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Background:Patients (pts) with multiple myeloma associated with high cytogenetic risk abnormalities have poor outcomes. In CASTOR, D‐Vd prolonged progression‐free survival (PFS) vs bortezomib and dexamethasone (Vd) alone, and exhibited a manageable safety profile in pts with RRMM. We conducted a subgroup analysis of D‐Vd vs Vd in CASTOR, based on cytogenetic risk.Aims:The purpose of this analysis was to determine the efficacy and safety of D‐Vd in CASTOR based on cytogenetic risk status.Methods:Eligible pts received ≥1 prior line of therapy. Cytogenetic risk was based on a combined analysis of next‐generation sequencing (NGS) and fluorescence in situ hybridization (FISH)/karyotype testing. High‐risk pts had t(4;14), t(14;16), or del17p abnormalities. Standard (std)‐risk pts were confirmed negative for all 3 abnormalities. Minimal residual disease (MRD; 10–5) was assessed via NGS using clonoSEQ® assay V2.0.Results:In CASTOR (D‐Vd, n = 251; Vd, n = 247), high‐risk was confirmed in 26.7% and 25.9% of pts in the D‐Vd and Vd groups, respectively. At a median follow up of 40.0 months (mo), D‐Vd prolonged PFS vs Vd in pts with high‐ (median 13.4 vs 7.2 mo; HR, 0.40 [95% CI, 0.24–0.65]; P = 0.0002) or std‐risk (median 18.4 vs 6.8 mo; HR, 0.28 [95% CI, 0.20–0.37]; P <0.0001). Higher ORR was seen with D‐Vd vs Vd (high risk: 84.8% vs 60.0%; P = 0.0226; std risk: 85.4% vs 65.0%; P <0.0001), including deep responses of ≥CR (high risk: 33.3% vs 8.3%; std risk: 29.9% vs 10.2%) and ≥VGPR (high risk: 65.2% vs 35.0%; P = 0.0049; std risk: 64.3% vs 28.0%; P <0.0001). Higher rates of MRD negativity (high risk: 17.9% vs 0%; P = 0.0003; std risk: 13.3% vs 2.4%; P = 0.0003), and sustained MRD negativity for ≥6 mo (high risk: 16.4% vs 0%; P = 0.0006; std risk: 6.1% vs 1.8%; P = 0.0859) and ≥12 mo (high risk: 7.5% vs 0%; P = 0.0581; std risk: 1.8% vs 0%; P = 0.2477) were seen with D‐Vd vs Vd. D‐Vd significantly prolonged PFS vs Vd in pts with one prior line of therapy only (high risk: median 20.1 vs 8.4 mo; HR, 0.30 [95% CI, 0.14–0.64]; P = 0.0012; std risk: median 32.6 vs 7.9 mo; HR, 0.18 [95% CI, 0.11–0.29]; P <0.0001; Figure). Additionally, D‐Vd significantly prolonged PFS2 (high risk: median 27.9 vs 18.6 mo; HR, 0.59 [95% CI, 0.37–0.94]; P = 0.0258; std risk: median 40.1 vs 21.6 mo; HR, 0.43 [95% CI, 0.32–0.59]; P <0.0001) regardless of cytogenetic risk status.Additional data including safety analyses will be presented.Summary/Conclusion:Adding daratumumab to Vd demonstrates significant efficacy in pts with high‐risk RRMM including PFS2. Among high‐risk RRMM pts, MRD negativity was only achieved with D‐Vd. These findings support use of D‐Vd for high‐risk RRMM. NCT02136134image

9506 Background: Survival is poor in mUM and treatment options are limited. MET kinase is over-expressed on UM and the MET inhibitor cabo showed activity in an early trial. Methods: A091201 was a 2:1 randomized phase II study testing progression-free survival (PFS) of cabo (60 mg daily) vs chemo (DTIC/TMZ). We studied baseline metastatic tumor samples (n = 19; 1 lung, 18 liver) by whole exome sequencing (WES) and RNAseq. We correlated data with OS and made comparisons for mUM vs. primary tumors from TCGA (n = 80). Results: 46 patients were accrued with 96% and 63% with liver metastases and elevated LDH, respectively. Toxicities were similar to prior reports of cabo and chemo. The trial stopped at interim analysis due to no difference in PFS (p = 0.964; HR = 0.99) or OS (p = 0.580; HR = 1.21). WES showed tumor mutational burden of 46±4 (mean±SEM) and did not separate OS at 1 year (p = 0.14, two-sided Wilcoxon rank sum test) in A091201. Recurrent known mutations included GNAQ/11, SF3B1, BAP1; novel mutations included GOLGA6L10, PKD1L3, and FAM228B. Gene expression signatures differed significantly between A091201 and TCGA cohorts including MET signaling (p = 7.87e-22), T cell-inflamed (p = 0.004), homologous recombination deficiency (p = 0.004), proliferation (p = 0.009) and hypoxia (p = 5.2e-10) (two-sided Student’s t-test). Tumor immune cell enrichment analysis revealed significant differences with lower M1:M2 macrophage (p = 1.2e-10) and higher Tregs (p = 6.0E-21) in mUM relative to TCGA (two-sided Wilcoxon rank sum test). Epithelial-mesenchymal transition gene expression signature was significantly associated with worse OS in A091201 (p = 0.02) with angiogenesis signature trending toward significance (p = 0.21) (log-rank test). OS separated by differentially expressed genes with OS ≤ 1 year associating with increased expression of the angiogenesis/immune-associated molecule neuropilin 1. Conclusions: These results provide insights between primary and mUM indicating potential novel therapeutic approaches. Support: U10CA180821, U10CA180882, T32GM007019, Exelixis. https://acknowledgments.alliancefound.org ; Clinical trial information: NCT01835145.

3539 Background: Previous studies suggest a possible gender-specific response to Bev in mCRC, showing a benefit in males, while the effect in females is less significant. Therefore, we evaluated response to Bev according to gender. Methods: Data from 3369 mCRC patients enrolled on 4 first-line randomized trials testing Bev (2000-2007) were pooled. Association between gender and progression-free survival (PFS)/overall survival (OS) was evaluated by stratified Cox regression model, adjusted for potential confounders. Predictive value was evaluated by interaction (inter.) effect between gender and treatment. In a pre-planned secondary analysis, analyses were stratified using an age cut-point of 60 years (commonly used in breast cancer trials) to evaluate the possible role of menopausal-related effects. Results: OS was not statistically different between males and females (median OS [mOS], 18.8 vs. 17.6 months [mo], adjusted hazard ratio [HRadj], 0.93, 95% confidence interval [CI], 0.84-1.03, p, 0.15) in the overall population. Bev was associated with an improved mOS in males and females, with a 2.3 and 0.6 mo benefit, respectively, as well as an improved PFS. There was no statistically significant interaction effect between gender and treatment (see table). Further stratified by age (< vs. ≥ 60 years), Bev resulted in improved PFS and OS in both genders, at all ages, except for the effect in young females which did not reach statistical significance (see table). Conclusions: Our results confirmed the mOS benefit from addition of Bev to first-line chemotherapy in mCRC in both genders, although the benefit in females was < 1 month. For females under the age of 60, there are uncertainties for mOS benefit from addition of Bev and further evaluation is needed. [Table: see text]

SUMMARY Volumetric laser endomicroscopy (VLE) uses optical coherence tomography (OCT) for real-time, microscopic cross-sectional imaging. A US-based multi-center registry was constructed to prospectively collect data on patients undergoing upper endoscopy during which a VLE scan was performed. The objective of this registry was to determine usage patterns of VLE in clinical practice and to estimate quantitative and qualitative performance metrics as they are applied to Barrett's esophagus (BE) management. All procedures utilized the NvisionVLE Imaging System (NinePoint Medical, Bedford, MA) which was used by investigators to identify the tissue types present, along with focal areas of concern. Following the VLE procedure, investigators were asked to answer six key questions regarding how VLE impacted each case. Statistical analyses including neoplasia diagnostic yield improvement using VLE was performed. One thousand patients were enrolled across 18 US trial sites from August 2014 through April 2016. In patients with previously diagnosed or suspected BE (894/1000), investigators used VLE and identified areas of concern not seen on white light endoscopy (WLE) in 59% of the procedures. VLE imaging also guided tissue acquisition and treatment in 71% and 54% of procedures, respectively. VLE as an adjunct modality improved the neoplasia diagnostic yield by 55% beyond the standard of care practice. In patients with no prior history of therapy, and without visual findings from other technologies, VLE-guided tissue acquisition increased neoplasia detection over random biopsies by 700%. Registry investigators reported that VLE improved the BE management process when used as an adjunct tissue acquisition and treatment guidance tool. The ability of VLE to image large segments of the esophagus with microscopic cross-sectional detail may provide additional benefits including higher yield biopsies and more efficient tissue acquisition. Clinicaltrials.gov NCT02215291

PURPOSE Adequately prioritizing the numerous therapies and biomarkers available in late-stage testing for patients with glioblastoma (GBM) requires an efficient clinical testing platform. We developed and implemented INSIGhT (Individualized Screening Trial of Innovative Glioblastoma Therapy) as a novel adaptive platform trial (APT) to develop precision medicine approaches in GBM. METHODS INSIGhT compares experimental arms with a common control of standard concurrent temozolomide and radiation therapy followed by adjuvant temozolomide. The primary end point is overall survival. Patients with newly diagnosed unmethylated GBM who are IDH R132H mutation negative and with genomic data available for biomarker grouping are eligible. At the initiation of INSIGhT, three experimental arms (neratinib, abemaciclib, and CC-115), each with a proposed genomic biomarker, are tested simultaneously. Initial randomization is equal across arms. As the trial progresses, randomization probabilities adapt on the basis of accumulating results using Bayesian estimation of the biomarker-specific probability of treatment impact on progression-free survival. Treatment arms may drop because of low probability of treatment impact on overall survival, and new arms may be added. Detailed information on the statistical model and randomization algorithm is provided to stimulate discussion on trial design choices more generally and provide an example for other investigators developing APTs. CONCLUSION INSIGhT (NCT02977780) is an ongoing novel biomarker-based, Bayesian APT for patients with newly diagnosed unmethylated GBM. Our goal is to dramatically shorten trial execution timelines while increasing scientific power of results and biomarker discovery using adaptive randomization. We anticipate that trial execution efficiency will also be improved by using the APT format, which allows for the collaborative addition of new experimental arms while retaining the overall trial structure.

PURPOSE The Congress of Neurological Surgeons (CNS) has developed a series of guidelines for the treatment of adults with metastatic brain tumors, including systemic therapy and supportive care topics. ASCO has a policy and set of procedures for endorsing clinical practice guidelines that have been developed by other professional organizations. METHODS Two CNS guidelines were reviewed for developmental rigor by methodologists, and an independent multidisciplinary Expert Panel was formed to review the content and assess agreement with the recommendations. The Expert Panel voted to endorse the two guidelines, and ASCO and Society for Neuro-Oncology (SNO) independently reviewed and approved the ASCO/SNO guideline endorsement. RESULTS The ASCO/SNO Expert Panel determined that the recommendations from the CNS anticonvulsants and steroids guidelines, published January 9, 2019, are clear, thorough, and based on the most relevant scientific evidence. ASCO/SNO endorsed these two CNS guidelines with minor alterations. RECOMMENDATIONS Key recommendations include the following: prophylactic antiepileptic drugs were not recommended for routine use; and corticosteroids, specifically dexamethasone, were recommended for temporary symptomatic relief in patients with neurologic symptoms and signs related to mass effect from brain metastases. Additional information is available at www.asco.org/neurooncology-guidelines .