EORTC 18961: Post-operative adjuvant ganglioside GM2-KLH21 vaccination treatment vs observation in stage II (T3-T4N0M0) melanoma: 2nd interim analysis led to an early disclosure of the results.

• Abstract No: 9004
• Citation: J Clin Oncol 26: 2008 (May 20 suppl; abstr 9004)
• Author(s): A. M. Eggermont, S. Suciu, W. Ruka, J. Marsden, A. Testori, P. Corrie, S. Aamdal, P. A. Ascierto, P. Patel, A. Spatz, EORTC Melanoma Group

Abstract
Background: EORTC 18961 assessed in the largest adjuvant phase III trial to date in stage II melanoma the efficacy and toxicity of Ganglioside GM2-KLH21 Vaccination (VAC) Treatment vs Observation (OBS).

Methods
Patients (Pts)\ were observed or received vaccine sc once weekly week 1-4, every 3 months from week 12 for first 2 years and every 6 months during third year (total of 14 vaccinations).

Stratification Factors for Randomization
Breslow thickness, ulceration, being staged yes vs no by Sentinel Node (SNLD) or Elective Lymph Node Dissection (ELND), sex and institution.

Relapse-free survival (RFS) was the primary endpoint; Distant metastasis-free survival (DMFS) and overall survival (OS) were the prespecified secondary endpoints.

Intent-to-treat analysis was performed.

Results

• Between March 2002 and Dec. 2005, 1,314 pts entered the trial.
• Patient demographics showed perfect balance for prognostic factors.
  
• The 2nd interim analysis was performed when 267 RFS events were reported, i.e. 67% of the total number required at final analysis.
  
• Median follow-up was 1.8 years.
  

Similar Treatment Differences

• Obtained in lympnhnode-staged (N=644) or non-staged (N=670) patients.
• Grade 3 - toxicities occurred in < 2%.(VAC) and in < 1% (OBS).
• Grade 2 - toxicities comprised fatigue (15% vs 3%), fever (9% vs 1%), nausea (3% vs 1%).
  
• Local grade 3 - toxicity occurred in 4 % (VAC).
  
• The EORTC IDMC reviewed both safety and efficacy data.
  
• For the primary endpoint, RFS, the criteria for stopping for futility were met. 
• For DMFS and OS, the results pointed in the direction of a detrimental effect of the vaccine.
  

The IDMC recommended trial 18961 to be stopped and vaccinations to be halted in pts still receiving VAC. Pts should continue to be followed for the trial's endpoints.

Conclusions
Adjuvant GM2-KLH21 vaccination is ineffective and could even be detrimental in stage II melanoma patients.

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The following was written by Linda Pilkington:

"German powerhouse Bayer is to pull a formulation of its anti-infective Leukine (sargramostim) from the USA following a spike in the number of adverse events reported, particularly fainting and hypotension.

Bayer says that the rise in AEs corresponds to a formulation change to include edetate disodium, a chelator that is approved separately in the USA as an emergency treatment to combat high levels of calcium in the blood or heart rhythm problems following digitalis poisoning.

The firm says it now plans to reformulate the 500mcg vial - the only one to include EDTA - and will open a special access programme to enable patients with life threatening conditions preferential treatment using the 250mcg vial, which does not contain the substance in question.

Leukine is a growth factor designed to boost the immune system and combat infections in AML and transplantation patients."

Full details can be found at Bayer's  press release.

Robert W. Weber, MD is an oncologist and the Director of the Northern California Melanoma Center. Dr. Weber talks about clinical trial design, phases, selection, and logistics, and how you might benefit from participating in a clinical trial. Watch video.

You can view an Online Webcast entitled Advances in Immunotherapy For Malignant Melanoma at the following site: http://www.imedex.com/webcasts/4907/index.html .

It occurred to us that many patients might be interested in the unique perspective of a physician diagnosed with stage IV disease.

The patient’s past history included several orthopedic procedures for sports related injuries and chronic benign idiopathic neutropenia previously worked up including bone marrow studies. The family history was non-contributary.The primary lesion was several inches below the collar line on the upper back. Diagnostic biopsy revealed a desmoplastic malignant melanoma of at least Clark’s IV. Following an extensive pre-op work-up that was negative for metastatic disease, a wide excision with sentinal node biopsy was performed. Pathology revealed the lesion to be 5 mm. in depth without node involvement. At this time it was decided to follow up with a wide local field of external beam radition over the course of 5 weeks. High dose interferon was discussed but not chosen. The patient experienced some moderate degree of radiation necrosis, but the incision site eventually healed with the expected scarring. The patient was N.E.D. at 6 month PET scan and assymptomatic, however the one year CT scan revealed a solitary lesion in the right lung. This was shown to be metastatic by needle biopsy.

Another very extensive pre-op evaluation revealed this to be the only site of metastatic disease. The patient had an uneventful lobectomy and did well post-operatively.

Because of the short time between the primary and diagosis of stage IV disease, the patient was advised to evaluate the experimental protocols available at the time. ( 10/02)

Because of my pre-existing neutropenia, it seemed reasonable to me to pursue an immunologicic course of treatment. In addition, the idea of very high dose interferon and likely inability to continue to play tournament tennis was not very appealing. Therefore, I enrolled in the Duke vaccine study while at the same time consulting with Dr. Spitler. Since there was no contraindication to following the GM-CSF protocol while doing the vaccine program, I elected to do them together in order to give myself the best chance possible against the miserable prognosis that  I was facing.

I was unable to self-inject in the lower abdomen because of severe burning, swelling and pruritis. Therefore, I used the anterior thigh for my three years of two weeks on and two weeks off therapy. My white count went from 1200 to as high as 8000 in a cyclical response pattern. I experienced only moderate intermittent bone pain, but did have moderate to severe gagging, nausea and intractable cough that only seemed to dissipate for 2-3 days a month. In addition, I experienced a loss of  my usually robust appetite. The vaccine injections from Duke caused only minimal irritation for the 7 month protocol.

It is now almost 5 years since my lung surgery and almost 2 years that I am off the GM-CSF. I have had so many total body CT scans that I glow in the dark and some many MRIs that I de-magnetize credit cards, BUT all have been negative.

Perhaps my special perspective as a physician and a patient allows me to offer some advice.

• First, think about anything in your personal or family history that might be unusual, such as my neutropenia.
  
• Second, find doctors that you feel good about and then trust them to do the right thing for you. I think it is much more important to spend a lot of energy getting the right people on your team rather than trying to micro-manage the disease yourself.
  
• Third, no matter what statistics say, you are an individual and you might be the one that survives.
  
• Finally, you can make a choice to lay down and die or you can push through any side effects of  treatment and live your life to the fullest.   
  

Hank Gardstein M.D. 

A European Clinical Trials Study Group, the EORTC, reported on the effects of long-term (5 years) pegylated interferon-alpha2b (a long-acting form of interferon, PEG-IFN) administration as adjuvant therapy for patients with stage III melanoma. These are patients who have had metastasis of melanoma to the lymph nodes, which were surgically excised. Thus the patients were clinically disease-free, but at high risk for recurrence due to microscopic deposits of melanoma cells that might remain after the surgery.

This was the largest adjuvant trial ever conducted in patients with stage III melanoma; 1,256 patients participated in the study. Patients were randomized to receive PEG-IFN or observation (control subjects). The results showed that the administration of PEG-IFN had no effect on overall survival in the treated patients but did cause a delay in the time to recurrence, termed relapse-free survival. These results are similar to those reported in the US and elsewhere for non-pegylated interferon-alpha.

EORTC 18991: Long-term adjuvant pegylated interferon-alpha2b (PEG-IFN) compared to observation in resected stage III melanoma, final results of a randomized phase III trial.
Sub-category: Melanoma
Category: Melanoma
Meeting: 2007 ASCO Annual Meeting
Abstract No: 8504
Citation: Journal of Clinical Oncology, 2007 ASCO Annual Meeting Proceedings Part I. Vol 25, No. 18S (June 20 Supplement), 2007: 8504
Author(s): A. M. Eggermont, S. Suciu, M. Santinami, W. Kruit, A. Testori, J. Marsden, C. Punt, A. Hauschild, M. Gore, U. Keilholz, EORTC Melanoma Group

Abstract: Background: EORTC 18991 is the largest adjuvant trial ever conducted in stage III melanoma. It assessed the efficacy and toxicity of long term PEG-IFN vs Observation (Obs.). Methods: PEG-IFN (Induction at 6µg/Kg/wk, sc, 8 weeks; followed by Maintenance at 3µg/Kg/wk, sc) for a total treatment duration of 5 years was compared to Obs. in 1256 patients (pts) with stage III melanoma (anyTN1-2M0 without in-transit metastases).

Randomization was stratified for nodal involvement N1 (microscopic) vs N2 (palpable nodes), # of nodes, Breslow and ulceration of primary, sex and center. Distant Metastasis-Free Survival (DMFS) was the primary endpoint. Relapse-Free Survival (RFS) was the pre-specified regulatory primary endpoint. Overall survival (OS) was the secondary endpoint. Intent-to-treat analysis was performed.

Results: Median follow-up was 3.8 yrs: HR = Hazard Ratio; NR = Not Reached In N1-pts (n=543) the benefit of PEG-IFN seemed more pronounced than in N2-pts (n=713): RFS (HR 0.73 p=0.02 and HR 0.86 p=0.12 for N1 and N2, respectively), DMFS (HR 0.75 p=0.03 and HR 0.94 p=0.53) and OS (HR 0.88 p=0.43 and HR 1.01 p=0.91). PEG-IFN therapy relative dose intensity (actual/planned dose while treated) reached median 88% (induction) and 83% (maintenance). 251 pts (40 %) stopped PEG-IFN because of toxicity. Grade 3-4 - mostly grade 3 - toxicities were reported in 45% (PEG-IFN), vs 12% (Obs.), including most frequently fatigue (15%), hepatotoxicity (10%) and depression (6%) with ECOG 0-1 Performance Status maintained in 83% of pts during maintenance.

Conclusions: Long term PEG-IFN therapy in stage III melanoma had a significant and sustained impact on RFS, but not on DMFS and OS. Pts with only microscopic nodal involvement (Sentinel Node positive) seemed to have greater benefit in terms of both RFS and DMFS. Similar better effects of adjuvant IFN therapy in pts with lower disease burden are observed in 2 consecutive EORTC trials (18952 and 18991) involving 2644 pts.

	RFS		DMFS		OS
	Obs.	PEG-IFN	Obs.	PEG-IFN	Obs.	PEG- IFN
Nb. events	368	328	325	304	263	262
4-year rates	39%	46%	45%	48%	56%	57%
Median (yrs)	2.1	2.9	3.0	3.8	NR	NR
HR (95%CI)	0.82 (0.71-0.96)		0.88 (0.75-1.03)		0.98 (0.82-1.16)
p- value	0.01		0.11		0.78