Ipilimumab in patients with melanoma and brain metastases – Authors' reply

Kim Margolin and colleagues addressed the issue of systemic treatment in patients with malignant melanoma and brain metastases. Such treatment is a crucial component of care because most of these patients have metastases outside the brain that restrict survival after successful local management (ie, surgical resection or radiotherapy, or both). In their openlabel, phase 2 study of ipilimumab, they reported that some patients responded and that the toxicity profi le was similar to those from other investigations. The feasibility of such treatment is good news. However, the study had several limitations. In cohort A (asymptomatic patients not receiving concomitant corticosteroid treat ment), 39 (76%) of 51 patients had progressive brain metastases after 12 weeks (assessed with modifi ed WHO criteria) and median brain progression-free survival was 1·5 months (median overall survival 7·0 months). Only 21 (41%) patients in this cohort had undergone previous brain radiotherapy. Together with the apparent disconnect be tween progression-free survival and overall survival, one might spec u late that many patients might have been subsequently irradiated. The use and potential eff ect of such salvage treatment was not reported by Margolin and co-workers. Additionally, further information about the cause of death (brain metastases vs extracranial progression) would be interesting because the main eff ect of ipilimumab could be improved extracranial control. Eight (16%) patients in cohort A achieved partial responses in the brain after 12 weeks, with no complete responders. Details about these patients were not provided. Patients who had completed brain radiotherapy at least 14 days before the start of ipilimumab could be included in the trial. If such patients were among those who responded, the prevailing cause of response might in fact have been radiotherapy. Da Silva and colleagues reported that 22·6% of melanoma metastases decreased in volume by more than 15% within 30 days of radiosurgery, and that imaging response could continue well beyond the fi rst month. Another radiosurgery study showed that 14% of patients had complete responses and 42% partial responses. Therefore, such highly effi cacious treatment should be part of routine management of patients with few small brain metastases and good performance status (only patients with ECOG performance status of 0 or 1 and index lesions ≤3 cm were included by Margolin and co-workers). In cohort B (symptomatic metastases controlled with cortico steroids; only 24% had had previous brain radiotherapy), 19 (90%) of 21 patients had progressive brain metastases after 12 weeks and median brain progression-free survival was 1·2 months (median overall survival 3·7 months). With the high cost of ipilimumab, the short and provocative interpretation of these results could be that such treatment is diffi cult to justify. Additional, unreported prognostic factors—eg, number of brain metastases and serum lactate dehydrogenase concentration—could help to identify the few patients with fairly favourable survival prognosis who might be candidates for ipilimumab treatment. Further information about baseline parameters and salvage treatment, particularly in responders, could contribute to an improved understanding of ipilimumab’s eff ects in patients with brain metastases. Eff ective systemic treatment is urgently needed in this patient population.