tbuckley/cabot-search huggingface dataset:
Preliminary results from CLASSICAL-Lung, a phase 1b/2 study of pepinemab (VX15/2503) in combination with avelumab in advanced NSCLC.
Authors: Michael Rahman Shafique, Terrence Lee Fisher, Elizabeth E. Evans, John E. Leonard, Desa Rae Electa Pastore, Crystal L. Mallow, Ernest Smith, Maurice Zauderer, Andreas Schröder, Kevin M. Chin, J. Thaddeus Beck, Megan Ann Baumgart, Ramaswamy Govindan, Rachel E. Sanborn, Jonathan Wade Goldman
Journal: Journal of Clinical Oncology (2019)

2601 Background: Rational combination therapies are needed to overcome resistance mechanisms in NSCLC. Pepinemab is an IgG4 humanized monoclonal antibody targeting semaphorin 4D (SEMA4D, CD100). In vivo preclinical models demonstrated antibody blockade of SEMA4D promoted immune infiltration and reduced function and recruitment of immunosuppressive myeloid cells within the tumor. Importantly, preclinical combinations of anti-SEMA4D with various immunotherapies enhanced T cell activity and tumor regression. The CLASSICAL-Lung clinical trial tests the combination of pepinemab with avelumab to couple immune activation via checkpoint inhibition with beneficial modifications of the immune microenvironment via pepinemab. Methods: This ongoing phase 1b/2, open label, single arm, first-in-human combination study is designed to evaluate the safety, tolerability and efficacy of pepinemab in combination with avelumab in 62 patients (pts) with advanced (stage IIIB/IV) NSCLC (NCT03268057). The trial is split into dose escalation (n = 12) and dose expansion (n = 50) phases and includes 2 cohorts; 1) pts who are immunotherapy naïve, and 2) pts whose tumors progressed during or following immunotherapy (IO failure). Pts in the dose escalation cohorts received ascending doses of pepinemab i.v. (5, 10, 20 mg/kg, Q2W) in combination with avelumab i.v. (10mg/kg, Q2W). Results: Dose escalation is complete and the RP2D was selected as 10mg/kg pepinemab, Q2W. No pts experienced a TRAE leading to study discontinuation or death. The most frequent related AEs were grades 1 or 2 fatigue, pyrexia, or chills; no grade 3 AEs occurred in more than one subject. One DLT, a grade 3 pulmonary embolism occurred in the 10mg/kg pepinemab cohort, and resolved without reoccurrence. The disease control rate for pts treated &gt; 2 months is 90% (19/21), and, at this early stage, a PR with a 49% reduction in target lesion was observed in at least 1 of 8 pts in the IO failure cohort. Updated data from the dose expansion phase will be presented. Conclusions: Preliminary data suggest the combination is well tolerated and shows initial signals of antitumor activity. Dose escalation is complete and the expansion phase is ongoing. Clinical trial information: NCT03268057.
Opportunity for performance measurement: 30-day mortality following cancer surgeries across U.S. hospitals.
Authors: Allison Lipitz-Snyderman, Jessica A. Lavery, Peter Bach, Diane G. Li, Annie Yang, Vivian E. Strong, Ashley Russo, Katherine Panageas
Journal: Journal of Clinical Oncology (2019)

e18221 Background: While public reporting of surgical outcomes for non-cancer conditions is common, measures of outcomes following surgery for cancer have generally been excluded. This is true even though numerous studies show large variations between hospitals. We assessed whether prerequisites for quality reporting are present for the measure of 30-day cancer surgical mortality: low burden for timely reporting, hospital variation, and potential for public health gains. Methods: We used Fee-for-Service (FFS) Medicare claims to examine the extent of variation in 30-day mortality between 3,860 U.S. hospitals performing cancer surgery for patients ≥66 years, 2011-2013. Hierarchical mixed-effects logistic regression models adjusted for patient and hospital characteristics and with a random hospital effect were fit to obtain hospital-specific risk-standardized mortality rates (RSMRs) and 99% confidence intervals (CI). From these models we calculated a hospital odds ratio to describe the difference in the mortality risk for a hospital above versus below average quality and estimated the potential reduction in mortality under a scenario of improved quality for the lowest performers. Outcomes included extent of hospital variability in 30-day mortality after cancer surgery; and impact on lives saved from improving performance at outlier hospitals. Results: Over the three-year observation period, the median number of cancer surgeries performed per hospital was 34. For individual cancer sites, it was &lt; 10, except for breast (median 17) and colorectal (median 14). The median RSMR overall was 2.41% (99% CI 2.28%, 2.66%). Breast had the lowest RSMR (median 0.24%) and gastroesophageal the highest (median 5.72%). In aggregate and for most individual cancers, variation between hospitals exceeded that due to differences in patient and hospital characteristics, and was robust to excluding emergent cases. For individual cancer sites, relative differences exceeded 20% in the risk of 30-day mortality between patients undergoing surgery at a hospital below average quality versus above average quality, with the potential for an estimated 500 deaths prevented annually given hypothetical improvements. Conclusions: Quality measurement and reporting of 30-day mortality for cancer surgery is worthy of consideration.
Computational design of novel tetra-specific antibody (PD-1/CD47/VEGF/TGF-ß) with IgG-like architecture against non-small cell lung cancer (NSCLC).
Authors: Lei Zhao, Fan Zhang, Lingling Li, Shixue Chen, Yi Hu
Journal: Journal of Clinical Oncology (2019)

e14002 Background: Although monoclonal antibodies (mAbs) are widely used for the treatment of cancer, the acquired resistance is one of the prime obstacles for cancer treatment. There is an urgent need to development of novel antibodies with potent anti-tumor activities and specificities against cancer. Due to the complexity and heterogeneity of cancer, mAb with a single target could not be significantly improved to combat cancer. Nowadays, bispecific antibodies with the capacity to blockade of multiple targets or binding sites are showing improved therapeutic efficacy against cancer both in clinical trials and preclinical studies, suggesting that multi-specific antibodywith great potential for administration of cancer in near future. Although more than 30 bispecific antibodies with IgG architecture are being explored in clinical trials, tetra-specific antibody with IgG-like architecture against NSCLC has not been reported. Methods: Recently, we have successfully solved the correct assembling of heavy-heavy chain and heavy-light chain of multi-specific antibody through the Lock-and-Key and FabX technologies we have previously described. By using these two technologies, we have designed the tetra-specific antibody with IgG-like architecture against NSCLC. Then, we have performed long-time molecule dynamic simulation (6 µs) to evaluate and improve the structure stability of tetra-specific antibody. Results: With the benefits of tetra-specific antibody and whole IgG architecture, the tetra-specific antibody PD-1/CD47/VEGF/TGF-ßexhibits potent anti-tumor efficacy than the parent antibody Atezolizumab, Hu5F9-G4, Bevacizumab or Fresolimumab and the combination of these parent antibodies. Conclusions: Tetra-specific antibody with IgG-like structure shows the advantages in cancer treatment. Antagonism of PD-1, CD47, VEGF and TGF-ß through multi-specific antibody could be a promising anti-tumor strategy against NSCLC.
Pathogenic germline mutation hotspots in east Asian cancer genomes.
Authors: Xiaoshun Shi, Allen Menglin Chen, Kailing Huang, Zhouxia Zheng, Zhuona Chen, Sylvia Young, Jiexia Zhang, Xiaoying Dong, Xiguang Liu, Di Lu, Siyang Feng, Grant Morahan, Kaican Cai
Journal: Journal of Clinical Oncology (2019)

e13011 Background: To summarise the prevalence of pathogenic germline variants in East Asian cancer genomes and to develop an online resource and reference for genetic analysis of cancer susceptible germline mutation hotspots. Methods: We performed the most extensive investigation of germline mutations in East Asian cancer population based on publicly available data collected from multiple institutions over 1,600 patients with 15 cancer types. The pathogenic cancer susceptibility gene mutations were called by analyzing whole exome sequencing data generated from the normal control samples from the cancer patients deposited on the SRA database. Results: Compared with 9,435 East Asian controls in the gnomAD dataset, we identified pathogenic recurrent germline mutations based on our MaGiC analysis pipeline including quality controlled, filtration and annotation. More than 150 variants were found, and the top 3 hotspot mutations are TP53 in 5 types of cancer, BRCA2 in 3 types of cancer and PIK3CA in 4 types of cancer. The hotspot variants(same cancer predisposition gene set, but different pathogenic mutations) were of population difference in comparison with Caucasian population. Conclusions: Our work is the first comprehensive analysis of East Asian cancer predisposition germline mutations. It provides informative references for cancer genetic consulting and early prevention in more than 20% of world population. The update of our database covering larger populations and more cancer types is needed and still ongoing.
Genomic biomarkers of recurrence in low-grade, early-stage endometrial adenocarcinoma.
Authors: Katie Lee Hwang, William L. Hwang, Brooke E. Howitt, Martin T. King, Elizabeth Stover, Ursula A. Matulonis, Larissa Janeen Lee
Journal: Journal of Clinical Oncology (2019)

5588 Background: Endometrial cancer is the most common gynecologic malignancy in developed countries with over 60,000 new cases diagnosed in the United States each year. Adjuvant therapy is often omitted for low-risk, early-stage disease (FIGO stage IA, grade 1) but 1 in 20 women suffer recurrence after surgery alone. Hence, there is an important need for biomarkers of recurrence in this population to guide therapeutic management. Methods: We retrospectively analyzed 74 patients with FIGO stage 1A, grade 1 endometrial endometrioid adenocarcinoma treated at our institution with hysterectomy alone between 2009-2016. All patients had targeted genomic assessment of their tumors (OncoPanel; somatic mutations, copy number variations and structural variants across 300 cancer genes). The primary outcome of interest was freedom from recurrence (FFR). Outcomes were compared by the logrank test and survival estimates calculated by Kaplan-Meier method. Results: We identified 14 patients who recurred at a median time of 23.6 months after surgery and 60 patients without recurrence at a median follow-up of 38.9 months. Age (median 57 years; log-rank p = 0.91) and BMI (median 31 kg/m2; log-rank p = 0.21) were not associated with risk of recurrence. The median somatic mutation count in the cohort was 8. Patients with more than 8 somatic mutations had a significantly higher risk of recurrence (3-year FFR: 74% vs 90%; log-rank p = 0.004). At the level of individual genes, there were four genes that were significantly associated with recurrence: CTNNB1 (p = 0.046), RHPN2 (p = 0.020), SF1 (p = 0.044), SQSTM1 (p = 0.034). Patients with a mutation in one or more of these four genes had a significantly higher risk of recurrence (3-year FFR: 62% vs 93%; log-rank p = 0.0004). Conclusions: We have identified overall somatic mutation burden and mutations in a subset of four genes ( CTNNB1, RHPN2, SF1, SQSTM1) as determined by a validated 300-gene panel used in routine clinical practice as prognostic biomarkers for patients with low-risk, early-stage endometrial endometrioid adenocarcinoma. These patients may benefit from the addition of adjuvant therapy. Validation with larger cohorts and prospective studies is warranted.
De novo malignancy in recipients of solid organ transplant from donors with intracranial cancer.
Authors: Katie Carsky, Christopher Carr, Cassidy Werner, Helmi Khadra, John Blair Hamner, Anil S Paramesh, Aaron S Dumont
Journal: Journal of Clinical Oncology (2019)

e13507 Background: In 2016, 33,610 organ transplants were performed in the US. Nevertheless, there is a critical deficiency of available organs. Currently, malignant neoplasms in the donor preclude organ donation, with some exceptions, such as certain CNS tumors without metastatic disease. The literature illustrates the risk of CNS tumor transmission with organ transplantation as 0-3% in the absence of additional risk factors, but organs from fewer than 0.5% of the 13,000 patients that die of glioma annually are procured. Given the critical need, we sought to reaffirm the safety of organs from donors with intracranial cancer by examining de novo malignancy outcomes in a large dataset. Methods: We examined the UNOS database to determine whether recipients of solid organ transplant from donors with intracranial cancer were at increased risk of de novo malignancy. Included were 119,430 subjects ages 18 to 65 who underwent heart, heart and lung, intestine, kidney, kidney and pancreas, liver, lung, or pancreas transplant from 1987 to 2012 and for whom there was complete data on donor history of intracranial cancer. 2-by-2 contingency tables were used to calculate odds ratios of exposure to donors with intracranial cancer. Outcomes included five-year survival, composite development of any malignancy, and development of specific malignancies including melanoma, esophageal, stomach, small intestine, pancreas, larynx, mouth, colorectal, primary liver tumor, and metastasis to liver. A p value of ≤ 0.05 was statistically significant. Results: 718 (0.60%) organs came from donors with intracranial cancer. 437 (79.02%) recipients of organs from donors with intracranial cancer survived 5 years, versus 71,055 (77.64%) recipients of organs from donors without intracranial cancer (p = 0.47). 113 (15.74%) recipients of organs from donors with intracranial cancer developed de novo malignancy, versus 17,963 (15.13%) recipients of organs from donors without intracranial cancer (p = 0.60). Of 17 contingency analyses of development of specific malignancies, we detected only 1 statistically significant positive association, de novo colorectal cancer in recipients of solid organ transplant from donors with intracranial cancer (p = 0.048, OR = 2.56). Given the large number of analyses and marginal significance of this in a very large dataset, it is likely type I error. Conclusions: Metastasis of primary CNS tumors beyond the CNS is a rare occurrence without additional risk factors. With the current organ shortage, donors with primary CNS malignancy are ideal candidates for organ donation.
Predictors of survival in chemorefractory colorectal liver metastases treated with Y90 radioembolization.
Authors: Alexander Michael Dabrowiecki, Tina Sankhla, Kaitlin Shinn, Zachary Louis Bercu, Robert Mitchell Ermentrout, Janice Newsome, Walid Labib Shaib, Kenneth Cardona, Nima Kokabi
Journal: Journal of Clinical Oncology (2019)

e15044 Background: The aim of the study was to evaluate molecular signatures and timing of yttrium-90 (Y90) as prognostic factors of survival following Y90 radioembolization (RE) in patients with chemorefractory colorectal liver metastases (CRLM). Methods: In a retrospective single-institution study, patients with unresectable, chemorefractory CRLM who had undergone genomic analysis prior to Y90 RE from 2013 to 2018 were identified. Timing of Y90 (following failure of first line vs following multiple lines of chemotherapy) and oncogenic mutation status (MAPK and PI3K pathways) were evaluated as predictors of survival length following Y-90. Survival was measured from first Y90 using Kaplan-Meier estimation and predictors of outcome were identified using log-rank analysis. Results: Overall, 58 patients with chemorefractory CRLM who underwent genomic analysis prior to Y-90 were identified. Of these, 26 (44.8%) had MAPK mutations, and 2 (3.5%) had PI3K mutations. Median survival after first Y-90 RE was 12.9 months. There was significantly prolonged overall survival (OS) in patients receiving Y90 immediately following failure of the first line of chemotherapy (FOLFOX ± bevacizumab) versus patients who underwent multiple lines of chemotherapy prior to Y90 (median OS of 16.9 vs 11.4 months for others; p = 0.023). When stratifying the cohort based on the timing of Y90, patients with WT-MAPK (n = 8) had prolonged OS if they underwent Y-90 following failure of the first line of chemotherapy (median OS of 22.3 vs 12.9 mo; p = 0.019). Patients with WT-PI3K (n = 19) had prolonged OS if they underwent Y90 following failure of the first line of chemotherapy (median OS of 16.9 vs 12 mo; p = 0.037). When analyzing the entire cohort non-stratified by timing of Y90, genetic mutation was not found to be a predictor of prolonged OS. Conclusions: Y90 RE after failure of first line of chemotherapy in CRLM appears to confer prolonged survival specifically for WT-MAPK and WT-PI3K oncogenes. Conversely, the prognosis of more favorable genetic status appears to be negated if Y90 RE is performed after failure of second or third line chemotherapies.
A randomized double-blind placebo-controlled phase II trial comparing gemcitabine monotherapy to gemcitabine in combination with adavosertib in women with recurrent, platinum resistant epithelial ovarian cancer: A trial of the Princess Margaret, California, Chicago and Mayo Phase II Consortia.
Authors: Stephanie Lheureux, Michael Cabanero, Mihaela C. Cristea, Gina Mantia-Smaldone, Alexander Olawaiye, Susan Ellard, Johanne I Weberpals, Andrea Elisabeth Wahner Hendrickson, Gini F. Fleming, Stephen Welch, Neesha C. Dhani, Anna Piskorz, Susie Tan, Karen Chang, Lisa Wang, Charles Kunos, Trevor John Pugh, James D. Brenton, Amit M. Oza
Journal: Journal of Clinical Oncology (2019)

5518 Background: Platinum resistant ovarian cancer (OC) remains a therapeutic challenge. High grade serous OC (HGSOC) harbors TP53 mutations leading to increased dependency on S- and G2-phase checkpoints. Wee1 inhibition with Adavosertib (AZD 1775) (A) induces G2 checkpoint escape. Gemcitabine (G) is an antimetabolite therapy and blocks the progression of cells through the G1/S phase. We hypothesized that combining G+A would be synergistic and overcome resistance. Methods: We conducted a multicentre double-blind 2:1 randomized phase 2 trial to assess the progression free survival (PFS) in women with recurrent platinum-resistant/refractory HGSOC receiving G+A or G+placebo (P) (NCT02151292). Eligibility required measurable disease and feasibility of paired tumor biopsies; no limitation in prior lines of therapy. Non HGSOC histologic subtypes were enrolled in a separate non-randomized exploratory cohort. A/P was given orally at 175mg QD on D1-2, D8-9 and D15-16 with G 1000mg/m² IV D1, D8 and D15 in a 28-day cycle until progression or unacceptable AE. Tumor staging was scheduled every 8 weeks. TP53 mutations were analyzed on archival tissue with Sanger sequencing, TAm-Seq and IHC. TP53 mutation will be also assessed in circulating tumor DNA (ctDNA). Whole exome and RNA sequencing were performed on paired tumor tissues. Results: 124 patients (pts) with median of 3 prior lines of therapy (range 1-10) from 12 centres across Canada and US were enrolled between Sep 2014 to May 2018, with 99 pts randomized (65 in Arm G+A and 34 in G+P). 5 pts were ineligible; 64 pts have died. The median follow-up was 14.3 months. Main related AE was hematologic toxicity (Anemia G≥3: 31% in G+A vs 18% in G+P; Thrombocytopenia G≥3: 31% vs 6%; Neutropenia G≥3: 62% vs 30%). PFS was significantly improved from 3.0 to 4.6 months (HR 0.56 (95%CI: 0.35-0.90, p=0.015 Log rank). There was a significant improvement in overall survival (OS) from 7.2 to 11.5 months (HR 0.56 (95%CI: 0.34-0.92, P=0.022). Partial response by RECIST 1.1 was observed in 13 (21%) and 1 (3%) pts for Arms G+A and G+P, respectively (p=0.02). From the 25 pts in the exploratory cohort, 3 (12%) partial responses were observed. Final results will be reported at the meeting. Conclusion: Addition of adavosertib to gemcitabine in women with platinum resistant/refractory OC improved response rate, PFS and OS with manageable toxicity. Clinical trial information: NCT02151292.
Depressive symptoms, mental health-related quality of life, and survival among older patients with multiple myeloma.
Authors: Ali Alobaidi, Nadia Azmi Nabulsi, Brian Talon, Alemseged Ayele Asfaw, Jifang Zhou, Lisa K. Sharp, Karen Sweiss, Pritesh Rajni Patel, Brian C-H Chiu, Naomi Ko, Gregory Sampang Calip
Journal: Journal of Clinical Oncology (2019)

e18232 Background: Few studies have evaluated the impacts of depressive symptoms and mental health on patients diagnosed with multiple myeloma (MM). The aim of this study was to examine associations between depressive symptoms and poor mental health-related quality of life in relation to survival in a cohort of older MM patients. Methods: We conducted an analysis using a prospective cohort from the Surveillance, Epidemiology, and End Results (SEER)-Medicare Health Outcomes Survey (MHOS) of patients aged 65 years and older diagnosed with first primary MM between 1998 and 2014. Subjects were required to have completed at least 1 pre-diagnosis survey and depressive symptoms were determined based on positive responses to at least 1 of 3 depression screening questions. Veterans-RAND-12 mental component scores (MCS) were also analyzed to evaluate mental health-related quality of life. We used multivariable Cox proportional hazards models to estimate hazard ratios (HR) and 95% confidence intervals (CI) for the association between pre-diagnosis depressive symptoms and risks of all-cause and cancer-specific mortality. Secondary analyses examined mortality risks in relation to pre-diagnosis MCS. Results: Of 522 multiple myeloma patients, the mean (SD) age at diagnosis was 76.9 (6.1) years and 158 (30%) self-reported positive depressive symptoms. Patients with depressive symptoms had a higher number of comorbid conditions and nearly all (84%) scored below the median MCS. Pre-diagnosis depressive symptoms were not associated with all-cause (HR 1.01, 95% CI: 0.79-1.29) or cancer-specific mortality (HR 0.94, 95% CI: 0.69-1.28). Myeloma patients scoring in the second MCS tertile (versus the highest tertile) had a modestly increased risk of all-cause (HR 1.19, 95% CI 0.91-1.55) and cancer-specific mortality (HR 1.17, 95% CI 0.86-1.60), but these estimates were not statistically significant. Conclusions: Pre-diagnosis depressive symptoms and lower mental health-related quality of life are not associated with survival for MM. Nevertheless, the considerably high prevalence of depressive symptoms and poor mental health status among older patients with multiple myeloma deserves clinical attention.
Sister Mary Joseph Nodule Arising From a Metastatic Serous Papillary Carcinoma
Authors: Sheenagh George, Richard M. Haber
Journal: JAMA Dermatology (2019)

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