tbuckley/cabot-search huggingface dataset:
Phase-II study of toripalimab combined with neoadjuvant chemotherapy for the treatment of resectable esophageal squamous cell carcinoma.
Authors: Delin Liu, Qin Zhang, Jinghua Zhu, Ting Qian, Rong Yin, Zhaohui Fan, Feng Jiang, Houhuai Li, Jianwei Lu, Guochun Cao
Journal: Journal of Clinical Oncology (2021)

e16029 Background: Compared with neoadjuvant chemotherapy alone，Neoadjuvant radiochemotherapy can significantly increase pCR rate in esophageal squamous cell carcinoma and improve patient overall survival. However, the addition of radiotherapy increases the risk of adverse reactions and surgery. Neoadjuvant radiochemotherapy is currently used in &lt; 5% of Chinese patients.The purpose of this phase II study is to assess the efficacy and safety of toripalimab combined with paclitaxel and cisplatin as neoadjuvant treatment for resectable locally advanced esophageal squamous cell carcinoma(clinical trial registration number: ChiCTR1900025318). Methods: Patients 18–75 years old with esophageal squamous cell carcinoma confirmed by endoscopic biopsy, assessed to be locally advanced esophageal squamous cell carcinoma (cT1–cT2, N+; cT3–cT4 a, any N), and expected to be resectable were given toripalimab (240 mg d1 + PTX 175 mg/m 2 + PDD 75 mg/m 2 q3w) before surgery for two treatment cycles, followed by efficacy assessment. A consultation meeting with thoracic surgeons was held to assess radical surgery for patients with resectable lesions 4–6 weeks after neoadjuvant therapy was completed. pCR and postoperative-stage statistical analysis were conducted based on postoperative pathology test results. These results were used to determine the efficacy and safety of PD-1 monoclonal antibody combined with chemotherapy as neoadjuvant therapy for locally advanced esophageal cancer. Results: By December 2020, 23 subjects were enrolled. Of the subjects, five withdrew without undergoing surgery (three subjects refused surgery and switched to radical radiochemotherapy, one subject progressed to PD after two cycles of neoadjuvant therapy and switched to palliative treatment, and one subject could not undergo surgery after neoadjuvant treatment and gave up the treatment) and 18 evaluable patients underwent surgery. The R0 resection rate was 100%, and T0–Tis 33.3% (6/18) achieved pCR. Among these patients, 61.1% (11/18) achieved T0–T1 after surgery, and 72.2% (13/18) achieved N0. Moreover, stage reduction effects were significant compared with preoperative TN staging. Common side-effects include nausea, vomiting, neutropenia, thrombocytopenia, rash, asthenia, constipation, and muscle soreness. Most adverse events were grades 1–2, and grades 3/4 adverse events include one case of grade 3 neutropenia and one case of grade 3 diarrhea (suspected immune-related colitis), which improved after symptomatic treatment. Conclusions: Toripalimab combined with the TP scheme showed preliminary efficacy and controllable safety in the treatment of resectable locally advanced esophageal squamous cell carcinoma and is worthy of further exploration. Clinical trial information: ChiCTR1900025318.
Target-responsive subcellular catabolism analysis for early-stage antibody–drug conjugates screening and assessment
Authors: Hua Sang, Jiali Liu, Fang Zhou, Xiaofang Zhang, Jingwei Zhang, Yazhong Liu, Guangji Wang, Hui Ye
Journal: Acta Pharmaceutica Sinica B (2021)

Events including antibody‒antigen affinity, internalization, trafficking and lysosomal proteolysis combinatorially determine the efficiency of antibody-drug conjugate (ADC) catabolism and hence the toxicity. Nevertheless, an approach that conveniently identifies proteins requisite for payload release and the ensuing toxicity for mechanistic studies and quality assessment is lacking. Considering the plethora of ADC candidates under development, we developed a target-responsive subcellular catabolism (TARSC) approach that examines ADC catabolism and probes changes in response to targeted interferences of proteins of interest. We firstly applied TARSC to study the commercial T-DM1 and the biosimilar. We recorded unequivocal catabolic behaviors regardless of the absence and presence of the targeted interferences. Their negligible differences in TARSC profiles agreed with their undifferentiated anti-tumoral efficacy according to further in vitro viability and in vivo tumor growth assays, highlighting TARSC analysis as a useful tool for biosimilarity assessment and functional dissection of proteins requisite for ADC catabolism. Additionally, we employed TARSC to investigate the catabolic behavior of a new trastuzumab-toxin conjugate. Collectively, TARSC can not only characterize ADC catabolism at (sub)cellular level but also comprehensively determine which protein targets affect payload release and therapeutic outcomes. Future use of TARSC is thus anticipated in early-stage screening, quality assessment and mechanistic investigations of ADCs.
Can online patient reviews be used to assess oncologist competency? RateMD as a cancer care evaluation tool.
Authors: Nina Morena, Nicholas Zelt, Diana Nguyen, Carrie A. Rentschler, Devon Greyson, Ari N. Meguerditchian
Journal: Journal of Clinical Oncology (2021)

e18656 Background: Medical oncology (MEDONC) requires a combination of skills in collaboration, communication, and professionalism, ultimately delivering technical and clinical knowledge in practice. Standard assessment tools (e.g. written examination, OSCE) are not effective in evaluating competencies beyond technical skills and fail to define the cancer care experience holistically. This explorative, descriptive study aims to identify the potential of unstructured, unsolicited, open access online patient reviews (OPRs) as a tool to assess physician competency. Methods: University-affiliated MEDONCs in Ontario (Canada) were selected. All OPRs were identified on RateMD using every name permutation; physician names and institutional affiliations were removed from comments. A descriptive analysis of the cohort was completed. The CanMEDS Framework, defining physician standards, was used with its hierarchy of roles, concepts, and competencies. Two reviewers, a communication studies researcher and a healthcare professional, independently assessed comments and identified common themes. Competency-level assessments were evaluated using kappa with linear weights. Results: 473 OPRs were identified for 49 MEDONCs (71% male, 29% female). Of these, 23% were written by care providers. Competencies defining roles of Medical Expert, Communicator, and Professional were most prevalent (64%, 38%, and 27% respectively). Agreement levels were high in all roles (wK = 0.71 - 1.00). Themes identified were similar in positive and negative evaluations. Most commonly discussed positive themes were knowledge translation and compassionate interpersonal skills. Most common negative themes centered on lack of humility, compassion, and communication skills. 38% of comments were marked helpful, indicating engagement with other OPRs as a key characteristic of rating tools. In addition to the physician in question, 21% of OPRs reported on healthcare delivery by staff. Conclusions: OPRs emphasize experiential competencies related to interpersonal skills and suggest an alternative format to evaluating such aspects of MEDONC competencies.[Table: see text]
MyPathway HER2 basket study: Pertuzumab (P) + trastuzumab (H) treatment of a large, tissue-agnostic cohort of patients with HER2-positive advanced solid tumors.
Authors: Funda Meric-Bernstam, John Hainsworth, Ron Bose, Howard A. Burris III, Claire Frances Friedman, Razelle Kurzrock, Charles Swanton, Yong Wang, Jonathan Levy, Katja Schulze, Richard Price, Arisha Patel, Christopher Sweeney
Journal: Journal of Clinical Oncology (2021)

3004 Background: HER2 ( ERBB2) amplification and/or overexpression is observed in 2–3% of solid tumors, and is often associated with more aggressive disease. Thus far, HER2-targeted therapies are FDA-approved only for breast, gastric, and gastroesophageal cancers. MyPathway (NCT02091141) is a non-randomized, phase 2a multi-basket study assessing the activity of FDA-approved targeted therapies in non-indicated advanced solid tumors with relevant molecular alterations. We report results from the MyPathway HER2 basket, comprising a large, tissue-agnostic cohort of patients (pts) with HER2-altered tumors treated with P + H. Methods: Pts in this analysis were aged ≥18 years and had HER2-amplified and/or overexpressed tumors. Pts received P (840-mg IV loading dose, then 420-mg every 3 weeks [q3w]) + H (8-mg/kg IV loading dose, then 6-mg/kg q3w). The primary efficacy endpoint was investigator-assessed objective response rate (ORR). Other endpoints included disease control rate (DCR, defined by objective response or stable disease &gt;4 mos) and duration of response (DOR). Subgroup analyses were completed by tumor type and KRAS status. Results: Pts were fully enrolled from April 14, 2014 to June 15, 2020. By January 22, 2021, 260 pts were efficacy-evaluable. Confirmed ORR (cORR) was 23.1% (60/260, including 5 complete responses; 95% confidence interval [CI] 18.1–28.7), DCR was 44.2% (115/260, 95% CI 38.1–50.5), and median DOR was 7.9 mos (95% CI 6.2–9.3). In 199 pts with wild-type KRAS tumors, cORR was 25.6% (51/199, 95% CI 19.7–32.3), DCR was 48.7% (97/199, 95% CI 41.6–55.9), and median DOR was 8.3 mos (95% CI 6.2–10.8). In comparison, in 26 pts with KRAS-mutated tumors, cORR was 3.8% (1/26, responder had colorectal cancer; 95% CI 0.1–19.6), DCR was 3.8% (1/26, 95% CI 0.1–19.6), and DOR was 2.7 mos. KRAS status was unknown in 35/260 pts (cORR 22.9% [8/35, 95% CI 10.4–40.1]; median DOR 6.7 mos [95% CI 2.5–12.7]). Clinical outcomes by tumor type are shown in the Table. Conclusions: P+H was active in a wide variety of KRAS wild-type HER2-amplified/overexpressed tumor types, but had limited activity in KRAS-mutated tumors. Clinical trial information: NCT02091141. [Table: see text]
Outcomes in peripheral T-cell lymphomas: An analysis of patients treated at a single academic institution.
Authors: Philippos Apolinario Costa, Jesus Antonio Ocejo Gallegos, Georgios Pongas
Journal: Journal of Clinical Oncology (2021)

e19524 Background: T-cell lymphomas are a heterogeneous group of lymphomas, including the cutaneous T cell lymphoma (CTCL) and the peripheral T cell lymphomas (PTCL). Regarding the PTCL, it’s a heterogeneous group including approximately 23 different diseases with the peripheral T-cell lymphoma not otherwise specified (PTCL NOS), angioimmunoblastic lymphoma (AITL), and anaplastic large cell lymphoma (ALCL) being the most frequent subtypes. In contrast with the B cell lymphomas, most of the PTCL have a worse prognosis. We aim in our study to quantify the prognosis in each of the most frequent subtypes of PTCL. Methods: We analyzed patients with either PTCL NOS, AITL, or ALCL treated at Sylvester Comprehensive Cancer Center between 2010 and 2020. We calculated overall survival (OS) using the Kaplan-Meier method with Log-Rank Test to estimate the 95% confidence interval. Results: 98 patients belonged to 1 of the 3 major T-cell lymphoma subtypes: 43 to PTCL NOS, 33 to AITL, and 20 to ALCL, being 7 ALK-positive and 13 ALK-negative. Mean age in PTCL NOS, AITL and ALCL was 56 years (ranging from 8-88), 62 (8-89), and 52 (1-79), respectively. In PTCL NOS, AITL and ALCL respectively, 21 (46%), 15 (45%) and 7 (35%) of patients were female. The three-year and five-year overall survival was 62% (95% CI 42-82) and 30% (95% CI 6-54%) in PTCL NOS, 64% (95% CI 44-84) and 42% (95% CI 4-78%) in AITL, 75 (95% CI 51-99) and 67% (95% CI 33-100) in ALK-negative ALCL. There were no reported deaths in ALK-positive ALCL. The mean survival was lowest in PTCL NOS (p = 0.02), being 3,6 years, while AITL it is 5.2 and in ALCL it is 8.4. Conclusions: Amongst the three major subtypes of PTCL, PTCL NOS have the worse prognosis. Future research is needed to develop a risk stratification tool in each subtype.
Phase I/Ib study with INT-1B3, a novel LNP-formulated micro-RNA (miR-193a-3p mimic) therapeutic for patients with advanced solid cancer.
Authors: Nuria Kotecki, Frans Opdam, Debbie Robbrecht, Michiel Strijbos, Karlijn Kroon, Michel Janicot, Sanaz Yahyanejad, Bryony Telford, Marion van den Bosch, Farshid Alemdehy, Thijs de Gunst, Harm den Boer, Rogier M. Vos, Laurens van Pinxteren, Roel Schaapveld
Journal: Journal of Clinical Oncology (2021)

TPS2666 Background: MicroRNAs (miR) are naturally-occurring small non-coding RNA molecules involved in the regulation of gene expression and their dysregulation plays a fundamental role in several pathological conditions including cancer. The miR-193a-3p acts as a tumor suppressor and is downregulated in many cancer types. INT-1B3 is a novel lipid-nanoparticle (LNP) formulated 1B3, a 22-nucleotide double stranded chemically-modified miR-193a-3p mimic. INT-1B3 showed significant tumor growth inhibition in a large panel of human and syngeneic tumor models. It directly targets tumor cells and the tumor microenvironment by specific modulation of multiple signaling pathway components. Furthermore, in syngeneic mice models for e.g. TNBC (4T1) and HCC (H22), INT-1B3 was able to modulate the immune tumor microenvironment by turning ‘cold’ tumors into ‘hot’ tumors via upregulation of cytokines (e.g., IL-2 and IFN-g), decreasing immunosuppressive cells/Treg (e.g., CD4+ /LAG3+ and CD3+ /FoxP3+) and triggering cytotoxic CD8+ T cell-mediated long-term memory immune protection against re-challenge with tumor cells. These preclinical results suggest potential clinical benefit in a broad range of cancer indications, and a reduced potential to develop drug resistance due to its multi-targeted mode of action. Methods: This is a 2-part, multi-center, open-label, multiple ascending dose, first-in-human, clinical study to evaluate the safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy of INT-1B3 in the treatment of patients with advanced solid tumors. The phase 1 part follows a ‘hybrid’ 3+3 study design in ‘all-comer’ cancer patients enrolled and treated in cohorts to define the recommended phase 2 dose (RP2D). Upon completion of the dose escalation phase of the study, 2 expansion cohorts are planned to further confirm the safety, tolerability, and preliminary efficacy of the RP2D of INT-1B3 in patients with hepatocellular carcinoma and triple negative breast cancer. Major eligibility criteria include evaluable disease according to RECIST 1.1 and no more than one prior line of anti-PD-1/PD-L1 therapy. Patients will receive INT-1B3 via 60-min i.v. infusions twice a week in 21-day cycles. The first patient was enrolled on January the 14 th 2021. Clinical trial information: NCT04675996.
Population-based impacts of new therapies on outcomes for stage IV non-small cell lung cancer.
Authors: Rebekah Rittberg, Oliver Bucher, Lin Xue, Zeb Aurangzeb, Shantanu Otto Banerji, David Dawe
Journal: Journal of Clinical Oncology (2021)

9120 Background: Over 15 years, diagnostic and therapeutic algorithms for Stage IV non-small cell lung cancer (NSCLC) have dramatically progressed. While clinical trials demonstrate overall survival (OS) advantages, population level impact remains uncertain. Here we evaluate real world, population-based outcomes for Stage IV NSCLC to assess impact of changing therapies on referral, treatment patterns and OS, which may help explain ongoing stigma/nihilism. Methods: A retrospective cohort analysis was completed to evaluate de novo Stage IV NSCLC diagnosed in Manitoba from 2006 to 2015. We evaluated treatment received (not seen by specialist, saw a specialist but did not receive therapy, radiation therapy (RT) only, and systemic therapy (mutation unknown and known)) and treatment era of diagnosis (2006-2009, 2010-2013 and 2014-2015). Multivariable logistic regression assessed systemic therapy predictors. Kaplan-Meier curve and Cox proportional hazard models evaluated OS. Results: 3,601 patients were diagnosed with Stage IV NSCLC, 53% male. Only 21% received systemic therapy, mean age of 62. Within the cohort, 973 (27%) patients did not see a specialist, 610 (17%) saw a specialist but did not receive therapy, 1248 (35%) only received RT, and 771 (21%) received systemic therapy (17% mutation status unknown and 4% known). Younger patients and those with confirmed histology were more likely to see a specialist and receive treatment, each (p &lt; 0.001). Patients who received systemic therapy had lower comorbidity and higher income quintile, each (p &lt; 0.001). Median OS did not differ between treatment era with median OS of 3.0, 2.9 and 2.8 months for 2006-2009, 2010-2013 and 2014-2015 respectively, p = 0.082. When survival analysis was restricted to patients who received systemic therapy, median OS improved by era to 10.9, 11.2 and 15.6 months respectively, p = 0.001. Variables found to be independently associated with survival included treatment type, age, sex and comorbidity. Conclusions: Improved systemic therapy and molecular testing has improved OS for patients who receive systemic therapy. However, due to the large proportion of Stage IV NSCLC patients who never receive systemic therapy we do not see improved survival at a population level between treatment eras.
A phase I study of mirvetuximab soravtansine (MIRV) and gemcitabine (G) in patients (Pts) with selected frα-positive solid tumors: Results in the ovarian cancer (EC) cohort.
Authors: Mihaela C. Cristea, Nora H. Ruel, Paul Henry Frankel, Timothy W. Synold, Daphne B. Stewart, Edward Wenge Wang, Alex Jung, Sharon Wilczynski, Michael Tran, Gottfried E. Konecny, Melissa Eng, Lindsay Kilpatrick, Yi-Jen Chen, Scott Glaser, Thanh Hue Dellinger, Amy Hakim, Stephen Lee, Robert Morgan, Ernest Soyoung Han
Journal: Journal of Clinical Oncology (2021)

5542 Background: Mirvetuximab soravtansine (MIRV) is an ADC comprising a FRα-binding antibody, cleavable linker, and the maytansinoid DM4, a potent tubulin-targeting agent. MIRV has promising single agent activity in FRα-positive medium/high expression epithelial ovarian cancer (EOC), at 6 mg/kg, based on adjusted ideal body weight (AIBW) IV every (q) 21 days. This study evaluated MIRV and G in recurrent EOC, endometrial and triple negative breast cancer. The recommended phase 2 dose (RP2D) was established at MIRV 6 mg/kg AIBW IV, day 1 and G 800 mg/m2 IV, d1, 8 q21 days (J Clin Oncol 37, 2019, Abs. #3009). Here we report the results from the EOC cohort. Methods: Patients (pts) with FRα-positive platinum resistant EOC with ≤4 prior chemotherapy (CT) regimens, were eligible. FRα positivity was initially defined as ≥ 25% of cells with PS2+ staining intensity (low to high FRα expression) and was subsequently revised to require medium/high FRα expression (≥50%/ ≥75% of cells with PS2+ staining intensity). Results: From 10/2017 to 12/2020, 113 EOC pts underwent FRα screening, with 74 FRα-positive results. Thirty total EOC pts (with median 3 prior lines of therapy) were treated; 8 pts during dose escalation and 22 EOC pts at the RP2D (all evaluable for response). Fifteen (50%) pts had high FRα, 10 pts (33%) medium FRα, and 5 pts (17%) low FRα expression. Eleven (36%) of the 30 EOC pts achieved a partial response (PR), 15 pts (50%) had SD and 4 pts (13%) progressed. Among the 11 responders, 5 pts had high FRα, 4 pts medium FRα and 2 pts low FRα expression. Non-heme clinically significant adverse events (AEs) included: G2 sensory neuropathy (4 pts) G3 diarrhea (3 pts), G3 fatigue (2 pts), G3 pneumonitis (2 pts), and 1 pt with G5 respiratory failure (secondary to pneumonia but drug-induced pneumonitis could not be ruled out). Conclusions: MIRV in combination with G has promising clinical activity in late line platinum resistant FRα-positive EOC, with best responses observed in high FRα expression. The regimen is well tolerated with expected AEs based on the known toxicities of each agent. This study was approved and funded by the National Comprehensive Cancer Network (NCCN) Oncology Research Program from general research support provided by ImmunoGen Corp and Cancer Center Support Grant P30CA033572. Clinical trial information: NCT02996825.
Phase II trial of atezolizumab (A) + carboplatin (C) + pemetrexed (P) + bevacizumab (B) in pts with stage IV non-squamous non-small cell lung cancer (NSq-NSCLC): Big Ten Cancer Research Consortium Study LUN 17-139.
Authors: Fatemeh Ardeshir-Larijani, Sandra K. Althouse, Ticiana Leal, Lawrence Eric Feldman, Taher Abu Hejleh, Malini Patel, Ryan D. Gentzler, Adam Ryan Miller, Nasser H. Hanna
Journal: Journal of Clinical Oncology (2021)

9034 Background: The addition of A to C+ Paclitaxel (Pac) + plus B improved progression free survival (PFS) and overall survival (OS) compared with C + Pac + B alone in pts with metastatic NS-NSCLC. However, C + Pem is more commonly used for this patient population with a shorter infusion time and favorable toxicity profile compared with Pac. Methods: Multicenter single arm phase II clinical trial of chemo and immunotherapy-naïve pts with stage IV NSq-NSCLC. All pts received A (1200 mg, D1) + C (AUC 5, D1) + P (500 mg/m2, D1) + B (15mg/kg D1) q3 week x4. If non-PD, pts could receive maintenance APB until PD or intolerable side effects. The primary endpoint was 1 yr. PFS. Sample size of 42 planned with 87% power and two-sided type I error of 0.05 for 1 yr PFS. Secondary endpoints included ORR, disease control rate (DCR) [defined by CR + PR + SD], and toxicity. Results: 30 pts were enrolled from 11/15/2018 to 10/5/2020. The study was closed early due to 3 patient deaths, possibly related to treatment (VTE, Febrile neutropenia, colonic perforation). Median age 64 (range 38-83); M/F 20/10; mutations in EGFR/ALK/KRAS/BRAF (5/1/4/2); PD-L1 TPS &lt; 1%/1-49%/ &gt; 50% (9/14/6) and one pt did not have PDL-1 status. Median f/u was11.6 mos (range 1-20). ORR 35.71% (95% CI: 18.64%-55.95%), DCR 92.85% (95% CI: 83%-100%). 1yr PFS and OS were 55.27% and 82.90% respectively. The most common G III and G II toxicity were HTN (20%) and fatigue (33.3%).3 pts had G IV toxicity (Anemia, Febrile neutropenia and colonic perforation) and 2 pts had Grade (G) V toxicity (VTE, Hypoxia/Sepsis). Conclusions: Atezolizumab + Carboplatin + Pemetrexed + Bevacizumab was associated with longer DCR, PFS, and OS than historical controls. 3 on-treatment deaths, possibly related to therapy (more likely bevacizumab), prompted early closure. A phase 3 study evaluating this regimen is ongoing by another group NCT03786692. Clinical trial information: NCT03713944.
MCDB: A comprehensive curated mitotic catastrophe database for retrieval, protein sequence alignment, and target prediction
Authors: Le Zhang, Lei Zhang, Yue Guo, Ming Xiao, Lu Feng, Chengcan Yang, Guan Wang, Liang Ouyang
Journal: Acta Pharmaceutica Sinica B (2021)

Mitotic catastrophe (MC) is a form of programmed cell death induced by mitotic process disorders, which is very important in tumor prevention, development, and drug resistance. Because rapidly increased data for MC is vigorously promoting the tumor-related biomedical and clinical study, it is urgent for us to develop a professional and comprehensive database to curate MC-related data. Mitotic Catastrophe Database (MCDB) consists of 1214 genes/proteins and 5014 compounds collected and organized from more than 8000 research articles. Also, MCDB defines the confidence level, classification criteria, and uniform naming rules for MC-related data, which greatly improves data reliability and retrieval convenience. Moreover, MCDB develops protein sequence alignment and target prediction functions. The former can be used to predict new potential MC-related genes and proteins, and the latter can facilitate the identification of potential target proteins of unknown MC-related compounds. In short, MCDB is such a proprietary, standard, and comprehensive database for MC-relate data that will facilitate the exploration of MC from chemists to biologists in the fields of medicinal chemistry, molecular biology, bioinformatics, oncology and so on. The MCDB is distributed on http://www.combio-lezhang.online/MCDB/index_html/.