Kurzrock, Razelle

Abstract Castleman disease (CD) describes a group of heterogeneous hematologic disorders with characteristic histopathological features. CD can present with unicentric or multicentric (MCD) regions of lymph node enlargement. Some cases of MCD are caused by human herpesvirus-8 (HHV-8), whereas others are HHV-8–negative/idiopathic (iMCD). Treatment of iMCD is challenging, and outcomes can be poor because no uniform treatment guidelines exist, few systematic studies have been conducted, and no agreed upon response criteria have been described. The purpose of this paper is to establish consensus, evidence-based treatment guidelines based on the severity of iMCD to improve outcomes. An international Working Group of 42 experts from 10 countries was convened by the Castleman Disease Collaborative Network to establish consensus guidelines for the management of iMCD based on published literature, review of treatment effectiveness for 344 cases, and expert opinion. The anti–interleukin-6 monoclonal antibody siltuximab (or tocilizumab, if siltuximab is not available) with or without corticosteroids is the preferred first-line therapy for iMCD. In the most severe cases, adjuvant combination chemotherapy is recommended. Additional agents are recommended, tailored by disease severity, as second- and third-line therapies for treatment failures. Response criteria were formulated to facilitate the evaluation of treatment failure or success. These guidelines should help treating physicians to stratify patients based on disease severity in order to select the best available therapeutic option. An international registry for patients with CD (ACCELERATE, #NCT02817997) was established in October 2016 to collect patient outcomes to increase the evidence base for selection of therapies in the future.

348 Background: Patients (pts) with mUC have few treatment options beyond the second-line setting. HER2 gene amplification has been reported in a minority of pts with UC, but there have been anecdotal reports of the activity of HER2-targeted agents. MyPathway is a multi-basket study evaluating the efficacy and safety of targeted therapies in non-indicated tumor types harboring relevant molecular alterations. We present preliminary data for pts with HER2-positive mUC receiving HER2-targeted treatment with pertuzumab + trastuzumab. Methods: MyPathway (NCT02091141) is an open-label, multicenter, phase IIA study. Pts in this subset analysis had refractory mUC with HER2 amplification or putative activating mutations by gene sequencing, FISH, or IHC. Pts received standard doses of pertuzumab + trastuzumab without chemotherapy until disease progression or unacceptable toxicity. The primary endpoint is investigator-assessed overall response rate (RECIST v1.1). Results: As of July 31, 2016, 12 pts with platinum-resistant HER2-positive mUC (HER2-amplified, n=9; HER2-mutated, n=3) have been enrolled. At a median follow-up of 5.4 (range 0.9–14.5) mos, 1 pt had complete response (CR, ongoing at 12.5 mos), 2 had partial responses (PR; duration of response, 3.7 and 5.5 mos), and 2 had stable disease (SD) for >4 mos (Table). Safety was consistent with the product labels. Conclusions: Preliminary results indicate that the combination of pertuzumab + trastuzumab has activity in previously treated HER2-amplified mUC, including a durable CR in a pt with peritoneal metastases. Accrual to MyPathway is ongoing. Clinical trial information: NCT02091141. [Table: see text]

Key Points An international panel established the first ever diagnostic criteria for iMCD based on review of 244 clinical cases and 88 tissue samples. The criteria require multicentric lymphadenopathy with defined histopathology, ≥2 clinical/laboratory changes, and exclusion of iMCD mimics.

Abstract Purpose: Neurofibromatosis type 2 (NF2) is a rare autosomal dominant disorder associated primarily with bilateral schwannomas seen on the superior vestibular branches of the eighth cranial nerves. Significant morbidity can result from surgical treatment of these tumors. Meningiomas, ependymomas, and other benign central nervous system tumors are also common in NF2. The lack of effective treatments for NF2 marks an unmet medical need. Experimental Design: Here, we provide recommendations from a workshop, cochaired by Drs. D. Gareth Evans and Marco Giovannini, of 36 international researchers, physicians, representatives of the biotechnology industry, and patient advocates on how to accelerate progress toward NF2 clinical trials. Results: Workshop participants reached a consensus that, based on current knowledge, the time is right to plan and implement NF2 clinical trials. Obstacles impeding NF2 clinical trials and how to address them were discussed, as well as the candidate therapeutic pipeline for NF2. Conclusions: Both phase 0 and phase II NF2 trials are near-term options for NF2 clinical trials. The number of NF2 patients in the population remains limited, and successful recruitment will require ongoing collaboration efforts between NF2 clinics. (Clin Cancer Res 2009;15(16):5032–9)