tbuckley/cabot-search huggingface dataset:
Early circulating tumor (ct)DNA dynamics and efficacy of lorlatinib in patients (pts) with advanced ALK-positive non-small cell lung cancer (NSCLC).
Authors: Alice Tsang Shaw, Jean-Francois Martini, Benjamin Besse, Todd Michael Bauer, Chia-Chi Lin, Ross A. Soo, Gregory J. Riely, Sai-Hong Ignatius Ou, Antonello Abbattista, Francesca Toffalorio, Holger C. Thurm, Miyako Satouchi, D. Ross Camidge, Steven Chuan-Hao Kao, Rita Chiari, Shirish M. Gadgeel, Enriqueta Felip, Benjamin J. Solomon
Journal: Journal of Clinical Oncology (2019)

9019 Background: Lorlatinib is a selective, potent, brain-penetrant, 3 rd generation (gen) ALK/ROS1 TKI approved for pts with advanced ALK + NSCLC previously treated with a 2 nd gen ALK TKI. We recently showed that ALK mutation tumor genotyping after failure of a 2 nd gen ALK TKI may identify pts more likely to respond to lorlatinib. 1 To identify other molecular response correlates, we evaluated if early ctDNA dynamics predict clinical outcome on lorlatinib. Methods: In pts enrolled on the ongoing ph 2 study (NCT01970865), plasma samples were prospectively collected for ctDNA analysis at baseline (BL), cycle 3 day 1 (C3D1, or 6 weeks) and end of treatment. Plasma DNA was analyzed using Guardant360. Change in variant allele fraction (dVAF) 2 of ALK alterations (fusions and/or mutations) was calculated as (mean VAF C3D1 ) – (mean VAF BL ); dVAF &lt; 0 indicated decreased ctDNA at C3D1. BOR, PFS and OS were evaluated according to dVAF. Results: Of 121 paired BL/C3D1 samples collected from 158 ALK + pts previously treated with one or more 2 nd gen ALK TKIs, 57 (47%) harbored a detectable ALK alteration at BL. At C3D1, mean VAF of ALK fusions and/or mutations was significantly decreased compared to BL (-1.07, p = 0.0014). Mean tumor volume was reduced by 26% in pts with dVAF &lt; 0 (n = 40), but only by 12% in pts with dVAF ≥0 (n = 13) (p = 0.049). Mean dVAF at C3D1 was significantly decreased compared to BL for pts with CR/PR, while there was no significant difference with SD or PD/IND; mean dVAF -1.84, -0.74, and +0.35 in pts with CR/PR, SD, or PD/IND, respectively (p = 0.0011, 0.1444 and 0.3383). Median PFS was 6.6 months (mo) in pts with dVAF &lt; 0 (n = 44) and 2.6 mo in pts with dVAF ≥0 (n = 13) (HR = 2.6, 95% CI: 1.2, 5.8). Median OS was 18.0 mo in pts with dVAF &lt; 0 (n = 34) and 8.6 mo in pts with dVAF ≥0 (n = 13) (HR 2.0, 95% CI, HR 0.9–4.6). Conclusions: Early ctDNA dynamics may predict lorlatinib efficacy in ALK + NSCLC, with decreased ctDNA at 6 wks associated with better response and longer PFS. Further studies are needed to validate these findings and to determine whether early intervention based on dynamic ctDNA monitoring may improve outcome. References: 1. Shaw, et al. J Clin Oncol. 2019. 2. Raja, et al. Clin Cancer Res. 2018. Clinical trial information: NCT01970865.
Clinicopathologic predictors of worse outcome in early onset colorectal cancer (EO-CRC): A single-institution experience.
Authors: Devika Rao, Ana Acuna Villaorduna, Meghan Kaumaya, Nadia Ashai, Seda Tolu, Adel Chergui, Lakshmi Rajdev, Sanjay Goel
Journal: Journal of Clinical Oncology (2019)

e15064 Background: A growing body of evidence indicates an increasing incidence of CRC diagnosis prior to age 50 years. Despite improvements in morbidity and mortality in metastatic CRC (mCRC), racial disparities persist. Limited data is available on the influence of clinical and pathologic factors on outcomes in EO-CRC. We aim to analyze variables which may serve as prognostic markers in a racially diverse, under-served EO-CRC population. Methods: All mCRC patients (n=321) diagnosed between 2004-12 were identified through the institutional tumor registry and charts were reviewed for age at diagnosis, gender, race, site of primary and metastatic tumors and histologic grade. Clinical outcome was measured in terms of overall survival (OS). Clinicopathologic characteristics were compared with a t test between EO and standard onset (SO) groups. Multivariate analyses were performed to assess influence on EO-CRC. Results: Of the 321 patients, 60 (18.7%) had EO-CRC, with median age at diagnosis 42 years. Both groups showed a female preponderance (Table), with colon being the prevalent primary site (~70%). On analysis of racial distribution, non-Hispanic whites (NHW) and non-Hispanic blacks (NHB) had a lower incidence of EO-CRC compared with Hispanic (H) and Asian (A) patients (12.7% v 17.6% v 26.7% v 40%, p= 0.07). Additionally, EO-CRC had a higher incidence of high-grade histology (42.6% v 25.8%, p=0.09), which on multivariate analysis had a significant influence on clinical outcome (p&lt;0.01). Median OS in the EO group was 2.1 years compared to 2.7 years in the SO group. Conclusions: EO-CRC is an aggressive malignancy with distinct pattern of racial distribution. Histologic grade has the potential to serve as a negative prognostic marker. Further analysis of patients diagnosed between 2013-18 is underway. [Table: see text]
First-in-human (FIH) phase 1 (Ph1) study of MORAb-202 in patients (pts) with advanced folate receptor alpha (FRA)-positive solid tumors.
Authors: Toshio Shimizu, Yutaka Fujiwara, Kan Yonemori, Takafumi Koyama, Akihiko Shimomura, Kenji Tamura, Satoru Iwasa, Jun Sato, Shigehisa Kitano, Hiroki Ikezawa, Maiko Nomoto, Ryo Nakajima, Takuma Miura, Noboru Yamamoto
Journal: Journal of Clinical Oncology (2019)

5544 Background: MORAb-202 is an antibody drug conjugate consisting of farletuzumab (a humanized monoclonal antibody that binds to FRA) paired with a cathepsin B-cleavable linker to eribulin mesylate (a microtubule dynamics inhibitor). We report preliminary results from a FIH Ph1 study of MORAb-202 in pts with FRA-positive solid tumors. Methods: This open-label, ongoing, FIH study evaluated the safety, tolerability, pharmacokinetics, pharmacodynamics, maximum tolerated dose, and/or the recommended dose of MORAb-202 (Part 1: Dose finding part with accelerated modified toxicity probability interval design; Part 2: Expansion part). Eligible pts had FRA-positive solid tumors who failed standard therapy and an ECOG PS of ≤1. MORAb-202 was administered by intravenous injection once every 3 weeks and dose-limiting toxicities (DLTs) were assessed during the first 21-day cycle. Efficacy endpoints were assessed with RECIST v1.1 by investigator assessment. Results: As of Nov 16, 2018, 16 pts with confirmed FRA-positive tumors were enrolled and treated with MORAb-202 across 4 dose levels in Part 1 (0.3mg/kg: n = 3 [2 endometrial and 1 ovarian], 0.45mg/kg: n = 3 [3 ovarian], 0.68mg/kg: n = 3 [1 NSCLC, 1 ovarian, and 1 TNBC], 0.9mg/kg: n = 7 [4 ovarian, 1 endometrial, 1 NSCLC, and 1 TNBC]); all completed &gt; 1 cycle. One pt in the 0.9mg/kg cohort experienced DLTs of alanine aminotransferase increased (grade 3) and gamma-glutamyl transferase increased (grade 3). Treatment-emergent adverse events (TEAEs) occurred in 15 pts (93.8%). The most common TEAEs were leukopenia and neutropenia (50% each). The objective response rate based on RECIST v1.1 was 37.5% (6/16 pts) in Part 1 with 1 complete response (ovarian) at 0.9mg/kg and 5 partial responses including 2 pts (both ovarian) at 0.9mg/kg, 1 pt (endometrial) at 0.3mg/kg, and 2 pts (1 TNBC and 1 NSCLC) at 0.68mg/kg. The disease control rate was 75% (12/16 pts). Exposure to MORAb-202 was dose proportional across the dose range investigated. Conclusions: MORAb-202 escalation to 0.9mg/kg was manageable with encouraging initial antitumor activity in pts with FRA-positive solid tumors. Clinical trial information: NCT03386942.
Dose-survival relationship in patients with hepatocellular carcinoma undergoing stereotactic body radiation therapy.
Authors: Ting-Shi Su, Shi-Xiong Liang, Lequn Li
Journal: Journal of Clinical Oncology (2019)

e15592 Background: Stereotactic body radiation therapy (SBRT) has become a treatment for hepatocellular carcinoma (HCC) from palliative to radical treatment. But there is no clear evidence of a dose-survival relationship among commonly-utilized radiation therapy schedules. We aimed to determine the comparative effectiveness of different SBRT dosing regimens for HCC. Methods: The dataset collected from Guangxi Zhuang Autonomous Region in China was used. In this large single-centered retrospective study, 604 patients treated with SBRT were included from 2011 to 2017. Biologically effective dose (BED 10 ) and equivalent dose in 2 Gy fractions (EQD 2 ) were assumed at an α/β ratio of 10. Overall survival (OS) was the primary endpoint. OS rates were estimated using Kaplan–Meier curves with a log-rank test. Results: The median tumor size was 5.2 cm (interquartile range [IQR], 1.1–21.0 cm). Median follow-up was 21 months in surviving patients (IQR, 3–82 months). The 1-, 3-, and 5-year OSs were 87.1%, 64.7%, and 60.9% in Barcelona Clinic Liver Cancer (BCLC)-A group; 72.9%, 37.2%, and 30.7% in BCLC-B group; and 44.3%, 18.6%, and 12.8% in BCLC-C group; respectively. Increasing the RT dose was associated with improved overall survival. Stereotactic ablative radiotherapy (SART) with BED 10 ≥100 Gy, SBRT with EQD 2 ≥74 Gy and BED 10 &lt; 100 Gy, and stereotactic conservative radiotherapy (SCRT) with EQD 2 &lt; 74 Gy have 3 separate curves for long-term survival post-SBRT. On multivariate analysis, Clinical factors associated with improved OS were BED, alanine aminotransferase (ALT) , and BCLC stage. On the subgroup analysis, BED10 ≥100 Gy was still beneficial against HCCs of BCLC stage A, B, and C. Conclusions: Individualized dose for SBRT are recommended for the treatment of HCC due to different degrees of cirrhosis and liver volume. The RT dose was classified into three levels. If tolerated by normal tissue, SART with BED 10 ≥100 Gy as a first-line ablative dose or SBRT with EQD 2 ≥74 Gy as a second-line radical dose is recommended. Otherwise, SCRT with EQD 2 &lt; 74 Gy is recommended as palliative irradiation.
An analysis of growth patterns of targeted therapies (TTs) using keywords from ASCO annual meeting abstracts.
Authors: Yutao Gong, Julie A Schneider, Gideon Michael Blumenthal
Journal: Journal of Clinical Oncology (2019)

e18084 Background: The number of TTs approved to treat cancer patients has increased dramatically in the past decades. We analyzed how frequently 27 oncology targets (and associated therapies) appeared in ASCO meeting abstracts since 2005 to explore if future drug development patterns could be predicted. Methods: We obtained abstracts from the ASCO Center for Research &amp; Analytics. We used keyword abstraction to calculate the percentage of abstracts referencing 27 specific target/drug combinations each year, and we categorized them into high (HV), medium (MV), and low volume (LV) groups based on percentage in 2018. Results: Table shows data since 2012 for the HV group. The percentages of MV (BCR/ABL, CDK4/6, CD20, MEK, CTLA4, iMID, PARP, PI3K, proteasome inhibitors) and LV (BCL2, BTK, CD19, CD30, CD38, HDAC, IDH1, IDH2, and NTRK) in 2018 were less than 1.7%. The HV group was associated with more FDA-approved therapies (41) than the MV (23) and LV (13) groups. The HV and MV groups are likely enriched for more mature targets, as the median date of relevant drug approvals is earlier (11/2012 and 4/2013, respectively) than the LV group (4/2016). Growth patterns are consistent with key regulatory milestones. The number of abstracts with PD-1/PD-L1-related keywords has grown more rapidly than any other drug/target combination. This growth begins soon before FDA approvals for a diversity of relevant indications. Continued growth likely reflects ongoing clinical trials of several other PD-1/PD-L1 inhibitors and combinations. We identified similar growth trends for other targets just prior to key regulatory approvals. Conclusions: Our analysis revealed interesting growth patterns for key oncology target/drug combinations. Future work will explore whether we can extend the analysis to help predict the evolution of development programs for new targets. [Table: see text]
Lung cancer: Improving screening in rural clinic.
Authors: Thuy Thanh Thi Le, Helen Johnson-wall, Katherine Hu
Journal: Journal of Clinical Oncology (2019)

e13060 Background: Lung cancer is the leading cause of overall cancer-related deaths in both men and women in the United States. In 2009, cancer surpassed cardiovascular disease as the leading cause of death in North Carolina. Between 2010-2014, the age-adjusted incidence rate for lung and bronchus cancers in North Carolina was 70 per 100000 persons per year. Between 2010-2014, the age-adjusted mortality rate for lung and bronchus cancers in North Carolina was 50.6 per 100000 persons per year. It is documented that about half of lung and bronchus cancer cases were diagnosed at the distant stage and about 60 percent of deaths occurred in adults ages 65-84. In 2011, 32 percent of cancer death was from lung/bronchus cancer in Robeson County. A chart review in a rural primary care clinic identified patients not being appropriately screened for targeted intervention. Methods: Our retrospective chart review at Lumberton Medical Clinic, a rural outpatient Internal Medicine Clinic, reviewed 91 records from adults aged 55 to 80 years old during the timeframe of September 2017 through August 2018. Patients with a known history of lung cancer were excluded from this study. Patient records were assessed for compliance with USPTF lung cancer screening guidelines. USPTF recommends adults aged 55 to 80 who have a 30 pack-year smoking history and currently smoke or have quit within the past 15 years to have an annual low-dose computed tomography of the chest to screen for lung cancer. Results: The review showed that during the timeframe studied, 42% of patients who qualified received appropriate screening, while 58% of those qualified were found to have no documentation of screening. Following data analysis, intervention to increase screening rates has been initiated. This involves provider education, posters, and individualized letters mailed to patients found deficient during the study. The success of this direct patient outreach effort will be measured over six months. Conclusions: It is the responsibility of providers to emphasize the importance of proper lung cancer screening. This retrospective review found that a large percentage (58%) of adults were not being adequately screened in our rural clinic. Direct outreach is underway to increase compliance rates in this high-risk population served by our rural clinic.
The cell-penetrating FOXM1 N-terminus (M1-138) demonstrates potent inhibitory effects on cancer cells by targeting FOXM1 and FOXM1-interacting factor SMAD3
Authors: Zhenwang Zhang, Huitong Bu, Jingwei Yu, Yan Chen, Chaozhu Pei, Li Yu, Xiaoqin Huang, Guixiang Tan, Yongjun Tan
Journal: Theranostics (2019)

Transcription factor FOXM1 is involved in stimulating cell proliferation, enhancing DNA damage repair, promoting metastasis of cancer cells, and the inhibition of FOXM1 has been shown to prevent the initiation and progression of multiple cancers and FOXM1 is considered to be an effective target for tumor therapeutic drug development.The N-terminus of FOXM1 has been found to prevent transcriptional activities of FOXM1 and to mediate the interaction between FOXM1 and SMAD3.Methods: A recombinant FOXM1 N-terminal domain (1-138aa) fused with a nine arginine cell-penetrating peptide is produced with an E. coli expression system and named as M1-138.The effects of M1-138 on the proliferation, migration, and tumorigenic ability of cancer cells are analyzed in vitro with cell counting, transwell assays, and colony formation assays.Electrophoretic mobility shift assays (EMSAs) and Luciferase activity assays are used to test the DNA binding ability and transcriptional activity of transcription factors.The levels of mRNAs and proteins are measured by quantitative-PCR, Western blotting or Immunohistochemistry.The interactions among proteins are analyzed with Pull-down and Co-immunoprecipitation (Co-IP) assays.The nude mouse engrafted tumor models are used to test the inhibitory effects of M1-138 in vivo.Results: M1-138 diminishes the proliferation and migration abilities of cancer cells through binding to FOXM1 and FOXM1-interacting factor SMAD3, and consequently attenuating FOXM1 transcriptional activities from both direct and indirect FOXM1-promoter binding mechanisms and interfering with the interaction between FOXM1 and SMAD3.Treatment of M1-138 prevents tumorigenicity of cancer cells and inhibits tumor growth in nude mouse xenograft models with no obvious signs of toxicity.Conclusion: M1-138 is a promising drug candidate for the development of anti-cancer therapeutics targeting FOXM1 and SMAD3.
Tislelizumab (BGB-A317) + concurrent chemoradiotherapy (cCRT) followed by tislelizumab monotherapy for newly diagnosed locally advanced, unresectable, stage III non-small cell lung cancer (NSCLC) in a phase III study (RATIONALE 001).
Authors: Luis G. Paz-Ares, Suresh Senan, David Planchard, Luhua Wang, Alicia Cheong, Marie Huong Nguyen, Ruta Slepetis, Everett E. Vokes
Journal: Journal of Clinical Oncology (2019)

TPS8574 Background: cCRT improves survival vs RT alone and is a global standard of care in patients (pts) with stage III NSCLC, but survival remains poor for these pts. Combining PD-1/PD-L1-targeting immunotherapies and cCRT may lead to synergistic activity and improved outcomes. Tislelizumab (anti–PD-1) demonstrated clinical activity and tolerability in solid tumors, including NSCLC. This phase III, randomized, double-blind, placebo-controlled study (RATIONALE 001) will evaluate efficacy and safety of tislelizumab + cCRT. Methods: Pts (N ≈ 840) will be randomized 1:1:1 in a 3-arm study design to evaluate whether the timing of giving tislelizumab earlier upfront with cCRT in addition to as consolidation (Arm 1) or giving tislelizumab as consolidation only (Arm 2) will improve outcomes vs cCRT alone (Arm 3; Table). RT will be given in 2 Gy fractions to a target dose of 60 Gy (30 fractions). Chemotherapy will be investigator’s choice of cisplatin + etoposide or carboplatin + paclitaxel. A safety analysis specific to the cisplatin + etoposide component of the cCRT + tislelizumab combination is planned. All sites must pass a radiation quality assurance review process. The primary endpoint is PFS. Secondary endpoints include ORR, OS, OS at 24 months, and safety. As an exploratory endpoint, blood and tumor biomarkers will be assessed for correlations with clinical benefit. With a one-sided α of 1.25%, a total of 580 PFS events are required to allow ≈ 90% power to detect a HR for progression or death of 0.7 for either pairwise comparison (Arm 1 vs Arm 3 or Arm 2 vs Arm 3). Key eligibility criteria are locally advanced, unresectable, stage III NSCLC; FDG-PET and brain imaging confirmation of stage III status; no prior treatment; and ECOG PS ≤ 1. PD-L1 expression assessment is not required prior to randomization. EudraCT number 2018-001132-22. Clinical trial information: NCT03745222. [Table: see text]
Severe immune-related adverse events in anti-PD-1-treated patients are clustered into distinct subtypes by peripheral blood T-cell profiles.
Authors: Kyung Hwan Kim, Jinhyun Cho, Joon Young Hur, Bo Mi Ku, Jiae Koh, Jong-Mu Sun, Se-Hoon Lee, Jin Seok Ahn, Keunchil Park, Myung-Ju Ahn, Eui-Cheol Shin
Journal: Journal of Clinical Oncology (2019)

2564 Background: Although anti-programmed death-1 (PD-1) treatment has shown remarkable anti-tumor efficacy, immune-related adverse events (irAEs) develop with heterogeneous clinical manifestations. Immunological understanding of irAEs is currently limited. In the present study, we analyzed peripheral blood T cells obtained from cancer patients who received anti-PD-1 treatment to determine the immunological characteristics of severe irAEs. Methods: This study included 31 patients with refractorythymic epithelial tumor (TET) who were enrolled in a phase II trial of pembrolizumab (NCT02607631) and 60 patients with metastatic non-small cell lung cancer (NSCLC) who received pembrolizumab or nivolumab. T-cell profiling was performed by multi-color flow cytometry using peripheral blood obtained immediately before treatment and 7 days after the first dose of anti-PD-1 antibodies. Results: Severe irAEs (≥ grade 3) occurred in 7 TET patients (22.6%) and 6 NSCLC patients (10.0%). Patients with severe irAEs exhibited a significantly lower fold increase in the frequency of effector regulatory T (eTreg) cells after anti-PD-1 treatment, higher ratio of T helper-17 (Th17) and T helper-1 cells at baseline, and higher percentage of Ki-67 + cells among PD-1 + CD8 + T cells post-treatment. In clustering analysis, patients with severe irAEs were grouped into four distinct subtypes: Th17-related, TNF-related,Treg-related, and CD8-related. Conclusions: Severe irAEs after anti-PD-1 treatment were clustered into four immunological subtypes, indicating that development of severe irAEs is not attributed to a single mechanism. Further investigations in larger cohorts are needed to validate our current findings.
Phase 1 study of AMG 757, a half-life extended bispecific T cell engager (BiTE) antibody construct targeting DLL3, in patients with small cell lung cancer (SCLC).
Authors: Marie-Anne Damiette Smit, Hossein Borghaei, Taofeek Kunle Owonikoko, Horst-Dieter Hummel, Melissa Lynne Johnson, Stéphane Champiat, Ravi Salgia, Hibiki Udagawa, Michael J. Boyer, Ramaswamy Govindan
Journal: Journal of Clinical Oncology (2019)

TPS8577 Background: SCLC is an aggressive neuroendocrine tumor; response to initial chemotherapy and radiotherapy is often followed by recurrence, rapid progression, and resistance to current therapies. Delta-like ligand 3 (DLL3) is an inhibitory ligand of Notch receptors that is expressed in most SCLC tumors but minimally expressed in normal tissues. DLL3 may therefore be a promising target for T cell–redirecting immunotherapy. AMG 757 is a half-life extended BiTE antibody construct that is designed to transiently connect DLL3-positive cells to CD3-positive T cells and induce T cell–mediated cell lysis and concomitant T cell proliferation. AMG 757 induces potent killing of SCLC cell lines in vitro and inhibits tumor growth in the SHP-77 human SCLC xenograft model in vivo. AMG 757 was well tolerated in a preclinical multi-dose toxicology study in cynomolgus monkeys, with no evidence of tissue damage at weekly doses up to 4.5 mg/kg. Methods: NCT03319940 is an open-label, ascending, multiple dose, phase 1 study evaluating AMG 757. The study will initially enroll adult patients with relapsed/refractory SCLC who have progressed after at least 1 platinum-based chemotherapy regimen. Additional inclusion criteria include ECOG performance status 0–2, at least 2 measurable lesions per modified RECIST 1.1, no untreated or symptomatic brain metastases, and adequate organ function. Primary objectives are to evaluate safety and tolerability and to determine the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D). Secondary objectives are to characterize pharmacokinetics (PK) and evaluate preliminary antitumor activity. In the dose exploration phase, patients will be monitored for dose-limiting toxicities during the first 28 days. A Bayesian logistic regression model will be used to inform dose escalation/de-escalation decisions. The dose expansion phase will confirm the MTD or RP2D and collect further safety and efficacy data. AMG 757 will be administered as a short-term intravenous infusion once every 2 weeks. Alternative dosing schedules may be explored based on emerging PK and safety data. Clinical trial information: NCT03319940.