Search

Background: Tumor mutational burden (TMB) is a potential biomarker to predict tumor response to immuno-oncology agents in patients with metastatic non-small cell lung cancer (NSCLC). Materials and Methods: A multi-site cohort study evaluated patients diagnosed with stage IV NSCLC between 2012 and 2019 who had received comprehensive genomic profiling (CGP) and any NSCLC-related treatment at 9 U.S. cancer centers. Baseline characteristics and clinical outcomes were compared between patients with TMB 10 showed a significant association towards longer overall survival (OS) (HR: 0.43, 95% CI: 0.21–0.88, p = 0.02) and progression-free survival (PFS) (HR: 0.43, 95% CI: 0.21–0.85, p = 0.02) in patients treated with first-line immunotherapy and tested by Foundation Medicine or Caris at treatment initiation. Conclusions: TMB levels greater than or equal to 10 mut/Mb, when tested by Foundation Medicine or Caris at treatment initiation, were significantly associated with improved OS and PFS among patients treated with first-line immunotherapy-containing regimens. Additional prospective research is warranted to validate this biomarker along with PD-L1 expression.

PURPOSE To assess whether reirradiation (re-RT) and concurrent bevacizumab (BEV) improve overall survival (OS) and/or progression-free survival (PFS), compared with BEV alone in recurrent glioblastoma (GBM). The primary objective was OS, and secondary objectives included PFS, response rate, and treatment adverse events (AEs) including delayed CNS toxicities. METHODS NRG Oncology/RTOG1205 is a prospective, phase II, randomized trial of re-RT and BEV versus BEV alone. Stratification factors included age, resection, and Karnofsky performance status (KPS). Patients with recurrent GBM with imaging evidence of tumor progression ≥ 6 months from completion of prior chemo-RT were eligible. Patients were randomly assigned 1:1 to re-RT, 35 Gy in 10 fractions, with concurrent BEV IV 10 mg/kg once in every 2 weeks or BEV alone until progression. RESULTS From December 2012 to April 2016, 182 patients were randomly assigned, of whom 170 were eligible. Patient characteristics were well balanced between arms. The median follow-up for censored patients was 12.8 months. There was no improvement in OS for BEV + RT, hazard ratio, 0.98; 80% CI, 0.79 to 1.23; P = .46; the median survival time was 10.1 versus 9.7 months for BEV + RT versus BEV alone. The median PFS for BEV + RT was 7.1 versus 3.8 months for BEV, hazard ratio, 0.73; 95% CI, 0.53 to 1.0; P = .05. The 6-month PFS rate improved from 29.1% (95% CI, 19.1 to 39.1) for BEV to 54.3% (95% CI, 43.5 to 65.1) for BEV + RT, P = .001. Treatment was well tolerated. There were a 5% rate of acute grade 3+ treatment-related AEs and no delayed high-grade AEs. Most patients died of recurrent GBM. CONCLUSION To our knowledge, NRG Oncology/RTOG1205 is the first prospective, randomized multi-institutional study to evaluate the safety and efficacy of re-RT in recurrent GBM using modern RT techniques. Overall, re-RT was shown to be safe and well tolerated. BEV + RT demonstrated a clinically meaningful improvement in PFS, specifically the 6-month PFS rate but no difference in OS.

Background Hematological adverse events (HAEs) are common during treatment for glioblastoma (GBM), usually associated with temozolomide (TMZ). Their clinical value is uncertain, as few investigations have focused on outcomes for HAEs during GBM treatment. Methods We combined data from two randomized clinical trials, RTOG 0525 and RTOG 0825, to analyze HAEs during treatment for GBM. We investigated differences between chemoradiation and adjuvant therapy, and by regimen received during adjuvant treatment. Results 1454 patients participated in these trials, of which 1154 (79.4%) developed HAEs. During chemoradiation, 44.4% of patients developed HAEs (54% involving more than one cell line), and were most commonly lymphopenia (50.6%), and thrombocytopenia (47.5%). During adjuvant treatment, 45% of patients presented HAEs (78.6% involving more than one cell line), and were more commonly leukopenia (62.7%), and thrombocytopenia (62.3%). Median overall survival (OS) and progression free survival (PFS) were longer in patients with HAEs (OS 19.4 months and PFS 9.9 months) compared to those with other or no adverse events (OS 14.1 months and PFS 5.9 months). There was no significant difference in survival between grade 1 and/or 2 versus grade 3 and/or 4 HAEs. History of HAEs during chemoradiation was a protective factor for presentation of HAEs during adjuvant therapy. Conclusion HAEs are common during GBM treatment, and often involve more than one cell line (more likely during adjuvant therapy). HAEs may be associated with prolonged OS and PFS, particularly during adjuvant therapy. HAEs during chemoradiation was a protective factor for HAEs during adjuvant therapy.

ImportanceGlioblastoma is the most lethal primary brain cancer. Clinical outcomes for glioblastoma remain poor, and new treatments are needed.ObjectiveTo investigate whether adding autologous tumor lysate-loaded dendritic cell vaccine (DCVax-L) to standard of care (SOC) extends survival among patients with glioblastoma.Design, Setting, and ParticipantsThis phase 3, prospective, externally controlled nonrandomized trial compared overall survival (OS) in patients with newly diagnosed glioblastoma (nGBM) and recurrent glioblastoma (rGBM) treated with DCVax-L plus SOC vs contemporaneous matched external control patients treated with SOC. This international, multicenter trial was conducted at 94 sites in 4 countries from August 2007 to November 2015. Data analysis was conducted from October 2020 to September 2021.InterventionsThe active treatment was DCVax-L plus SOC temozolomide. The nGBM external control patients received SOC temozolomide and placebo; the rGBM external controls received approved rGBM therapies.Main Outcomes and MeasuresThe primary and secondary end points compared overall survival (OS) in nGBM and rGBM, respectively, with contemporaneous matched external control populations from the control groups of other formal randomized clinical trials.ResultsA total of 331 patients were enrolled in the trial, with 232 randomized to the DCVax-L group and 99 to the placebo group. Median OS (mOS) for the 232 patients with nGBM receiving DCVax-L was 19.3 (95% CI, 17.5-21.3) months from randomization (22.4 months from surgery) vs 16.5 (95% CI, 16.0-17.5) months from randomization in control patients (HR = 0.80; 98% CI, 0.00-0.94; P = .002). Survival at 48 months from randomization was 15.7% vs 9.9%, and at 60 months, it was 13.0% vs 5.7%. For 64 patients with rGBM receiving DCVax-L, mOS was 13.2 (95% CI, 9.7-16.8) months from relapse vs 7.8 (95% CI, 7.2-8.2) months among control patients (HR, 0.58; 98% CI, 0.00-0.76; P P = .03).Conclusions and RelevanceIn this study, adding DCVax-L to SOC resulted in clinically meaningful and statistically significant extension of survival for patients with both nGBM and rGBM compared with contemporaneous, matched external controls who received SOC alone.Trial RegistrationClinicalTrials.gov Identifier: NCT00045968

PURPOSE Multidisciplinary molecular tumor boards (MTBs) interpret next-generation sequencing reports and help oncologists determine best therapeutic options; however, there is a paucity of data regarding their clinical utility. The purpose of this study was to determine if MTB-directed therapy improves progression-free survival (PFS) over immediately prior therapy in patients with advanced cancer. METHODS This single-arm, prospective phase II clinical trial enrolled patients with advanced cancer with an actionable mutation who received MTB-recommended targeted therapy between January 1, 2017, and October 31, 2020. MTB-recommended both on-label (level 1 evidence) and off-label (evidence levels 2 and 3) therapies. Of the 93 enrolled patients, 43 were treated frontline and 50 received second-line or greater-line therapy. The primary outcome was the probability of patients treated with second-line or greater-line MTB-directed therapy who achieved a PFS ratio ≥ 1.3 (PFS on MTB-directed therapy divided by PFS on the patient's immediately prior therapy). Secondary outcomes included PFS for patients treated frontline and overall survival and adverse effects for the entire study population. RESULTS The most common disease sites were lung (35 of 93, 38%), gynecologic (17 of 93, 18%), GI (16 of 93, 17%), and head and neck (7 of 93, 8%). The Kaplan-Meier estimate of the probability of PFS ratio ≥ 1.3 was 0.59 (95% CI, 0.47 to 0.75) for patients treated with second-line or greater-line MTB-directed therapy. The median PFS was 449 (range 42-1,125) days for patients treated frontline. The median overall survival was 768 (range 22-1,240) days. There were four nontreatment-related deaths. CONCLUSION When treated with MTB-directed therapy, most patients experienced improved PFS compared with immediately prior treatment. MTB-directed targeted therapy may be a strategy to improve outcomes for patients with advanced cancer.

Background We explore the applications of Narrative Medicine (NM) in the clinical care of brain cancer patients whose self-identity and quality of life are challenged by their disease and treatment. This paper considers how NM may help patients retain and rediscover self-identity during treatment. Methods We performed a retrospective review of NM sessions at our institution in 2016 with focus on life perspectives and priorities along with outlook or attitude and any changes in their symptoms and possible impact on their lives. Results The narratives shared by four brain cancer patients provided examples of loss of self-identity during illness and treatment, along with ways that NM sessions encouraged patient resilience and discovery of meaning. Conclusions NM sessions made visible contributions for the patients mentioned in these case studies. Understanding the patient’s story is critical for evaluating the significance of impairments due to brain cancer and treatment relative to the patient’s unique sense of self and quality of life. NM is at the nexus of clinical management and quality of life concerns for brain cancer patients. Insights from NM sessions may also help the treatment team as they assess patient needs, attitudes, and abilities.

Background Immune-mediated therapies have transformed the treatment of metastatic melanoma and renal, bladder, and both small and non-small cell lung carcinomas. However, immunotherapy is yet to demonstrate dramatic results in brain tumors like medulloblastoma for a variety of reasons. Recent pre-clinical and early phase human trials provide encouraging results that may overcome the challenges of central nervous system (CNS) tumors, which include the intrinsic immunosuppressive properties of these cancers, a lack of antigen targets, antigenic variability, and the immune-restrictive site of the CNS. These studies highlight the growing potential of immunotherapy to treat patients with medulloblastoma, a disease that is a frequent cause of morbidity and mortality to children and young adults. Methods We conducted an inclusive review of the PubMed-indexed literature and studies listed in clinicaltrials.gov using combinations of the keywords medulloblastoma, immunotherapy, CNS tumors, brain tumors, vaccines, oncolytic virus, natural killer, and CAR T to identify trials evaluating immunotherapy in preclinical experiments or in patients with medulloblastoma. Given a limited number of investigations using immunotherapy to treat patients with medulloblastoma, 24 studies were selected for final analysis and manuscript citation. Results This review presents results from pre-clinical studies in medulloblastoma cell lines, animal models, and the limited trials involving human patients. Conclusion From our review, we suggest that cancer vaccines, oncolytic viral therapy, natural killer cells, and CAR T therapy hold promise against the innate immunosuppressive properties of medulloblastoma in order to prolong survival. There is an unmet need for immunotherapy regimens that target overexpressed antigens in medulloblastoma tumors. We advocate for more combination treatment clinical trials using conventional surgical and radiochemotherapy approaches in the near-term clinical development.

Background Targeting vascular endothelial growth factor (VEGF) alone does not improve overall survival (OS) in recurrent glioblastoma (rGBM). The angiopoiein (Ang)-TIE2 system may play a role in tumor survival under VEGF inhibition. We conducted a phase 2, double-blinded, placebo-controlled trial of bevacizumab plus trebananib (a novel Fc fusion protein that sequesters Ang1/Ang2) over bevacizumab alone in rGBM. Methods Patients ≥18 years of age with a Karnofsky performance status ≥70 and GBM or variants in first or second relapse were randomized to bevacizumab 10 mg/kg every 2 weeks plus trebananib 15 mg/kg every week or bevacizumab plus placebo. The primary endpoint was 6-month progression-free survival (PFS). Results After an initial 6-patient lead-in cohort confirmed the safety of combining bevacizumab and trebananib, 115 eligible patients were randomized to the control (n = 58) or experimental treatment (n = 57). In the control arm, 6-month PFS was 41.1%, median survival time was 11.5 months (95% CI, 8.4-14.2 months), median PFS was 4.8 months (95% CI, 3.8-7.1 months), and radiographic response (RR) was 5.9%. In the experimental arm, 6-month PFS was 22.6%, median survival time was 7.5 months (95% CI, 6.8-10.1 months), median PFS was 4.2 months (95% CI, 3.7-5.6 months), and RR was 4.2%. The rate of severe toxicities was not significantly different between arms. Conclusion The combination of bevacizumab and trebananib was well tolerated but did not significantly improve 6-month PFS rate, PFS, or OS for patients with rGBM over bevacizumab alone. The shorter PFS in the experimental arm with a hazard ratio of 1.51 (P = .04) suggests that the addition of trebananib to bevacizumab is detrimental.

93 Background: Chemotherapy Induced Peripheral Neuropathy (CIPN) is a debilitating side effect associated with many chemotherapeutic agents. It significantly impacts quality of life during treatment, causes lasting neuropathy, and may also shorten the treatment regimen, potentially impacting clinical benefit. The pathology of CIPN is still not completely understood, however, increasing evidence suggests sphingosine-1-phosphate (S1P) may be an important signaling molecule. Altered neuronal sphingolipid metabolism has been linked to neuropathic pain, evidenced by elevated plasma levels of S1P in patients receiving chemotherapy. Methods: BXQ-350 is a nanovesicle of Saposin C, an allosteric activator of sphingolipid metabolism, that lowers systemic S1P. BXQ-350 was investigated in an adult Phase 1 dose-escalation safety study in heavily pretreated all-comer cancer patients with advanced solid malignancies ( NCT02859857 ). The primary objective was to determine the safety profile and potential clinical activity of BXQ-350 as monotherapy. Samples were collected to explore potential biomarkers. Results: BXQ-350 was safe and well tolerated. Clinical signs of activity were observed in 13 patients (~17.8% of evaluable patients) experiencing a clinical benefit (PR, SD) up to cycle 6 and beyond including: 4 CRC, 1 pancreatic, and 1 GIST patient. Two patients are still on study six years after enrollment, including 1 CRC. Interestingly, a pancreatic cancer patient with chronic CIPN at time of enrollment spontaneously reported a significant improvement of her neuropathic symptoms shortly after receiving BXQ-350. Investigation of potential improvements in patients with chronic CIPN at time of enrollment revealed that 4 out of 10 patients experienced an improvement of their symptoms that seemed to be associated with a decrease in S1P systemic levels following BXQ-350 administration. BXQ-350 was subsequently investigated in a murine oxaliplatin-CIPN preclinical model with results showing a dose-dependent prevention/resolution of CIPN correlating with decreasing systemic S1P levels. Conclusions: Results of this Phase 1 study in heavily pretreated patients shows that BXQ-350 was well tolerated and seems to generate a clinical benefit via modulation of S1P. There were preliminary signs that BXQ-350 may alleviate symptoms of CIPN in relation to decreasing S1P concentration. Additional studies are underway to better understand this novel mechanism of action. Clinical trial information: 02859857 .

154 Background: Sphingolipids are a class of bioactive signaling molecules implicated in multiple cellular processes and molecular pathways. Many publications have demonstrated that ceramides are proapoptotic, synergize with cancer treatments, and mitigate chemoresistance. Findings also demonstrated that sphingosine-1-phosphate (S1P) is a key sphingolipid that promotes cancer cell proliferation, activates multiple oncogenic pathways, and stimulates immuno-suppressor cell populations promoting a pro-tumoral microenvironment. Several studies of colorectal cancer patients have shown high levels of ceramides being associated with improved survival, while high S1P levels are associated with a poor prognosis. Hence, modulation of sphingolipid metabolism continues to be a promising treatment approach. Methods: BXQ-350 is a nanovesicle of Saposin C, an allosteric activator of sphingolipid metabolism, that lowers systemic S1P and increases C18 ceramide. BXQ-350 was investigated in a Phase 1 dose-escalation safety study in an all-comer cancer patients with advanced solid malignancies ( NCT02859857 ) to determine its safety profile and potential clinical activity as monotherapy. Samples were collected to explore potential biomarkers. Results: 13 patients (~17.8% of evaluable patients) had a clinical benefit up to cycle 6 (PR, SD), with the majority experiencing a decrease in systemic S1P levels and an increase in C18 levels. 8 patients (~11% of evaluable patients) had PFS > 6 months, with 2 patients still on study six years after enrollment. Analysis of plasma samples also revealed an increase in anti-tumoral cytokines (IFNg, TNFa, IL-2) and a decrease in pro-tumoral ones (IL-6, 8, 10). Among patients with PFS > 6 months, there were 4 recurrent CRC patients (1PR, 3SD): 1 patient had a PFS of ~12 months, 2 of ~18 months, and 1 is still on study after 6 years. Conclusions: Results of this Phase 1 study in heavily pretreated patients show BXQ-350 was well tolerated and seem to generate a clinical benefit in CRC patients via modulation of S1P and ceramides. A phase 2 trial of BXQ-350 in combination with FOLFOX/Bevacizumab in newly diagnosed mCRC is on-going with plans to further investigate this novel mechanism of action. Clinical trial information: 02859857 .

IMPORTANCE: Nearly 96% of patients with high-grade glioma (HGG) report moderate-to-severe fatigue. Armodafinil is a psychostimulant that might help cancer-related fatigue in patients with HGG. OBJECTIVE: To determine whether armodafinil reduces fatigue in patients with HGG and moderate-to-severe fatigue. DESIGN, SETTING, AND PARTICIPANTS: In this randomized multicenter, phase 3, double-blinded, placebo-controlled clinical trial, adults with HGG and moderate-to-severe fatigue who were clinically stable at least 4 weeks after completing radiation therapy were randomized to receive armodafinil daily (150 mg or 250 mg) or placebo over 8 weeks. A score of at least 6 out of 10 on severity scale for the brief fatigue inventory scale, with 10 being the worst, was required to suggest moderate-to-severe fatigue. Patients were allowed stable doses of corticosteroids but were excluded if they required increasing amounts of corticosteroids, were receiving some other treatment for fatigue, or had an uncontrolled seizure disorder. The study was conducted from June 2013 to December 15, 2019. INTERVENTIONS: Patients were randomized to 150 mg of armodafinil, 250 mg of armodafinil, or placebo for a total of 8 weeks with assessments at weeks 4 and 8. MAIN OUTCOMES AND MEASURES: The primary outcome was efficacy in treating cancer-related fatigue. Secondary outcomes included safety, neurocognitive function, and quality of life. Patients were evaluated at baseline and at weeks 4 and 8. Efficacy between the placebo and the 2 doses of study drug was determined by an improvement by 2 points on the 0 to 10 brief fatigue inventory scale. Kruskal-Wallis and χ(2) tests were used and followed by confirmatory analyses. RESULTS: A total of 328 patients were enrolled, of whom 297 had evaluable end point data. Of these, 103 received 150 mg of armodafinil (mean [SD] age, 58.5 [11.9] years; 42 women [40.8%]), 97 250 mg of armodafinil (mean [SD] age, 56.6 [12.5] years; 37 women [38.1%]), and 97 placebo (mean [SD] age, 57.1 [12.5] years; 39 women [40.2%]). There was no difference in the proportion of patients who achieved clinically meaningful fatigue reduction between arms (28% [95% CI 20%-30%] for 150 mg of armodafinil, 28% [95% CI 19%-38%] for 250 mg of armodafinil, and 30% [95% CI 21%-40%] for placebo). There was a statistically significant reduction in global fatigue for corticosteroid users compared with nonusers (−0.7 [95% CI, −1.5 to −0.3] vs −1.7 [95% CI, −2.1 to −1.3]; P

Simple Summary Germline pharmacogenomic variants impact the toxicity of many cancer treatment drugs. Though testing for pharmacogenomic variants prior to initiating systemic cancer treatment is not routine, the Clinical Pharmacogenetics Implementation Consortium recommends dosing modifications for six cancer treatment drugs based on variant genotypes: irinotecan and UGT1A1; 5-fluorouracil and capecitabine and DPYD; 6-mercaptopurine and thioguanine and TPMT; and tamoxifen and CYP2D6. The purpose of this study was to assess the frequency of cancer treatment-relevant germline pharmacogenomic variants in patients with cancer using residual germline whole-exome sequencing. We also evaluated the association of disease-relevant pharmacogenomic variants with treatment-associated toxicities. Approximately one-quarter of cancer patients carried a disease-relevant pharmacogenomic variant. Patients with toxicity-associated pharmacogenomic variant genotypes were more likely to experience drug-related toxicity than their wild-type counterparts. Universal pharmacogenomic screening is feasible using whole-exome sequencing originally obtained for quality control purposes and may be an effective germline pharmacogenomic screening strategy for patients who are candidates for irinotecan, 5-fluorouracil, capecitabine, or 6-mercaptopurine. Abstract The purpose of this study was to determine the frequency of clinically actionable treatment-relevant germline pharmacogenomic variants in patients with cancer and assess the real-world clinical utility of universal screening using whole-exome sequencing in this population. Cancer patients underwent research-grade germline whole-exome sequencing as a component of sequencing for somatic variants. Analysis in a clinical bioinformatics pipeline identified clinically actionable pharmacogenomic variants. Clinical Pharmacogenetics Implementation Consortium guidelines defined clinical actionability. We assessed clinical utility by reviewing electronic health records to determine the frequency of patients receiving pharmacogenomically actionable anti-cancer agents and associated outcomes. This observational study evaluated 291 patients with cancer. More than 90% carried any clinically relevant pharmacogenetic variant. At least one disease-relevant variant impacting anti-cancer agents was identified in 26.5% (77/291). Nine patients with toxicity-associated pharmacogenomic variants were treated with a relevant medication: seven UGT1A1 intermediate metabolizers were treated with irinotecan, one intermediate DPYD metabolizer was treated with 5-fluorouracil, and one TPMT poor metabolizer was treated with mercaptopurine. These individuals were more likely to experience treatment-associated toxicities than their wild-type counterparts (p = 0.0567). One UGT1A1 heterozygote died after a single dose of irinotecan due to irinotecan-related adverse effects. Identifying germline pharmacogenomic variants was feasible using whole-exome sequencing. Actionable pharmacogenetic variants are common and relevant to patients undergoing cancer treatment. Universal pharmacogenomic screening can be performed using whole-exome sequencing data originally obtained for quality control purposes and could be considered for patients who are candidates for irinotecan, 5-fluorouracil, capecitabine, and mercaptopurine.

Background Cancer arises through accumulation of somatically acquired genetic mutations. An important question is to delineate the temporal order of somatic mutations during carcinogenesis, which contributes to better understanding of cancer biology and facilitates identification of new therapeutic targets. Although a number of statistical and computational methods have been proposed to estimate the temporal order of mutations, they do not account for the differences in the functional impacts of mutations and thus are likely to be obscured by the presence of passenger mutations that do not contribute to cancer progression. In addition, many methods infer the order of mutations at the gene level, which have limited power due to the low mutation rate in most genes. Results In this paper, we develop a Probabilistic Approach for estimating the Temporal Order of Pathway mutations by leveraging functional Annotations of mutations (PATOPA). PATOPA infers the order of mutations at the pathway level, wherein it uses a probabilistic method to characterize the likelihood of mutational events from different pathways occurring in a certain order. The functional impact of each mutation is incorporated to weigh more on a mutation that is more integral to tumor development. A maximum likelihood method is used to estimate parameters and infer the probability of one pathway being mutated prior to another. Simulation studies and analysis of whole exome sequencing data from The Cancer Genome Atlas (TCGA) demonstrate that PATOPA is able to accurately estimate the temporal order of pathway mutations and provides new biological insights on carcinogenesis of colorectal and lung cancers. Conclusions PATOPA provides a useful tool to estimate temporal order of mutations at the pathway level while leveraging functional annotations of mutations.

Aims The management of cranial chordomas is controversial. We provide a comprehensive review of the evolving patterns of care of cranial chordomas in the USA. Materials and methods We analysed the National Cancer Database (NCDB) and the Surveillance, Epidemiology, and End Results (SEER) database between 2004 and 2014 for clinical characteristics and long-term survival, and the National Surgical Quality Improvement Program (NSQIP) dataset between 2005 and 2016 for perioperative characteristics and surgical morbidity. Results In total, 936 patients were identified from the NCDB, 405 patients from SEER and 64 patients from the NSQIP. Most patients were men (56.2, 54.8 and 57.8% in NCDB, SEER and NSQIP, respectively) and White (80.9 and 83.2% in NCDB and SEER, respectively). Surgery was the preferred treatment modality (87.3% in NCDB and 86.2% in SEER). Surgery was carried out alone (41.8% in NCDB and 40.7% in SEER) or in combination with radiation (42.1% in NCDB and 45.4% in SEER). Proton therapy was the most common type of radiation (32.2% in NCDB), particularly after 2011. The median operative time, median hospital length and postoperative morbidity were significantly higher in chordoma patients compared with patients who underwent other skull-base procedures. The 5-year survival rate was 79.8% in NCDB and 76.9% in SEER. There was a trend towards longer survival in patients receiving surgery and radiation, which has been increasingly used since 2004. Patients younger than 60 years had a decreased risk of mortality. Conclusions Our analysis reflects patterns of care in the USA. The use of surgery and radiation is increasing, with a trend towards longer survival. Surgery is complicated with long operative time, hospital stay and a higher rate of complications.

Background Meningiomas are the most common central nervous system tumor. We describe current trends in treatment and survival using the largest cancer dataset in the United States. Methods We analyzed the National Cancer Database from 2004 to 2014, for all patients with diagnosis of meningioma. Results 201,765 cases were analyzed. Patients were most commonly White (81.9%) females (73.2%) with a median age of 64 years. Fifty percent of patients were diagnosed by imaging. Patients were reported as grade I (24.9%), grade II (5.0%), grade III (0.7%), or unknown WHO grade (69.4%). Patients diagnosed by imaging were older, received treatment in community facilities, had higher Charlson-Deyo score, and a lower rate of private insurance. Watchful waiting was the most common treatment modality (46.7%), followed by surgery only (40%). Grade II and III patients were more likely to receive therapy. Watchful waiting increased from 35.2% in 2004 to 51.4% in 2014. Younger age, male gender, private insurance, and treatment in academic facilities were determinants for receipt of surgery and/or radiation. Median survival was 12.6 years, higher in histologically confirmed cases (13.1 years). Older patients, Blacks, males, those that received radiation plus surgery, and were treated in community facilities had an increased risk of mortality. Conclusions Over half of patients were diagnosed by imaging, suggesting a higher role of clinical determinants over histological confirmation in treatment decisions. Watchful waiting as initial management is increasing. Our survival analysis favored histological confirmation. Patients receiving radiation and surgery had an increased risk of mortality.

INTRODUCTION: Neurological immune-related adverse events are a rare but potentially deadly complication after immune checkpoint inhibitor (ICI) treatment. As multiple sclerosis (MS) is an immune mediated disease it is unknown how ICI treatment may affect outcomes. METHODS: We analyzed the United States Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) database for pembrolizumab, atezolizumab, nivolumab, ipilimumab, avelumab, and durvalumab two years prior their FDA approval until December 31, 2017, to include all cases with confirmed diagnosis/relapse of MS. We also included cases reported in the literature and a patient from our institution. RESULTS: We identified 14 cases of MS with median age of presentation of 52 years. Indications for ICI included melanoma in 7 (36.36%) cases, non-small cell lung carcinoma in 2 (18.18%) cases, 1 case (9.09%) each of pleural mesothelioma, renal cell carcinoma, and colorectal cancer, and unreported in 2 (18.18%) cases. History of MS was confirmed in 8 (57.1%) cases. Median time to beginning of symptoms was 29 days with rapid disease progression; 2 patients died due to their relapse. Median time for symptom resolution was 8 weeks. Outcomes did not vary by comparing CTLA-4 and PD-1/PD-L1 inhibitors. CONCLUSIONS: Reported MS relapses after ICI are rare but the adverse events described include rapid neurologic progression and death. Larger and prospective studies are warranted to assess disability and long-term outcomes and outweigh the risks of starting immunotherapy in patients with MS.

PURPOSE With the introduction of precision medicine, treatment options for non–small-cell lung cancer have improved dramatically; however, underutilization, especially in disadvantaged patients, like those living in rural Appalachian regions, is associated with poorer survival. Molecular tumor boards (MTBs) represent a strategy to increase precision medicine use. UK HealthCare at the University of Kentucky (UK) implemented a statewide MTB in January 2017. We wanted to test the impact of UK MTB review on overall survival in Appalachian and other regions in Kentucky. METHODS We performed a case-control study of Kentucky patients newly diagnosed with non–small-cell lung cancer between 2017 and 2019. Cases were reviewed by the UK MTB and were compared with controls without UK MTB review. Controls were identified from the Kentucky Cancer Registry and propensity-matched to cases. The primary end point was the association between MTB review and overall patient survival. RESULTS Overall, 956 patients were included, with 343 (39%) residing in an Appalachian region. Seventy-seven (8.1%) were reviewed by the MTB and classified as cases. Cox regression analysis showed that poorer survival outcome was associated with lack of MTB review (hazard ratio [HR] = 8.61; 95% CI, 3.83 to 19.31; P < .0001) and living in an Appalachian region (hazard ratio = 1.43; 95% CI, 1.17 to 1.75; P = .004). Among individuals with MTB review, survival outcomes were similar regardless of whether they lived in Appalachia or other parts of Kentucky. CONCLUSION MTB review is an independent positive predictor of overall survival regardless of residence location. MTBs may help overcome some health disparities for disadvantaged populations.

9060 Background: Inactivating STK11 genomic alterations are prevalent in non-squamous (nsq) NSCLC and define a patient (pt) subgroup with poor prognosis and inferior response to immune checkpoint inhibitors (CPIs). PARP inhibitors (PARPi) can potentiate response to CPIs in preclinical models. We conducted a single arm Phase II study within Lung-MAP to evaluate the efficacy and safety of talazoparib in combination with avelumab in patients (pts) with previously treated nsq NSCLC harboring pathogenic STK11 genomic alterations. Methods: Eligibility: STK11 pathogenic somatic mutation or bi-allelic loss on tumor identified via LUNGMAP screening; stage IV or recurrent nsq NSCLC, receipt of one prior line of anti-PD-1/anti-PD-L1 therapy and platinum-based chemotherapy for stage IV or recurrent disease (sequentially or in combination) and disease progression > 42 days following treatment initiation, a ECOG PS of 0-1, adequate organ function and no previous PARPi exposure. Pts received talazoparib (1000 mg PO daily) plus avelumab (800 mg IV Q2W). Co-primary objectives were to evaluate the best objective response rate (ORR) and disease control rate at 12 weeks (DCR12) after study registration, assessed by RECISTv1.1. Rejection of an ORR of 10% required ≥ 8 responses or rejection of a DCR12 of 30% required ≥18 w/ disease control at 12 weeks and ≥4 responses. Results: 47 pts enrolled from January 16 - November 16, 2020; 42 pts met eligibility (50% male, 50% female). 54% of pts had PD-L1 TPS < 1%. The median TMB was 8.83 Mut/Mb and 45% of pts had KRAS mutations. 52% of the pts had received ≥2 prior lines of treatment for stage IV disease. As of the November 24, 2021 data cutoff, 3 pts remain on treatment, the ORR was 2% (n = 1) and the DCR12 was 40% (n = 17). 26 pts (62%) had SD as best objective response. One responding pt remained on treatment for > 14 mo. The median progression-free survival (39 events) was 2.7 mo (95% CI, 1.6-3.9 mo) and the median overall survival (30 events) was 7.6 mo (95% CI, 6.3-12.2 mo). There were no reported grade 5 treatment toxicities and most grade 3-4 toxicities were hematologic. Additional biomarker analysis to assess effects of key co-mutations on clinical outcomes will be presented. Conclusions: Treatment with talazoparib and avelumab did not meet the pre-specified threshold for efficacy in previously treated STK11-mutant NSCLC in this biomarker-driven Phase II study, though durable disease stabilization was observed. Further studies are required to determine optimal therapeutic approaches for this challenging subset of NSCLC pts. Funding: NIH/NCI grants U10CA180888, U10CA180819. Talazoparib was provided by Pfizer. Avelumab was provided by Pfizer, as part of an alliance between Pfizer and the healthcare business of Merck KGaA, Darmstadt, Germany (CrossRef Funder ID: 10.13039/100004755). Clinical trial information: NCT04173507.

e15045 Background: Chemical Induced Peripheral Neuropathy (CIPN) is a debilitating and serious side-effect associated with many chemotherapeutic treatments. Often, CIPN is a dose-limiting toxicity, and its effects can be long-lasting in some patients. The pathology of CIPN is thought to involve not only cytotoxicity of neuronal cells, but also inflammation and immune responses. Hence, it is not surprising that the sphingolipid sphingosine-1-phosphate (S1P) is thought to be a key contributor to CIPN. Methods: BXQ-350, a nanovesicle comprised of recombinantly expressed Saposin C and dioleoylphosphatidylserine, has broad anticancer activity. It modulates sphingolipid metabolism and signaling, lowers S1P and increases pro-apoptotic ceramides, and induces an anti-tumoral immune response. BXQ-350 was investigated in a Phase 1 dose-escalation safety study of all-comer cancer patients with advanced solid malignancies, including high grade gliomas ( NCT02859857 )*. Multiple secondary parameters were included to characterize BXQ-350’s pharmacokinetics, efficacy profile and to elucidate potential biomarkers. Results: Interestingly, several patients with established CIPN spontaneously reported improvement of their neuropathy-related symptoms following BXQ-350 administration. Plasma samples from those patients revealed changes in circulating levels of sphingolipids and cytokines, including reduction of circulating levels of S1P and of IL-6, IL-8, cytokines, following BXQ-350 dosing. These properties of BXQ-350 were subsequently investigated in a murine oxaliplatin-CIPN preclinical model; results showed a dose-dependent prevention/resolution of CIPN, which also correlated with decreasing systemic S1P levels. Additional plasma based CIPN specific biomarkers were investigated, and preclinical results suggest that BXQ-350 may also favorably inhibit specific immune cells that favor CPIN. Conclusions: These preclinical and clinical observations related to CIPN, coupled with the fact that BXQ-350 acts synergistically with many chemotherapies and radiation, warrant further its investigation into preventing or improving CIPN related symptoms in cancer patients. Clinical trial information: 02859857.

e15007 Background: BXQ-350 was investigated in a Phase 1 dose-escalation safety study of all-comer cancer patients with advanced solid malignancies, including high grade gliomas ( NCT02859857 ) (safety/efficacy results reported in a separate abstract). The primary objective of this single agent study was to describe the safety profile and to determine the maximum tolerated dose. Multiple secondary parameters were included to characterize BXQ-350’s pharmacokinetic parameters, efficacy profile and elucidation of potential biomarkers. BXQ-350 is a nanovesicle of recombinantly expressed Saposin C (SapC) and dioleoylphosphatidylserine. In nature, SapC is a protein encoded by the Psap gene, and serves as an allosteric activator of several enzymes involved in sphingolipid/ceramide metabolism, enzymes which are being investigated as novel therapeutic targets in cancers. Indeed, sphingolipids are a class of bioactive signaling molecules implicated in multiple cellular processes and molecular pathways. Amongst these sphingolipids, Sphingosine-1-Phosphate (S1P) induces cancer cell survival and proliferation, activates multiple oncogenic pathways, and promotes a pro-tumoral microenvironment. SapC has broad anticancer activity, lowering S1P and increasing ceramides, also inducing an anti-tumoral immune response. Methods: Lipodomic analysis (sphingolipids) and cytokines were analyzed in plasma samples of a subset of patients enrolled in this study. Results: Analysis of plasma biomarker samples, collected throughout the period patients were on study, reveals notable changes of circulating sphingolipids and cytokines. A subset of patients exhibited clinical benefits following BXQ-350 administration (see other presentation for details; ̃17% of the evaluable patients remained on study up to Cycle 6; and 8 patients (̃11%) with PFS> 6 months). Concomitant circulating changes in S1P and other ceramides may be indicative of treatment effect. Also, concurrent changes in circulating levels of pro/antitumoral cytokines were noted. Conclusions: While these results are exploratory and preliminary in nature, these initial results warrant further investigation. These observations will be further explored in specific cancer and non-cancer indications. Clinical trial information: 02859857.

e15059 Background: Bexion recently completed an all-comer Phase 1 clinical study of BXQ-350 in patients with advanced solid tumors including high grade gliomas to evaluate the safety profile and to determine the maximum tolerated- or biologically effective dose. BXQ-350 is a nanovesicle comprised of recombinantly expressed Saposin C (SapC) and dioleoylphosphatidylserine. SapC, a human protein encoded by the Psap gene, is an allosteric activator of several enzymes involved sphingolipid metabolism. Sphingolipids are bioactive signaling molecules implicated in multiple cellular processes including apoptosis and immune stimulation/inhibition. In nonclinical studies, BXQ-350 evidences broad anticancer activity, selectively inducing apoptosis of cancer cells by modulating sphingolipids (ceramides/S1P), and BXQ-350 acts synergistically with multiple classes of anticancer agents and treatments. Methods: In the trial (NTC02859857), performed at four US sites, BXQ-350 was administered intravenously for a minimum of 6 cycles over 28 weeks at escalating doses from 0.7 mg/kg up to 2.4 mg/kg. Multiple secondary parameters were included to characterize its pharmacokinetics, efficacy profile and identify potential biomarkers. Results: Results indicate that: i) BXQ-350 was safe and well-tolerated as no DLT was observed and an MTD was not reached; ii) treatment related adverse events leading to discontinuation were typical for this patient population and disease related; iii)* biomarker analyses suggest positive modulation of sphingolipid metabolism and stimulation of the immune system; iv)* surprisingly, some patients noted improvement of existing peripheral neuropathies. RANO or RECIST ver 1.1 criteria were used to evaluate tumor response: 13 patients reached Cycle 6 restaging (17% ORR); 8 patients (11.0% of evaluable patients) demonstrated progression free survival over more than 6 months; and 2 patients (a GBM and CRC patient) are still on study after 5 years. * subject of separate abstracts. Conclusions: In conclusion, BXQ-350 is a first-in-human and first-in-class novel biologic whose Phase 1 results suggest that it may have clinical utility either as a monotherapy or when combined with other targeted agents. Clinical trial information: 028559857.

Although it is known that lung cancer is prevalent in Kentucky, the exact scope and nature of the problem was unknown. We report extraordinarily high lung cancer incidences, shifted subtype distributions, late disease presentation, and poor survival in Kentucky and Appalachian Kentucky. Our findings indicate that Kentucky lung cancer patients may benefit from expanded efforts in prevention, drug discovery, and health care delivery, especially in the rural and Appalachian regions. INTRODUCTION: Kentucky is recognized as the state with the highest lung cancer burden for more than 2 decades, but how lung cancer differs in Kentucky relative to other US populations is not fully understood. PATIENTS AND METHODS: We examined lung cancer reported to the Surveillance, Epidemiology, and End Results (SEER) Program by Kentucky and the other SEER regions for patients diagnosed between 2012 and 2016. Our analyses included histologic types, incidence rates, stage at diagnosis, and survival in Kentucky and Appalachian Kentucky relative to other SEER regions. RESULTS: We found that both squamous cell carcinomas and small-cell lung cancers represent larger proportions of lung cancer diagnoses in Kentucky and Appalachian Kentucky than they do in the SEER registries. Furthermore, age-adjusted cancer incidence rates were higher in Kentucky for every subtype of lung cancer examined. Most notably, for Appalachian women the rate of small-cell carcinomas was 3.5-fold higher, and for Appalachian men the rate of squamous cell carcinoma was 3.1-fold higher, than the SEER rates. In Kentucky, lung cancers were diagnosed at later stages and lung cancer survival was lower for adenocarcinoma and neuroendocrine carcinomas than in SEER registries. Squamous cell carcinomas and small-cell carcinomas were most lethal in Appalachian Kentucky. CONCLUSION: Together, these data highlight the considerable disparities among lung cancer cases in the United States and demonstrate the continuing high burden and poor survival of lung cancer in Kentucky and Appalachian Kentucky. Strategies to identify and rectify causes of these disparities are discussed.

Purpose Large-scale genomic sequencing studies are driving oncology drug development. However, rural populations, like those residing in Appalachian Kentucky, are underrepresented in these efforts. In this study, we determined the frequency of participation, reasons for nonparticipation, and factors predicting the decision to participate in the Total Cancer Care (TCC) prospective genomic cohort study. Methods A total of 1,188 patients were invited to enroll in the TCC prospective cohort from December 2018 to May 2019. Declining patients were queried for their rationale for nonparticipation and their patient data were obtained from the Kentucky Cancer Registry (KCR). Logistic regression was used to assess the association between characteristics and study participation. The association of study participation with survival was modeled with Cox proportional-hazards regression. Results 90.9% (1,081) patients consented to participate. In multivariate analysis, factors significantly associated with participation were age, gender, treatment status, and race. Though overall more women participated in the study, men were more likely to participate than women when invited (OR 1.57). Younger, Caucasian individuals who had received chemotherapy, but not surgery, were also more likely to participate. Patients in the Kentucky Appalachian cohort were primarily rural, had less educational attainment, and lower socioeconomic status. Kentucky Appalachian patients were no less likely to enroll in TCC than non-Appalachian patients. Consented individuals had higher overall survival compared to those who declined. Conclusion Though minorities, those with low socioeconomic status, and rural populations are underrepresented in genomic studies, they were no less likely to participate when given the opportunity, and participation was associated with better clinical outcomes.

EML4-ALK alterations are more common in adenocarcinomas and are rarely found in squamous cell histology. In documented cases, the majority of EML4-ALK translocations are identified in squamous cell histology and occur in patients with no or light smoking history. We report an EML4-ALK4 translocation in a 50-year-old patient with squamous cell carcinoma and an 18 pack-year smoking history. The patient had a near complete response in the CNS to alectinib treatment. Our observation suggests that EML4-ALK genomic testing may be clinically useful in patients with heavy smoking history.

Glioblastoma in children is an aggressive disease with no defined standard therapy. We evaluated hospital‐based demographic and survival patterns obtained through the National Cancer Database to better characterize children with glioblastoma. Our study identified 1173 patients from 0 to 19 years of age between 1998 and 2011. Comparisons were made among demographics, clinical characteristics, treatment, and survival variables. Fifty‐four percent of patients were over 10 years of age. Approximately 80% of patients underwent either partial or complete resection. Adjuvant therapy was used variably, and its use increased with patient age. Forty‐eight percent of patients received the combination of surgery, radiation, and chemotherapy, and 4% did not receive any treatment. As expected, patients ≤5 years of age had better 5‐year survival than those ages 6–10 (P = 0.01) or 11–19 years (P = 0.0077). Other factors associated with poor survival included black race and central tumor location. Better outcomes were associated with treatment that included surgery, radiotherapy, and chemotherapy compared to any other treatment combinations. Radiotherapy had no impact on survival in the 0 to 10‐year‐old age group, but was associated with improved survival for patients 11–19 years. We report an extensive demographic and survival analysis of pediatric glioblastoma. The observed differences likely reflect variances in tumor biology and likelihood of treatment receipt. Improved survival was associated with the use of surgery, radiotherapy, and chemotherapy. Radiation therapy was not associated with survival in patients younger than 10 years of age.

Background: Most metastatic spinal cord lesions are located either in the intradural, extramedullary, or in the epidural compartments. Intramedullary spinal cord metastasis (ISCM) is a rare central nervous system spread of cancer. The aim of this report was to evaluate ISCM in the published literature. Methods: A literature review of PubMed from 1960 to 2016 was undertaken for the publications having demographic, clinical, histological, and outcome data. Results: A total of 59 relevant papers were identified, showing 128 cases of intramedullary metastasis from lung cancer. The incidence of lung cancer as the primary malignancy with intramedullary metastasis was 56%. The median time from diagnosis of primary to intramedullary metastasis was 6 months. Survival improved with multimodality therapy compared to monotherapy (4 months vs. 6.3 months) (hazard ratio = 0.501; 95% confidence interval, 0.293–0.857). Conclusion: Lung cancer is the predominant cause of intramedullary involvement of the spinal cord. Overall prognosis is poor, although a multimodality approach was associated with improved survival. Keywords: Intramedullary, Lung, Metastasis, Neurology, Oncology, Spinal cord

The novel anti-mitotic based tumor treating fields (TTFields) is FDA approved for recurrent glioblastoma. Recently the phase III upfront trial combining the Novo TTF-100A device, called Optune, with temozolomide following concurrent radiation therapy and chemotherapy, demonstrated improvement in survival. Wider use of this novel therapy is expected. The most common adverse event is dermatologic, which dominates compared to the next most frequently observed adverse event of headaches, the incidence of which was even in both arms in the phase III registration trial for recurrent glioblastoma. Our case review outlines the presentation, treatment, and outcome of representative patients using TTFields. In summary, preventative strategies to inform and educate patients and operators can prevent many of these dermatological events. Skin toxicity in the setting of concurrent use of TTFields with other therapies such as bevacizumab is an unknown and will need to be closely followed.

Background Describe a single-center real-world experience with comprehensive genomic profiling (CGP) to identify genotype directed therapy (GDT) options for patients with malignancies refractory to standard treatment options. Methods Patients who had CGP by a CLIA-certified laboratory between November 2012 and December 2015 were included. The medical records were analyzed retrospectively after Institutional Review Board (IRB) approval. The treating oncologist made the decision to obtain the assay to provide potential therapeutic options. The objectives of this study were to determine the proportion of patients who benefited from GDT, and to identify barriers to receiving GDT. Results A total of 125 pediatric and adult patients with a histologically confirmed diagnosis of malignancy were included. Among these, 106 samples were from adult patients, and 19 samples were from pediatric patients. The median age was 54 years for adults. The majority had stage IV malignancy (53%) and were pretreated with 2–3 lines of therapy (45%). The median age was 8 years for pediatric patients. The majority had brain tumors (47%) and had received none or 1 line of therapy (58%) when the profiling was requested. A total of 111 (92%) patients had genomic alterations and were candidates for GDT either via on/off-label use or a clinical trial (phase 1 through 3). Fifteen patients (12%) received GDT based on these results including two patients who were referred for genomically matched phase 1 clinical trials. Three patients (2%) derived benefit from their GDT that ranged from 2 to 6 months of stable disease. Conclusions CGP revealed potential treatment options in the majority of patients profiled. However, multiple barriers to therapy were identified, and only a small minority of the patients derived benefit from GDT.

Radiation optic neuropathy (RON) is an iatrogenic complication that causes severe, irreversible vision loss within months to years following radiation to lesions close to the visual pathway. The authors describe a case of RON in glioblastoma after radio-sensitisation with temozolomide with sequential involvement of both optic nerves. This case provides a timeline for clinical and imaging findings with RON and specifically resolution of nerve enhancement. The authors also highlight the potential of an increase in incidence of RON in glioblastoma with advances in survival seen with greater use of second-line chemotherapy and even re-radiation.

BACKGROUND Like most proliferating tumors, GBM relies heavily on accurate DNA repair for maintenance of genome stability. Dysfunction in repair of both single and double strand DNA breaks by PARP inhibition and impairment of homologous recombination, respectively, would be synthetically lethal. In this study we combined the PARP inhibitor olaparib with cediranib, a pan VEGF receptor inhibitor. Cediranib may mediate disruption in the homologous recombination pathway through its antiangiogenic properties. METHODS Through the Experimental Therapeutics Clinical Trials Network, we performed an open-label randomized phase II study of bevacizumab (BEV)- naive adult patients with first or second recurrence of glioblastoma after radiation and temozolomide. Patients were randomized 1:1 to receive either olaparib 200 mg by mouth twice daily with cediranib 30 mg by mouth daily or BEV 10 mg/kg IV every 2 weeks. The primary endpoint was progression-free survival at 6 months (PFS6). Secondary endpoints included safety and overall survival. Exploratory objectives included blood, tissue and imaging-based biomarkers of response to treatment. RESULTS Seventy patients were enrolled. Median age was 60.5 years (range: 19–79), 39% females, median KPS was 90 (range: 60–100). Baseline characteristics were well balanced. With a data cut-off of 5/2/2019, PFS6 was 14% [95% CI 4–30%] in the cediranib/olaparib arm vs 30.9% [95% CI 12.7–51.2%] in the BEV arm. Median OS was 247 days in the cediranib/olaparib arm vs 201 days in the BEV arm, HR 0.816, 95% CI (0.431, 1.546). Related grade 3, 4 or 5 toxicity was experienced in 29% vs 12% of patients for the cediranib/olaparib vs BEV arm. CONCLUSION Treatment with cediranib/olaparib failed to increase PFS and OS in patients with recurrent GBM. Blood, tissue and imaging correlates will be presented to help understand why this treatment combination was unsuccessful.

Introduction The purpose of this study was to evaluate the efficacy and tolerability of carfilzomib plus irinotecan (C/I) in patients with relapsed small-cell lung cancer (SCLC). Patients and Methods Patients with SCLC who progressed after 1 platinum-containing regimen for recurrent or metastatic disease were eligible. Patients were stratified as: sensitive (SS) (progressive disease > 90 days after chemotherapy) or refractory (RS) (progressive disease 30 to 90 days after chemotherapy) and received up to 6 cycles of C/I; imaging was performed every 2 cycles. The primary endpoint was 6-month overall survival (OS). Results All 62 patients enrolled were evaluable for efficacy and adverse events. 6-month OS was 59% in the platinum SS and 54% in the platinum RS. The overall response rate was 21.6% (2.7% complete response, 18.9% partial response) in SS (n = 37) and 12.5% (all partial response) in RS (n = 25). The disease control rate was 68% (SS) and 56% (RS). Progression-free survival and OS were 3.6 months (95% confidence interval [CI], 2.6-4.6 months) and 6.9 months (95% CI, 4.3-12.3 months) in SS, and 3.3 months (95% CI, 1.8-3.9 months) and 6.8 months (95% CI, 4.1-11 months) in RS. Twenty-nine (47%) patients experienced ≥ grade 3 adverse events; 8 (12.9%) subjects had grade 4 toxicities. Three treatment-related deaths occurred: myocardial infarction (possible), lung infection (possible), and sepsis (probable). Conclusion In patients with relapsed SCLC, C/I was effective in the treatment of SS and RS. With 4.8% grade 5 toxicity, C/I is a viable option for relapsed patients with SCLC with performance status 0 to 1, particularly in platinum-resistant patients, or subjects who cannot receive immunotherapy.

BackgroundGlioblastoma is an aggressive disease with a defined standard of care offering crucial survival benefits. Disparities in care may influence treatment decisions. This study seeks to evaluate potential patterns in care delivery using the National Cancer Database (NCDB).MethodsWe evaluated the NCDB from 1998 to 2011 for patients diagnosed with glioblastoma older than 20 years of age in order to describe current hospital-based demographics, rates of treatment modality by age, race, gender, likelihood of receiving treatment, and survival probabilities.ResultsFrom 1998 to 2011, 100672 patients were diagnosed with glioblastoma in the United States. Of these, 54% were younger than 65 years of age, while 20% were 75 years of age or older. The most common type of treatment was surgery (73%), followed by radiation (69%) and chemotherapy (50%). Eleven percent of patients did not receive any form of therapy. Patients receiving no form of treatment were more likely to be older, female, black, or Hispanic. Tumors that did not involve brainstem, ventricles, or the cerebellum were associated with more aggressive treatment and better overall survival. The median survival was 7.5 months. The use of concomitant surgical resection, chemotherapy, and radiation demonstrated greater survival benefit.ConclusionsMedian survival for glioblastoma is significantly less than reported in clinical trials. Sociodemographic factors such as age, gender, race, and socioeconomic status affect treatment decisions for glioblastoma. The elderly are greatly undertreated, as many elderly patients receive no treatment or significantly less than standard of care.

Chloroquine and hydroxychloroquine (HCQ) are robust inducers of the tumor suppressor Par-4 secretion from normal cells. Secreted Par-4 causes paracrine apoptosis of tumor cells and inhibits metastasis in mice. We report the clinical results with pharmacodynamic analyses of our Phase I trial using neoadjuvant administration of HCQ in patients with surgically removable early stage solid tumors. This was a single-institution trial of oral HCQ (200 or 400 mg twice daily) given for 14 days prior to planned surgery. Dose escalation was based on isotonic regression to model safety and biological effect based on plasma Par-4 analysis. Eight of the nine patients treated with HCQ showed elevation in plasma Par-4 levels over basal levels. No toxicities were observed with these dose regimens. The resected tumors from the eight HCQ-treated patients with elevated plasma Par-4 levels, but not the resected tumor from the patient who failed to induce plasma Par-4 levels, exhibited TUNEL-positivity indicative of apoptosis. Resected tumors from all nine HCQ-treated patients showed p62/sequestosome-1 induction indicative of autophagy-inhibition by HCQ. Our findings indicate that both dose levels of HCQ were well-tolerated and that Par-4 secretion but not induction of the autophagy-inhibition marker p62 correlated with apoptosis induction in patients' tumors.

3085 Background: Hydroxychloroquine (HCQ) is an inducer of the tumor suppressor Par-4 (prostate apoptosis response-4) secretion from normal cells. Secreted Par-4 causes paracrine apoptosis of tumor cells in mice. Established dosing of HCQ 200 mg bid induces Par-4 secretion but not the autophagy-inhibition marker p62 and correlates with apoptosis induction in patients' tumors. Methods: This is a single-arm, single institute phase II study to characterize the biological effects of 3-months of HCQ at fixed-dose (200 mg p.o. twice a day) on plasma Par-4 levels in adults with resected solid tumors. The primary endpoint is proportion of patients who will exhibit a two-fold increase in Par-4 levels from baseline compared to 3 months of follow-up. 12-month progression free survival (PFS) is one of the secondary endpoints. A Simon's two-stage design was used to test the null hypothesis that the proportion of patients exhibiting a two-fold increase in Par-4 is equal to 50% compared to 70% using a one-sided alternative. These hypothesized assumptions are based on a small pilot human data and from a phase I clinical trial on a small number of patients (n = 9). The first stage of interim analysis will be performed after a total of 15 patients have been accrued. If there are eight or fewer responses occurred, the study will be stopped. Otherwise, 28 additional patients will be accrued for a total of 43 subjects. Results: A total of 19 patients were enrolled in the trial. Per protocol, the interim analysis and stopping boundary is based on the first 15 patients. A total of 4 out of 15 patients (26.7%) 95% CI: 8% - 55% exhibited a >2-fold increase in Par-4 levels at 3 months. This did not surpass the stopping bound for futility and thus indicates stopping of patient accrual based on the assumptions used for the Simon's two-stage design. 7 out of 19 patients (36.8%) 95% CI: 16% - 62% who exhibited at least a 2-fold increase at either 2 or 3 months of follow-up, 50% (95% CI: 26% - 74%) and 56% (95% CI: 31% -79%) exhibited a 1.5-fold and 1.25-fold increase respectively. To date, 10/19 patients finished 12-month follow-up, 4/19 and 5/19 finished 6-month and 3-month follow up respectively. 2 of 12 patients with less than 2-fold increase of Par-4 developed disease progression. None of 7 patients with 2-fold increase of Par-4 showed disease progression. Conclusions: Despite that the study was terminated prematurely, to our knowledge this is the first study in human to identify dynamic changes of serum Par-4 while on long-term of usage of HCQ. We also demonstrate trend of PFS benefit especially for subjects having 2-fold increase of Par-4 induction. Identification of tumors more Par-4 sensitive and predictive biomarkers of Par-4 induction are necessary to continue our investigation. Clinical trial information: NCT02232243.

TPS2069 Background: High-grade gliomas (WHO grade III-IV) patients experience marked morbidity and mortality. While the standard of care for newly diagnosed high-grade glioma patients is surgery followed by concurrent chemotherapy and radiation therapy (RT), the outcomes remain poor. BMX-001 (MnTnBuOE-2-PyP5+) is a metalloporphyrin with differential action in response to radiation therapy and chemotherapy-induced oxidative stress. As shown in preclinical evaluations, BMX-001, when used with radiation, can protect normal, healthy tissues and augment cell kill in malignant cancer cells, notably, human glioblastoma xenografts. We evaluated the safety of BMX-001 in combination with concurrent RT and temozolomide (TMZ) in a phase 1 study of newly diagnosed high-grade glioma patients and we found that BMX-001 is safe and well-tolerated in this population. The maximum tolerated dose of BMX-001 during concurrent RT and TMZ was determined to be 28 mg delivered subcutaneously (SC) followed by 16 biweekly SC doses at 14 mg (Peters et al., Neuro-Oncology 2018). Methods: For this multi-site, open-label, phase 2 study (NCT02655601), we will randomize approximately 160 patients 1:1 to concurrent RT and TMZ with BMX-001 versus concurrent RT and TMZ alone. Key eligibility criteria include newly diagnosed histologically confirmed high-grade glioma (WHO III-IV), 18 ≥ years, and Karnofsky performance status ≥ 70%. The primary endpoint is overall survival. Secondary endpoints are objective cognitive performance, bone marrow protection, safety and tolerability, progression-free survival, overall tumor response rate, and plasma pharmacokinetics. Exploratory endpoints are patient-reported outcomes of health-related quality of life (as assessed by Functional Assessment of Cancer Therapy–Brain, Functional Assessment of Cancer Therapy-Cognition, and Functional Assessment of Chronic Illness Therapy-Fatigue), qualitative hair loss, and white matter integrity (as measured by MRI diffusion tensor/susceptibility imaging). Since November 2018, this phase 2 study has enrolled 147 of 160 high-grade glioma patients at nine sites in US. Clinical trial information: NCT02655601.

12112 Background: Previous randomized trials in cancer patients suggest that DOACs are non-inferior to LMWHs for preventing recurrent venous thromboembolism (VTE). However, patients’ perspectives have not been reported. Objective: CANVAS compared LMWHs to DOACs for preventing recurrent VTE in cancer patients. Key 2° endpoints were: 1) health-related quality of life (QOL); and, 2) treatment satisfaction. Methods: CANVAS was an unblinded hybrid comparative effectiveness non-inferiority trial. Between 12/2016 and 4/2020, 671 participants were randomized and followed for 6-months. Patients were assigned 1:1 to receive either a DOAC or a LMWH. Physicians could select any DOAC or LMWH at standard dosing, and patients assigned to LMWH were allowed to transition to Warfarin. Patients from 67 US practices with any invasive solid tumor, lymphoma, multiple myeloma or CLL and a diagnosis of VTE within 30 days of enrollment were eligible. The 1° analysis was conducted in the randomized modified intent-to-treat population, (all subjects who received assigned treatment). Key 2° endpoints were to establish: 1) non-inferior change in HR-QOL; 2) greater perception of benefit; and 3) lower perception of burden for participants receiving DOACs versus LMWHs. Participants reported QOL at 0, 3 and 6 months on the SF-12 survey. At 3 and 6 months, they also reported satisfaction via the Anti-Clot Treatment Scale (ACTS), which includes a burden and a benefit scale. A 2-point change was pre-specified as significant. Results: Neither QOL nor patients’ perceptions of treatment benefits differed between groups. However, patients on DOACs reported lower treatment burden compared to those assigned LMWHs. Conclusions: Among adult cancer patients with VTE, the use of a DOAC compared with a LMWH resulted in no difference in QOL but higher patient-reported satisfaction stemming from decreased perception of the burden of treatment. Clinical trial information: NCT02744092. [Table: see text]

2628 Background: Preclinical models demonstrate that combined RT with immune checkpoint inhibitor (ICI) results in specific CD8+ T-cell phenotype associated with a tumor-reactive population resulting in significant tumor response. Sequential treatment could allow radiation to release tumor antigens from immune inaccessible areas and provide robust anti-tumor immune response with ICI. We report an interim analysis of the phase II clinical trial evaluating the efficacy and safety of the combination. Methods: Advanced NSCLC and HNSCC patients who had initiated on FDA approved single-agent ICI were eligible. Patients were given SBRT (BED>100Gy) or 30 Gy fractionated RT delivered as a 3-dimensional dose to a single metastatic site within 14 days of the first ICI dose. Primary objective was 6-month PFS and secondary objectives were safety and tolerability, 1Y PFS and OS. This interim analysis was done after enrollment of 43 patients. Results: Between 10/2017 to 1/2021, 43 patients were enrolled, and 38 included in this analysis. Median age was 62 years; 26 patients were male. 9 patients received ICI for NSCLC as first-line, 7 for NSCLC second-line and 22 for HNSCC second-line. 24 patients received pembrolizumab and 14 nivolumab; 21 had SBRT and 17 fractionated RT. Median follow up duration was 11.8m (range: 2.7 - 31.4m) for patients without progressive disease (PD). 10 patients were off-study, 7 continuing treatment. 15 died and 26 had PD. 14 patients died of malignancy and cause of death for one patient was unknown. 6-month PFS was 49.19% with median PFS of 5.5 months. (table) Fifty-two grade-3-5 adverse events (AEs) were reported among 21 subjects. Most common were transaminitis (n=15), lymphopenia (n=8), and GI side effects (n=4). Treatment related AEs included 19 grade-3 events, and none were grade 4/5. Two grade-5 AEs were from PD (oral bleeding and unspecified). There were 20 grade-1/2 and 3 grade-3 immune related adverse events (IRAEs). No grade-4/5 IRAEs were reported. Two patients discontinued treatment due to grade 3 transaminitis. Conclusions: Interim analysis shows that 6m PFS was acceptable with majority of patients being second-line metastatic HNSCC who historically had mPFS of 2.1-2.3 months and mOS 7.7-8.4 months in Checkmate-141/KEYNOTE-040 trials. Hence, the combination is of further interest and accrual will continue to reach the goal. The combination therapy was tolerable without unexpected AEs. Majority of deaths were from disease progression. No treatment related grade 4/5 adverse events were reported. Two patients discontinued treatment due to grade-3 IRAE. Clinical trial information: NCT03313804. [Table: see text]

12020 Background: Previous randomized trials in cancer patients suggest that DOACs are non-inferior to LMWH for preventing recurrent VTE but have higher risk of bleeding. However, the balance of benefits and burdens remains uncertain. Objective: The CANVAS pragmatic trial compared recurrent VTE, bleeding and death in cancer patients following an initial VTE treated with either DOAC or LMWH therapy. Methods: CANVAS was an unblinded hybrid comparative effectiveness non-inferiority trial, with randomized and preference cohorts. Between 12/16 and 4/20, 671 participants were randomized and followed for 6-months. Between 12/16 and 12/17, 140 participants declined randomization, chose their preferred anticoagulant and were followed for 6-months. The preference cohort was closed when predetermined stopping criteria were met. Final follow-up was 11/30/20. Randomized patients were assigned 1:1 to receive either a DOAC or a LMWH. If assigned to LMWH, transitions to warfarin were allowed. Physicians and patients could choose among any DOAC or LMWH. Doses were suggested based on FDA-approved labeling but not mandated. Patients from 67 practices in the US with any invasive solid tumor, lymphoma, multiple myeloma or CLL and a diagnosis of symptomatic or radiographically detected VTE within 30 days of enrollment were eligible. The 1° analysis was conducted in the randomized modified-into to treat popululation, (all subjects who received study drug). The 1° outcome was recurrent VTE. The aim was to establish noninferiority of anticoagulation with a DOAC as defined by the upper limit of the 2-sided 90% CI for the difference in the event rate at 6 months of < 3%. Secondary outcomes included death and bleeding. Hypothesis testing included only the randomized cohort but propensity score adjusted results for the preference and combined cohorts are also shown. Results: The non-inferiority criteria for recurrent VTE was met. Conclusions: Among adult cancer patients with VTE, the use of a DOAC compared with a LMWH resulted in a noninferior risk of recurrent VTE with no differences in rates of bleeding or death in randomized patients. Clinical trial information: NCT02744092. [Table: see text]

12007 Background: Up to 96% of patients with high grade glioma (HGG) report moderate to severe fatigue. Armodafinil, the R-enantiomer of modafinil, is a psychostimulant with low potential for abuse that has shown potential for improving severe fatigue in HGG patients. Methods: In this phase III double blinded placebo-controlled study, adults with HGG and moderate to severe fatigue, > 4 weeks after completing radiotherapy, were randomized to receive armodafinil daily (150 mg or 250 mg) or placebo for a total of 8 weeks. The primary outcome was efficacy in treating severe fatigue. Secondary outcomes included evaluation of tolerability, neurocognitive function, and quality of life. Patients were evaluated at baseline, 4 and 8 weeks. Results: A total of 328 patients were enrolled between 6/3/13-3/1/19. There were 103 (150 mg arm), 97 (250 mg arm) and 97 (placebo arm) evaluable patients with primary endpoint data available. The median age was 60 years (20-85) with a median Brief Fatigue Inventory (BFI) worst fatigue score of 8 (6-10). 60.3% were male, 80.5% received concomitant chemotherapy, and 39.7% were on corticosteroids. The global fatigue score at end of weeks 4 and 8 were lower than at baseline (p0.05) or week 8 (p>0.05) between arms. More patients reported insomnia on the 250 mg arm (p=0.0083). Conclusions: There is no meaningful benefit of the use of armodafinil to reduce moderate to severe fatigue in patients with HGG. In certain cases there may be benefit of armodafinil 150 mg to aid concentration without the risk of insomnia.Support: UG1CA189823;U10CA180868 (NRG). Clinical trial information: NCT01781468 .

TPS2577 Background: Patients diagnosed with malignant high-grade gliomas (WHO grade III-IV) experience significant morbidity and mortality associated with these cancers. While the mainstay of therapy for patients with newly diagnosed high-grade glioma is surgery followed by concurrent chemotherapy and radiation therapy (RT), the outcomes remain very poor. BMX-001 (MnTnBuOE-2-PyP5+) is a metalloporphyrin with differential action in response to radiation therapy and chemotherapy-induced oxidative stress. Early preclinical studies demonstrated BMX-001’s ability to act as a radioprotectant to healthy tissue such as a central nervous white matter and as a radiosensitizer to cancer cells, in particular, human glioblastoma xenografts. We evaluated the safety of BMX-001 in combination with concurrent RT and temozolomide (TMZ) in a phase I study of newly diagnosed high-grade glioma patients, and we found that BMX-001 is safe and well-tolerated in this population. The maximum tolerated dose of BMX-001 during concurrent RT and TMZ was determined to be 28 mg delivered subcutaneously (SC) followed by 16 biweekly SC doses at 14 mg (Peters et al., Neuro-Oncology 2018). Methods: For this multi-site, open-label, phase II study (NCT02655601), we will randomize approximately 160 patients 1:1 to concurrent RT and TMZ with BMX-001 versus concurrent RT and TMZ alone. Key eligibility criteria include newly diagnosed histologically confirmed high-grade glioma (WHO III-IV), 18 ≥ years, and Karnofsky performance status ≥ 70%. The primary endpoint is overall survival. Secondary endpoints include cognitive performance as assessed by standardized cognitive testing, bone marrow protection, safety and tolerability, progression-free survival, overall tumor response rate, and plasma pharmacokinetics. Exploratory endpoints are health-related quality of life (as assessed by Functional Assessment of Cancer Therapy–Brain, Functional Assessment of Cancer Therapy-Cognition, and Functional Assessment of Chronic Illness Therapy-Fatigue), qualitative hair loss, and white matter integrity (as measured by MRI diffusion tensor/susceptibility imaging). Since November 2018, this phase II study has enrolled 64 of 160 high-grade glioma patients at six sites with future sites planned to be implemented. Clinical trial information: NCT02655601 .

Brain tumor treatment and survival information is generally limited in large-scale cancer datasets. We provide a clinical investigation of current patterns of care and survival estimates for central nervous system (CNS) tumors treated in the United States. We analyzed the National Cancer Database from 2004–2015 for all patients with diagnosis of primary CNS tumors. We describe patient demographics, treatment modality, and analyzed survival estimates. 512,168 patient tumor records were examined. The most common histology was meningioma (43.6%), followed by glioblastoma (22.0%), and nerve sheath tumors (10.6%). Patients had a median age of 60 years, with a female (57.9%), white (85.0%), and non-Hispanic (87.8%) predominance. Tumors were reported as World Health Organization (WHO) grade I for 55.9% of the patients, grade II for 5.9%, grade III for 4.4%, grade IV for 24.3%, and grade unknown or not applicable for 9.4%. Overall, 56% underwent surgical procedures, 30.4% received radiation, and 20.6% received chemotherapy. Radiation plus chemotherapy and surgery was the most common treatment modality in high-grade tumors (40.5% in WHO grade III and 49.3% in WHO grade IV), while surgery only or watchful waiting was preferred in low-grade tumors. Older age, male gender, non-Hispanic origin, higher number of comorbidities, and lower socioeconomic status were identified as risk factors for mortality. Our analysis provides long-term survival estimates and initial treatment decisions for patients with CNS tumors in hospitals throughout the United States. Age, comorbidities, gender, ethnicity, and socioeconomic characteristics were determinants of survival.

BACKGROUND: Glioblastoma (GBM) is an aggressive neoplasm that continues to show recurrence despite recent advances in therapy. Tumor Treating Fields (TTFields) is a non-invasive, regional antimitotic treatment modality, delivering low-intensity (1–3 V/cm), intermediate-frequency (100–300 kHz), alternating electric fields to tumors via transducer arrays placed on the scalp of GBM patients. TTFields disrupts cell division processes in cancer cells. However, some mechanisms of escape have been described, in particular, out-of-field tumor recurrence. The brainstem dose not receive high intensity electric field stimulation during TTFields therapy, and represents one possible region of tumor recurrence following treatment. METHODS: Six cases were identified via retrospective chart review from multiple providers that have experience with prescribing and planning treatment with TTFields. Clinical and radiographic reviews were performed after de-identification of patient records. Cases were compared according to demographics, tumor location and region of recurrence. RESULTS: The median patient age at diagnosis was 62 years (Range: 10–69) with 3/6 patients being male and 3/6 patients being female. Tumors were initially located in the frontal (3/6), parietal (2/6), and temporal lobes (1/6). Three patients received TTFields therapy at initial diagnosis in combination with surgery and chemoradiation, while the remaining patients received TTFields therapy at initial recurrence in conjunction with bevacizumab. Following TTFields treatment, tumors recurred predominantly in the pons (1/6), left cerebellar peduncles (3/6), and right cerebellar peduncles (2/6). The average time to brainstem recurrence following TTFields therapy was 152 days (Range: 49–228). CONCLUSIONS: Treatment options for patients with GBM are limited, however TTFields has been shown to improve overall survival when combined with temozolomide. TTFields can only be delivered in therapeutic intensities to the supratentorial brain. Brainstem recurrence may occur as field intensity in the brainstem is sub-therapeutic. Further investigation is warranted to determine optimal treatment for brainstem recurrences for patients receiving TTFields therapy.