The future appears a bit brighter for patients with advanced melanoma and brain metastases, according to two studies presented at the 35th ESMO Congress, held October 8-12 in Milan, Italy. A subgroup analysis of a larger trial showed encouraging activity for ipilimumab in patients with a history of brain metastases,¹ and a second preliminary study showed dramatic shrinkage of brain metastases with an investigational BRAF inhibitor called GSK2118436.2

'Exciting Beginning'

Ipilimumab is active in patients with advanced melanoma and a history of brain metastases, according to a subgroup analysis¹ of a large phase III trial originally presented at the 2010 ASCO Annual Meeting. MDX010-20 was the first randomized phase III trial to demonstrate a survival improvement for any drug in advanced melanoma, and this was considered a major advance in the field. In the subgroup analysis, ipilimumab had comparable safety in patients with and without a history of brain metastases.

"This is a beginning [in patients with brain metastases], but it is a very exciting beginning. An ongoing phase II study is currently investigating ipilimumab activity in patients with active brain metastasis to get a more complete story," said Céleste Lebbé, MD, Hôpital St. Louis, Paris, France.

Ipilimumab is a monocolonal antibody that blocks CTLA-4 downregulation of T cells. The effect of the monoclonal antibody is to potentiate T cells.

In the overall trial, ipilimumab achieved a significant survival benefit in 676 previously treated patients with advanced melanoma, when administered with the gp100 vaccine (P = .0004) and without the vaccine (P = .0026) vs the vaccine alone. The 1- and 2-year survival rates were nearly doubled in both groups treated with ipilimumab, and the survival benefit was consistent across all subgroups of patients, regardless of gender, age, melanoma stage at study entry, baseline LDH level, previous use of interleukin-2 (Proleukin), and history of central nervous system (CNS) metastasis.

The subpopulation of 77 patients with a history of brain metastases (ie, not active at time of trial enrollment) had improved overall survival when treated with ipilimumab, although the magnitude of improvement was smaller than in the 338 patients with no history of brain metastases.

'Benefit Comes with a Price'

"The benefit of ipilimumab comes with a price," said Dr. Lebbé.

In the overall trial, the major adverse event was immune-related toxicity (eg, enterocolitis, dermatitis), which was manageable with vigilant follow-up and early steroids. The rate of grade 3/4 toxicity was 17% and 23% for ipilimumab given with and without a vaccine, respectively, compared to 11% for the vaccine alone. Grade 3/4 immune-related toxicity in the three arms was 10%, 15%, and 0.8%, respectively. Treatment-related deaths occurred in 2.1%, 3.1%, and 2%, respectively; and immune-related deaths occurred in 1.3%, 1.5%, and 0%.

In the subgroup analysis, safety was consistent between the groups with and without a history of brain metastases. No new neurologic concerns were evident in those with brain metastases.

Formal discussant of the subgroup analysis, Cornelis J. A. Punt, MD, of Nijmegen Medical Center in the Netherlands, said the good news is that there is finally an active drug in advanced melanoma, but the bad news is that it is given only after other drugs fail.

"We have no good drugs for first-line treatment of melanoma," he said. "The other bad news is that the new drug has toxicity," he added.

Issues for Further Study

Dr. Punt raised several important issues for further study. In the MDX010-20 trial, HLA-A2 matching was required for use of the Gp100 vaccine, which was the control arm of the trial and included in one experimental arm combined with ipilimumab. It is not clear whether the activity of ipilimumab is restricted to patients with the HLA-A2 subtype, and more data are needed. It is also not clear whether gp100 was the optimal control arm, he continued.

The 23% rate of grade 3/4 toxicity and the 3.1% rate of toxic deaths in the ipilimumab-alone arm suggest that the optimal dose of ipilimumab remains to be determined.

Regarding the subgroup analysis, Dr. Punt commented, "These authors are to be commended for including patients who are usually excluded from clinical trials. The favorable effect of ipilimumab in patients with a history of brain metastases is promising."

Potentially 'Miraculous' Results

A small phase I/II study of 10 patients with advanced melanoma and active brain metastases treated with a new oral drug called GSK2118436 produced "miraculous" preliminary results,² according to Caroline Robert, MD, PhD, formal discussant of this late-breaking abstract at the ESMO meeting.

The investigational compound, known as GSK2118436, is an inhibitor of BRAF, a gene that is mutated in 50% of melanomas. The drug binds to the active BRAF protein on melanoma cells and inhibits proliferation, explained lead author Georgina Long, MD, Melanoma Institute Australia and Westmead Hospital in Sydney, Australia.

"The compound is only active in patients with BRAF mutations, and this drug is showing robust clinical activity," she emphasized.

All 10 patients had untreated brain metastases at study entry, and 9 patients experienced tumor shrinkage ranging from 20% to 100%. Responses were seen in those with multiple metastases; in fact, one of the responding patients had over 10 metastases, she said. Prior to treatment, all brain metastases were 3 mm or greater in diameter.

Dr. Long said a similar effect of the BRAF inhibitor was seen in a separate phase I/II study of patients with melanoma and extra-CNS metastases (ie, breast, pelvis, axillae, liver, and spleen), with a response rate of 77% at last update at the Society of Melanoma Research Conference 2010, in Sydney, Australia.

The most frequent side effects of the new drug are fatigue, pyrexia, and dehydration.

Other Surprising Findings

Dr. Robert, of the Institut Gustave Roussy, Villejuif, France, called these preliminary results "astonishing."

"Median overall survival for melanoma patients with brain metastases is under 4 months, and there are no good treatments. Chemotherapy, surgery, and radiotherapy don't work," she told listeners. "Ongoing studies are looking at ipilimumab. The results with this new oral compound are surprising, in that there is a parallel response in the brain and in extra-CNS sites."

Areas for further study include the durability of response, impact on survival, efficacy for larger brain metastases, and efficacy in the adjuvant setting, she continued.

"We are confronted here with extremely promising results. Only the future will tell us if these miraculous results hold up," she concluded. ■

References

1. Lebbé C, McDermott DF, Robert C, et al: Ipilimumab improves survival in previously treated, advanced melanoma patients with poor prognostic factors: Subgroup analysis from a phase III trial. 35th ESMO Congress. Abstract 13240. Presented October 10, 2010.

2. Long GV, Kefford RF, Carr PJA, et al: Phase 1/2 study of GSK2118436, a selective inhibitor of V600 mutant (mut) BRAF kinase: Evidence of activity in melanoma brain metastases (mets). 35th ESMO Congress. Abstract LBA27. Presented October 10, 2010.