The potent antitumour impact of IFN-α can be suppressed by mechanisms that give rise to tumour immunological tolerance, which explains the limited clinical activity of alpha interferon as a monotherapy in metastatic melanoma. CTLA-4 is a key element in immune tolerance and preclinical studies suggested that it serves as a natural braking mechanism for T-cell activation. The inhibitory signal produced by CTLA-4 is blocked by anti–CTLA-4 antibodies, such as tremelimumab or ipilimumab, and T-cell activation is enhanced. Tremelimumab has been demonstrated to have an immune modulating role in which it unlocks the immune response by disrupting CTLA-4, enhances proinflammatory T-cell cytokine production and increases T-cell infiltration in responding tumours.

This phase II study tested the hypothesis that the combination of tremelimumab and interferon alfa-2b acting via different and possibly synergistic mechanisms would overcome tumour immune tolerance and lead to significant and durable clinical responses in patients with metastatic melanoma.

The study involved 37 patients with American Joint Committee on Cancer stage IV (9M1a, 6M1b, and 22M1c) who received IV tremelimumab 15 mg/kg/course (three cycles [one cycle = 4 weeks]) every 12 weeks. High-dose interferon alfa-2b (HDI) was administered concurrently, including IV induction at 20 MU/m2/d for 5 days/week for 4 weeks followed by maintenance at 10 MU/m2/d subcutaneously three times a week for 8 weeks per course. From course 2 onward, HDI maintenance was administered subcutaneously.

The following response data were available for 35 patients:

• The best objective response rate by intention to treat was 24% (4 complete responses and 5 partial responses).

• 14patients (38%) had stable disease that lasted 1.5 to 21 months.

• The median progression-free survival was 6.4 months (95% CI, 3.3 to 12.1 months).

• The median overall survival was 21 months (95% CI, 9.5 to not reached).

Grades 3 and 4 toxicities included neutropenia (n=6; 17%), diarrhoea/colitis (n=4; 11%), liver enzyme increase (n=4; 11%), rash (n=4; 11%), fatigue (n=15; 40%), and anxiety/depression (n=5; 14%).

The researchers conclude from these preliminary findings that HDI can be combined with tremelimumab with acceptable toxicity and promising durable antitumor efficacy that warrant further testing in a randomised trial.