Ipilimumab had dose-dependent effect in advanced melanoma

Ipilimumab demonstrated a dose-dependent effect in patients with advanced melanoma, with overall response improving as the dose increased, according to the findings of a phase-2 trial.

Findings from earlier studies showed antitumor activity with various doses and regimens of ipilimumab. The researchers of this study assessed the dose-responsiveness of the drug.

The researchers conducted a trial at 66 centers in 12 countries. They randomly assigned patients with previously treated stage III or stage IV melanoma to ipilimumab 0.3 mg/kg (n=73), 3 mg/kg (n=72) or 10 mg/kg (n=72) every three weeks for four cycles followed by maintenance therapy every three months.

Median follow-up was 8.3 months for 0.3 mg/kg, 8.7 months for 3 mg/kg and 10.7 months for 10 mg/kg.

The best overall response rate was 11.1% (95% CI, 4.9-20.7) in the group assigned 10 mg/kg. Patients in the 3 mg/kg had an overall response rate of 4.2% (95% CI, 0.9-11.7) and those assigned 0.3 mg/kg had a rate of 0% (95% CI, 0.0-4.9).

The HRs for median OS between groups were 0.770 (95% CI, 0.525-1.130) for 10 mg/kg vs. 0.3 mg/kg; 0.875 (95% CI, 0.593-1.291) for 10 mg/kg vs. 3 mg/kg; and 0.879 (95% CI, 0.604-1.279) for 3 mg/kg vs. 0.3 mg/kg.

Overall, immune-related adverse events were noted in 19 patients in the 0.3 mg/kg group, 46 patients in the 3 mg/kg group and 50 patients in the 10 mg/kg group.

Grade-3 and grade-4 gastrointestinal immune-related adverse events occurred in no patients assigned to 0.3 mg/kg, two patients assigned to 3 mg/kg and 11 patients assigned to 10 mg/kg. Grade-3 and grade-4 diarrhea occurred in none of the patients assigned 0.3 mg/kg, one assigned 3 mg/kg and 10 assigned 10 mg/kg.

“Further investigations of ipilimumab efficacy and safety at 10 mg/kg in patients with advanced melanoma are warranted,” the researchers said.

Wolchok JD. Lancet Oncol. 2009;doi:10.1016/S1470-2045(09)70334-1.

This randomized, double blind, phase-2 study is designed to further explore ipilimumab, an immunotherapeutic agent (a human anti-CTLA4 antibody), in patients with refractory advanced melanoma. In murine models, antibody blockade of CTLA4 enhances immune responses resulting in tumor regression. Previous clinical trials have shown the antitumor activity of ipilimumab in patients with refractory advanced melanoma. The data of this study showed a dose-dependent effect of Ipilimumab on clinical efficacy and safety measures. The overall response rates were 11.1% for 10 mg/kg, 4.2% for 3 mg/kg, and 0% for 0.3 mg/kg. However, immune-related adverse events, as well as adverse events that led to discontinuation of the treatment, were also dose dependent with 70% and 27% observed in the 10 mg/kg cohort.

The PFS rate at 24 weeks was low in all three cohorts: 18.9%, 12.9% and 2.7%, respectively. More than 80% of all patients were unable to receive maintenance therapy after their initial induction therapy. The reported improved median OS of 8 months to 11 months is an unlikely result of this immunotherapy.

It was reported previously that ipilimumab can induce durable objective responses in less than 5% of patients, which is related to the induction of immune-related adverse events (IRAEs). However, despite the hundreds of melanoma patients that have received this immunotherapeutic agent, the prognostic and/or predictive factors related to the clinical responses remain unknown. Because of the high incidence of grade-3 to grade-4 IRAEs and low response rate, the majority of treated patients could not benefit from this immunotherapy. Future development of this agent needs to focus on better understanding of how patients respond to this therapy and management of IRAEs. With this knowledge, we will be able to select appropriate patients who can benefit from this novel immunotherapy.

– Wen-Jen Hwu, MD, PhD
HemOnc Today Editorial Board member