bluuebunny/crossref_metadata_2025_split huggingface dataset:
Dosing, drug reduction, drug interruption, and drug discontinuation rates among U.S. FDA approved tyrosine kinase inhibitors.
Authors: Reddy Neha K. , Roszik Jason , Norris David Carl , Groisberg Roman , Coleman Niamh , Alhalabi Omar , Ludmir Ethan B. , Taniguchi Cullen M. , Subbiah Ishwaria Mohan , Subbiah Vivek 
Published: June 2021

3112 Background: The advent of tyrosine kinase inhibitors (TKIs) has altered the therapeutic landscape of multiple hematological and solid malignancies. FDA approved starting doses of TKIs are based on the recommended phase 2 dose (RP2D) in clinical trials. Since many of these drugs are continuously dosed, ongoing toxicities may lead to drug reductions and drug discontinuations. Hence in practice, many patients are started on lower doses due to tolerability concerns or are dose-reduced subsequently for toxicity. Herein, we assessed the dosing, drug reduction rates, and drug discontinuation rates among FDA approved TKIs. Methods: We established a database of all FDA approved TKIs from the FDA online label repository. We extracted descriptive data for indications and usage, type of approval, approval dosage, dose reduction recommendation, median age, dose reduction rates, drug discontinuation rates, dose modification, warnings, adverse reactions, clinical trial experience, and geriatric use above 65 yrs and 75 yrs. Results: TKIs were approved for 143 different indications, ranging from 1 indication to 11 indications (eg. Imatinib) from data arising from 7 patients to 2816 patients for a specific indication. Among all TKIs, median dose was 150 mg and average dose was 237 mg; 34 (23.8%) were approved bid vs 71 (49.7%) qd. Specifically for oncology, 54 indications were biomarker based (eg. EGFR mutant NSCLC) and 52 were non-biomarker based for specific diseases (eg. metastatic RCC). Among approved indications range of dose reduction rate (DRR), drug interruption rates (DIR), drug discontinuations rates (DDR) were 0.80-89%, 3%-89%, and 1-39% respectively. Most common reasons for DRR, DIR, and DDR were diarrhea, fatigue, nausea, vomiting, hepatotoxicity, rash, and hypertension. Geriatric use was listed in 99 indications ( > 65 yrs, 6-68%; > 75 yrs, 0.50-24%). Patient reported outcomes were not available. Conclusions: TKIs have a variable dose reduction and drug discontinuation rate. Clinical trials should evaluate multiple dosing regimens and schedules to lessen the toxicity burden and improve QOL in patients. Future studies are warranted to look into flat dosing vs alternative dosing, like weight-based dosing for TKIs, and to report patient reported outcomes.
Phase I expansion study of the first-in-class monocarboxylate transporter 1 (MCT1) inhibitor AZD3965 in patients with diffuse large B-cell lymphoma (DLBCL) and Burkitt lymphoma (BL).
Authors: Halford Sarah E. R. , Walter Harriet , McKay Pamela , Townsend William , Linton Kim , Heinzmann Kathrin , Dragoni Ilaria , Brotherton Laura , Veal Gareth , Siskos Alexandros , Keun Hector C , Bacon Chris , Wedge Steve , Dyer Martin J.S. , Plummer Elizabeth Ruth 
Published: June 2021

3115 Background: Tumours rely on lactate transporters (MCT1-4) to maintain glycolytic flux and avoid intracellular acidification. In haematological tumours the MCT1 transporter acts as a lactate and pyruvate exporter. AZD3965 is a potent and specific inhibitor of MCT1 causing intracellular lactate accumulation. In vivo efficacy was observed in xenografts of DLBCL and BL, expressing high levels of MCT1 and no or low levels of MCT4. In the AZD3965 phase I (NCT01791595) dose-escalation an oral recommended phase 2 dose (RP2D) of 10mg twice-daily (bd) was determined. Pharmacokinetic (PK) showed exposure estimated to produce a minimum MCT1 occupancy of 90% (based on modelling). DLTs were primarily on-target dose-dependent, reversible, asymptomatic alterations in retinal function seen on ERG. Methods: This expansion cohort enrolled patients with relapsed/refractory DLBCL and BL. Expression of MCT1/MCT4 was assessed by immunohistochemistry. Pharmacokinetic (PK) sampling was performed and pharmacodynamic assessments included [18F]FDG-PET/CT imaging and plasma/urine metabolomics. Results: 11 DLBCL patients were treated with AZD3965 10mg bd. PK showed exposure to be broadly in line with the escalation cohort. No significant ERG changes were observed. One patient experienced a dose-limiting SUSAR of Troponin I increase. MCT1 is expressed in erythrocytes, however no serious events of anaemia were seen, with one non-clinically significant episode of grade 3 anaemia reported. Urine analysis showed increased excretion of lactate and ketone bodies post AZD3965 treatment consistent with renal target engagement. No alteration was detected in plasma. Ongoing stable disease at cycle 5 was observed in one patient and an additional patient had a confirmed complete response (CR) lasting 15 months, with no significant toxicity. In the patient showing CR a reduction in tumour FDG uptake was observed on day 3 of cycle 1. The other four patients who consented to research imaging did not have a clinical response and no changes were observed on FDG-PET. Conclusions: AZD3965 can be safely administered at 10mg bd. In one DLBCL patient monotherapy activity was observed with changes in FDG-PET providing evidence indicative of proof of mechanism. These changes in FDG uptake as early as on day 3 in the responding patient warrant further investigation of FDG-PET as a predictive biomarker. Further biomarker analysis and preclinical studies are ongoing to understand the biology and explore effective combinations with other agents targeting tumour cell metabolism Clinical trial information: NCT01791595.
Outcomes of active cancer patients with COVID-19 infection treated with COVID-19 neutralizing monoclonal antibodies.
Authors: Shaya Justin , Lee Aaron , Cabal Angelo , McKay Rana R. 
Published: June 2021

3137 Background: Treatment with COVID-19 (C19) neutralizing monoclonal antibodies (mAbs), including bamlanivimab and casirivimab/imdevimab, has been associated with decreased rates of C19-related hospitalizations in high-risk patients. Patients with active cancer are at high-risk for C19 complications and currently are candidates for C19-mAbs. Little is known about C19-related outcomes with mAb therapy in cancer patients. Here, we examine the outcomes of a cohort of active cancer patients infected with C19 who were treated with C19-neutralizing mAbs. Methods: Retrospective, single center cohort of patients with active cancer and mild-moderate C19 infection not requiring hospitalization who were treated with either bamlanivimab or casirivimab/imdevimab. Active cancer was defined as a solid or hematologic malignancy diagnosed within 90 days of C19 diagnosis or recurrent/metastatic disease. The primary endpoint was the rate of C19-related hospitalization. Secondary endpoints included the rate of C19-related mortality and adverse events associated with mAb therapy. Results: We identified 38 active cancer patients with C19 who were treated with mAbs. Median age was 65 years (range 20-89) and 47.4% (N = 18) had a hematologic malignancy. Among the cohort, 73.7% (N = 28) were on an anti-cancer therapy at the time of C19 diagnosis: targeted therapy (n = 18), cytotoxic chemotherapy (N = 5), immunotherapy (n = 3), or hormonal therapy (n = 2). 42.1% (N = 16) received bamlanivimab and 57.9% (N = 22) received casirivimab/imdevimab. Median time from C19 diagnosis to mAb infusion was 2 days (range 0-6 days). With a median follow-up of 21 days (range 7-71), 7.9% (N = 3) required hospitalization for C19-related complications. Median time from mAb infusion to hospitalization was 25 days (range 5-29). C19-related deaths occurred in 5.3% (N = 2) of the cohort. No significant adverse events were reported with either mAb formulation. Conclusions: Among a cohort of high-risk cancer patients treated with mAbs, rates of hospitalization and mortality due to C19 were low compared to previously described rates among active cancer patients. Key limitations of this analysis include the lack of a control group for comparison and a small sample size given the recent emergency use authorization of these agents. Given the high mortality rate of active cancer patients with C19, these data support the use of mAbs in cancer patients with C19.
KMT2C as a positive predictor for treatment of immune checkpoint inhibitor and correlation with immune infiltrates in colorectal cancer (CRC).
Authors: Zhang Ling , Song Jianping , Wang Yiting , Chen Yaoxu 
Published: June 2021

3538 Background: Lysine Methyltransferase 2C (KMT2C), a member of the myeloid/lymphoid or mixed-lineage leukemia (MLL) family, possesses histone methylation activity and is involved in transcriptional co-activation. Present study has shown that KMT2C is positive correlated with better efficacy of Immune checkpoint inhibitor (ICI) in NSCLC. However, the role of KMT2C in treatment of ICI on colorectal cancer (CRC) is still unknown. Methods: NGS (Next Generation Sequencing) was performed on 1628 CRC patients. TMB of these patients were analyzed. A public accessible cohort (Samstein2018) with data from 130 CRC patients were used to investigate the correlation between KMT2C mutation and efficacy of ICI. WES and survival data of TCGA database (1099 CRC) was used to analyze prognostic effect of KMT2C mutation. Furthermore, CIBERSORT was used to analyze the tumor-infiltrating immune cells present in COAD（colon adenocarcinoma, 404 patients）from TCGA database. Results: Among 1628 CRC patient, 230(14.1%) had KMT2C mutation. TMB was positive correlated with KMT2C mutation (Mut vs. WT, 30.75 vs. 7.26 mut/Mb, p < 0.0001). The Samstein2018 cohort showed that KMT2C mutations (15.4%, 20/130) were significantly associated with better OS (Mut vs. WT, 11.5 vs. 7.5 month, HR = 0.29; 95% CI, 0.1-0.81; P = 0.012), and a higher TMB was also observed in KMT2C-Mut group (p = 1.98e-08). In TCGA, no association between KMT2C mutation and OS was observed (P = 0.23), suggesting that was not prognostic factor. Moreover, we analyzed the relationship between KMT2C mutation and immune cell infiltration through CRC TCGA database. The results showed, in COAD, KMT2C mutation was positively correlated with the abundance of CD8+ T cells (P = 0.0014), B cells (P = 0.014), M1 macrophages (P = 0.015), neutrophil (P = 0.0019) and NK cells (P = 0.043), and negatively correlated with Treg cells (p = 0.0063). Conclusions: KMT2C has an impact on the immune microenvironment and may be used as a potential positive predictor for treatment of ICI on CRC patients. The role of KMT2C in immunotherapy warrant further studies.
Clinical performance of methylation-based liquid biopsy test COLVERA after optimization of test interpretation rules.
Authors: Vucetic Zivjena , Loayza Naima , Pedersen Susanne Kartin , Tuck Missy , LaPointe Lawrence Charles 
Published: June 2021

3546 Background: Clinical guidelines recommend surveillance for patients who complete primary treatment for colorectal cancer (CRC) with the aim of detecting recurrence when amenable to curative intent treatment. Currently recommended surveillance protocols, including imaging and CEA have limitations both in sensitivity and specificity, thus novel methods that detect circulating tumor DNA (ctDNA) have been introduced into clinical practice. COLVERA is a laboratory-developed, real-time PCR test that detects DNA methylation of BCAT1 and IKZF1 genes. These two genes are hypermethylated in 95% of CRC tissue and COLVERA showed improved sensitivity for detection of recurrent disease in comparison to CEA in several clinical populations. The current study evaluated the impact of optimizing the assay’s qualitative reporting method on actionability and clinical performance for recurrence detection in CRC surveillance setting. Methods: Two previously described cohorts of CRC patients (N=322 and N=144) who completed primary treatment and were undergoing surveillance were evaluated. Imaging and blood collections were performed at, or adjacent to, a standard of care visit. cfDNA was extracted from whole blood, bisulphite-treated and assayed in triplicates for BCAT1/IKZF methylation. Previously, any positive replicate of either target gene was reported as COLVERA “detected”. In the current study, COLVERA is “detected” when at least one replicate of IKZF1 or multiple replicates of either IKZF1 and/or BCAT1 are present. Sensitivity, specificity, and diagnostic odds ratio (DOR) for CRC recurrence detection from a single time-point blood sample was determined using radiological imaging as clinical reference standard. Results: In the first cohort (N=322), overall COLVERA test positivity was 6.5% (21/322) with a sensitivity of 59.3% (95% CI: 38.8 - 77.6) and specificity of 98.3% (96.1 - 99.5) for detecting recurrence at a time-point adjacent to imaging, representing improved specificity, from 91.5% (87.7 - 94.4%), with minimal decrease in sensitivity, from 63.0% (42.4 – 80.6). Similarly, in the second cohort (N=144) sensitivity was 62% (47.2 -75.4), compared to 66.0% (57.1 – 69.3) under the prior interpretation method, while specificity was 92.6% (85.3-97), compared to 90.4% (84.7 - 94.7). A high DOR of 84 (26 - 272) (previously 18 (7.6 – 44.4)) indicates that the revised COLVERA interpretation method is clinically more informative and differentiates with greater accuracy patients with and without the disease. Conclusions: This change in the COLVERA interpretation rule resulted in optimized clinical specificity with minimal impact on sensitivity. For an assay intended to aid in surveillance and early recurrence detection, improved accuracy allows the physician to have increased confidence in making actionable decisions based on test result, including further imaging or treatment.
RAMucirumab in combination with TAS102 versus TAS102 monotherapy in metastatic colorectal cancer: Safety results from the phase IIb part of the RAMTAS phase II/III trial of the German AIO (AIO-KRK-0316).
Authors: Kasper Stefan , Goetze Thorsten Oliver , Stintzing Sebastian , Hofheinz Ralf Dieter , Sinn Marianne , Dechow Tobias Nicolaas , Ettrich Thomas Jens , Keitel Verena , Graeven Ullrich , Fischer von Weikersthal Ludwig , Kolov Alexander , Edelmann Thomas , Stein Alexander , Trarbach Tanja , Junge Sabine , Pauligk Claudia , Virchow Isabel , Siveke Jens T , Al-Batran Salah-Eddin , Schuler Martin H. 
Published: June 2021

3566 Background: Patients (pts) with mCRC progressing on standard chemotherapy have limited therapeutic options. Trifluridine/tipiracil (TAS102) significantly improved survival in patients with refractory mCRC. Ramucirumab (ram) is approved in combination with FOLFIRI for second-line treatment. There is a strong rationale to evaluate the efficacy and safety of ram in combination with TAS102 in pts with refractory mCRC. Methods: This is a randomized, open-label, multicenter, starting as phase IIb and extended to a phase III study in pts with advanced mCRC. Eligible pts were randomized to receive either ram (8 mg/kg on d1+15, q4w) and TAS102 (35 mg/m² on d1-5 and d8-12, q4w, arm A) or TAS102 alone (arm B). The primary endpoint is overall survival. A total of 145 pts were enrolled into phase IIb. Here, we present the data from an interim safety analysis comprising the first 80 treated pts. The trial was extended to phase III including a total of 426 pts. Enrolment of additional 281 pts started in Dec 2020. The trial endpoints remained unchanged. Results: Pts (40 arm A, 40 arm B) received a median of 2.5 treatment cycles in arm A and 2 cycles in arm B; 31 pts in treatment arm A and 32 pts in arm B discontinued participation prematurely, mainly due to cancer progression. Most patients developed adverse events (AEs): grade 3 AEs were observed in 28 pts (70%) in arm A (24 treatment-related) and 27 pts (67%, 17 treatment-related) in arm B. More grade 4 AEs were seen in arm A (13 pts, 32.5%) than in arm B (5 pts, 12.5%). In total, 46 Serious AEs (SAEs) occurred, 27 in arm A (10 treatment-related) and 19 in Arm B (2 treatment-related). Five SAEs (3 in arm A, 2 in arm B) had a fatal outcome (one in arm A treatment-related). Within the analyzed population, no SUSAR occurred. Conclusions: This safety analysis demonstrates a minor increase in AEs in the experimental arm but no unexpected events. There were no excessive toxicity or unacceptable risks. In summary, a favorable risk-benefit-profile was confirmed. Based on these safety results and the ongoing need for efficient treatment in the tested population, the trial was extended to phase III. Clinical trial information: NCT03520946.
The role of PP2A variants to predict outcome in patients (pts) with metastatic colorectal cancer (mCRC): Data from FIRE-3 and TRIBE trials.
Authors: Wang Jingyuan , Millstein Joshua , Loupakis Fotios , Stintzing Sebastian , Arai Hiroyuki , Battaglin Francesca , Kawanishi Natsuko , Jayachandran Priya , Soni Shivani , Zhang Wu , Mancao Christoph , Cremolini Chiara , Heinemann Volker , Falcone Alfredo , Lenz Heinz-Josef 
Published: June 2021

3581 Background: Protein phosphatase 2A (PP2A) is a serine/threonine phosphatase with functions that counter-balance kinase-mediated phosphorylation throughout cell signaling networks. PP2A was reported to upregulate the angiogenesis, while negatively regulate the pathways downstream of receptor tyrosine kinases at multiple nodes. Previous studies showed PP2A variants were associated with the increased risk of cancer. Therefore, we hypothesized that PP2A variants may predict first-line treatment outcome in mCRC pts treated with bevacizumab (bev)/cetuximab (cet)-based chemotherapy. Methods: Genomic DNA from blood samples of pts enrolled in two independent randomized trials, TRIBE (bev arm, n=215, as discovery cohort) and FIRE-3 (bev arm, n=107, as validation cohort; cet arm, n=129, as control cohort), was genotyped through the OncoArray, a customized array manufactured by Illumina including approximately 530K SNP markers. The impact on outcome of 17 selected SNPs in 3 main PP2A core subunits (PPP2CA, PPP2R1B, PPP2R1A), one phosphatase activator (PPP2R4) and 2 endogenous inhibitors (TIPRL, CIP2A) was analyzed. Results: In the discovery cohort, pts with PPP2R4 rs2541164 A/A (N=16) showed significantly shorter overall survival (15.3 vs 27.3 months) compared to carriers of any G allele (N=198) in both univariate (hazard ratio [HR]=1.8; 95% confidence interval [CI]: 1.1-3.1; p=0.02) and multivariate (HR=2.4; 95%CI: 1.4-4.4; p=0.006) analysis. These data were validated in the FIRE-3 bev cohort in both univariate (A/A vs. Any G: 17.3 vs 39.9 months, HR=2.8, 95%CI: 1.4-5.9, p=0.004) and multivariate (HR=4.3, 95%CI: 1.5-12.2, p=0.0095) analysis. Conversely, pts carrying CIP2A rs13069780 C/C (N=24) only showed significantly longer progression-free survival (17.7 vs 12.3 months) than carriers of any T allele (n=105) in the FIRE-3 cet cohort in both univariate (HR=0.6; 95%CI 0.4-0.99; p=0.04) and multivariate (HR=0.5; 95%CI 0.3-0.94; p=0.02) analysis, but no association were observed in the bev cohort of TRIBE and FIRE-3. Conclusions: Our study demonstrated for the first time that PPP2R4 polymorphisms could predict outcomes of bev-based treatment in mCRC patients; Meanwhile CIP2A polymorphism could predict outcomes of cet-based treatment in mCRC patients. These findings support a possible role of the PP2A variants in contributing to resistance to anti-VEGF/EGFR treatment.
A phase II study of capecitabine plus concomitant radiation therapy followed by durvalumab (MEDI4736) as preoperative treatment in rectal cancer: PANDORA study first-stage.
Authors: Tamberi Stefano , Grassi Elisa , Corbelli Jody , Papiani Giorgio , Barbera Maria aurelia , Zingaretti Chiara , Carli Moretti Chiara , Montroni Isacco , Petracci Elisabetta , Caruso Dora , Nosseir Sofia , Nanni Oriana , Frassineti Giovanni Luca , Di Bartolomeo Maria , Marzola Marina , Bonetti Andrea , Gelsomino Fabio , Pinto Carmine , Tassinari Davide , Ugolini Giampaolo 
Published: June 2021

3607 Background: The combination of capecitabine plus long course radiotherapy (RT) is the standard preoperative therapy in cT3-4 cN+ rectal cancer. Pathologic Complete remission (pCR) can be considered as surrogate end point of efficacy of treatment in terms of disease free survival (DFS). Preclinical data points heavily toward a strong synergy between RT and immune treatments. Methods: This is a prospective phase II, open label, single arm, multi-centre study, conducted with support from AstraZeneca, in patient with locally advanced rectal cancer who receive concomitant CT/RT therapy (825 mg/m2 twice daily capecitabine every day and 5040 cGy radiotherapy for 5 days per week for 5 weeks) followed by durvalumab (1500 mg Q4W for 3 administrations). Surgery is performed after 10-12 weeks from neoadjuvant therapy. The primary endpoint is pCR rate after at least 1 cycle of durvalumab. The sample size has been estimated by using the optimal Simon’s two-stage design. If more than 4 complete responses are observed in the first 19 enrolled patients, 36 additional patients will be accrued for a total of 55 evaluable patients. Results: Between November 2019 and July 2020, 20 patients were accrued and 19 were evaluable for study objectives, concluding the first stage of the trial. Baseline characteristics of the first 19 evaluable patients enrolled are listed in the table. All patients received 3 infusions of durvalumab; 18 patients underwent surgery after a median of 13 weeks from CHT/RT end. Five complete pathological responses (ypT0N0) were observed, allowing to proceed to the second stage. About toxicity, four patients had Grade 3-4 adverse events (AE); the most frequent G3-4 AE related to the neoadjuvant therapy were anemia (n=1), diarrhea (n=2) and neuthropenia (n=2). No grade 3 and 4 adverse events related to Durvalumab treatment were observed. Eight patients had G1-2 AE related to durvalumab, the most common being asthenia (n=2) and nausea (n=2). Conclusions: At the end of study’s first stage the preoperative treatment with radiotherapy plus capecitabine followed by durvalumab showed a safe toxicity profile and promising activity in terms of pCR rate. The second part of the trial is ongoing, and the accrual is under completion (44 patients enrolled as of 10 February 2021). Clinical trial information: NCT04083365. [Table: see text]