tbuckley/cabot-search huggingface dataset:
Phase 1 study evaluating the safety, tolerability, pharmacokinetics (PK), and efficacy of AMG 510, a novel small molecule <i>KRAS<sup>G12C</sup></i> inhibitor, in advanced solid tumors.
Authors: Marwan Fakih, Bert O'Neil, Timothy Jay Price, Gerald Steven Falchook, Jayesh Desai, James Kuo, Ramaswamy Govindan, Erik Rasmussen, Phuong Khanh H. Morrow, Jude Ngang, Haby A. Henary, David S. Hong
Journal: Journal of Clinical Oncology (2019)

3003 Background: The KRAS G12C mutation is found in approximately 13% of lung adenocarcinomas and 1–3% of other solid tumors, but there is no approved therapy that targets this mutation. AMG 510 is a novel small molecule that specifically and irreversibly inhibits KRAS G12C by locking it in an inactive GDP-bound state. Methods: This phase 1, first-in-human, open-label, multicenter study (NCT03600883) is evaluating the safety, tolerability, PK, and efficacy of AMG 510 in adult patients (pts) with locally-advanced or metastatic KRAS G12C mutant solid tumors. The primary endpoint is safety; key secondary endpoints include PK, ORR (assessed every 6 weeks [wks]), DOR, and PFS. Key inclusion criteria: KRAS G12C mutation identified through DNA sequencing, measurable or evaluable disease, ECOG PS ≤2, life expectancy &gt;3 months (mo). Key exclusion criteria: active brain metastases, myocardial infarction within 6 mo. A dose exploration will determine the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D). A dose expansion will enroll pts with NSCLC, CRC, and other advanced solid tumors carrying the KRAS G12C mutation. AMG 510 will be given PO until disease progression, intolerance, or withdrawal of consent. Results: 22 pts (8 men, 14 women; median age 55.5 y) were enrolled in the first 3 dose cohorts. Tumor types: 6 NSCLC, 15 CRC, 1 other. Most pts (n=17) had ≥3 prior lines of treatment (tx). Median tx duration was 28 d (range: 8–134). 5 pts reported 10 treatment-related AEs (grade 1, n=9; grade 2, n=1); there were no DLTs. Tumor response was evaluated in 9 pts (4 with ≥2 assessments); 13 pts have not reached their first assessment.1 pt had a PR (NSCLC at wks 6 and 12, tx ongoing), 6 pts had SD (4 CRC and 2 NSCLC; median tx duration 9.7 wks [range: 6.3–19.1], tx ongoing), 2 pts had PD. 20 pts are continuing to receive AMG 510. A second PR (NSCLC at wk 6, tx ongoing) was reported after data cutoff. Conclusions: AMG 510 has been well tolerated at the dose levels tested and has shown antitumor activity when administered as monotherapy to patients with advanced KRAS G12C mutant solid tumors. MTD has not been determined, and enrollment into the dose exploration is ongoing. Clinical trial information: NCT03600883.
The Affordable Care Act and cost-related medication non-compliance in cancer survivors.
Authors: Justin Barnes, Kimberly J. Johnson, Eric Adjei Boakye, Mark Alex Varvares, Nosayaba Osazuwa-Peters
Journal: Journal of Clinical Oncology (2019)

106 Background: Cost-related medication non-compliance (CRN), which is associated with access-to-care barriers and poorer health outcomes, is more prevalent among cancer survivors than other adults. While CRN in survivors has been decreasing recently, evidence for a change driven by the Affordable Care Act (ACA) is limited. We aimed to quantify the impact of the ACA on CRN in non-elderly cancer survivors using population-based data and a quasi-experimental design. Methods: We utilized 2011-2017 National Health Interview Survey data. CRN was defined as not being able to afford medication or taking less than prescribed, skipping doses, or delaying prescription filling due to cost. Linear probability models applied to difference-in-difference analyses were used to compare CRN changes after the ACA in non-elderly ( &lt; 65 years) cancer survivors relative to control groups expected to be impacted less by ACA provisions--non-elderly adults without a cancer history, elderly survivors, and non-elderly survivors with high income. Results: We identified 6,176 non-elderly and 8,508 elderly cancer survivors and 142,732 other non-elderly adults. Non-elderly cancer survivors had a 6.31 (95% CI = 3.47, 9.15; p &lt; .001) percentage point (PP) decrease in CRN relative to non-elderly adults without a cancer history, particularly for those earning 125-249% of the federal poverty limit (FPL) (8.46 PP; 95% CI = 0.45, 16.46; p = .038) and &lt; 125% FPL (11.8 PP; 95% CI = 4.51 to 19.1; p = .002). Relative to elderly survivors, CRN decreased 6.01 PP (95% CI = 3.12, 8.90; p &lt; .001) in non-elderly survivors after the ACA, especially for individuals earning &lt; 125% FPL (15.7 PP; 95% CI = 7.7, 23.7; p &lt; .001). Relative to non-elderly survivors earning &gt; 400% FPL, those earning &lt; 125% FPL had an 8.36 PP (95% CI = 1.44, 15.3; p = .018) reduction in CRN. Conclusions: CRN decreased in non-elderly cancer survivors after the ACA relative to both elderly survivors and adults without a history of cancer. Furthermore, reductions in CRN were observed in low relative to high income survivors. Thus, the ACA is associated with decreasing CRN in cancer survivors, especially those with low income, and hence may improve health care access and affordability for this vulnerable population.
PD-L1 expression, DNA mismatch repair genes, and HPV types in cervical squamous cell carcinoma.
Authors: Tahmineh Haidary, Rachelle Pacaanas Mendoza, Yingyin Zhou, Wen-Ching Lee, Yi-Chun Lee, Raavi Gupta
Journal: Journal of Clinical Oncology (2019)

5533 Background: Previous studies observed low PD-L1 expression in cervical cancer, and that high PD-L1 expression is associated with deficient DNA mismatch repair genes and poor prognosis. No study has investigated the PD-L1 expression differences among HPV types in cervical cancer. We aim to determine PD-L1 expression in our patient population and its clinical significance. Methods: A total of 198 patients with SCC were identified and 60 had evaluable tumor specimens and clinical data. Immunohistochemistry on MMR genes and PD-L1 expression using tissue microarrays was performed. HPV analysis for 15 high-risk types was done by multiplex PCR and gel electrophoresis. Correlation between PD-L1 expression, MMR status, HPV types and other clinical parameters was analyzed using χ2 or Fisher's exact test. Cumulative 5-year survival was analyzed by Kaplan-Meier curves and log rank test. Results: Of the 60 patients, 90% were black, 55% between ages of 30-55 and 40% older than 55. 33 patients had poorly, 20 moderately, and 7 well-differentiated tumors. At 5-year follow up, 11 had recurrence, 14 patients died of disease and 7 lost to follow up. 93.3% of tumors had positive staining for PD-L1 with 56.7% showing high expression. Patients aged 30-55 showed a higher rate of PD-L1 expression. Majority had intact MMR (91.7%). High-risk HPV DNA was extracted in 41 specimens (68.3%), 11 of these were infected with ≥2 or more types, identifying 6 high-risk types not included in vaccine. Correlation analysis showed that there is significant correlation between age and PD-L1 expression on tumor cells (p = 0.047). No correlation between MMR status and PD-L1 expression. Mean disease free survival (DFS) was 43.7, 36.5, and 6.3 months for high, low and negative PD-L1 expression, respectively (p = 0.002). In patients with stage I-II disease, mean DFS was 52.2, 42.6 and 7.6 months for high, low and negative PD-L1 expression, respectively (p = 0.001). Similar direct relationship is observed with overall survival. Cases with mixed HPV infection are associated with late clinical stage at diagnosis (p = 0.037) and lower PD-L1 expression. Conclusions: Contrary to previous studies, our results showed remarkably high rate of PD-L1 expression in cervical SCC, which is associated with longer DFS and OS, especially in early stage tumors. Mixed HPV infection is associated with late clinical stage at diagnosis and lower PD-L1 expression.
Neoadjuvant versus adjuvant chemoradiotherapy for stage II–III esophageal squamous cell carcinoma: A propensity score-matched analysis.
Authors: Jiahua Lv, Tao Li, Qifeng Wang, Yongtao Han, Yuzhe Song, Long Liang, Meihua Chen, Yu Fan, Lei Wu, Lin Peng, Jinyi Lang
Journal: Journal of Clinical Oncology (2019)

e15524 Background: Many clinical trials have explored the value of neoadjuvant or adjuvant chemoradiation therapy in stage II–III squamous cell carcinoma (ESCC). However, these studies have produced conflicting results. This retrospective study was performed to investigate whether patients with stage II/III ESCC should receive neoadjuvant or adjuvant therapy in addition to surgery. Methods: A total of 206 patients with clinical stage II and III ESCC who underwent esophagectomy and either neoadjuvant or adjuvant chemoradiation were included. On the basis of the sequence of surgery and chemoradiation, the patients were divided into two groups: Neoadjuvant chemoradiation followed by surgery (neoadjuvant CRT group) and surgery followed by postoperative chemoradiation (adjuvant CRT group). Propensity score matching analysis was used to identify 62 well-balanced patients in each group for outcome comparison. Results: In all, 69 and 137 patients were in the neoadjuvant CRT group and adjuvant CRT group, respectively. Before matching, no differences were observed in the overall survival among the patients in these two groups (P = 0.209). After matching, the survival was similar between neoadjuvant CRT group and adjuvant CRT group (P = 0.933). The median survival times and 1, 3, 5-year overall survival (OS) rates for the neoadjuvant and adjuvant CRT groups were 40.4 versus 41.0 months, 83.3% versus 95.1%, 54.6% versus 54.0%, 37.0% versus 30.7%, respectively. In the subgroup analysis, patients with clinical T3/4 stage and N1 stage tumors were more likely to demonstrate an overall survival benefit from neoadjuvant CRT compared with adjuvant CRT. Conclusions: No survival and perioperative complications difference were observed among esophageal cancer patients in the neoadjuvant CRT and adjuvant CRT groups. However, neoadjuvant CRT is recommended for patients with clinical T3/4 stage and N1 stage tumors.
Comparison of normal saline versus heparin flush solutions for maintaining patency of central venous catheter in cancer patients.
Authors: Amy Pai, Alessandra Ferrajoli, Lee Cheng, Tam Huynh, Maria Alma Rodriguez
Journal: Journal of Clinical Oncology (2019)

6501 Background: Published guidelines recommend normal saline (NS) flushes for maintaining patency of central venous catheters (CVCs) in cancer patients. The practice at a large oncology ambulatory facility was modified to use NS flushes instead of heparin for CVC maintenance (centrally inserted catheters and peripherally inserted central catheters, excluding implanted ports). The number of catheter occlusion events, pre- and post-implementation, was utilized to determine the effectiveness and safety of this practice change. Methods: Retrospective data of patients aged 18 years and older who presented to the ambulatory centers were collected from the electronic health record (EHR). The number of alteplase instillations was used as a surrogate measure for occlusion events. Ambulatory line-days, defined as patients arriving for an appointment and with either an active CVC or a CVC placement, was the denominator. The numerator was the number of ambulatory line-days with a catheter line and alteplase dose(s) given. The pre-intervention CVC maintenance period using heparin flushes was March 2016 - April 2017. The post-intervention CVC maintenance period using NS flushes was May 2017 - September 2018. Results: 95,089 line-days and 4,452 unique patients were analyzed pre-intervention and compared to 115,194 line-days and 5,575 unique patients post-intervention. The baseline incidence rate of occlusion was 0.91%, compared to the post-intervention incidence rate was 2.67% ( p &lt; 0.01). The increase started immediately within the first month of the practice change (2.26%) and continued throughout the post-implementation observation time. Conclusions: In an ambulatory oncology-practice setting with a high volume of CVC utilization, an increase in line occlusions rate was observed after implementing the practice change of flushing CVCs from heparin to NS. This raises concerns regarding safety and additional burdens to patients and caregivers, and additional analyses are ongoing to evaluate the further impact of this evaluation.
PROSPERO: A study to determine the utility of focused genomic profiling to guide selection of drug therapy in salivary gland cancer.
Authors: Samuel Rack, Yonghan Li, Craig McKay, Andrew Wallace, Robert Metcalf
Journal: Journal of Clinical Oncology (2019)

6086 Background: For most patients with recurrent or metastatic salivary gland cancer (RM-SGC), there are no standard therapies. Many patients undergo genomic profiling to guide selection of targeted therapy. The MSK-IMPACT study applied a 468 gene next generation sequencing (NGS) panel, identifying actionable mutations in 34/114 patients (30%) with RM-SGC. Minimising cost will facilitate application within publically funded healthcare systems. We therefore sought to determine the utility of genomic profiling using a focused 24 gene targeted NGS panel to identify actionable mutations in RM-SGC with a sub-group analysis in adenoid cystic carcinoma (ACC) and non-ACC sub-types. Methods: From January 2017 to 2018, 125 patients with RM-SGC provided informed consent to an ethically approved study. Clinical and demographic characteristics were collected. DNA was extracted from FFPE samples and analysed using Qiagen GeneRead DNAseq Targeted Panel V2 in the Manchester Centre for Genomic Medicine Diagnostic Laboratory, an NHS clinically accredited lab. A custom bioinformatic pipeline was validated to detect single nucleotide variants and indels ( &lt; 40bp) to 5% mutant allele frequency. Alterations were categorised following American College of Medical Genetics guidelines and Association for Molecular Pathology tiering. Results: DNA from 101 tumours (69 major, 32 minor salivary gland) was sequenced with 95% coverage at &gt; 350x read depth over the target enrichment. 65 patients had adenoid cystic carcinoma (ACC) and 36 had non-ACC SGC. Median age was 55 years (range 18-80). 43 actionable alterations were identified in 33 patients within the following genes: TP53 (21%), PIK3CA (8%), ERBB2 (6%), PTEN (3%), BRAF (2%), EGFR (T790M) (1%), and AKT1 (1%). Targeted therapy was selected based on genomic findings in 12% of these patients. In ACC patients, actionable alterations were seen in 25% compared with 55% of non-ACC patients (9 adenocarcinoma, 5 salivary duct carcinoma, 3 carcinoma ex pleomorphic adenoma, 2 mucoepidermoid carcinoma and 1 myoepithelial carcinoma). Conclusions: This study identified actionable alterations in 33% of SGC patients using focused genomic profiling, demonstrating comparable utility to larger research panels. This focussed panel is being expanded to include emerging biomarkers such as NOTCH gene mutations, with NOTCH inhibitors currently in trials in ACC. Greater access to basket studies incorporating therapies matched to genomic alterations will maximise the clinical utility of this approach.
Survival outcomes in glioma patients with noncanonical IDH mutations: Beyond diagnostic improvements.
Authors: Enrico Franceschi, Dario De Biase, Annalisa Pession, Alicia Tosoni, Alexandro Paccapelo, Michela Visani, Giovanni Tallini, Chiara Maria Argento, Benedetta Urbini, Stefania Bartolini, Alba Ariela Brandes
Journal: Journal of Clinical Oncology (2019)

2028 Background: According to the 2016 WHO classification of Central Nervous System tumors, the assessment of exon 4 mutations in IDH1 or IDH2 genes is an essential step in the characterization of gliomas. The R132H mutation is the most frequent alteration in IDH1 gene, however other non-canonical IDH mutations have been identified. The aim of this study was to evaluate the prognostic role of IDH non-canonical mutations. Methods: We analyzed our institutional data warehouse for all consecutive patients (pts) with newly diagnosed, histologically proven grade II – IV IDH mutant gliomas. IDH sequencing was performed using the 454 GS-Junior next generation sequencer (NGS) (Roche Diagnostic, Mannheim, Germany). All analyses were performed on DNA from formalin fixed and paraffin embedded (FFPE) specimens. Results: The analysis included 493 pts with IDH mutations. We found 279 (56.6%) grade 2, 173 grade 3 (35.1%) gliomas, and 41 (8.3%) IDH mutant glioblastoma. Canonical IDH1 R132H mutation was found in 428 pts (86.8%). The remaining pts showed IDH2 (3.9%) or IDH 1 non-canonical mutations (mainly R132C, R132G, R132S – 9.3%). Median follow-up time was 80.5 months. Pts with non-canonical mutations showed a younger median age (32 vs 39 years, p &lt; 0.001). Other clinical characteristics and treatments were similar across IDH groups. Median survival was 145 months (95%CI: 137.7 - 152.9) and 198.6 (95%CI 155.2– 242.1) in patients with IDH R132H and non-canonical mutations, respectively (p = 0.013). In multivariate analysis grading (p &lt; 0.001), extent of surgery (p &lt; 0.001), 1p19q codeletion (p = 0.003) and presence of non-canonical mutations (p = 0.022) showed a significant role for improved survival. Conclusions: Detecting non-canonical IDH1 mutations is essential for diagnosis and for prognosis in patients with gliomas. Differential enzymatic activity of non-canonical IDH1 mutations, resulting in different levels 2-hydroxyglutaratecould be the reason of improved survival.
Retrospective study of capecitabine and temozolomide in advanced lung neuroendocrine neoplasms.
Authors: Taymeyah E. Al-Toubah, Brian Morse, Jonathan R. Strosberg
Journal: Journal of Clinical Oncology (2019)

8542 Background: Patients with advanced lung neuroendocrine neoplasms (NENs) have few treatment options. Capecitabine and temozolomide have recently showed significant activity in patients with pancreatic NETs, but data in lung NETs are limited. Methods: We retrospectively reviewed the records of patients treated at a large NET referral center to identify patients seen between 1/2008 and 9/2018 with metastatic lung NENs who received treatment with capecitabine and temozolomide (CAPTEM). Patients who were not seen at the center within the first month of treatment were excluded. Small cell lung cancer patients were also excluded. The primary endpoint was overall response rate per RECIST 1.1. Secondary endpoints included progression free survival, overall survival, and toxicity. Results: 20 patients were identified who received treatment with capecitabine/temozolomide. 14 (70%) were typical lung NETs, 5 (25%) atypical carcinoids, and 1 (5%) was defined as a large cell neuroendocrine carcinoma. 6 patients (30%) exhibited a best response of PR per RECIST 1.1 criteria, 11 (55%) SD, and 2 (10%) PD. 1 patient died 2 months after starting treatment. 11 eventually progressed (radiographically or clinically), only 6 of whom exhibited progression per RECIST 1.1 criteria. Median PFS was 11 months (95% CI, 6 – 16 months). Median OS was 68 months (95% CI, 35 – 101 months). Toxicity profile was mild with mainly grade 1, expected toxicities. 6 patients required dose reduction due to toxicity (2 for diarrhea and nausea, 1 for hand foot syndrome, 3 for thrombocytopenia). Conclusions: We identified a group of patients with metastatic lung NENs who received treatment with the CAPTEM regimen and exhibited a favorable response rate to treatment with a relatively tolerable toxicity profile. This regimen warrants further exploration in a prospective clinical trial.
JNJ-61186372 (JNJ-372), an EGFR-cMet bispecific antibody, in EGFR-driven advanced non-small cell lung cancer (NSCLC).
Authors: Eric B. Haura, Byoung Chul Cho, Jong Seok Lee, Ji-Youn Han, Ki Hyeong Lee, Rachel E. Sanborn, Ramaswamy Govindan, Eun Kyung Cho, Sang-We Kim, Karen L. Reckamp, Joshua K. Sabari, Meena Thayu, Kyounghwa Bae, Roland Elmar Knoblauch, Joshua Curtin, Nahor Haddish-Berhane, Laurie Jill Sherman, Matthew V. Lorenzi, Keunchil Park, Joshua Bauml
Journal: Journal of Clinical Oncology (2019)

9009 Background: JNJ-372 binds EGFR and cMet to block ligand binding, promote receptor degradation, and trigger antibody-dependent cellular cytotoxicity in models of EGFR-mutated (EGFRm) NSCLC. Here we describe the ongoing phase 1 safety, pharmacokinetics (PK), and activity of JNJ-372 in patients (pts) with NSCLC, including 3 rd generation tyrosine kinase inhibitor (3GTKI)-relapsed EGFRm NSCLC and EGFR Exon20ins disease. Methods: Pts received JNJ-372 (140–1400 mg) IV weekly for the first 28-day cycle and biweekly thereafter. 1050–1400 mg doses are being explored in dose expansion. Blood samples were collected for PK analyses. Efficacy by investigator per RECIST v1.1 in pts with EGFRm NSCLC treated at ≥700 mg is presented. Tumors were characterized by next-generation sequencing of circulating tumor (ct)DNA and/or tumor tissue. Results: As of 17 Jan 2019, 116 enrolled pts with NSCLC were treated. Median age was 63 years, 38% were male, 77% were Asian, and 97% had EGFR mutations. Mean duration of treatment was 3.8 months, longest exposure was 20 cycles. The PK data set included pts from Korea (77%) and the US (23%). At the 1050 mg dose, 72% of pts achieved average concentrations above the EC 90 based on preclinical models. Adverse events (AEs; ≥20%) were rash (59%), infusion related reaction (58%), paronychia (28%), and constipation (22%). Additional EGFR/cMet-related AEs include stomatitis (17%), pruritis (15%), peripheral edema (11%), and diarrhea (7%). Grade ≥3 AEs were reported in 34% (8% treatment-related) with dyspnea (6%) and pneumonia (3%) most frequently observed. Among response-evaluable pts, 25/88 (28%) achieved best timepoint response of partial response (PR). 10/47 pts with prior 3GTKI therapy had best timepoint response of PR (6 confirmed), including 4 with C797S, 1 with cMet amplification, and 5 without identifiable EGFR/cMet-dependent resistance. 6/20 pts with Exon20ins had best timepoint response of PR (3 confirmed). Conclusions: JNJ-372 has a manageable safety profile consistent with EGFR and cMet inhibition. Preliminary responses were achieved in 3GTKI-relapsed disease, including C797S and cMet amplification, and Exon20ins disease; enrollment in dose expansion is ongoing. Clinical trial information: NCT02609776.