bluuebunny/crossref_metadata_2025_split huggingface dataset:
Safety and efficacy of abivertinib (AC0010), a third-generation EGFR tyrosine kinase inhibitor, in Chinese patients with EGFR-T790M positive non-small cell lung cancer (NCSLC).
Authors: Zhou Qing , Wu Lin , Feng Luo , An Tongtong , Cheng Ying , Zhou Jianying , Li Junling , Feng Ji Feng , Zhang Li , Han Baohui , Xu Walson , Zhu Lvyu , Xu Li , Xu Xiao , Luo Feng Roger , Wu Yi-Long 
Published: March 2020

9091 Background: Abivertinib (AC0010) is a potent, selective third-generation EGFR tyrosine kinase inhibitor (TKI) that demonstrated clinical efficacy and manageable adverse events (AEs) in the phase 1 portion of the study in Chinese patients with EGFR T790M+ NSCLC. Here we report the results from patients enrolled to the phase 2 portion of the study (NCT02330367). Methods: The study enrolled locally advanced or metastatic NSCLC patients who were ≥ 18 years, progressed with the prior EGFR-TKI therapy, and must have T790M+ in tumor based on the central laboratory test. All patients received the recommended phase 2 doses of 300 mg twice daily [BID]. Results: As of March 5, 2018, 227 patients received treatment, majority of patients had adenocarcinoma (n = 220, 97%) with the median age of 59 years, 65% (n = 148) patients were female, most patients were non-smoker (n = 171, 75%), ECOG performance status of 1 (n = 162, 71%). The median treatment duration was 21 week. The treatment-related adverse events (AEs) were reported for 96.9% (n = 220) patients, mostly of grade 1 or 2 severity. The most common drug-related grade 3/4 AE (≥2%) was ALT increase (7.0%), AST increase (4.8%), diarrhea (4.4%), interstitial lung disease (4.0%), neutrophil count decrease (3.5%), and there was no drug-related grade 5 AEs. Among 209 response evaluable patients, per investigator’s assessment, 90.0% (n = 188) patients had tumor size reduction, the objective response rate (Complete Response + Partial Response [PR]) was 50.2% (n = 105; 95% CI 43.3%, 57.2%); 37.8% (n = 79) had stable disease, and the disease control rate was 88% (95% CI 82.9%, 92.1%). The median duration of response and progression-free survival estimated by Kaplan-Meier was 7.5 months (95% CI 6.0, 9.2) and was 7.5 months (95% CI 6.0, 8.8), respectively. Conclusions: Abivertinib demonstrated the clinical efficacy with manageable side-effects in patients with EGFR T790M+ NSCLC. Therefore, abivertinib could be a suitable treatment for patients with EGFR T790+ disease who have progressed on an EGFR-TKI. Clinical trial information: NCTNCT02330367.
Efficacy and safety of IBI305 compared with bevacizumab in advanced non-squamous NSCLC patients as first-line treatment in a randomized, double-blind, phase III study.
Authors: Zhang Li , Wu Bin , Huang Linian , Shi Meiqi , Liu Yunpeng , Zhao Yanqiu , Wang Lijun , Lu Shun , Chen Gongyan , Li Baolan , Xie Conghua , Fang Jian , Yang Nong , Zhang Yiping , Cui Jiuwei , Song Yong , Zhang Cuiying , Mei Xiaodong , Cao Bangwei , Yang Lan 
Published: March 2020

9095 Background: IBI305 is a recombinant humanized anti-VEGF monoclonal antibody, a biosimilar candidate to bevacizumab in analytical and functional comparisons. Pharmacokinetic similarity has been demonstrated in healthy males. Here we present primary efficacy and safety results from a phase 3 comparative study in non-small cell lung cancer (NSCLC). Methods: In this double-blind, active-controlled study, subjects with advanced non-squamous NSCLC on first-line treatment with carboplatin and paclitaxel were randomized (1:1) to IBI305 or bevacizumab (15 mg/kg IV Q3W). After six cycles, patients were on maintenance treatment with IBI305 or bevacizumab (7.5 mg/kg IV Q3W) till progression. Clinical equivalence of the primary endpoint, confirmed objective response rate (ORR) was evaluated by comparing the 2-sided 90% confidence interval (CI) of the risk ratio (RR) between study arms with the prespecified margin (0.75, 1.33). Results: A total of 450 subjects were randomized (IBI305: n = 224; bevacizumab: n = 226). Baseline characteristics were well balanced between treatment arms. ORR evaluated by Independent Radiological Review Committee (IRRC) in full analysis set (FAS) was 44.3% (98/221) for IBI305 and 46.4% (102/220) for bevacizumab; the RR for ORR was 0.95 (90% CI: 0.803, 1.135). Sensitive analysis result on RRs of ORR in Intention to Treat (ITT) population (IBI305: n = 224; bevacizumab: n = 226) and other analysis set were consistent and all within the prespecified equivalence margin. The medium PFS were 8.4 months for IBI305 and 8.3 months for bevacizumab and duration of response (DOR) was also similar in both arms. Treatment-emergent adverse events (TEAEs) were well balanced between treatment arms and consistent with the known adverse event profile of bevacizumab. Patients developing binding antibodies were 0.5% in the IBI305 arm vs 0% in the bevacizumab arm; no subject tested positive for neutralizing antibodies. Conclusions: This is the first released phase 3 clinical study with maintenance treatment for bevacizumab biosimilar in NSCLC patients till now. The comparative study met its predefined primary endpoint that the RR for confirmed ORR was within the prespecified equivalence margin. There was no significant difference between the two arms in safety profile and immunogenicity. Clinical trial information: NCT02954172.
Crizotinib versus pemetrexed-based chemotherapy in patients with advanced ROS1-rearranged non-small cell lung cancer.
Authors: Shen Lan , Lu Shun 
Published: March 2020

9101 Background: ROS1 rearrangement is an important therapeutic target that occurs in approximately 1-2% of patients with non-small cell lung cancer (NSCLC). It has been shown that ROS1-rearranged patients could benefit from crizotinib treatment. However, the efficacy of crizotinib as compared with pemetrexed-based chemotherapy in such patients is unknown. Methods: Advanced ROS1-rearranged NSCLC patients receiving crizotinib or pemetrexed-based chemotherapy as first-line treatment in Shanghai Chest Hospital between August 2010 and December 2017 were retrospectively reviewed. Clinical characteristics, treatments and survival outcomes data were abstracted. Results: Of 77 patients included, 30 patients (39.0%) received crizotinib and 47 patients (61.0%) received pemetrexed-based chemotherapy as their first-line treatment. The median follow-up was 26.8 months. The objective response rate was significantly better with crizotinib than with pemetrexed-based therapy (86.7% vs 44.7%, P < 0.001). The disease control rate wasc 96.7% with crizotinib, as compared with 85.1% with pemetrexed-based therapy (P = 0.140). The median progression-free survival was significantly longer with crizotinib versus pemetrexed-based therapy (18.4 months [95% confidence interval [CI]: 6.8-30.0] vs 8.6 months [95% CI:7.1-10.2], P < 0.001). No significant difference in overall survival (OS) was observed between the two groups (Not reach vs 28.1 months [95% CI:18.7-38.5], P = 0.173). Six patients (20%) in the crizotinib group switched to pemetrexed-based therapy in subsequent lines, while twenty-nine patients (61.7%) in the chemotherapy group crossed over to receive crizotinib after progression. There was no significant difference in median OS between patients who received crizotinib first and those who received pemetrexed-based treatment prior to crizotinib (38.6 months [95% CI: 0-81.0] vs 32.7 months [95% CI:14.3-51.1], P = 0.890). Conclusions: Crizotinib is superior to pemetrexed-based chemotherapy as an initial treatment for advanced ROS1-rearranged NSCLC patients. The sequence of crizotinib treatment and pemetrexed-based chemotherapy does not influence OS.
Determinants of early discontinuation of first-line chemotherapy, and associated outcomes among elderly with advanced non-small cell lung cancer.
Authors: Nadpara Pramit 
Published: March 2020

9102 Background: Chemotherapy is the primary treatment modality in elderly with Advanced-NSCLC (Adv-NSCLC), with ASCO/NCCN guideline recommending First-Line Chemotherapy (FL-Chemo) for at least 4 months. The objective of this study was to identify the determinants, and outcomes of early discontinuation of FL-Chemo, in a nationwide sample of elderly patients. Methods: We used NCI’s Surveillance, Epidemiology, and End Results registry linked Medicare (SEER-Medicare) 2007-2014 files. We included patients with NSCLC diagnosis in 2007-2013, age ≥65, AJCC Stage IIIB/IV, receiving only FL-Chemo (Identified using HCPCS/CPT codes), and surviving at least 9 months post-diagnosis. We excluded those with non-continuous Medicare enrollment, or HMO enrollment. Patients receiving 1-3 months (vs. 4-7 months) of FL-Chemo were characterized as those experiencing early discontinuation. Patient’s performance status and comorbidity burden were assessed using previously validated algorithms. Survival was calculated from the diagnosis date to the date of death/study end date. Chi-square test, logistic regression, survivor function, proportional hazards regression, and propensity score–adjusted modeling were conducted. Results: We identified 1,029 patients (meeting inclusion and exclusion criteria) with incident Adv-NSCLC during the study years. Of those, 43.2% patients experienced early discontinuation. Adjusted analysis revealed Age as the only significant factor associated with early FL-Chemo discontinuation, with odds increasing with increase in age (p < 0.035). Other patient factors (non-clinical and clinical factors including performance score, comorbidity) were not associated with early discontinuation in any model. Survival outcomes and mortality risk were poor among those experiencing early discontinuation, however the difference was not statistically significant (p < 0.165). Conclusions: A large proportion of elderly with Adv-NSCLC experience early discontinuation of FL-Chemo. Even after controlling for variability in patient performance score and comorbidity burden, Age remained a key factor associated with early discontinuation, raising a cause for concern. Future studies need to explore the impact of Age along with patient reported Quality of Life on early treatment discontinuation.
SM-88 therapy in high risk poor prognosis pancreatic cancer (PDAC).
Authors: Noel Marcus Smith , Wang-Gillam Andrea , Ocean Allyson J. , Chawla Sant P. , Chung Vincent , Del Priore Giuseppe , Picozzi Vincent J. 
Published: March 2020

e15714 Background: Refractory PDAC has no established therapy (JCO 37, 2019 supp 4; 226). SM-88 (D,L-alpha-metyrosine) is a novel oral therapy used with low doses of sirolimus, phenytoin and methoxsalen. Previous studies show safety and efficacy in compromised patients (JCO 37, 2019 supp 4; 200. JCO 37, 2019 supp 4; 310). We now report the dose optimization phase (NCT03512756). Methods: Randomized Phase 2 with dose optimization and expansion cohort of PDAC after 1 prior line, ECOG PS ≤2 and radiographic PD. Subjects randomized to 460 or 920 mg/d SM-88; all received phenytoin 50 mg, methoxsalen 10 mg and sirolimus 0.5 mg. Results: As of Jan 2019, 85 subjects consented, 41 ineligible, 38 randomized and 28 evaluable (1 cycle dosed). Average age 66.9 yrs, BMI 24.1, CA-19.9 median 2,562 (1.2 – 700,000), 2 prior lines 50%, 3 prior 14.3%, > 4 prior 21.4%; 85.7% had prior 5FU, 89.3% Gem, 71.4% taxanes, and 71.4% platinums. In both SM-88 doses, toxicity did not increase on treatment. AEs were not increased among high risk groups (age, sex, low BMI, low albumin, high CA-19.9 and prior radiotherapy). AEs increased with more prior lines of therapy, but were not dose dependent. There were 21 SAEs prior to dosing including 5 deaths among 14 patients. Two SAEs (rash and hypotension) were considered possibly related to SM-88 Therapy. No deaths were drug-related. 9 subjects had either a CEA or CA-19.9 decrease with 2 having both; 96.5% of subjects had CTCs detectable at baseline with 70% experiencing > 30% decline for at least 1 cycle with a median CTC best response decrease of 73%. Prior Lines of Therapy Subjects (n) Current Median OS 2-month Target Lesion Response CTCs Median Best OR % Alive 1 4 +5.7m 1 PR, 2 SD, 1 n/a* -74% 75% 2 14 +4.7m 6 SD, 3 PD, 5 n/a* -84% 79% 3+ 10 +3.5m 1 PR, 4 PD, 5 n/a* -55% 50% Total 28 +4.3m 2 PR, 8 SD, 7 PD, 11 n/a* -73% 68% *Not available RECIST clinical benefit (SD + PR) was 47.1% (8/17). 68% of subjects were alive at a median follow up of +4.3 months. EORTC global health and QOL measures did not deteriorate on treatment. Conclusions: Both doses of SM-88 were well tolerated without clinically significant toxicity. Anti-tumor activity was observed in this heavily pretreated population warranting expansion of the study for further efficacy evaluation. Clinical trial information: NCT03512756.
The bone marrow stroma capacity to confer resistance to leukemia cells from Ara-C treatment as a prognostic factor for overall survival in AML.
Authors: Macanas-Pirard Patricia , Vargas-Salas Sergio , Broekhuizen Richard , Coronado Romina , Bizama Carolina , Muñiz-Muñoz Sabrina , Torres Vivianne , Montecinos Viviana , Ernst Daniel , Melo Francisco , Roa Juan Carlos , Nervi Bruno 
Published: March 2020

e18500 Background: The interaction of acute myeloid leukemia (AML) with the bone marrow stroma (BMS) determines a protective microenvironment that favors leukemia development and resistance to chemotherapy. We developed an in vitro platform to study leukemia and stroma interaction, and showed that BMS secretes soluble factors protecting AML cells from Ara-C-induced apoptosis, which correlated with clinical patient outcomes. Methods: BMS from AML patients and healthy donors were cultured to perform chemo-sensitivity studies with Ara-C on THP-1 cells. A Resistance Factor was calculated (RF = IC50 stroma conditioned medium (CM)/IC50 control medium) to classify BMS as “protective” (PS: confers chemo-resistance) or “non-protective” (NPS: does not confer chemo-resistance). Characterization of myofibroblasts in BMS cultures was performed by WB. Quantification of cytokines from primary BMS CM was performed by Luminex. The differential expression of epithelial-mesenquimal-like (EMT-like) and stem cell-markers in THP-1 cells incubated with primary BMS CM was measured by qPCR. Results: We recruited 90 AML patients and 10 healthy BM donors. AML cohort showed 31 patients with PS and 59 patients with NPS. PS patients had a significant poor overall survival (OS) compared with NPS patients (44% versus 70% OS in 2.5 years, median survival 7.3 months versus 20.7 months, HR 2.36). The stroma from healthy BM donors did not confer resistance to THP-1 cells. BMS in both, PS and NPS have activated myofibroblasts and analysis of cytokine expression showed differential expression between groups. THP-1 cells incubated with PS showed significant expression of EMT- and stem cell-markers like Twist, Vimentin, CD44 and CD34 compared to THP-1 cells incubated with NPS and control medium. Conclusions: The capacity of the BMS from AML patients to modulate chemoresistance is a strong prognostic factor for OS, and PS patients have a worst OS compared with NPS patients. Stroma from healthy donors has a NPS phenotype. We propose that the leukemia is capable of educating the stroma to acquire secondarily the capacity to confer resistance to leukemia cells to favor tumor progression and chemoresistance.
Effects of obesity on overall survival (OS) of patients with acute myeloid leukemia (AML).
Authors: Dhakal Prajwal , Lyden Elizabeth , Lee Andrea , Michalski Joel , Al-Kadhimi Zaid S. , Maness Lori J. , Gundabolu Krishna , Bhatt Vijaya Raj 
Published: March 2020

e18510 Background: The relationship between obesity and prognosis of AML has not been established. Our retrospective study aimed to determine the effect of obesity on OS of AML. Methods: AML patients diagnosed from 2000-2016 at University of Nebraska Medical Center were included. Body mass index (BMI) at the time of AML diagnosis was divided into 3 groups: normal (18.5≤25 kg/m2) or underweight (<18.5 kg/m2); over-weight (25-30 kg/m2); and obese (≥30 kg/m2). Chi-square test, Kruskal-Wallis test and ANOVA were used to look at the association of different BMI groups with other patient characteristics. Mann-Whitney test was used for pairwise comparisons of hematopoietic cell transplant (HCT) co-morbidity index and Bonferroni correction was used to adjust p-values. OS, defined as time from diagnosis to death from any cause, was determined by Kaplan-Meier method and comparisons were done using log-rank test. Cox Regression was performed to detect survival effect of BMI (as continuous variable). P<0.05 was considered statistically significant. Results: A total of 314 patients were included in the study (Table): 46% were female, 35% had adverse cytogenetics, 15% had FLT3-ITD mutation, 68% received intensive chemotherapy and 30% underwent HCT. 38% of total patients were obese. Baseline characteristics were similar in all 3 BMI groups except co-morbidity index (p=0.04). OS for normal/underweight, overweight and obese groups at 1 year was 85%, 92%, and 94% respectively (p=0.84). BMI, as a continuous variable, was not a significant risk factor for death (HR 1.00, 95% CI 0.98-1.03). Conclusions: Obese patients, compared to non-obese patients, did not differ in baseline characteristics other than increased comorbidity burden. Obesity, when adjusted for other characteristics, did not have any effect on OS of patients with AML. Patient characteristics. [Table: see text]
Bayesian network meta-analysis (NMA) of complete remission without or with incomplete hematologic recovery (CR/CRi) to CPX-351, FLAG, and standard 7+3 (7+3) chemotherapy in the treatment of newly diagnosed secondary acute myeloid leukemia (sAML).
Authors: Oh Mok , Marini Bernard , Perissinotti Anthony , Benitez Lydia , Burke Patrick William , Bixby Dale L. , Pettit Kristen Marie , Abraham Ivo , McBride Ali 
Published: March 2020

e18514 Background: Patients (pts) sAML have poor outcomes (CR/CRi= 25-35%) with standard 7+3 induction chemotherapy (7+3). CPX-351 (liposomal encapsulated daunorubicin + cytarabine at a synergistic 5:1 molar ratio) was approved recently for sAML based on improvements in CR/CRi and survival but high cost and toxicity has discouraged its use. FLAG (fludarabine + high-dose cytarabine + granulocyte colony stimulating factor) have emerged as a lower cost, safe alternatives; however, outcomes between CPX-351 and FLAG have yet to be compared. In the absence of a direct trial, we aimed to estimate indirectly by Bayesian NMA the comparative efficacy of CPX-351, FLAG, and 7+3 therapy for sAML patients. Methods: Publications that compared FLAG or CPX-351 to 7+3 in newly diagnosed sAML were identified through a search of PubMed. CR/CRi rates were used in a Bayesian NMA to assess the direct (CPX-351 vs 7+3; FLAG vs 7+3) and indirect (CPX-351 vs FLAG) comparative efficacy of these regimens. Fixed (FE) and random effect (RE) analyses were conducted to estimate pooled odds ratios (OR) with 95% credible interval (CrI). Results: Of 169 identified articles, four studies (three RCT and one retrospective cohort) on a total of 781 pts in three treatment arms were retained. NMA showed no significant difference in pooled CR/CRi rates between CPX-351 and FLAG in both FE and RE models. However, pts receiving either FLAG or CPX-351 had significantly higher CR/CRi than those receiving 7+3 in both FE and RE models as shown in the table. Conclusions: This NMA suggests that both CPX-351 and FLAG prevail in CR/CRi efficacy over 7+3. In indirect comparison, CPX-351 and FLAG are equivalent in efficacy. The cost implications of these results remain to be established. [Table: see text]
Role of IL27 and IL35 as biomarkers and potential targets in acute myeloid leukemia.
Authors: Ahmed Heba A. , Maklad Ahmed M. , Elyamany Ashraf 
Published: March 2020

e18516 Background: Acute myeloid leukemia (AML) is one of the most common leukemia affecting adult. Regulatory T cells (Tregs) are a subset of CD4 (+) T cells that plays a central role immune tolerance. Objective: We aimed to explore the role of interleukin- 27 (IL27) & interleukin- 35 (IL35) produced by T regs and its associations with clinical characteristics and prognostic markers of AML patients. Methods: The study included 70 patients with acute myeloid leukemia (AML) and 30 healthy controls. We used flowcytometry immunophenotyping to confirm the diagnosis of AML. Serum level of interleukin- 27 (IL 27) & interleukin- 35 (IL 35) were measured at diagnosis by enzyme-linked immunosorbentassay (ELISA). Results: Higher levels of IL27 and IL35 were detected in AML patients than the control group (p ≤ 0.001). We used Receiver operating characteristic (ROC) analysis for detection of optimum IL27 & IL35 cut off level needed for predicting AML. ROC curve analysis demonstrated IL27 optimum cutoff is > 43, AUC 0.926 with a sensitivity 74% and Specificity 96.6% (P-value <0.00). IL35 optimum cutoff was > 27.8 AUC 0.972 with 88% and 98% sensitivity and specificity respectively (P-value <0.001). Serum IL27 & IL35 could well identify AML patients from healthy individuals. More importantly IL27 & IL35 correlated with clinical variable, and could be served as an independent prognostic factor. Conclusions: IL27 & IL 35 might have an application as a diagnostic and prognostic indicator for AML patients and could be served as an independent prognostic factor.
Survival outcomes in patients with good risk acute myeloid leukemia: A single-center retrospective review.
Authors: Bower Kathryn , Wen Sijin , Cumpston Aaron , Shah Nilay Arvind 
Published: March 2020

e18519 Background: Cytogenetics and gene mutations play a significant role in determining necessity of allogeneic transplant in patients with AML. Core binding cytogenetic factors (CBF) such as t(8;21), inv 16, and t(16;16) as well as molecular mutations in nucleophosmin-1 (NPM1) and bi-allelic CCAAT/enhancer binding protein alpha (CEBPA) mutations in cytogenetically normal patients have conferred improved relapse-free survival (RFS) and overall survival (OS) rates. We report outcomes of these “good-risk” patients in an Appalachian population, to evaluate differences from previous reports. Methods: A total of 79 patients with AML diagnosed between July 2007 and July 2017 at West Virginia University (WVU) who qualified for good-risk disease per ELN 2017 criteria were retrospectively analyzed for RFS and OS. Eighteen of these patients were excluded from our final analysis: 10 for primary refractory disease and 8 for proceeding to transplant in first remission. Results: A total of 61 patients were included in our analysis, with a median age of 56 (range 11-81), 32 females, and 29 males. Good-risk features included 29 patients with NPM1, no patients with CEBPA, 19 with inv 16, 9 with t(8;21), and 1 with t(16;16). All patients received cytarabine and an anthracycline induction chemotherapy, and a median of 4 cycles (range 1 -4) of high-dose cytarabine consolidation chemotherapy. The RFS and OS at 4 years was 36% and 50%, respectively. There were no occurrences of treatment-related mortality among the patients. Among the 22 patients relapsing, 12 (55%) were able to achieve a second remission and received allogeneic transplant. Conclusions: Our outcomes appear somewhat lower than previous reports, but continuing to highlight the ability to achieve long-term remissions in this subset of patients, without the need for allogeneic transplant. Continued efforts should focus on improving outcomes in these patients, to further prevent relapses.