaccine**
**Define Intermediate molecular endpoints**
**E3601: Phase IB trial of PEG IFN dose modulated according to bFGF levels**