AuthOr’s VIew OncoImmunology 1:7, 1197-1199; October 2012; © 2012 Landes Bioscience AuthOr’s VIew Ipilimumab in a Phase II trial of melanoma patients with brain metastases Kim Margolin university of washington; s eattle, wA us A Keywords: ipilimumab, brain, metastatic, metastases, melanoma In a Phase II clinical study enrolling individuals with melanoma brain metastases, 51 asymptomatic patients (cohort A) and 21 on a stable steroid dose (cohort B) received 4 courses of 10 mg/kg intravenous ipilimumab (induction), then (at 24 weeks) maintenance therapy with the same dose of ipilimumab every 12 weeks. Disease control rate at 12 weeks was 18% (according to the modified wh O criteria) and 26% (according to the immune-related response criteria) in cohort A (median survival = 7 mo) and 5% and 10% in cohort B (median survival = 4 mo). t oxicities were as previously reported for ipilimumab patients without brain metastases. Brain metastases are common in mela- noma and have been shown to be refrac- tory to nearly all standard therapies until recently. Surgery and stereotactic radio- therapy are the optimal treatments for local disease, but whole brain radiation is of limited value in preventing further brain metastases, which are—in a substan- tial fraction of patients—the predominant cause of melanoma morbidity and mor- tality. Systemic therapies available before 2011 were nearly devoid of activity, regard- less of their ability to cross the blood brain barrier. While antibodies are not believed to cross an intact blood-brain barrier, activated T cells may be able to penetrate the brain,1,2 providing a rationale for test- ing immunomodulatory therapies in this setting. Further support for testing this approach came from anecdotal reports of tumor regressions in patients with meta- static melanoma and brain metastasis. We have reported the results of a pro- spective clinical trial designed to evalu- ate the efficacy and safety of ipilimumab in patients with melanoma metastatic to the brain.3 Key eligibility criteria for our Phase II study were as described, with eligible patients enrolled in two cohorts based on whether they received corticoste- roids for symptoms or edema. Patients in cohort A were neurologically asymptom- atic with no systemic glucocorticosteroid therapy in the 10 d prior to the start of ipilimumab therapy. Patients receiving concurrent systemic corticosteroids for control of neurological signs and symp- toms related to brain metastases were enrolled in cohort B. Study treatment consisted of 10 mg/kg intravenous ipilimumab, every 3 weeks for 4 treatments (induction), followed at 24 weeks by maintenance therapy using the same dose every 12 weeks, for stable or responding patients without severe tox- icity. The primary endpoint was disease control rate (DCR), defined as an objec- tive response or stable disease after the 12-week time point, based on modified WHO (mWHO) criteria (bidimensional). We also applied the immune response- related criteria (irRC), in which new lesions are incorporated into the measure- ment of tumor burden rather than them- selves constituting progression. Seventy-two patients were enrolled between July 31, 2008 and June 3, 2009, 51 patients in cohort A and 21 in cohort B. The median number of doses of induc- tion therapy received by patients was 3 (range 1–4) for subjects in cohort A and 2 (range 1–4) for subjects in cohort B. Patients in cohort A who went on to maintenance therapy received a median of 6 doses (range 1–10), while patients in cohort B who went on to the maintenance Correspondence to: Kim Margolin; Email: kmargoli@seattlecca.org Submitted: 05/07/12; Accepted: 05/08/12 http://dx.doi.org/10.4161/onci.20687 phase (n = 2) received a median of 7 doses of ipilimumab. Response and disease control results are summarized in the Table 1, while overall survival (OS) is shown in Figure 1. Median OS was 7 mo (range 0.4–31+) for cohort A and 4 mo (0.5–25+) for cohort B. Survival rates at 6-, 12-, 18- and 24 mo were 55%, 31%, 26% and 26% for cohort A and 38%, 19%, 19% and 10% for cohort B. The most common adverse effects were fatigue, diarrhea, nausea, headache, rash and pruritus, with immune-related adverse effects clearly attributable to ipilimumab occurring in the reported and expected frequency. Of note is that CNS events were infrequent and attributable to the tumor, with no clearly drug- or immune-related adverse effects occurring in the CNS. Despite historical assumptions that most therapies would not effectively cross an intact blood brain barrier and the poor prognosis of melanoma patients with brain metastases, who de facto have rarely been allowed to participate in trials test- ing new therapies, objective responses of melanoma brain metastases to interleu- kin-2 (IL-2)-based approaches have been reported in references 4–7, suggesting the possibility of an effective control of CNS metastases by T-cell responses to immuno- modulatory therapies. Anecdotal reports www.landesbioscience.com OncoImmunology 1197