tbuckley/cabot-search huggingface dataset:
Fruquintinib in patients with metastatic colorectal cancer failed in previously bevacizumab-based therapy: A monocentric retrospective study.
Authors: Xiaoqiang Gu
Journal: Journal of Clinical Oncology (2021)

e15555 Background: Fruquintinib, a vascular endothelial growth factor receptor (VEGFR) inhibitor, is a new targeting anti-cancer agent for refractory metastatic colorectal cancer (mCRC). Promising antitumor effect of fruquintinib monotherapy was verified in a phase III FRESCO randomized study of mCRC patients, and only 30% patients were prior bevacizumab-treated. However, comprehensive effect evaluation of fruquintinib in mCRC patients who have previously failed in bevacizumab therapy were scarce. Methods: Forty patients with metastatic CRC who had previously failed at least 2 lines of standard regimen containing bevacizumab in Longhua Hospital affiliated to Shanghai University of Traditional Chinese Medicine from March 2019 to February 2020 were enrolled. These patients were administrated with fruquintinib (5mg orally, once daily) in cycles of 3 weeks on/ 1 week off. Furthermore, the primary endpoint was overall survival (OS). Secondary endpoints mainly included progression-free survival (PFS), disease control rate (DCR), objective response rate (ORR), and safety profile. Statistical analyses were performed using IBM SPSS statistics software and ‘R’ statistical software with the ‘forest plot’ package. Subsequently, the variables were screened and verified through LASSO regression with the R software “glmnet” package. Results: The mOS was 8.1months (95%CI, 5.6667-12.8667), mPFS was 4.1833 months (95% CI, 3.5333-5.0667), and DCR was 65% (26 SD in 40 patients). Particularly, gender (HR: 7.11, 95%CI:1.86-27.16,P = 0.005), age (HR:0.91, 95%CI:0.85-0.98,P = 0.012), ECOG(HR:3.75, 95%CI:1.13-12.42,P = 0.03), medication duration (HR:0.62, 95%CI:0.48-0.81,P＜0.001),and the number of metastases(HR:2.95,95%CI:1.21-7.18,P = 0.017) identified the statistically significant association with OS. Eliminating the influence of time factor, ECOG and medication cycle obtained by Lasso regression were the risk factors for OS. The most frequently reported adverse events were mainly hypertension, proteinuria, hand-foot skin reaction, fatigue and diarrhea, and any new safety signals were not observed. Conclusions: Fruquintinib showed an acceptable safety profile and promising efficacy in patients with metastatic colorectal cancer failed in previously bevacizumab-based therapy. Future studies of fruquintinib should focus on identifying the patients most likely to benefit and on minimizing toxicity.
Multifactorial analysis of cancer patients’ willingness for COVID-19 vaccination.
Authors: Paris A. Kosmidis, Christie Lagogianni, Thanos Kosmidis
Journal: Journal of Clinical Oncology (2021)

12062 Background: Public health authorities advocate vaccinations for the general population, including cancer patients and survivors. Since the onset of the COVID-19 pandemic, its vaccine has been eagerly awaited, but the extent of cancer patients’ willingness to get vaccinated is not clear. As health promotion is crucial for these individuals, it is important to measure and analyze their willingness to receive the vaccine. Methods: A few days after the regulatory approval for the first COVID-19 vaccine, the CareAcross online interactive platforms were used to evaluate the willingness of patients to get vaccinated. Through an online survey, within a few hours, 1106 cancer patients selected either “Yes, I plan to get the vaccine” or “No, I will not get the vaccine”. The patients were from the UK, Germany, France, Spain or Italy; they had been diagnosed with breast, lung, prostate or colorectal cancer. Their responses were analyzed to determine how their cancer diagnosis (including date, metastatic status, and other aspects), and their country of origin, affected their reported willingness to get vaccinated. Results: Overall, 70.6% of patients indicated willingness to get the vaccine (WTV), and 29.4% reported the opposite (NWTV). The strongest determinant of WTV was the patient’s country of origin: patients in the UK, Spain, Italy, Germany and France reported WTV of 84.1%, 64.2%, 58.7%, 47.4% and 38.3%, respectively. The next strongest determinant was the time elapsed since the patient’s diagnosis: for the largest population with available diagnosis date (451 UK patients), the average time since diagnosis for patients with WTV vs NWTV was: breast, 3.5 vs 2.5 years; lung, 1.6 vs 1.4 years; prostate, 2.4 vs 3.3 years; colorectal, 1.9 vs 1.5 years. Among patients from other countries with available diagnosis date: as the time since diagnosis increased, among 148 Italian patients WTV gradually increased; among 94 Spanish patients, WTV substantially decreased; among 85 French patients, WTV gradually decreased; among 50 German patients, WTV substantially increased. There was no significant correlation of WTV percentages with cancer type; metastatic status; triple negative vs non-triple negative among breast cancer patients; non-small cell vs small cell among lung cancer patients. Conclusions: Despite long-standing efforts of the scientific community for health promotion through the COVID-19 vaccine, a substantial percentage of cancer patients reported no willingness to get vaccinated. This appeared to depend on each patient’s country of origin, and the time elapsed since their diagnosis. This patient input was collected shortly after the first vaccine’s approval. With increasing evidence of efficacy and safety through more vaccinations of citizens and patients, willingness is expected to increase. We are in the process of conducting a follow-up survey to track these changes and update the results to be reportable during ASCO.
Extracellular vesicles from human iPSCs enhance reconstitution capacity of cord blood-derived hematopoietic stem and progenitor cells
Authors: Elżbieta Karnas, Małgorzata Sekuła-Stryjewska, Katarzyna Kmiotek-Wasylewska, Sylwia Bobis-Wozowicz, Damian Ryszawy, Michał Sarna, Zbigniew Madeja, Ewa K. Zuba-Surma
Journal: Leukemia (2021)

Abstract Cord blood (CB) represents a source of hematopoietic stem and progenitor cells (CB-HSPCs) for bone marrow (BM) reconstitution, but clinical CB application is limited in adult patients due to the insufficient number of CB-HSCPCs and the lack of effective ex vivo approaches to increase CB-HSPC functionality. Since human-induced pluripotent stem cells (hiPSCs) have been indicated as donor cells for bioactive extracellular vesicles (EVs) modulating properties of other cells, we are the first to employ hiPSC-derived EVs (hiPSC-EVs) to enhance the hematopoietic potential of CB-derived CD45 dim Lin - CD34 + cell fraction enriched in CB-HSPCs. We demonstrated that hiPSC-EVs improved functional properties of CB-HSPCs critical for their hematopoietic capacity including metabolic, hematopoietic and clonogenic potential as well as survival, chemotactic response to stromal cell-derived factor 1 and adhesion to the model components of hematopoietic niche in vitro. Moreover, hiPSC-EVs enhanced homing and engraftment of CB-HSPCs in vivo. This phenomenon might be related to activation of signaling pathways in CB-HSPCs following hiPSC-EV treatment, as shown on both gene expression and the protein kinases activity levels. In conclusion, hiPSC-EVs might be used as ex vivo modulators of CB-HSPCs capacity to enhance their functional properties and augment future practical applications of CB-derived cells in BM reconstitution.
Anticancer drugs associated with venous thromboembolic event: Analysis of the WHO pharmacovigilance database.
Authors: Angélique DA Silva, Joachim Alexandre, Damien Laneelle, Marion Sassier, Basile Chrétien, Sophie Fedrizzi, Florence Joly, George Emile, Laurent Bertoletti, Benoite Mery, Anne Flore Plane, Damien Legallois, Charles Dolladille
Journal: Journal of Clinical Oncology (2021)

3094 Background: Venous thromboembolic event (VTE) is a frequent complication of cancer, as of some classical cancer therapy, like chemotherapy and surgery. The advent of new therapies such as immunotherapy and targeted therapies has meant that new therapies may be associated with VTE. Reliable data concerning the association between ADs and VTE are scarce. Methods: On March 1st, 2020 we utilized VigiBase (International pharmacovigilance database) and performed a disproportionality analysis using reporting odds ratios (ROR) to determine the association between the 206 FDA- or EMA-labeled ADs and VTE, defined as deep vein thrombosis and pulmonary embolism. RORs were adjusted (aRORs) on population characteristics including the cancer risk of VTE with the primary tumor site according to Khorana classification and metastatic status. Results: A total of 50,438 VTE cases associated with at least one AD were identified. Thirteen ADs were associated with higher reporting of VTE of which 2 represented new VTE associations not previously confirmed in the summary of product characteristics or literature including sipuleucel-t and megestrol. ADs more reported with VTE were lenalidomide (n:5,796), bevacizumab (n:2,780) and thalidomide (n:1,700). ADs associated-VTE occurred mainly during the first 6 months after AD initiation. Conclusions: Although cancer itself may generate VTE, we identified 13 ADs associated with VTE overreporting. Recognition of AD most likely to cause VTE can help raise practitioner awareness and lead to earlier diagnosis and treatment. Futures studies should include ADs in VTE risk evaluation and evaluate the management of VTE when recurrences occur under AD favoring VTE. ClinicalTrial registration number: NCT04696250.
EPCT-16. LENALIDOMIDE ACTIVITY IN PILOCYTIC ASTROCYTOMA AND OPTIC PATHWAY GLIOMAS: REPORT ON CHILDREN’S ONCOLOGY GROUP ACNS1022
Authors: Katherine Warren, Gilbert Vezina, Linda Springer, Allen Buxton, Cody Peer, W Douglas Figg, Maryam Fouladi, Amar Gajjar, Mark Krailo, Daniel Bowers
Journal: Neuro-Oncology (2021)

Abstract Children with low-grade glioma have excellent survival rates but often suffer from the morbidity of treatment, particularly from cytotoxic chemotherapies. Targeted agents appear to have some activity but the long-term effects of inhibiting normal developmental pathways are unknown. Lenalidomide is an oral immunomodulatory agent with additional properties including anti-angiogenesis. Phase I studies indicated greater tolerability of this agent compared to adults, and a potential dose-response effect. We performed a Phase 2 trial of lenalidomide in children with pilocytic astrocytoma and optic pathway gliomas who failed initial therapy. The primary objective was to determine the objective response rate of children randomized to Regimen A low-dose (20 mg/m2 /dose) or Regimen B high-dose (115 mg/m2 /dose) lenalidomide, each administering lenalidomide daily x 21 days of each 28-day course. Secondary objectives included estimation of event-free survival (EFS) in this population and correlation of plasma lenalidomide concentration with toxicity and outcome. Results 74 eligible patients were enrolled (n=37 to each arm). The pre-defined activity level of interest was achieved for both arms. Objective responses were observed in both arms, with 4 partial responses in each. A total of n=18 patients completed 26 courses of therapy (Arm A, n=12, Arm B, n=6) The median number of courses on each arm was 14 (range 2–26) for Arm A and 11 for Arm B (range 1- 26). Of the 74 eligible patients who received study drug, 30 required a dose reduction for toxicity (Arm A, n=6, Arm B, n=24) and 16 discontinued treatment on protocol due to toxicity (Arm A, n=2, Arm B, n=14). Conclusion Lenalidomide demonstrates a sufficient level of activity in children with low-grade glioma to warrant further exploration in Phase 3 studies. Low-dose (20 mg/m2) lenalidomide appears to have better tolerability.
Efficacy of selpercatinib after prior systemic therapy in patients with <i>RET</i> mutant medullary thyroid cancer.
Authors: Lori J. Wirth, Eric Jeffrey Sherman, Daniela Weiler, Maria E. Cabanillas, Bruce Robinson, Antoine Italiano, Janessa J. Laskin, Vivek Subbiah, Alexander E. Drilon, Victoria Soldatenkova, Pearl Plernjit French, Jennifer Wright, Matthias Kroiss, Manisha H. Shah
Journal: Journal of Clinical Oncology (2021)

6074 Background: Selpercatinib is a first-in-class, CNS active, highly selective, and potent RET kinase inhibitor which has demonstrated durable antitumor activity in patients (pts) with RET altered thyroid cancer and is approved in multiple countries for the treatment of RET fusion+ lung or thyroid cancers. As response rates to cancer therapy usually decline on subsequent lines of therapy, the efficacy of selpercatinib was examined in the context of the last prior therapy received before trial enrollment. Methods: Pts with RET mutant medullary thyroid cancer (MTC) previously treated with multikinase inhibitors (cabozantinib and/or vandetanib) were enrolled in the global LIBRETTO-001 trial (NCT03157128). This post-hoc exploratory intrapatient analysis, based on March 30, 2020 data cutoff date, was performed to compare the retrospective physician-reported objective response rate (ORR) from the last systemic therapy prior to enrollment, as reported in pts case reports, to ORR by independent review committee per RECIST 1.1 with selpercatinib treatment, with each patient serving as his/her own control. Results: Efficacy-evaluable pts, 64% male, 90% white with a median age of 58 years, received prior therapy for MTC (n = 143). Pts had a median of 2 (range 1-8) prior systemic regimens. The ORR on selpercatinib (69%) was markedly higher than for the last prior therapy (10%) received before enrollment. ORR improvements with selpercatinib were observed regardless of prior therapy: cabozantinib (66% vs 14%) or vandetanib (71% vs 12%). Fewer pts had progressive disease as their best overall response with selpercatinib (2/143; 1.4%) compared to last prior therapy (33/143; 23.1%). Notably selpercatinib achieved 62% ORR in pts that did not respond to their previous line of therapy prior to enrolment. This shift from non-responder to responder on selpercatinib therapy was consistent regardless of prior cabozantinib or vandetanib treatment, where pts achieved 57% and 61% ORR respectively when subsequently treated with selpercatinib. In contrast, only 3% of patients did not respond to selpercatinib after a previous response to the immediate prior therapy. Similarly, 5% and 2% of patients were non-responders on selpercatinib after a prior response with cabozantinib and vandetanib therapy respectively. Conclusions: Prior to selpercatinib, response with previous multikinase therapy was rare. By contrast, selpercatinib demonstrated robust efficacy regardless of response to or specific prior therapy in pts with RET mutant MTC. Clinical trial information: NCT03157128.
Safety of immune checkpoint inhibitors in patients with preexisting autoimmune disorders.
Authors: Rohit Kumar, Abigail Sy Chan, Sudeepthi Bandikatla, Sarah Mudra, Smita Ranjan, Phuong Ngo
Journal: Journal of Clinical Oncology (2021)

e14568 Background: In recent years, immune checkpoint inhibitors (ICIs) have been approved for a growing number of cancer types. Approximately 10-30% of cancer patients have a concomitant diagnosis of autoimmune disorders (AID). Activation of the immune system with ICIs poses a potential risk of AID worsening. The majority of the ICI clinical trials excluded these patients from the study. There is a paucity of data regarding the benefits and risks of ICIs in cancer patients with AIDs. The primary objectives of this study were to determine the incidence of immunotherapy related AID worsening and all immunotherapy related adverse events (irAEs). Secondary outcomes were time to AID worsening and survival difference. Methods: All adult patients (age ≥18 years) with solid malignancy who received ICIs between Jan 2016 to June 2019 were identified using the University of Louisville pharmacy database. Medical records were reviewed to include all the patients with preexisting AIDs. Descriptive statistics were used to determine the incidence of AID worsening and all irAEs. Baseline characteristics were compared between cancer patients with versus without AID worsening using Pearson chi2 and Student’s t-test, where appropriate. Multivariate Cox regression analysis was used to compared survival between the 2 groups. Results: A total of 40 patients with AIDs were identified during the study period. The cancer types were melanoma (57.5%), lung (15%), breast (5%), and others (22.5%). AIDs were rheumatological (52.5%), gastroenterological (12.5%), neurological (12.5%), dermatological (20%) and hematological (2.5%). The incidence of all irAEs was 60% (grade ≥3 in 20%) and AID worsening was 40% (grade ≥3 in 15%). Baseline characteristics of the 2 comparison groups are shown in table. The median time from ICI initiation to AID worsening was 94.5 (range 21-431) days. In multivariate Cox regression analysis, adjusted for demographics, cancer type, and stage, survival was similar for patients who had AID worsening versus those who did not (HR 0.30 (95%CI 0.06-1.40, p=0.128). Conclusions: In our single-institution study, cancer patients with preexisting AID do have an increased risk of irAEs with high-grade toxicities in 20% compared to historically reported 5% in the general cancer population; about 15% of patients reported grade ≥3 worsening of their AIDs. However, though the risk of irAEs is numerically higher in patients with AID, it may be acceptable to the patients if the potential benefits of ICIs outweigh the risks. Baseline demographics and clinical characteristics.[Table: see text]
One size does not fit all: Evaluating disparities in lung cancer screening eligibility amongst Hispanic/LatinX and African Americans.
Authors: Coral Olazagasti, Matthew Ehrlich, Nina Kohn, Nagashree Seetharamu
Journal: Journal of Clinical Oncology (2021)

6538 Background: Lung cancer (LC) is the leading cause of cancer death among Hispanic men. African Americans (AA) have the highest LC mortality rate in the United States (US). We sought to identify the tendencies for screening eligibility amongst Hispanic/LatinX (H/L) and AA prior to their LC diagnosis according to the National Comprehensive Cancer Network (NCCN) and The United States Preventive Service Task Force (USPSTF) guidelines. Methods: We conducted an observational study in patients diagnosed with LC from 2016 to 2019. Current and former smokers were included in the analysis. Charts were reviewed for demographics, smoking history, family history, personal history of other malignancy, and prior exposures to assess screening their eligibility prior to LC. The chi-square test was used to examine the association between race and ethnicity with each screening criteria. Results: A total of 530 subjects were reviewed, of which 428 were included in the analysis. One hundred and fifty three and 245 subjects were ineligible for NCCN and USPSTF screening criteria prior to their LC diagnosis. Twenty-eight of the subjects failing to meet NCCN criteria identified as AA and 12 as H/L. Forty and 20 of the USPSTF ineligible subjects identified as AA and H/L. There was a significant association between ethnicity and individual screening eligibility, where 52% of H/L met NCCN eligibility compared to 20% of H/L who met USPSTF eligibility (p = 0.0010). There was a significant association between ethnicity and USPSTF criteria (p = 0.0166), as 80% of H/L subjects were screening ineligible under USPSTF criteria compared to 56% of non-Hispanic or other [Table]. Conclusions: In our study, H/L had significant lower tendencies of meeting the USPSTF LC screening eligibility criteria than non-H/L or other. Notably, there was a profound association between ethnicity and eligibility of screening criteria, where a proportionally higher number of H/L who were ineligible under USPSTF criteria met NCCN criteria. These findings suggest that leniency in the screening criteria can possibly lead to earlier detection of lung cancer in high-risk individuals. Our study is in line with developing data that minority individuals at high-risk for lung cancer can be missed, mainly if current USPSTF criteria was to be applied. Recently, USPSTF has modify their criteria which may benefit more of these individuals. To improve rates of screening and overall mortality of minorities, organizations should continue to re-evaluate and liberalize their screening guidelines.[Table: see text]
Development of orally bioavailable prodrugs of fulvestrant for the treatment of metastatic/advanced breast cancer.
Authors: Parva Purohit, Pathik Brahmkshatriya, Vishalgiri Goswami
Journal: Journal of Clinical Oncology (2021)

e13027 Background: Fulvestrant, a potent, selective estrogen receptor degrader, is a primary drug of choice for treating advanced metastatic hormone receptor-positive breast cancer in postmenopausal women following anti-estrogen therapy. However, the existing therapy limits to inconvenient intramuscular injections due to low solubility, weak permeation, high metabolism, and poor pharmacokinetics profile. Additionally, it takes 30 days to reach maximal steady-state plasma concentration, limiting clinical efficacy. To overcome these issues, we modulated physicochemical properties of fulvestrant, enabling its oral delivery to improve bioavailability. Methods: Structurally diverse pro-moieties were appended on fulvestrant to improve solubility and ADME profile. Thermodynamic solubility, plasma/liver microsomal stability, and Caco-2 permeability studies were performed to identify lead molecules. Pharmacokinetic studies were performed for selected molecules in mice. Antitumor activity of once-daily oral dose of three molecules was evaluated in female nude mice using the MCF-7 xenograft model. The efficacy of lead molecules was compared with subcutaneously administered faslodex in terms of percentage tumor growth inhibition. Results: Several prodrugs of fulvestrant were synthesized and evaluated for their intrinsic properties suitable for increasing bioavailability of fulvestrant. Remarkable improvements (̃500 to 2000-fold increase) were achieved in solubility and permeability. The PoC established an increase in systemic plasma exposure of fulvestrant upon oral administration of prodrugs in mice with enhanced bioavailability (1.5-8.7-fold) as compared to fulvestrant given subcutaneously (Table). Herewith, we report the identification of KSHN001022, KSHN001075, and KSHN001126, the prodrugs of fulvestrant, which showed enhanced efficacy with better tumor volume reduction (̃48-88% regression in tumor volume) as compared to that of fulvestrant (78%) in the estrogen-dependent MCF-7 xenograft model. Conclusions: KSHN001 lead candidates demonstrated significantly higher bioavailability, hence, provides a novel strategy to deliver fulvestrant orally to pursue the potential benefits in patients with advanced metastatic disease.[Table: see text]