Nivolumab combined with ipilimumab had clinically meaningful intracranial efficacy, concordant with extracranial activity, in patients with melanoma who had untreated brain metastases. (Funded by Bristol-Myers Squibb and the National Cancer Institute; CheckMate 204 ClinicalTrials.gov number, NCT02320058 .).

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Summary Melanoma central nervous system metastases are increasing, and the challenges presented by this patient population remain complex. In December 2015, the Melanoma Research Foundation and the Wistar Institute hosted the First Summit on Melanoma Central Nervous System (CNS) Metastases in Philadelphia, Pennsylvania. Here, we provide a review of the current status of the field of melanoma brain metastasis research; identify key challenges and opportunities for improving the outcomes in patients with melanoma brain metastases; and set a framework to optimize future research in this critical area.

The purpose of this study was to estimate magnetic resonance imaging-based brain perfusion parameters from combined multiecho spin-echo and gradient-echo acquisitions, to correct them for T₁₋, T₂₋, and T₂₋*-related contrast agent (CA) extravasation effects, and to simultaneously determine vascular permeability. Perfusion data were acquired using a combined multiecho spin- and gradient-echo (SAGE) echo-planar imaging sequence, which was corrected for CA extravasation effects using pharmacokinetic modeling. The presented method was validated in simulations and brain tumor patients, and compared with uncorrected single-echo and multiecho data. In the presence of CA extravasation, uncorrected single-echo data resulted in underestimated CA concentrations, leading to underestimated single-echo cerebral blood volume (CBV) and mean transit time (MTT). In contrast, uncorrected multiecho data resulted in overestimations of CA concentrations, CBV, and MTT. The correction of CA extravasation effects resulted in CBV and MTT estimates that were more consistent with the underlying tissue characteristics. Spin-echo perfusion data showed reduced large-vessel blooming effects, facilitating better distinction between increased CBV due to active tumor progression and elevated CBV due to the presence of cortical vessels in tumor proximity. Furthermore, extracted permeability parameters were in good agreement with elevated T1-weighted postcontrast signal values.

9501 Background: We previously reported efficacy and safety of NIVO+IPI in patients (pts) with untreated, asymptomatic, melanoma brain metastases (MBM) from the CheckMate 204 study. Here, we provide the first report of NIVO+IPI in pts with symptomatic MBM, and report updated data in pts with asymptomatic MBM. Methods: In this phase II trial, pts with ≥1 measurable, nonirradiated MBM 0.5–3.0 cm were enrolled into two cohorts: (1) those with no neurologic symptoms or steroid Rx (asymptomatic; cohort A); and (2) those with neurologic symptoms, whether or not they were receiving steroid Rx (symptomatic; cohort B). In both cohorts, pts received NIVO 1 mg/kg + IPI 3 mg/kg Q3W × 4, then NIVO 3 mg/kg Q2W until progression or toxicity. The primary endpoint was intracranial clinical benefit rate (CBR; proportion of pts with complete response [CR] + partial response [PR] + stable disease [SD] ≥6 mo). As of the clinical cutoff date on May 1, 2018, all treated pts (101 in cohort A and 18 in cohort B) had been followed for ~6 mo or longer. Results: In this updated analysis of cohort A (median follow-up of 20.6 mo), the CBR was 58.4% (Table). In cohort B, pts received a median of 1 NIVO+IPI dose and 2 of 18 pts (11%) received all 4 doses. At a median follow-up of 5.2 months in cohort B, intracranial objective response rate was 16.7% and the CBR was 22.2%. Grade 3/4 adverse events occurred in 54.5% of pts in cohort A and in 55.6% of pts in cohort B (6.9% and 16.7% in the nervous system, respectively), with one death related to treatment in cohort A (immune-related myocarditis). Conclusions: In pts with asymptomatic MBM, our updated results show a high rate of durable intracranial responses, further supporting NIVO+IPI as a first-line treatment in this population. Intracranial antitumor activity was observed with NIVO+IPI in pts with symptomatic MBM, but further study is needed to understand the biologic mechanisms of resistance to immunotherapy and to improve treatments in this challenging population. Clinical trial information: NCT02320058. [Table: see text]

9507 Background: Brain metastases (BMts) are a major cause of morbidity/death in MEL. We report the first efficacy data in MEL patients (pts) with BMts who received NIVO+IPI in study CheckMate 204. Methods: In this multicenter US trial (NCT02320058), MEL pts with ≥1 measurable BMt 0.5-3.0 cm and no neurologic symptoms or steroid Rx received NIVO 1 mg/kg + IPI 3 mg/kg Q3W x 4, then NIVO 3 mg/kg Q2W until progression or toxicity. Pts with severe adverse events (AEs) during NIVO+IPI could receive NIVO when toxicity resolved; stereotactic radiotherapy (SRT) was allowed for brain oligo-progression if an assessable BMt remained. The primary endpoint was intracranial (IC) clinical benefit rate (complete response [CR] + partial response [PR] + stable disease [SD] > 6 months). The planned 90-pt accrual is complete; we report efficacy and updated safety for 75 pts with disease assessment before the Nov 2016 database lock. Results: Median age was 59 yrs (range 22–79). Median number of induction doses was 3; 26 pts (35%) received 4 NIVO+IPI doses and 38 pts (51%) began NIVO maintenance. Response data are reported at a median follow-up of 6.3 months (Table). The IC objective response rate (ORR) was 56% (95% CI: 44–68); 19% of pts had a complete response. IC and extracranial responses were largely concordant. Rx-related grade 3/4 AEs occurred in 48% of pts, 8% neurologic, including headache and syncope. Only 3 pts (4%) stopped Rx for Rx-related neurologic AEs. One pt died of immune-related myocarditis. Conclusions: In CheckMate 204, prospectively designed to investigate NIVO+IPI in MEL pts with BMts, NIVO+IPI had high IC antitumor activity with objective responses in 56% of pts, CR in 19%, and no unexpected neurologic safety signals. The favorable safety and high anti-melanoma activity of NIVO+IPI may represent a new Rx paradigm for pts with asymptomatic MEL BMts and could change practice to avoid or delay whole brain RT or SRT. Clinical trial information: NCT02320058. [Table: see text]

The location and distribution of glioblastoma (GBM) within the brain parenchyma plays an important role in surgical and radiation planning. Prior studies have reported incidences of multiple lesions at the time of diagnosis ranging from 0.5 to 20 %. Multiple lesions can be further categorized as multifocal (multiple areas involved, but with a clear path of spread from one lesion to another) or multicentric (multiple lesions, no clear path of spread). In this retrospective study, we reviewed our experience with GBM and found the incidence of multiple lesions at time of diagnosis was 35 %, much higher than previously suggested in the literature. Patients with single lesions had an improved overall survival when compared to patients with multiple lesions (18 vs. 10 months). Patients with multicentric lesions fared the worst, with average survival of 3 months. However, the difference between single and multiple lesions (multifocal or multicentric) was no longer significant when taking into consideration age, Karnofsky performance score (KPS) and extent of resection by multivariate analysis. Age, KPS, gross total resection, and MGMT status were independent predictors of outcome. Multiple lesions did not independently confer a worse outcome, but were associated with lower KPS scores and inability to perform gross total resection. These findings suggest that single, multiple and multicentric imaging exams represent a spectrum of presentations of a single disease. The rate of multiple lesions reported here may be the result of improved imaging technology, suggesting that incidence of multiple lesions will continue to increase as imaging technology advances.

Purpose: Preclinical studies have demonstrated that postirradiation tumor revascularization is dependent on a stromal cell-derived factor-1 (SDF-1)/C-X-C chemokine receptor type 4 (CXCR4)-driven process in which myeloid cells are recruited from bone marrow. Blocking this axis results in survival improvement in preclinical models of solid tumors, including glioblastoma (GBM). We conducted a phase I/II study to determine the safety and efficacy of Macrophage Exclusion after Radiation Therapy (MERT) using the reversible CXCR4 inhibitor plerixafor in patients with newly diagnosed glioblastoma.Patients and Methods: We enrolled nine patients in the phase I study and an additional 20 patients in phase II using a modified toxicity probability interval (mTPI) design. Plerixafor was continuously infused intravenously via a peripherally inserted central catheter (PICC) line for 4 consecutive weeks beginning at day 35 of conventional treatment with concurrent chemoradiation. Blood serum samples were obtained for pharmacokinetic analysis. Additional studies included relative cerebral blood volume (rCBV) analysis using MRI and histopathology analysis of recurrent tumors.Results: Plerixafor was well tolerated with no drugattributable grade 3 toxicities observed. At the maximum dose of 400 mg/kg/day, biomarker analysis found suprathreshold plerixafor serum levels and an increase in plasma SDF-1 levels. Median overall survival was 21.3 months [95% confidence interval (CI), 15.9-NA] with a progression-free survival of 14.5 months (95% CI, 11.9-NA). MRI and histopathology support the mechanism of action to inhibit postirradiation tumor revascularization.Conclusions: Infusion of the CXCR4 inhibitor plerixafor was well tolerated as an adjunct to standard chemoirradiation in patients with newly diagnosed GBM and improves local control of tumor recurrences.