Citations

2502 Background: Patients with progressive or recurrent meningiomas have limited treatment options. Clinical trials of systemic therapies for meningiomas have failed to demonstrate benefit. FAK inhibition has a synthetic lethal relationship with NF2 loss. Given the predominance of NF2 mutations in meningiomas, we evaluated the efficacy of GSK2256098, a FAK inhibitor, as part of the first genomically-driven phase II study in recurrent or progressive grade I-III meningiomas. Methods: Eligible patients (pts) whose tumors screened positively for NF2 mutations were treated with GSK2256098 750mg po bid until progressive disease in 2 separate cohorts: grade I or II/III meningiomas. Two co-primary endpoints were used: progression-free survival at 6 months (PFS6) and response rate (RR) by Macdonald criteria; per study design, the trial would be declared positive if either endpoint was met. RR was evaluated across the overall cohort; PFS6 was evaluated within each subgroup. Historical benchmark data was obtained from Kaley et al. Neuro Oncol 2014. In the grade I group, 12 evaluable pts provided >79% power to detect a PFS6 rate >65% (vs. null hypothesis of 25%; alpha=0.014). In the grade II/III group, 24 evaluable pts provided >85% power to detect a PFS6 >41.5% (vs. null 15%; alpha=0.02). The threshold for promising results for PFS6 was: 7+/12(grade I) and 8+/24(grade II/III) pts. For RR, 36 evaluable pts provided >94% power to detect RR >20% (vs. null 2.5%; alpha= 0.012). Results: Of 322 pts screened for all mutation cohorts of the study, 36 eligible and evaluable pts with NF2 mutations were enrolled. Across all grades, one pt had a partial response and 24 had stable disease as best response to treatment. In Grade I pts, the observed PFS6 rate was 83% (10/12 pts; 95% CI: 52-98%). In Grade II/III pts, the observed PFS6 rate was 33% (8/24 pts; 95% CI: 16-55%). The study met PFS6 efficacy endpoint both for the Grade I and the Grade II/III cohorts. Treatment was well tolerated. Only 7 patients had a maximum grade-3 adverse event that was at least possibly related to treatment; toxicities across these pts included: proteinuria (2), rash (1), pain (1), ALT (1), AST (1), cholecystitis (1), hypertriglyceridemia (1), apraxia (1), and lymphopenia (1) with no grade 4 or 5 events. Conclusions: GSK2256098 had excellent tolerability andresulted in an improved PFS6 rate in pts with recurrent or progressive NF2-mutated meningiomas. Trial endpoint was met. FAK inhibition warrants further evaluation in this patient population. Support: U10CA180821, U10CA180882; https://acknowledgments.alliancefound.org Clinical trial information: NCT02523014 .

AbstractA recent meeting was held on March 22, 2019, among the FDA, clinical scientists, pharmaceutical and biotech companies, clinical trials cooperative groups, and patient advocacy groups to discuss challenges and potential solutions for increasing development of therapeutics for central nervous system metastases. A key issue identified at this meeting was the need for consistent tumor measurement for reliable tumor response assessment, including the first step of standardized image acquisition with an MRI protocol that could be implemented in multicenter studies aimed at testing new therapeutics. This document builds upon previous consensus recommendations for a standardized brain tumor imaging protocol (BTIP) in high-grade gliomas and defines a protocol for brain metastases (BTIP-BM) that addresses unique challenges associated with assessment of CNS metastases. The “minimum standard” recommended pulse sequences include: (i) parameter matched pre- and post-contrast inversion recovery (IR)–prepared, isotropic 3D T1-weighted gradient echo (IR-GRE); (ii) axial 2D T2-weighted turbo spin echo acquired after injection of gadolinium-based contrast agent and before post-contrast 3D T1-weighted images; (iii) axial 2D or 3D T2-weighted fluid attenuated inversion recovery; (iv) axial 2D, 3-directional diffusion-weighted images; and (v) post-contrast 2D T1-weighted spin echo images for increased lesion conspicuity. Recommended sequence parameters are provided for both 1.5T and 3T MR systems. An “ideal” protocol is also provided, which replaces IR-GRE with 3D TSE T1-weighted imaging pre- and post-gadolinium, and is best performed at 3T, for which dynamic susceptibility contrast perfusion is included. Recommended perfusion parameters are given.

Abstract Craniopharyngiomas are surgically challenging brain tumors. Postoperatively, quality of life is often significantly impaired due to neurological and endocrinological complications. Currently, FDA approved systemic treatments are not available for patients in whom craniopharyngiomas recur after surgery and radiation. Papillary craniopharyngiomas are characterized by the presence of BRAFV600E mutations. To date, five case reports have been published on the treatment of BRAFV600E mutant papillary craniopharyngiomas with BRAF and/or MEK inhibitors. In this presentation, authors from all five previously published reports share their collective experience and provide updated follow-up on their patients, thus generating an overview of all currently available information on targeted therapy in patients with BRAFV600E mutant papillary craniopharyngiomas. We have also included information on an additional patient with a papillary craniopharyngioma recently treated with BRAF and MEK inhibitors after tumor biopsy alone, in the absence of recurrence, highlighting the potential for a neo-adjuvant therapeutic approach. All six cases in our series showed dramatic responses to targeted treatment with BRAF (and MEK) inhibitors. Collectively, our cases are highly promising and informative for patient treatment, although uncertainty remains with regards to the optimal timing, the specific agents (single agent or dual therapy) to be used and the duration of treatment. The ongoing multicenter phase II Alliance A071601 trial (NCT03224767) of vemurafenib and cobimetinib for patients with biopsy-proven residual or recurrent papillary craniopharyngiomas should provide additional information to help guide patient management.

Abstract BACKGROUND The face of neuro-oncology providers has evolved over the century. We sought to evaluate if its culture has evolved concurrently. Women in NeuroOncology (“WiN.”) is a SNO subcomittee that identifies the needs of women in neuro-oncology and promotes advancement of the careers of women in neuro-oncology. We created this survey to examine bias within our field with the goal to implement future change. METHODS Following IRB approval, we surveyed both male and female SNO members and analyzed de-identified responses. RESULTS Of the 206 respondents, 25% identified as male, 84.9% were in academics, 73.7% were primarily research focused (69% clinical), and 59% were medical neuro-oncology focused. The majority of respondents were 36–45 years old (47%), followed by 46–55 (32%), and 21% aged 56+. 69.8% self-identified as white, followed by 22% Asian, 7.8% Latin, and 2.9% Black. The majority reported general professional bias at least “not infrequently”, with 11.7% reporting it “very commonly.” 59.9% reported “not being invited to participate and or being considered for an opportunity”, followed by 46.1% “being minimized, teased or disrespected”, 44.3% “being passed over for professional opportunities”, and 41.9% salary disparity. Furthermore, of those reporting general professional bias, 42.9% reported a lack of effective mentorship and 94% reported some frequency of burnout, with 34% “commonly, very commonly”, followed by 28.3% “not infrequently.” Notably, although only 25% of responders were men, 82.4% of total respondents reported some frequency of gender bias in the workplace, with “not infrequently” being the most commonly reported (48%). CONCLUSIONS In this survey, we identified SNO members who have experienced bias. Based on quantitative and qualitative responses, many reported bias manifesting as missing academic opportunities, salary disparity, burnout, and lack of mentorship. As we cultivate the next generation, we will use these results to engage those in leadership to promote unbiased equality.

SummaryBackgroundBecause most pancreatic intraductal papillary mucinous neoplasms (IPMNs) will never become malignant, currently advocated long‐term surveillance is low‐yield for most individuals.AimTo develop a score chart identifying IPMNs at lowest risk of developing worrisome features or high‐risk stigmata.MethodsWe combined prospectively maintained pancreatic cyst surveillance databases of three academic institutions. Patients were included if they had a presumed side‐branch IPMN, without worrisome features or high‐risk stigmata at baseline (as defined by the 2012 international Fukuoka guidelines), and were followed ≥ 12 months. The endpoint was development of one or more worrisome features or high‐risk stigmata during follow‐up. We created a multivariable prediction model using Cox‐proportional logistic regression analysis and performed an internal‐external validation.Results875 patients were included. After a mean follow‐up of 50 months (range 12‐157), 116 (13%) patients developed worrisome features or high‐risk stigmata. The final model included cyst size (HR 1.12, 95% CI 1.09‐1.15), cyst multifocality (HR 1.49, 95% CI 1.01‐2.18), ever having smoked (HR 1.40, 95% CI 0.95‐2.04), history of acute pancreatitis (HR 2.07, 95% CI 1.21‐3.55), and history of extrapancreatic malignancy (HR 1.34, 95% CI 0.91‐1.97). After validation, the model had good discriminative ability (C‐statistic 0.72 in the Mayo cohort, 0.71 in the Columbia cohort, 0.64 in the Erasmus cohort).ConclusionIn presumed side branch IPMNs without worrisome features or high‐risk stigmata at baseline, the Dutch‐American Risk stratification Tool (DART‐1) successfully identifies pancreatic lesions at low risk of developing worrisome features or high‐risk stigmata.

Papillary craniopharyngiomas (PCPs) are characterized by the presence of BRAF V600E mutations, which are emerging as a useful guide for diagnosis and treatment decision making. The ongoing multicenter phase 2 Alliance A071601 trial is evaluating the efficacy of BRAF and mitogen‐activated protein kinase kinase (MEK) inhibitors for patients with PCPs. With continued successful responses, it is proposed that BRAF (and MEK) inhibitors be evaluated for the neoadjuvant treatment of patients with PCPs.