Biotherapy Maintenance in Metastatic Melanoma

NEW YORK—For some stage IV melanoma patients who achieve only a partial response or stable disease on a regimen of biochemotherapy, a maintenance strategy using interleukin-2 (IL-2) may prolong survival and in some instances produce durable complete responses, California researchers have discovered. Steven J. O’Day, MD, associate director, medical oncology, John Wayne Cancer Institute at St. John’s Health Center, Santa Monica, reported the encouraging results of a pilot study of the biotherapy maintenance strategy at the Chemotherapy Foundation Symposium XVIII.

Among the first 23 patients, 5 achieved an objective response during the treatment, which followed an initial intensive biochemotherapy regimen. "Four of these were complete remissions," Dr. O’Day said. "Of these 5 patients, 4 remain alive more than 2 years out." The one death in this subset was due to progression of central nervous system metastases.

Patients in the maintenance trial were drawn from a prior study of poor-prognosis patients treated with a regimen that included IL-2 given in a rapid decrescendo dosing pattern. Given over the first 4 days of each 21-day cycle, the IL-2 doses were 18, 9, 4.5, and 4.5 mIU/m². "The concept," Dr. O’Day explained, "was high dose early, then rapid tapering of IL-2 to affect the immune response maximally and decrease toxicity."

Also included in the inpatient bioche-motherapy regimen were dacarbazine, vinblastine, cisplatin (Platinol), and interferon-alfa-2b (Intron A). G-CSF (Neu-pogen) was begun on day 6 after discharge from the hospital.

Of the 45 patients in this study, 62% had metastases to three or more organs, Dr. O’Day reported. More than 60% had non-lung visceral metastases, including sites in bone, brain, and liver.

The overall response rate was 57%, with 23% achieving a complete remission. "But what’s interesting is that, in addition to the complete responding patients, about 55% of patients [34% partial response, 20% stable disease] seem to have arrested tumor growth with this regimen," Dr. O’Day said.

The researchers wanted to focus on those 55% because they have a uniformly poor survival rate, with about 100% progressing within 12 months and a median time to progression of only 3 months. "It’s an all-or-nothing phenomenon with biochemotherapy," he said. "Patients who achieve a complete remission have a chance of long-term survival, but anything less isn’t important in terms of survival." Thus, the researchers decided to immediately follow biochemotherapy with an immune strategy that was less toxic but might salvage some of these patients.

In the maintenance regimen, IL-2 was given subcutaneously at a low dose of 1 mIU/m² for 5 days. GM-CSF was given on a schedule of 14 days on, 14 days off. Periodically, patients were hospitalized for 48 hours for high-dose decrescendo pulses of IL-2. These pulse doses were more frequent in the first 6 months than in the next 6, when only 3 were given.

None of the patients had to discontinue the program because of toxicity, Dr. O’Day said. About 10% to 20% of patients, he estimated, have presented with "an interesting immune phenomenon"—vitiligo, immune thyroiditis, and immune-mediated thrombocytopenia. "All of this has been relatively easily treated and managed," he said, "but this is clearly a sign of immune activation."

Although encouraged by the four complete remissions achieved with the maintenance strategy, Dr. O’Day and his colleagues were more interested in its effect on disease progression and survival.

Progression-free survival at 12 months, he reported, was about 30%, compared with the 6% in historical controls from his institution who were treated with biochemotherapy with no maintenance biotherapy.

The biotherapy maintenance strategy also appears to have lengthened survival, Dr. O’Day reported. While the overall median survival was 9.1 months among comparable historical patients, it increased to 14.1 months in the maintenance group.

Among the historical controls, 31% survived for 1 year, he noted, while 69% of the maintenance group were alive 12 months after beginning the initial bio-chemotherapy regimen.

Program Extended

Initially conceived as a 12-month protocol, the program has now been extended to include a second year, with IL-2 pulses given every other month to patients who wish to continue. "If it works early," Dr. O’Day said, "there’s no reason that we have to stop at a year. It’s a lot of treatment, but given the prognosis and the motivation of these patients, they’re more than willing to do it."

Additional patients have also been put on the protocol, and the total who have received it is now more than 40. Analyses of data from 42 patients, Dr. O’Day said, shows that that the survival advantage seen in the initial group is holding up.

A multicenter single-arm trial is being launched, Dr. O’Day announced, in which 130 stage IV melanoma patients will receive induction biochemotherapy, and those with stable disease or an objective response will go on to maintenance biotherapy. "If we can reproduce these data in the larger multicenter trial," he said, "then the strategy would be eligible for a phase III study."