Kumthekar, Priya

Abstract Sorafenib blocks nonstructural protein 5A (NS5A)-recruited c-Raf–mediated hepatitis C virus (HCV) replication and gene expression. Release of Raf-1-Ask-1 dimer and inhibition of Raf-1 via sorafenib putatively differ in the presence or absence of doxorubicin. Cancer and Leukemia Group B (CALGB) 80802 (Alliance) randomized phase III trial of doxorubicin plus sorafenib versus sorafenib in patients with advanced hepatocellular carcinoma (HCC), showed no improvement in median overall survival (OS). Whether HCV viral load impacts therapy and whether any correlation between HCV titers and outcome based on HCV was studied. In patients with HCV, HCV titer levels were evaluated at baseline and at multiple postbaseline timepoints until disease progression or treatment discontinuation. HCV titer levels were evaluated in relation to OS and progression-free survival (PFS). Among 53 patients with baseline HCV data, 12 patients had undetectable HCV (HCV-UN). Postbaseline HCV titer levels did not significantly differ between treatment arms. One patient in each arm went from detectable to HCV-UN with greater than 2 log-fold titer levels reduction. Aside from these 2 HCV-UN patients, HCV titers remained stable on treatment. Patients who had HCV-UN at baseline were 3.5 times more likely to progress and/or die from HCC compared with HCV detectable (HR = 3.51; 95% confidence interval: 1.58–7.78; P = 0.002). HCV titer levels remained unchanged, negating any sorafenib impact onto HCV titer levels. Although an overall negative phase III study, patients treated with doxorubicin plus sorafenib and sorafenib only, on CALGB 80802 had worse PFS if HCV-UN. Higher levels of HCV titers at baseline were associated with significantly improved PFS. Significance: Sorafenib therapy for HCC may impact HCV replication and viral gene expression. In HCV-positive patients accrued to CLAGB 80802 phase III study evaluating the addition of doxorubicin to sorafenib, HCV titer levels were evaluated at baseline and different timepoints. Sorafenib did not impact HCV titer levels. Despite an improved PFS in patients with detectable higher level HCV titers at baseline, no difference in OS was noted.

Abstract BACKGROUND Craniopharyngiomas, primary brain tumors of the pituitary-hypothalamic axis, can cause significant clinical sequelae. Treatment using surgery, radiation, or both often entails significant morbidity. In prior work, we demonstrated that ninety-five percent of papillary craniopharyngiomas (PCP) harbor BRAF V600E mutations (Brastianos et al. Nature Genetics 2014). In this multicenter National Cancer Institute cooperative group trial (Alliance A071601), we evaluated the safety and efficacy of BRAF/MEK inhibition in patients with PCP without prior irradiation. METHODS Eligible patients, with measurable disease and whose PCP screened positively for BRAF mutations, without prior radiation, received the BRAF/MEK inhibitor combination vemurafenib/cobimetinib in 28-day cycles. The primary endpoint of objective response rate at 4 months based on centrally determined volumetric data was evaluated in 16 patients on this single arm phase 2 trial. RESULTS Based on volumetric response criteria by central radiology review, 15 of 16 patients (94%; 95% CI: 70% to 100%) had a durable objective partial response to therapy. Thus, this study met primary endpoint for overall response rate. The median tumor reduction was 91% (range of 68% to 99%). Median follow-up was 22 months (95% CI: 19 to 30 months) and median number of treatment cycles was 8. Median progression-free survival and duration of response were not yet reached. Three patients progressed during follow-up after therapy was discontinued; none have died. The sole non-responder stopped treatment after eight days due to toxicity. Grade 3 toxicities at least possibly related to treatment occurred in 12 patients (rash in 6 patients). Grade 4 toxicities were observed in two patients: hyperglycemia (n=1) and increased creatine phosphokinase (n=1). Three patients discontinued treatment for adverse events. CONCLUSIONS Our study indicates that BRAF/MEK inhibitors are a safe and effective treatment for PCP without prior irradiation. Support: U10CA180821, U10CA180882; U24CA196171, U10CA180868 (NRG); Genentech; . ClinicalTrials.gov Identifier: NCT03224767.

Abstract Purpose: To assess whether higher plasma 25-hydroxyvitamin D [25(OH)D] is associated with improved outcomes in colon cancer and whether circulating inflammatory cytokines mediate such association. Experimental Design: Plasma samples were collected from 1,437 patients with stage III colon cancer enrolled in a phase III randomized clinical trial (CALGB/SWOG 80702) from 2010 to 2015, who were followed until 2020. Cox regressions were used to examine associations between plasma 25(OH)D and disease-free survival (DFS), overall survival (OS), and time to recurrence (TTR). Mediation analysis was performed for circulating inflammatory biomarkers of C-reactive protein (CRP), IL6, and soluble TNF receptor 2 (sTNF-R2). Results: Vitamin D deficiency [25(OH)D <12 ng/mL] was present in 13% of total patients at baseline and in 32% of Black patients. Compared with deficiency, nondeficient vitamin D status (≥12 ng/mL) was significantly associated with improved DFS, OS, and TTR (all Plog-rank<0.05), with multivariable-adjusted HRs of 0.68 (95% confidence interval, 0.51–0.92) for DFS, 0.57 (0.40–0.80) for OS, and 0.71 (0.52–0.98) for TTR. A U-shaped dose–response pattern was observed for DFS and OS (both Pnonlinearity<0.05). The proportion of the association with survival that was mediated by sTNF-R2 was 10.6% (Pmediation = 0.04) for DFS and 11.8% (Pmediation = 0.05) for OS, whereas CRP and IL6 were not shown to be mediators. Plasma 25(OH)D was not associated with the occurrence of ≥ grade 2 adverse events. Conclusions: Nondeficient vitamin D is associated with improved outcomes in patients with stage III colon cancer, largely independent of circulation inflammations. A randomized trial is warranted to elucidate whether adjuvant vitamin D supplementation improves patient outcomes.

PURPOSE Patients with progressive or recurrent meningiomas have limited systemic therapy options. Focal adhesion kinase (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 1-3 meningiomas. PATIENTS AND METHODS Eligible patients whose tumors screened positively for NF2 mutations were treated with GSK2256098, 750 mg orally twice daily, until progressive disease. Efficacy was evaluated using two coprimary end points: progression-free survival at 6 months (PFS6) and response rate by Macdonald criteria, where PFS6 was evaluated separately within grade-based subgroups: grade 1 versus 2/3 meningiomas. Per study design, the FAK inhibitor would be considered promising in this patient population if either end point met the corresponding decision criteria for efficacy. RESULTS Of 322 patients screened for all mutation cohorts of the study, 36 eligible and evaluable patients with NF2 mutations were enrolled and treated: 12 grade 1 and 24 grade 2/3 patients. Across all grades, one patient had a partial response and 24 had stable disease as their best response to treatment. In grade 1 patients, the observed PFS6 rate was 83% (10/12 patients; 95% CI, 52 to 98). In grade 2/3 patients, the observed PFS6 rate was 33% (8/24 patients; 95% CI, 16 to 55). The study met the PFS6 efficacy end point both for the grade 1 and the grade 2/3 cohorts. Treatment was well tolerated; seven patients had a maximum grade 3 adverse event that was at least possibly related to treatment with no grade 4 or 5 events. CONCLUSION GSK2256098 was well tolerated and resulted in an improved PFS6 rate in patients with recurrent or progressive NF2-mutated meningiomas, compared with historical controls. The criteria for promising activity were met, and FAK inhibition warrants further evaluation for this patient population.

2001 Background: PolyADP-ribose polymerase (PARP) is an important modulator of DNA repair following temozolomide (TMZ) therapy. Pre-clinical testing demonstrated significant survival benefit for the combination of TMZ and PARP inhibitor veliparib in a subset of GBM pt-derived xenografts with MGMT promoter hypermethylation. Methods: After central pathology review and MGMT testing, patients (pts) with newly diagnosed, MGMT promoter hypermethylated GBM who had completed concurrent radiation and TMZ were randomized to adjuvant therapy with TMZ (Days 1-5 q28 days) combined with either placebo or veliparib (Days 1-7 q28 days). Veliparib/placebo+TMZ treatment was continued for up to 6 cycles. Pts accrued on the phase II and III portions of the trial were included in the primary endpoint analysis of overall survival (OS), with 90% power to detect a hazard ratio of 0.71 using a one-sided log-rank test with type I error rate of 0.05. The planned phase III sample size was 400 pts with data maturity after 302 deaths. Results: The phase II and III portions of the trial were open to accrual from 12/15/2014 to 2/6/2017 and 11/8/2017 to 10/15/2018, respectively; 447 pts were accrued to the trial and used in this intention to treat analysis. The two treatment groups were well balanced for prognostic factors, 421 pts initiated treatment, median follow-up was 57.8 months (mos), 380 pts had disease progression and 335 pts have died. There was no difference in OS (p = 0.15; HR 0.89 (0.71-1.11), median OS 28.1 vs. 24.8 mo. for TMZ+veliparib vs. TMZ+placebo, respectively) and no difference in secondary endpoint progression free survival (PFS, p = 0.31; HR 1.05 (0.86-1.30), median 13.2 vs. 12.1 mo, respectively). There was a notable trend for extended OS with TMZ+veliparib treatment at intermediate time-points between 24 and 42 mos (3-year OS 36.6% vs. 28.9% with TMZ+placebo, p = 0.09). In an unplanned exploratory analysis, treatment with TMZ at the time of first recurrence was associated with extended post-recurrence OS (p = 0.03) for pts treated on the experimental arm; median post-recurrence OS with TMZ salvage was 17.0 mo in the TMZ+veliparib arm and 12.6 mo in the TMZ+placebo arm, as compared to 9.6 mo in either arm if TMZ salvage was not used. These data are consistent with a possible effect of veliparib limiting the emergence of TMZ resistance in a subset of GBM pts. Conclusions: Veliparib combined with adjuvant TMZ therapy was not associated with significant extension in OS or PFS in newly diagnosed, MGMT hypermethylated GBM pts. However, a subset of pts treated with TMZ+veliparib may have an extended survival following re-treatment with TMZ at first recurrence. Clinical trial information: NCT02152982.

2026 Background: Validation of the 2016 RANO MRI scorecard for leptomeningeal metastasis failed for multiple reasons. Accordingly, this joint EORTC Brain Tumor Group and RANO effort sought to prospectively validate a revised MRI scorecard for response assessment in leptomeningeal metastasis. Methods: Coded paired cerebrospinal MRI of 20 patients with leptomeningeal metastases from solid cancers at baseline and follow-up after treatment and instructions for assessment were provided via the EORTC imaging platform. The Kappa coefficient was used to evaluate the inter-observer pairwise agreement. Results: Thirty-five raters participated, including 9 neuroradiologists, 17 neurologists, 4 radiation oncologists, 3 neurosurgeons and 2 medical oncologists. Among single leptomeningeal metastases-related imaging findings at baseline, the best median concordance was noted for hydrocephalus (Kappa = 0.63), and the worst median concordance for spinal linear enhancing disease (Kappa = 0.46). The median concordance of raters for the overall response assessment was moderate (Kappa = 0.44). Notably, the interobserver agreement for the presence of parenchymal brain metastases at baseline was fair (Kappa = 0.29) and virtually absent for their response to treatment. 394 of 700 ratings (20 patients x 35 raters, 56%) were fully completed. In 308 of 394 fully completed ratings (78%), the overall response assessment perfectly matched the summary interpretation of the single ratings as proposed in the scorecard instructions. Conclusions: This study confirms the principle utility of the new scorecard, but also indicates the need for training of MRI assessment with a dedicated reviewer panel in clinical trials. Electronic case report forms with “blocking options” may be required to enforce completeness and quality of scoring.

Abstract Brain metastases occur commonly in patients with advanced solid malignancies. Yet, less is known about brain metastases than cancer-related entities of similar incidence. Advances in oncologic care have heightened the importance of intracranial management. Here, in this consensus review supported by the Society for Neuro-Oncology (SNO), we review the landscape of brain metastases with particular attention to management approaches and ongoing efforts with potential to shape future paradigms of care. Each coauthor carried an area of expertise within the field of brain metastases and initially composed, edited, or reviewed their specific subsection of interest. After each subsection was accordingly written, multiple drafts of the manuscript were circulated to the entire list of authors for group discussion and feedback. The hope is that the these consensus guidelines will accelerate progress in the understanding and management of patients with brain metastases, and highlight key areas in need of further exploration that will lead to dedicated trials and other research investigations designed to advance the field.

Abstract Background Patients with glioblastoma (GBM) have a poor prognosis and limited effective treatment options. Bevacizumab has been approved for treatment of recurrent GBM, but there is questionable survival benefit. Based on preclinical and early clinical data indicating that CD105 upregulation may represent a mechanism of resistance to bevacizumab, we hypothesized that combining bevacizumab with the anti-CD105 antibody TRC105 may improve efficacy in recurrent GBM. Methods Phase I dose-escalation/comparative randomized phase II trial in patients with GBM. During phase I, the maximum tolerated dose (MTD) of TRC105 in combination with bevacizumab was determined. In phase II, patients were randomized 1:1 to TRC105 and bevacizumab or bevacizumab monotherapy. Patients received TRC105 (10 mg/kg) weekly and bevacizumab (10 mg/kg) every 2 weeks. Efficacy, as assessed by progression-free survival (PFS), was the primary endpoint; safety, quality of life, and correlative outcomes were also evaluated. Results In total, 15 patients were enrolled in phase I and 101 in phase II; 52 patients were randomized to TRC105 with bevacizumab and 49 to bevacizumab monotherapy. The MTD was determined to be 10 mg/kg TRC105 weekly plus bevacizumab 10 mg/kg every 2 weeks. An increased occurrence of grade ≥3 adverse events was seen in the combination arm, including higher incidences of anemia. Median PFS was similar in both treatment arms: 2.9 months for combination versus 3.2 months for bevacizumab monotherapy (HR = 1.16, 95% CI = 0.75–1.78, P = .51). Quality of life scores were similar for both treatment arms. Conclusions TRC105 in combination with bevacizumab was well tolerated in patients with recurrent GBM, but no difference in efficacy was observed compared to bevacizumab monotherapy.

Abstract Background Validation of the 2016 RANO MRI scorecard for leptomeningeal metastasis failed for multiple reasons. Accordingly, this joint EORTC Brain Tumor Group and RANO effort sought to prospectively validate a revised MRI scorecard for response assessment in leptomeningeal metastasis. Methods Coded paired cerebrospinal MRI of 20 patients with leptomeningeal metastases from solid cancers at baseline and follow-up after treatment and instructions for assessment were provided via the EORTC imaging platform. The Kappa coefficient was used to evaluate the interobserver pairwise agreement. Results Thirty-five raters participated, including 9 neuroradiologists, 17 neurologists, 4 radiation oncologists, 3 neurosurgeons, and 2 medical oncologists. Among single leptomeningeal metastases-related imaging findings at baseline, the best median concordance was noted for hydrocephalus (Kappa = 0.63), and the worst median concordance for spinal linear enhancing disease (Kappa = 0.46). The median concordance of raters for the overall response assessment was moderate (Kappa = 0.44). Notably, the interobserver agreement for the presence of parenchymal brain metastases at baseline was fair (Kappa = 0.29) and virtually absent for their response to treatment. 394 of 700 ratings (20 patients x 35 raters, 56%) were fully completed. In 308 of 394 fully completed ratings (78%), the overall response assessment perfectly matched the summary interpretation of the single ratings as proposed in the scorecard instructions. Conclusion This study confirms the principle utility of the new scorecard, but also indicates the need for training of MRI assessment with a dedicated reviewer panel in clinical trials. Electronic case report forms with “blocking options” may be required to enforce completeness and quality of scoring.