Abstract 8504: E4697: Phase III Cooperative Group Study of Yeast Derived GM-CSF vs Placebo as Adjuvant Treatment of Patients with Completely Resected Stage III-IV Melanoma

DH Lawson, SJ Lee, AA Tarhini, KA Margolin, MS Ernstoff, JM KirkwoodWinship Cancer Institute of Emory University, Dana-Farber Cancer Institute, University of Pittsburgh Cancer Institute, University of Washington, Dartmouth Hitchcock Medical Center

Objectives

• Primary objective:– To compare OS of patients given GM-CSF vs

placebo• Secondary objectives

– To compare DFS of patients with GM-CSF vs placebo

– To compare DFS of HLA-A2+ patients given peptide vaccine vs. placebo

– To compare OS of HLA-A2+ patients given peptide vaccine vs. placebo

GM-CSF+ Peptide Vaccine

Placebo+ Peptide Vaccine

GM-CSF+ Peptide Placebo

Placebo+ Peptide PlaceboRA

ND

OM

IZE

GM-CSF

GM-CSF Placebo

RA

ND

OM

IZE

HLA-A2Positive

HLA-A2Negative

Stratify:

HLA-A2 Status

1. Positive 2. Negative

Site of Metastases

1. Visceral 2. Non-visceral 3. Visceral/Non-visceral

Number of Metastases

1. 1 2. 2 - 3 3. 4 or more

Eligibility for E4697: Stage III• Intransit metastases including local recurrence

• Gross extracapsular extension

• Recurrence in previously resected nodal basin

• Four or more involved nodes

• Ulcerated primary with any clinically involved nodes

• Locoregional recurrence after IFN or S0008

Eligibility for E4697

• Resected locoregional mucosal melanoma

• Completely resected stage IV melanoma,– Cutaneous, mucosal, ocular, and unknown

1º

Treatment Plan

• GM-CSF 250 mcg SC 14 days of 28 for one year (13 cycles)

• Patients with resectable recurrences encouraged to continue 6 months past recurrence or for one year, whichever is longer

• Disease assessments every 3 mos

•

Treatment Plan

• Vaccinations on days 1 and 15 of first cycle, then day 1 of subsequent cycles.

• Peptides used:–Tyrosinase: 368-376 (370D)–gp-100: 209-217 (210M)–MART-1: 27-35

Statistical Considerations• 800 patients gives 80% power to

detect a 33% increase in median survival from 40 to 53 months with 2-sided type 1 error rate of 0.05

• 80% power to detect 24% increase in DFS from 11 to 13.6 months

• Placebo controlled to enhance validity of the DFS endpoint

E4697: Accrual

• 815 pts accrued between December 29, 1999 and October 31, 2006 – 53.5% HLA-A2+– 46.5% HLA-A2-

• 72 ineligible• 743 included in this analysis

– 368 received GMCSF– 375 received GMCSF-placebo

Data Analyses

Unblinding specified in protocol at 30 months from completion of treatment of the last patient (April, 2009) even if full information not reached by then.

Data Analyses

September 2009 analysisPositive effect of GM-CSF on DFS (p=.03) with Hazard Ratio (HR) 0.82, 95% CI(.69, .98)

No significant effect on OS (p=.55) with HR 0.94, 95% CI (.75, 1.16)

Data Analyses

Updated analysis for ASCO planned

for April 2010

Current Status

• 345 deaths

• 86% information time

• Full information anticipated in 2014

• Results of April, 2010 analysis presented today

DFS by GM-CSF (n=743)

P = 0.14

HR = 0.88, 95% CI(.73,1.04)

Median DFS•Placebo: 9.2 mos, 95% CI (7.68, 12.48)•GM-CSF:11.5 mos, 95% CI (9.72, 15.48)

OS by GM-CSF Treatment Status

P= 0.78HR= 0.96, 95% CI(.78,1.04)

Median OS:• Placebo : 62.4 mos, 95% CI (45.6, -)• GM-CSF: 69.6 mos, 95% CI (50.4, -)

Effect of Peptide Vaccination on Disease Free and Overall Survival in HLA-A2+ Patients

DFS by PEP in HLA-A2+ (n=398)

P=.709HR=.93, 95%CI(.73,1.27)

OS by PEP in HLA-A2+ (n=398)

P =.670HR=.94, 95%CI(.70,1.26)

Subset Analysis of Effect of GMCSF on OS and DFS by Stage

• Stage IIIB and IIIC: 374 pts• Stage IV: 258 pts

Stage III Melanoma

p = 0.52HR=.92, 95%CI(.72,1.17)

DFS OS

p = 0.80HR=.97, 95%CI(.71,1.31)

Stage IV MelanomaDFS OS

P= 0.04HR=.74, 95%CI(.56,.99)

P= 0.07HR=.72, 95%CI(.50,1.02)

Conclusions

• Neither GMCSF nor peptide vaccination achieved OS and DFS objectives

• There is a suggestion of favorable effect of GMCSF on DFS

• Subset analysis suggests effects of GMCSF on DFS and OS are largest among Stage IV subjects

Conclusions

• Further study of adjuvant GMCSF is warranted (patients, dose, duration)

• Use of GMCSF in the adjuvant setting is worthy of discussion (IFN failures, resected stage IV)

• Laboratory immunologic responses in relation to clinical outcome are under investigation

Acknowledgements

• Coordinating Centers of ECOG, SWOG, and CALGB

• PI’s, Research Nurses and Coordinators at the sites

• Carol Hill, RN, PIN nurse• As always, our patients and their

families