IPILIMUMAB EFFECTIVE IN MELANOMA PATIENTS WITH BRAIN METASTASES

March 26, 2012 — Patients with advanced melanoma who have developed brain metastases are traditionally excluded from clinical trials, but this practice should stop, according to experts commenting on a study published online today in the Lancet Oncology.

The small phase 2 trial is one of the first ever conducted specifically in patients with advanced melanoma and brain metastases. It found that benefits from the novel immunotherapy ipilimumab (Yervoy, Bristol-Myers Squibb) were similar to those seen in patients with advanced melanoma without brain metastases.

"We believe these data are sufficient to support use of ipilimumab in selected patients with brain metastases, particularly metastases that are small and asymptomatic," write the researchers, led by Kim Margolin, MD, from the University of Washington in Seattle.

They are "encouraging" and suggest that the activity of ipilimumab is "real," Drs. Fisher and Larkin note. The data show that the presence of brain metastases should not prevent the use of ipilimumab, they add.

These results have several important implications, according to an accompanying comment by Rosalie Fisher, MD, and James Larkin, MD, PhD, from the Royal Marsden Hospital in London, United Kingdom.

"Brain metastases are a major problem for patients with advanced melanoma and their families, and we need to offer them active drugs as a matter of urgency," Drs. Fisher and Larkin write.

In addition, and "perhaps most importantly, the era in which patients with brain metastases are excluded from clinical trials must end," they declare.

First Trial to Address This Problem

Estimates of the frequency of brain metastases among patients with advanced melanoma vary from 10% to 50%, but results from autopsies suggest that the frequency could be even higher — around 66% to 75%, the researchers report.

The management of these patients is particularly challenging, they write. Melanoma is frequently resistant to radiotherapy and cytotoxic chemotherapy, and the median overall survival after a diagnosis of brain metastases is only 4 months, they note.

This study is one of the first to specifically and prospectively address this clinical problem, Drs. Fisher and Larkin point out.

The trial involved 72 patients with advanced melanoma and brain metastases. The cohort consisted of 51 patients who were neurologically asymptomatic and not receiving corticosteroids at study entry and 21 patients who were symptomatic and on stable doses of corticosteroids.

All patients were scheduled to receive 4 doses of ipilimumab 10 mg/kg intravenously once every 3 weeks. This is a higher dose than is currently licensed (3 mg/kg every 3 weeks for 4 doses), note Drs. Fisher and Larkin; they point out that the 2 different doses will be compared directly in a phase 3 trial that is planned (NCT01515189).

Assessment at 12 weeks showed disease control in 9 of the 51 asymptomatic patients (18%) and in 1 of the 21 symptomatic patients (5%).

In addition, the research team assessed disease control in the brain alone (reported in 24% of asymptomatic and 10% of symptomatic patients) and disease control outside of the brain (reported in 27% of asymptomatic and 5% of symptomatic patients).

The median overall survival was 7 months in asymptomatic and 3.7 months in symptomatic patients.

Long-term survival was similar to that reported for patients with advanced melanoma without brain metastases, the researchers note. Nearly one third of patients in both groups were still alive at 1 year; 26% of asymptomatic and 10% of symptomatic patients were still alive at 2 years.

Patients who survived and were clinically stable at week 24 were eligible to receive maintenance therapy with 10 mg/kg ipilimumab every 12 weeks. Only 11 asymptomatic and 2 symptomatic patients received maintenance therapy (mean, 6 or 7 doses).

Adverse effects seen in this study were similar to those reported previously with ipilimumab in patients with advanced melanoma and no brain metastases, the researchers note. The most common grade 3 adverse effects were diarrhea, fatigue, dehydration, hyperglycemia, rash, and raised liver enzymes. One asymptomatic patient died from drug-related complications of immune-related colitis, despite treatment with corticosteroids.

"Overall, our trial shows that the activity of ipilimumab is similar in patients with advanced melanoma with and without brain metastases," the researchers conclude.

Negative Effect of Steroids?

Dr. Margolin and colleagues speculate that the "apparent low rate of benefit" in symptomatic patients might be related to the negative effect of steroids on ipilimumab activity. Further study is needed, they note, because it appears that steroid treatment at the initiation of ipilimumab could abrogate or downmodulate immune response to the drug.

However, they caution against overinterpretation of these data. "The study design did not permit the assessment of other potentially unfavorable prognostic factors in [symptomatic patients], such as tumor size, number and extent of peritumor edema, and previous therapies," they said in a statement.

The trial was funded by Bristol-Myers Squibb, the manufacturer of ipilimumab. Three coauthors are company employees, and several report serving as consultants and receiving honoraria from Bristol-Myers Squibb. Dr. Margolin, 3 coauthors, and Dr. Fisher have disclosed no relevant financial relationships. Dr. Larkin reports receiving honoraria from Bristol-Myers Squibb and GlaxoSmithKline.

Lancet Oncol. Published online March 26, 2012. Abstract, Comment