Ipilimumab in Uveal Melanoma: Long-Lasting Responses in 25%

Zosia Chustecka

December 02, 2014

The first trial of the immunomodulator ipilimumab (Yervoy, Bristol-Myers Squibb Company) conducted in patients with malignant uveal melanoma has shown efficacy in some patients.

"After almost 2 years' follow-up, we can see that almost 25% of patients are still alive, and that is very encouraging in this population of patients with very bad outcome," lead investigator Josep Piulats, MD, PhD, from the Institut Catala d'Oncologia and L'Hospitalet del Llobregat in Spain, told Medscape Medical News.

The results from the study, known as GEM1, were presented in a poster at the recent Society of Melanoma Research (SMR) 2014 International Congress, in Zurich, Switzerland.

Although the study was small (only 32 patients) and open-label, and although it just missed its primary endpoint of improving overall survival, the researchers say they are encouraged by finding "objective responses in a population of highly metastatic patients."

The disease control rate was close to 50%, with stable disease seen in 39.71% and partial response in 6.45%.

Most Common Intraocular Malignancy

Uveal melanoma is the most common intraocular malignancy in adults, and the uvea is the second most common location for primary melanoma after skin. Overall survival in these patients is low, say the researchers, owing to a high incidence of liver metastases that are usually fatal within 4 to 9 months of diagnosis.

Patients with uveal melanoma have been excluded from the large studies of ipilimumab in cutaneous melanoma. Because these trials have shown long-term survival in some patients, the researchers thought they would try ipilimumab in this patient population, in which there is no standard treatment and in which chemotherapy is not effective.

Dr Piulats and colleagues conducted an open-label, single-arm, phase 2 study at five centers in Spain, enrolling 32 patients from July 2011 to September 2013. Patients had progressive disease and had not previously received any systemic therapy. One patient was ineligible because of the absence of metastatic disease at baseline, the researchers note.

Ipilimumab was given at 10 mg/kg intravenously every 3 weeks for 4 doses (induction), and then every 12 weeks (maintenance) until progression of disease, intolerance of the drug, or withdrawal from the trial. During the induction part of the study, five patients progressed and died, and one patient withdrew from the study. Only four patients went on to receive the maintenance therapy, the researchers note. Among the others, six had clinical progression of disease, and six withdrew from the trial, four because of toxicity and two for personal reasons.

The most common adverse event was an increase in liver enzymes, seen in 56% of patients (grade 4 in 31%), followed by fatigue (37.5%), infection (22%), skin rash (19%), and diarrhea (18.7%, mostly grade 2).

"Drug toxicity was manageable now that we are familiar with ipilimumab toxicity," Dr Piulats commented. He said that the 10-mg/kg dose of ipilimumab was chosen for this trial because previous reports from compassionate use programs that used the 3-mg/kg dose showed experiences in uveal melanoma that were not encouraging.

Some Patients Have Long-Lasting Responses

The median overall survival was 9.8 months. The researchers had calculated that survival of 10.28 months was needed to reject the null hypothesis, so the trial missed its primary endpoint, but only just: "it was close," they said.

"Nowadays we know that that overall survival might not be a good and reliable endpoint in a single-arm trial with ipilimumab," Dr Piulats commented.

The researchers are encouraged by the long-term survival in a small subgroup of patients, with nearly 25% of the original 32 patients still alive at 2 years' follow-up.

"As we show in the poster, the overall survival correlates with absolute lymphocyte number change between baseline and week 7, so we can expect that ipilimumab could be behind longer overall survival observed in few patients," he said.

A similar pattern of response has been seen with ipilimumab in cutaneous melanoma ― in which around 20% of patients have long-term responses, with some patients living for up to 10 years. For some patients, it seems that a short treatment with ipilimumab is enough to reset the immune system and reach a new balance, with a homeostasis in which tumor cells are still present but are being kept in check by the immune system.

Dr Piulats and colleagues are hoping to conduct further studies in uveal melanoma. Two other studies with ipilimumab are ongoing, and there is also a trial ongoing with the MEK-inhibitor selumetinib (under development by AstraZeneca), which has shown some promising results, he commented.

The results with selumetinib in uveal melanoma were hailed as a breakthrough when they were first reported in 2013, and this drug is currently being tested in an international phase 3 trial known as SUMIT.

"In my opinion, clinical trial should be the first option in these patients," Dr Piulats said.

The study was funded by Bristol-Myers Squibb, the manufacturer of ipilimumab.

Society of Melanoma Research (SMR) 2014 International Congress.

The results that were reported in the poster presentation have been published in Pigment Cell Melanoma Research (Pigment Cell Melanoma Res 2014;27:1219).

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