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.


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 reaction All 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.

 

Related Information

References:

On DermNet NZ:

Other websites:

Books about skin diseases:

See the DermNet NZ bookstore

Note:

The New Zealand approved datasheet is the official source of information for this prescription medicine, including approved uses and risk information. Check the New Zealand datasheet on the Medsafe website.