Key evidence from clinical trials for interferon for melanoma

Introduction

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

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

Peginterferon alfa-2b (Sylatron®)

• In 2011, the FDA approved peg-interferon alfa-2b for melanoma how assistant surgical treatment in patients with microscopic or gross nodal participation, within 84 days of definitive surgery resection full included lymphadenectomy.
• The approval of the drug was based on a period of 5 years, open, multicenter clinical trial of 1256 patients with melanoma (EORTC [European Organization for Research and Treatment of [European Organization for Researchand Treatment ofCancer]18991).
• Patients were randomly assigned to observation (no therapy) (n = 629) or to peginterferon alfa-2b (n = 627) at a dose of 6 µg / kg per subcutaneous injection once a week for 8 doses followed by a subcutaneous injection of 3 µg / kg once a week for a total treatment period of up to 5 years
• Patients were evaluated 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 mean 7.6 years follow-up, there had been 384 recurrences or deaths in the peginterferon alfa-2b group versus 406 recurrences or death in the observation group (hazard ratio [HR], 0.87; interval CI 95% confidence, 0.76 to 1.00; P = 0,55).
• At mean 7.6-year follow-up, patients taking 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%, 0.35 to 0.97; P = 0.006) were prolonged with treatment with peginterferon alfa-2b.
• 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.

Interferon alfa-2b (Intron®A)

• In 1996, the FDA approved interferon alfa-2b as an adjunctive treatment for surgery in evil one melanoma patients at high risk of systemic reappearance.
• The approval was based on safety and effectiveness The results of interferon alfa-2b evaluated in melanoma patients who were disease-free (after surgery) but at high risk for systemic recurrence as reported in the ECOG [European Cooperative Oncology Group] trial 1684 and ECOG trial 1690.

ECOG 1684

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

ECOG 1690

• Patients with resected high-risk melanoma were randomized equally to one of three groups: high-dose Intron® A treatment for 1 year (same schedule as ECOG 1684), low-dose Intron® A treatment for 2 years (3 million international units / day 3 times per week SC), and observation.
• Consistent with the 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 observed in the observation arm.
• Neither high-dose nor low-dose Intron® A therapy showed an overall survival benefit compared to 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. White blood cell interferon gene inserted 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 been shown to be objective regression of cutaneous and visceral tumors on therapy with Roferon®-A 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 adjunctive treatment of patients with malignant melanoma (tumor thickness> 1.5 mm) surgically removed and having no nodes or distant metastasis before starting treatment.
• The European Union approval was based on the results of 2 randomized phase III trials conducted in France and Austria.

French melanoma cooperative group trial

• In the French Cooperative Group Trial, the efficacy of Roferon®-A was evaluated in patients with primary cutaneous melanoma thicker than 1.5 mm and without clinically detectable lymph node metastases in a large randomized 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 the relapse-free interval (p = 0.035) but there was no statistically significant difference in overall survival (p = 0.059) in patients treated with Roferon®-A compared to the controls. The overall effect of treatment was a 25% reduction in the risk of relapse.
• Only 10% of patients experienced WHO grade 3 or 4 treatment-related adverse events.
• The 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 adjuvant Roferon®-A treatment (n = 154) or observation (n = 157), after excision of the primary tumor
• Interferon alfa-2a was administered daily at a dose of 3 million international units (mIU) subcutaneously (sc) for 3 weeks (induction phase), then a dose of 3 mIU sc three times a week for 1 year ( maintenance phase).
• In an average observation time of 41 months, a significantly prolonged period (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 is not approved in the US for the adjunctive treatment of malignant melanoma.
• The US FDA Drug Cancer Advisory Committee has refused to recommend approval of Roferon®-A (recombinant interferon alfa-2a, Hoffmann-La Roche) for the adjunctive treatment of surgically resected malignant melanoma, with no evidence nodal disease clinic.

Future directions

• Adjuvant interferon alfa-2b has been used commonly for the treatment of advanced malignant melanoma in the US and Europe.
• However, interferon alfa-2b remains a controversial therapy.
• Toxicity is substantial, with neuropsychiatric, constitutional, and liver toxicity being the main problems.
• Efficacy is considered modest by many, especially when compared to toxicity which has a substantial impact on quality of life.
• Meta-analyzes have shown highly significant effects of interferon alfa-2b treatment 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 lymph node metastases.
• As such, ongoing efforts to maximize benefit and limit toxicity by examining dose and schedule remain relevant.
• The emergence of new approaches to treating melanoma in the advanced disease setting creates opportunities for better tolerated therapies in the adjuvant setting.
• The finding that melanomas They frequently contain conductive oncogenes. The approach to the management of patients with advanced disease has changed.
• the BRAF vemurafenib and dabrafenib inhibitors and the MEK inhibitor trametinib significantly improves survival in patients with advanced disease.
• The efficacy of the checkpoint inhibitors ipilimumab and nivolumab in the advanced setting also requires evaluation of these therapies in the adjuvant setting.