By ecancer reporter Jo Armstrong

The immune system is a powerful natural agent against cancer. Cytotoxic T lymphocyte antigen 4 (CTLA-4), a key negative regulator of T-cell responses, can restrict the anti-tumour immune response. Ipilimumab is a fully human, monoclonal antibody that overcomes CTLA-4-mediated T-cell suppression to enhance the immune response against tumours. Pre-clinical and early clinical trials of ipilimumab as monotherapy or combined with other therapies including chemotherapy, vaccines and cytokines, have shown it to be well tolerated and have demonstrated clear evidence of immunological and anti-tumour activity. These studies have provided the basis for further trials. The results of a large study in 676 HLA-A*0201-positive patients with pretreated, unresectable stage III or IV melanoma were reported at ESMO 2010. Ipilimumab produced durable objective responses in these patients, compared to gp100 peptide vaccine.¹ The responses were associated with long-term survival in some patients. In an extension of the study, overall median survival was significantly greater for ipilimumab versus gp100 peptide vaccine (10 months versus 6.4 months, p=0.0026), with 23.5% of patients on ipilimumab monotherapy versus 13.7% for the vaccine surviving 2 years.² As part of this trial, the impact of ipilimumab on patient health-related quality of life (HRQL) was assessed. It was found that ipilimumab, either alone or in combination with gp100 peptide vaccine, and gp100 peptide vaccine alone did not have a significant negative impact on patient HRQL in the 12 week induction period.³ Patients whose disease progressed after a confirmed objective response at first tumour assessment, or with stable disease for ≥6 months were eligible for re-induction with originally assigned treatment. Forty patients received re-induction therapy. Among patients who received re-induction with ipilimumab, disease control rate was 52-67%. The safety profile during re-induction was consistent with that of overall study.⁴

The effect of systemic steroids, which are given to manage immune-related adverse events, on clinical response was also assessed. It was found that the clinical benefit rate was similar regardless of whether patients received prior corticosteroids.⁵

An assessment of pharmacokinetic (PK) interaction between ipilimumab and chemotherapy demonstrated no clinically relevant PK interactions between ipilimumab and paclitaxel/carboplatin or dacarbazine.⁶ It was concluded that ipilimumab could be combined with these chemotherapy regimens without dose adjustment in advanced melanoma patients.

1. C Ottensmeier et al. Poster 1326P: Ipilimumab produces durable objective responses in patients with previously treated, advanced melanoma: results from a phase III trial.

2. JB Haanen et al. Poster 1327P: Ipilimumab improves overall survival in patients with previously treated, advanced melanoma: long-term survival results from a phase III trial.

3. D Revicki et al. Poster 1328P: Health related quality of life (HRQL) outcomes of ipilimumab treatment in patients with previously treated unresectable stage III or IV melanoma (USIII/IV Mel).

4. C Robert et al. Poster 1330P: Re-induction with ipilimumab, gp100 peptide vaccine, or a combination of both in a phase III study of previously-treated patients with advanced melanoma: update of clinical characteristics of patients.

5. P Lorigan et al. Poster 1331P: Clinical response to ipilimumab: effect of systemic corticosteroids used to manage immune-related adverse events (irAEs).

6. JS Weber et al. Poster 1329P: Assessment of pharmacokinetic interaction between ipilimumab and chemotherapy in a randomized study.