Key clinical-trial evidence for interferon for melanoma

Author: Anoma Ranaweera B.V. Sc; PhD (Clinical Biochemistry, University of Liverpool, UK). Chief Editor: Dr Amanda Oakley, Dermatologist, Hamilton, New Zealand, December 2015.


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Three types of interferon-alpha are commercially available: peginterferon alfa-2b (Sylatron®; Schering-Plough Corporation, Madison New Jersey [NJ], USA), interferon alfa-2b (Intron® A; Schering-Plough Corporation, Madison NJ , USA), and interferon alfa-2a (Roferon&reg-A;, Hoffmann-La Roche, Madison, NJ, USA); each differs minimally in their amino-acid sequence.

All preparations are available in New Zealand except peginterferon alfa-2b.

Peginterferon alfa-2b (Sylatron®)

  • In 2011, the FDA approved peg-interferon alfa-2b for melanoma as adjuvant treatment to surgery in patients with microscopic or gross nodal involvement, within 84 days of definitive surgical resection including complete lymphadenectomy.
  • The drug's approval was based on a 5-year, open-label, multicentre clinical trial of 1256 patients with melanoma (EORTC [European Organisation for Research and Treatment of Cancer] 18991).
  • Patients were randomized to observation (no therapy) (n=629) or to peginterferon alfa-2b (n=627) at a dose of 6 µg/kg by subcutaneous injection once weekly for 8 doses followed by a 3 µg/kg subcutaneous injection once weekly for a period of up to 5 years total treatment
  • Patients were assessed for metastasis every 3 months for the first 2 years, and every 6 months for the remaining years.
  • The main outcome measure was relapse-free survival (RFS), defined as the time from randomization to the earliest date of any relapse (local, regional, in-transit, or distant), or death from any cause. Secondary outcome measures included overall survival.
  • At 7.6 years median follow-up, 384 recurrences or deaths had occurred in the peginterferon alfa-2b group versus 406 recurrences or death in the observation group (hazard ratio [HR], 0.87; 95% confidence interval CI, 0.76 to 1.00; p = 055).
  • At 7.6 years median follow-up, patients who took peginterferon alfa-2b had an estimated median RFS of 34.8 months (95% CI, 26.1 - 47.4).
  • Patients who did not take peginterferon alfa-2b had an estimated median RFS of 25.5 months (95% CI, 19.6 - 30.8).
  • In stage III-N1 ulcerated melanoma, RFS (HR, 0.72; 99% CI, 0.46 to 1.13; p = 0 .06), distant metastasis free survival (HR, 0.65; 99% CI, 0.41 to 1.04; p = 0.02), and overall survival (HR, 0.59; 99% CI, 0.35 to 0.97; p = 0.006) were prolonged with peginterferon alfa-2b treatment.
  • Peginterferon alfa-2b did not affect overall survival between the 2 groups of patients (p = 0 .57).
  • PEG-interferon alfa-2b was discontinued for toxicity in 37% of patients.
Peginterferon. Drug-related adverse reactions in >5% of patients
Sylatron® (n = 629)Observation (n = 628)
 
Adverse reactionAll grades (%)All Grades (%)
General disorders and administration site conditions
Fatigue 94 41
Pyrexia 75 9
Chills 63 6
Injection site reactions 62 0
Gastrointestinal disorders
Diarrhoea 37 8
Nausea 64 11
Vomiting 26 4
Respiratory disorders
Dyspnoea 6 2
Cough 5 2
Skin disorders
Rash 36 4
alopecia 34 1
Musculoskeletal disorders    
Arthralgia 51 22
Myalgia 68 23
Nervous system disorders
Headache 70 19
Dizziness 35 11
Liver function
Increased AST 77 26

Interferon alfa-2b (Intron®A)

  • In 1996, the US FDA approved interferon alfa-2b as adjuvant treatment to surgery in malignant melanoma patients at high risk for systemic recurrence.
  • Approval was based on safety and efficacy results of interferon alfa-2b evaluated in patients with melanoma who were free of disease (post-surgery) but at high risk for systemic recurrence as reported in ECOG [European Cooperative Oncology Group] trial 1684 and ECOG trial 1690.

ECOG 1684

  • Included 287 patients with melanoma lesions of Breslow thickness > 4mm, or patients with lesions of any Breslow thickness with primary or recurrent nodal involvement.
  • 143 patients were randomised to receive interferon alfa-2b at 20 million IU/m2 intravenously five times per week for 4 weeks (induction phase) followed by 10 million IU/m2 subcutaneously three times per week for 48 weeks (maintenance phase).
  • The remaining 137 patients were observed.
  • Interferon alfa-2b therapy was begun ≤ 56 days after surgical resection.
  • Median time to relapse for the interferon alfa-2b treated patients versus observation patients was 1.72 years versus 0.98 years (p<0.01, stratified Log Rank).
  • The estimated 5-year relapse-free survival rate, using the Kaplan-Meier method, was 37% for interferon alfa-2b treated patients versus 26% for observation patients.
  • Median overall survival time for interferon alfa-2b treated patients vs observtion was 3.82 years versus 2.78 years (p=0.047, stratified Log Rank).
  • The estimated 5-year overall survival rate, using the Kaplan-Meier method, was 46% for interferon alfa-2b treated patients versus 37% for observation patients.
  • Interferon alfa-2b therapy was discontinued because of adverse events in 8% of the patients during induction and 18% of the patients during maintenance.
  • The most frequently reported adverse reaction was fatigue which was observed in 96% of patients.
  • Other adverse reactions that were recorded in >20% of interferon alfa-2b treated patients included neutropenia (92%), fever (81%), myalgia (75%), anorexia (69%), vomiting/nausea (66%), increased hepatic AST (63%), headache (62%), chills (54%), depression (40%), diarrhoea (35%), alopecia (29%), altered taste sensation (24%), dizziness/vertigo (23%), and anaemia (22%).

ECOG 1690

  • Resected high-risk melanoma patients, were randomized equally to one of three groups: high-dose Intron® A therapy for 1 year (same schedule as ECOG 1684), low-dose Intron® A for 2 years (3 million international units/day 3 times per week SC), and observation.
  • Consistent with results of ECOG 1684, high-dose Intron® A therapy demonstrated an improvement in relapse-free survival (3-year estimated RFS 48% versus 41%; median RFS 2.4 versus 1.6 years, p =not significant).
  • Relapse-free survival in the low-dose Intron® A arm was similar to that seen in the observation arm.
  • Neither high-dose nor low-dose Intron® A therapy showed a benefit in overall survival compared with the observation group.

Interferon alfa-2a (Roferon® -A)

  • Interferon alfa-2a is produced biosynthetically using recombinant DNA technology.
  • It is the product of a cloned human leukocyte interferon gene inserted into and expressed in a bacterium called Escherichia coli.
  • Interferon alfa-2a has been approved in the European Union for the treatment of advanced malignant melanoma.
  • Patients with advanced malignant melanoma have shown objective regression of cutaneous and visceral tumours on Roferon®-A therapy alone or in combination with dacarbazine in small clinical trials.
  • In June 1999 interferon alfa-2a was also approved in the European Union for the adjuvant treatment of patients with malignant melanoma (tumour thickness > 1.5mm) surgically removed and who had no nodal or distant metastases before treatment commences.
  • European Union approval was based on results from 2 phase III randomised trials conducted in France and Austria.

French Melanoma Cooperative Group Trial

  • In the French Cooperative Group Trial, the efficacy of Roferon®-A in patients with primary cutaneous melanoma thicker than 1.5 mm and without clinically detectable node metastasis was assessed in a large randomised study involving 253 patients.
  • Patients received Roferon®-A at a dose of 3 million IU SC three times a week for 18 months, compared with 246 untreated controls.
  • After a median follow-up of 4.4 years, there was a significant extension of relapse-free interval (p=0.035) but no statistically significant difference in overall survival (p=0.059) in Roferon®-A treated patients compared with controls. The overall treatment effect was a 25% reduction in the risk of relapse.
  • Only 10% of patients experienced WHO grade 3 or 4 treatment-related adverse events.
  • Treatment was compatible with normal daily life.

Austrian Melanoma Cooperative Group Trial

  • In the Austrian Melanoma Cooperative Group study, 311 melanoma patients with a Breslow thickness > or = 1.5 mm were assigned to either adjuvant Roferon®-A treatment (n = 154) or observation (n = 157), after excision of the primary tumour.
  • Interferon alfa-2a was given daily at a dose of 3 million international units (mIU) subcutaneously (s.c.) for 3 weeks (induction phase), then a dose of 3 mIU sc three times per week over 1 year (maintenance phase).
  • At a mean observation time of 41 months, a significantly prolonged (p = 0.02) disease-free survival was observed in patients treated with interferon alfa-2a versus those who underwent surgery alone, in an intention-to-treat analysis.
  • Interferon alfa-2a has is not approved in USA for the adjuvant treatment of malignant melanoma.
  • The Oncologic Drugs Advisory Committee to the US FDA has refused to recommend approval of Roferon®-A (interferon alfa-2a recombinant, Hoffmann-La Roche) for the adjuvant treatment of surgically resected malignant melanoma, without clinical evidence of nodal disease.

Future directions

  • Adjuvant interferon alfa-2b has been commonly used for the treatment of advanced malignant melanoma in USA and Europe.
  • However, interferon alfa-2b remains a controversial therapy.
  • Toxicity is substantial, with neuropsychiatric, constitutional, and hepatic toxicity being the major issues.
  • Efficacy is seen by many as modest, particularly when balanced against the toxicity that has substantial impact on quality of life.
  • Meta-analyses have shown highly significant effects of interferon alfa-2b therapy on relapse-free survival (hazard ratios, 0.82-0.87) and small, but statistically significant, improvements in overall survival (hazard ratios, 0.89-0.93) in patients with predominantly regional nodal metastases.
  • As such, ongoing efforts to maximize benefit and limit toxicity by examining dose and schedule remain relevant.
  • The emergence of new approaches for treating melanoma in the advanced disease setting, generates opportunities for better-tolerated therapies in the adjuvant setting.
  • The finding that melanomas frequently contain driver oncogenes has changed the approach to managing patients with advanced disease.
  • The BRAF inhibitors vemurafenib and dabrafenib and the MEK inhibitor trametinib significantly improve survival in patients with advanced disease.
  • The efficacy of the checkpoint inhibitors ipilimumab and nivolumab in the advanced setting also necessitates evaluating these therapies in the adjuvant setting.
New Zealand approved datasheets are the official source of information for prescription medicines, including approved uses and risk information. Check the individual New Zealand datasheet on the Medsafe website.

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Text: Miiskin