bluuebunny/crossref_metadata_2025 huggingface dataset:
Education on reactive oxygen species to lay the foundation for understanding therapeutic advances in anticancer therapy.
Authors: Parikh Kinjal , Warren Charlotte , Caracio Richard
Published: January 2021

478

Background: The disruption of redox balance is increasingly thought to be one of the most important underlying factors contributing to the development, progression, and metastasis of cancers in human cells. This imbalance in redox homeostasis has been shown to be induced by the generation of free radicals, predominantly reactive oxygen species (ROS). Emerging data have established ROS as a new potential therapeutic target. Understanding the mechanisms associated with tumorigenesis is important to integrate novel potential therapeutic targets and understand which tumors or patient populations may benefit from ongoing research. Shortcomings in oncologists’ knowledge and confidence can hamper the integration of new treatments into the care of patients with cancer. Methods: An online continuing education (CME) activity consisted of a multi-media 30-minute video panel of two panelists discussing the mechanism, pathophysiology, and the premises for novel anti-cancer therapies. Educational effect was assessed using a repeated paired pre-/post-assessment study design. A McNemar’s test was used to identify differences between pre- and post-assessment responses. Effect size was calculated using Cohen’s d test by determining the strength of the association between the activity and the outcomes (d < .20 is modest and d ≥ .80 is large). P values were calculated and those < .05 were considered statistically significant. The activity launched 5/14/2020 and data are represented through 8/6/2020. Results: A total of 1,033 learners, of which there are 656 physicians, participated in the activity. Participating in education resulted in statistically significant improvements and noticeable educational effect and data for oncologists that answered all pre- and post-assessment questions are represented below (n = 45, p < .001, Cohen’s d = .454). Percentages represent relative rates of improvement The role of ROS on cancer cell proliferation, cancer cell toxicity, and the tumor microenvironment (67%, p < .05) The interplay of antioxidants to aid in the development of therapies to induce DNA-damaged cell death (100%; p < .001) The potential biomarkers to aid in the development of therapies to induce DNA-damaged cell death (34%; p < .05). Conclusions: This online, interactive, expert-led, CME-certified educational activity resulted in significant gains in oncologist knowledge and confidence regarding the ROS pathway and associated clinical pipeline developments Upon completion of the initiative, only 11% of oncologists were able to answer all 3 matched pre/post questions correctly, signifying the need for further education The novelty of the information to many learners demonstrate the need to continue highlighting clinical advances and molecular pathways that may have potential implications in cancer therapy progress.
Predictors of uptake of aspirin (ASA) chemoprevention in Lynch syndrome (LS).
Authors: Hall Michael J. , Clapper Margie , Chang Wen-Chi J , Chertock Yana , Nguyen Minhhuyen J
Published: January 2021

49

Background: Substantial data support efficacy of ASA in colorectal adenoma and cancer (CRC) chemoprevention. In 2011, the CaPP2 Phase 3 trial showed benefit of 600 mg ASA daily for prevention of LS-associated CRC (HR 0.41,p=0.02) in persons w/ASA adherence >2 yrs. Anecdotally, uptake of ASA by LS pts has been low, but few data exist. We examined uptake and predictors of ASA chemoprevention among LS pts receiving follow-up at our center since 2011. Methods: Pts evaluated by Fox Chase’s Risk Assessment Program receive in-person medical recommendations and written information about cancer (CA) prevention measures including ASA. Medical records of 127 LS pts were retrospectively reviewed. Demographics, gene affected, personal Hx of CA, ASA use, and ASA dose were collected. Majority (94.5%) of cohort had documentation of ongoing LS endoscopic screening at our center—only 3.2% had no recent follow-up (past 3 yrs) and 2.4% had recently died (past 3 yrs). Chi-square tests and multivariable logistic regression were used in analyses. Results: Overall 24.4% (31/127) of pts reported ASA use for chemoprevention (see Table). Nearly half (48.4%) of ASA users took 81 mg ASA daily, and only 22.6% reported taking >600 mg ASA daily. ASA use was associated with older age, MLH1/ MSH2+ vs MSH6/ PMS2+, and personal Hx of CRC. In the multivariable logistic model, older age (OR 2.80, p=0.04) and MLH1/ MSH2+ (OR 2.64,p=0.07) were significant and borderline significant, respectively. Adding race/ethnicity and gender strengthened the effect of age>60 (OR 3.11, p=0.03), and improved fit (pseudoR2=16.8%). Conclusions: Uptake of ASA chemoprevention by LS pts is overall modest, but older age is associated with ASA uptake for chemoprevention. Among ASA users, fewer than 1 in 4 take the 600 mg daily dose shown effective in CaPP2. Confirmatory trials as well as efforts to elucidate barriers to ASA chemoprevention in LS are needed. [Table: see text]
Development and clinical validation of a blood test for early detection of colorectal adenomas and cancer.
Authors: Friedland Shai , Pan Jennifer Y. , Watson Drew , Chen Yu , Nimgaonkar Ashish , Gulzar Zulfiqar , Gupta Pratyush , Atkins Alex , Lai Jr-Ming , Hsieh Ben , Su Stephen , Ciu Iris , Setthasap Ploy , Sninsky John , Mei Rui
Published: January 2021

50

Background: Many of the 50,000 annual colorectal cancer (CRC) deaths can be attributed to 1/3 eligible Americans not following screening guidelines or approximately 1/2 of the population not adherent to the follow-up post-polypectomy guidelines. The new understanding of the natural history and shared etiology of adenomas and CRC inform integration of clinically relevant biomarkers. The two objectives of CRC screening and surveillance are early detection to improve survival and prevention of CRC through removal of adenomas using colonoscopy. Adenomas account for 98% of actionable colonoscopies. Stool tests have low sensitivity for advanced adenomas (AA, 24-42%). Methods: A prospective, blinded study was conducted at the VA Palo Alto Health Care System. Patients had blood drawn prior to colonoscopy. The test analyzes two biomarkers: circulating gastrointestinal epithelial cells and somatic mutations of cell-free DNA. The probability of advanced neoplasia was obtained by ordinal/nominal logistic regression methods together with SEER-incidence rate and prior history of AA on a training set of 346 subjects. The cutpoint for the quantitative score was fixed and the remaining 112 subjects were tested. Results: Interim results for 458 patients with no prior diagnosis of colorectal cancer (CRC) are presented. The cohort included both screening (239) and surveillance (219) subjects. Indications for colonoscopy were 86% asymptomatic and 14% with symptoms or positive-FIT. Balanced distribution of roughly 3/4th subjects in each disease category were randomly selected for training and algorithm development and the remaining 1/4th subjects were used for validation. A cutpoint was selected to obtain a test specificity (non-neoplastic finding or negative colonoscopy) of 90% resulting in a sensitivity of 100% and 80.0% for detection of CRC and advanced neoplasia (AN = CRC+AA), respectively, on the training subjects. The area under the ROC curve is 0.91. Validation using the fixed cutpoint and 112 test subjects achieved 91.4% specificity and 100% and 75.0% sensitivity for CRC and AN. Conclusions: This blood test has high sensitivity for colorectal advanced neoplasia while retaining high specificity. The quantitative nature of the score has the potential to enable stratification of patients for screening or post-polypectomy surveillance colonoscopy. [Table: see text]
Examining patterns of and reasons for delays to treatment in colon cancer.
Authors: Kalam Ali , Arientyl Vanessa , Schriner Jacob B , Kopp Adam , Friedmann Patricia , Qin Jiyue , In Haejin
Published: January 2021

52

Background: Delays in colon cancer (CC) treatment can impact patient outcomes. Detailed examination into the patterns and reasons for delay in the diagnostic and pre-treatment work up are understudied, hindering the development of strategies to improve timeliness of care. Methods: CC patients diagnosed at an urban academic institution in 2018 were investigated. Chart review yielded presentation location, diagnostic-work up, treatment and patient characteristics. Time between presentation to the healthcare provider to treatment initiation of ≥ 60 days was considered a delay (Total_Delay). Total time further examined as 3 phases: presentation to diagnosis (PtoD), diagnosis to staging completion (DtoS), and staging completion to treatment (StoT). Delays for each phase was defined as ≥ 30 days. Total_Lt60d vs non-Total_Ge60d were compared. A logistic regression model was used to calculate odds ratio (OR) and 95% confidence intervals (CI) to identify associations with Total_Ge60d. Results: Among 121 CC patients, the median time and interquartile range (IQR) between presentation and treatment initiation was 29 (IQR 8, 53) days. Total_Delay occurred in 21% of patients. The median time between presentation and treatment and interquartile range (IQR) for Total_Delay was 106 (IQR 82, 162) and 16 (IQR 6, 39) for non-Total_Delay. Age, sex, race, and comorbidities were similar between Total_Delay and non-Total_Delay. Total_Delay patients were generally more functionally independent (92% vs 74%, p < .06), presented to locations other than the emergency department (64% vs 42%, p < .075) and were less likely to have hospital admission work-up (20% vs 60%, p < .001) compared to non-Total_Delay. The logistic model showed that Total_Delay is associated with non-hospital work-up (OR 8.3, 95% CI 1.9-45.3), adjusting for comorbidities, symptoms, functional status, cancer severity, and insurance. Delays similarly occurred in all three phases for Total_Delay patients; 48% had delay during PtoD, 60% during DtoS, and 48% during StoT. The most common reason for delay by phase was the following; in the PtoD phase, 5 of 11 (46%) was due to obtaining endoscopy, in DtoS and StoT, 6 of 15 (40%) and 5 of 11 (46%), respectively, was in getting outpatient specialty appointments. Delays due to patient factors (PtoD 18%, DtoS 27%, StoT 28%) were less frequent. Conclusions: Delays to treatment for CC are largely driven by health systems delays. Bundling of diagnostic evaluation and pre-treatment that mimics work-up during a hospital admission may overcome delays in cancer care.
Cost effectiveness of DPYD genotyping to screen for dihydropyrimidine dehydrogenase (DPD) deficiency prior to adjuvant chemotherapy for colon cancer.
Authors: Brooks Gabriel A. , Tapp Stephanie , Daly Allan T. , Busam Jonathan , Tosteson Anna N.A.
Published: January 2021

55

Background: Fluoropyrimidine chemotherapy agents, including 5-fluorouracil and capecitabine, are the backbone of adjuvant treatment for colon cancer, and adjuvant chemotherapy substantially reduces recurrence and mortality after surgical resection of stage 3 colon cancer. While fluoropyrimidine chemotherapy is generally safe, the risk of severe, potentially fatal chemotherapy toxicity is substantially increased for the 2-3% of U.S. patients with DPD deficiency caused by pathogenic variants in the DPYD gene. DPYD genotype testing is readily available in the U.S. but has not been widely adopted. We evaluated the cost effectiveness of DPYD genotyping prior to adjuvant chemotherapy for colon cancer in the U.S. Methods: We constructed a Markov model to simulate screening for DPD deficiency with DPYD genotyping (versus no screening) among patients receiving fluoropyrimidine-based adjuvant chemotherapy for stage 3 colon cancer. Screen-positive patients were modeled to receive dose-reduced fluoropyrimidine chemotherapy. Model transition probabilities for treatment-related toxicities were derived from published clinical trial data with annotation of DPYD genotype and chemotherapy dosing strategy. Our analysis is from the healthcare perspective, with a time horizon of five years and an annual discount rate of 3% for future costs and benefits. Direct healthcare costs and health utilities were estimated from published sources and converted to 2020 US dollars, and post-treatment survival was modeled from SEER data. The primary outcome was the incremental cost-effectiveness ratio (ICER), defined as dollars per quality-adjusted life year (QALY). We used a value of $100,000/QALY as the cost-effectiveness threshold. One-way sensitivity analyses were used to examine model uncertainty. Results: Compared with no screening, screening for DPD deficiency with DPYD genotyping increased per-patient costs by $106 and improved quality-adjusted survival by 0.0028 QALYs, leading to an ICER of $37,300/QALY. In one-way sensitivity analyses, the ICER exceeded $100,000/QALY when the carrier frequency of pathogenic DPYD gene variants was less than 1.17%, and when the specificity of DPYD genotyping was less than 98.9%. Cost-effectiveness estimates were not sensitive to the cost of DPYD genotyping, the cost of toxicity-related hospitalizations, or the health utility associated with grade 3-4 toxicity. Conclusions: Among patients receiving adjuvant chemotherapy for stage 3 colon cancer, screening for DPD deficiency with DPYD genotyping is a cost-effective strategy for preventing infrequent but severe, sometimes fatal toxicities of fluoropyrimidine chemotherapy.
Short-course radiotherapy and subsequent CAPOX plus camrelizumab followed by delayed surgery for locally advanced rectal cancer:Short-term results of a phase II trial.
Authors: Lin Zhenyu , Cai Ming , Zhang Peng , Li Xin , Cai Kailin , Nie Xiu , Tao Kaixiong , Zhang Tao
Published: January 2021

63

Background: Chemoradiotherapy followed by radical surgery is standard treatment for patients with locally advanced rectal cancer (LARC). Short-course radiotherapy (SCRT), either with immediate or delayed surgery, provides similar oncological results compared with long-course radiotherapy with delayed surgery. Delayed surgery with the addition of neoadjuvant immunotherapy may bring better downstaging effect and minimize the risk of distant relapse. We conducted this single-arm phase 2 trial to investigate the efficacy and safety of SCRT combined with subsequent capecitabine and oxaliplatin (CAPOX) plus Camrelizumab (anti-PD-1 antibody) followed by delayed surgery in patients with LARC. Methods: Patients with histologically confirmed T3–4N0M0 or T1-4N+M0 rectal cancer, previously untreated disease, and ECOG performance status of 0-1, received SCRT (5×5 Gy) with subsequent two 21-day cycles of CAPOX (oxaliplatin 130 mg/m2 ivgtt, d1; capecitabine 1000 mg/m2 po bid, d1-14) plus Camrelizumab (200 mg iv drip, d1) after 1 week, followed by radical surgery after 1 week. Adjuvant therapy was decided by the investigator. The primary endpoint was pathological complete response (pCR) rate, defined as the absence of viable tumor cells in the primary tumor and lymph nodes. The study is ongoing to follow up the survival outcomes and obtain the results of next generation sequencing and PD-L1 expression. The data cutoff date was September 8, 2020. Results: From November 2019 to September 2020, a targeted number of patients (n = 29) were enrolled and are expected to complete the surgery by November 2020. The median age was 57 (range 31-73) years, 55% (16/29) of patients had ECOG performance status of 1, and the median distance from tumor to the anal verge was 5 (range, 1.9-9) cm. At data cutoff, 10 patients had undergone the surgery, with R0 resection rate of 100%. The pCR rate was 60% (6/10), including 56% (5/9) for those with mismatch repair-proficient, and 100% (1/1) for those with mismatch repair-deficient. Of 4 patients without pCR, 2 only received one cycle of CAPOX plus Camrelizumab due to the outbreak of COVID-19 in Wuhan, and 1 had signet-ring cell rectal carcinoma. At data cutoff, 20 patients had received at least one dose of Camrelizumab. Immune-related adverse events (irAEs) were all grade 1-2, and the most common irAE was reactive cutaneous capillary endothelial proliferation in 10 (50%) of 20 patients. Postoperative bleeding and infection occurred in 1 (10%) and 2 (20%) of 10 patients, respectively. No treatment-related death was observed. Conclusions: SCRT combined with subsequent CAPOX plus Camrelizumab followed by delayed surgery showed promising pCR rate with good tolerance in patients with LARC, regardless of the mismatch repair status, suggesting a candidate strategy for the neoadjuvant therapy. Clinical trial information: NCT04231552.
A single-institution experience using total neoadjuvant therapy to treat locally advanced rectal cancer.
Authors: Friedrich Tyler , Glode Ashley Elizabeth , Lentz Robert William , Herter Whitney , Davis S. Lindsey , Leal Alexis Diane , Kim Sunnie S. , Purcell William T. , Ahrendt Steven Arthur , Birnbaum Elisa , McCarter Martin , Gleisner Ana , Schefter Tracey E. , Vogel Jon , Messersmith Wells A. , Lieu Christopher Hanyoung
Published: January 2021

64

Background: The management of locally advanced rectal cancer has historically included preoperative chemoradiation followed by surgery and then adjuvant chemotherapy. Recently there has been an increasing utilization of preoperative chemotherapy in addition to standard chemoradiation, a strategy known as total neoadjuvant therapy (TNT). TNT has been offered to patients at the University of Colorado Cancer Center since 2015. Methods: Records of all patients presenting to the University of Colorado colorectal multidisciplinary clinic since 2015 were screened for treatment with TNT. Data collected on these patients included demographic information, diagnosis and initial staging, preoperative treatment received, and surgical outcomes including treatment response and pathological stage. TNT included preoperative chemotherapy with oxaliplatin combined with either 5-FU (FOLFOX) or capecitabine (CAPOX) as well as chemoradiation, generally given with concurrent capecitabine. Patients then underwent surgical resection; if a complete clinical response was achieved with TNT, non-operative management (NOM) was offered. Results: A total of 81 patients thus far have undergone TNT followed by resection or, if complete clinical response and preferred by the patient, NOM. The mean age of patients was 56 years, ranging from 23 to 87, and 60% of patients were male. The majority of patients (67) had stage III disease at presentation while 1 had stage 1 (T2N0) disease, 11 had stage II disease and 2 patients had oligometastatic disease. Ultimately 13 patients (16%) opted for non-operative management after being found to have a complete clinical response following TNT. Of the 68 patients who underwent surgical resection, 21 (31%) had a pathological complete response, with another 14 (21%) with near-complete response. 28 patients (41%) had a partial treatment response and 5 (7%) had no treatment response. In total, the rate of complete clinical or pathologic response was 42%. Treatment was overall well-tolerated with 90% of patients receiving the full planned dose of radiation and 98% of patients completing all planned cycles of chemotherapy, though most of them with typical dose reductions needed. Of the patients who underwent surgery, 49 (72%) had low anterior resection and 19 (28%) had an abdominoperineal resection. Of patients with temporary ileostomies, 85% of them had their ileostomy reversed within 10 weeks of surgery. Conclusions: Treatment of locally advanced rectal cancer by a total neoadjuvant approach is well-tolerated and results in a high rate of clinical and pathological complete response.
Application of new treatment strategies for mCRC: Effect of online education on clinician knowledge and confidence.
Authors: Fisher Geoff Roy , Koekkoek Sanneke , Vandenbroucque Juliette , Taieb Julien
Published: January 2021

67

Background: This study determined whether online continuing medical education could improve the knowledge and confidence of cliniciansin the application of the latest strategies for the treatment of mCRC. Methods: A 30-minute online video panel discussion was launched for physicians outside the USA in March 2020. Data was collected to May 2020. Educational effect assessed with repeated-pairs pre-/post-activity, where individual participants served as their own control. 3 multiple-choice, knowledge questions and 1 self-efficacy, 5-point Likert scale confidence question were analyzed. Chi-squared test assessed pre- to post-activity change (5% significance level, P < .05). Magnitude of change in total number of correct responses overall, and for each question, were determined with Cramer’s V ( < .06 = Modest, 0.06-0.15 = Noticeable, .16-.26 = Considerable, > .26 = Extensive). Results: 108 oncologists (oncs) and 33 gastroenterologists (gastros) completed pre- and post-activity questions. A positive educational effect was observed for oncs (noticeable effect, V = .123, P < .01); average % correct increased from 71 to 81%. For gastros, there was a noticeable effect (V = .06) but P was not significant; correct responses increased from 49 to 56%. Clinicians with 3/3 answers correct increased post-activity (37 to 54% for oncs, 18 to 24%, for gastros). For oncs, improvements in % of correct responses post-activity were seen for questions on tailoring treatment to primary tumour location, outcome of the CRICKET trial on cetuximab re-challenge, and outcome of the BEACON trial in BRAF mutated mCRC (11%, 21%, and 13% relative changes, respectively). Relative changes of 25%, 18% and -17%, respectively, were observed for gastros. % of clinicians mostly or very confident with selecting optimal treatment strategy across the continuum of care improved post-activity, increasing from 33 to 58% for oncs and from 27 to 36% for gastros. Conclusions: This on-demand, online video panel discussion resulted in a positive education effect. However, the sample size for gastros was small and the post-activity change was not significant. Knowledge gaps remained post-activity, indicating the need for further education to support optimisation of the treatment of mCRC.
Initial experience of patients treated in a real-world clinical setting with bevacizumab-awwb: The first FDA-approved biosimilar to bevacizumab.
Authors: Jin Ran , Accortt Neil A , Sandschafer Darcie , Lawrence Tatiana , Loaiza-Bonilla Arturo
Published: January 2021

81

Background: Bevacizumab-awwb is the first anti-cancer biosimilar and the first biosimilar to bevacizumab approved by the FDA. It was launched in the United States on July 19, 2019. Bevacizumab-awwb approval was based on a phase 3 study in a pre-determined sensitive population of non-squamous non-small cell lung cancer (NSCLC) patients. This study investigated initial use of bevacizumab-awwb, across its approved indications for advanced cancer management, in real-world US community and academic oncology practices. Methods: This retrospective observational study described demographic and clinical characteristics of patients who received bevacizumab-awwb using structured patient-level data from the nationwide de-identified Oncology Services Comprehensive Electronic Records (OSCER), a Flatiron Health EHR-derived database. The database is longitudinal, demographically and geographically diverse, and includes more than 2.2 million US cancer patients from >280 cancer clinics. This analysis included adult patients who received ≥1 bevacizumab-awwb infusion between July 30, 2019 and April 30, 2020 and focused on describing initial biosimilar uptake in cancer patient populations beyond NSCLC. Results: First use of bevacizumab-awwb was in mCRC and occurred within 10 days of product launch. All bevacizumab-awwb approved cancer indications were represented among 2,422 patients treated with bevacizumab-awwb. Initial use of bevacizumab-awwb across indications: mCRC (68%), NSCLC (14%), brain cancer (11%), cervical cancer (5%), metastatic renal cell carcinoma (1%). Among 1657 mCRC patients treated with bevacizumab-awwb, 55% were male with a median age of 65 years (y). Most patients were white (60%), with ECOG scores of 0/1 (84%), and median body weight was 78 kg. Among mCRC patients, 59% had received the reference product before receiving the biosimilar. Among patients with other tumor types, 42-50% had prior bevacizumab exposure. Among mCRC patients with prior exposure to bevacizumab, 67% received bevacizumab-awwb within 28 days of last infusion of reference product (Table). Demographic and clinical characteristics were comparable between patients with and without prior bevacizumab use. Conclusions: Early evidence suggests physicians are comfortable initiating or transitioning patients to the first FDA-approved biosimilar to bevacizumab, with little evidence that demographic characteristics differ between patients with and without previous treatment with bevacizumab. Future analyses will determine whether these patterns persist across all indications. [Table: see text]
Development of a cure model for the estimation of long-term outcomes in patients with microsatellite instability(MSI)-high metastatic colorectal cancer (mCRC) receiving immune-checkpoint inhibitors (ICIs).
Authors: Pietrantonio Filippo , Infante Gabriele , Lonardi Sara , Corti Francesca , Intini Rossana , Salati Massimiliano , Fenocchio Elisabetta , Belli Carmen , Cremolini Chiara , Fucà Giovanni , Prete Alessandra Anna , Quarà Virginia , Manca Paolo , Spallanzani Andrea , Morano Federica , Di Bartolomeo Maria , Curigliano Giuseppe , De Braud Filippo G. , Zagonel Vittorina , Miceli Rosalba
Published: January 2021

87

Background: Anti-PD-(L)1-based therapy yielded unprecedented efficacy in patients with MSI-high mCRC. A relevant proportion of subjects may achieve long-term disease control when receiving ICIs, particularly anti-PD-1 plus anti-CTLA-4 combo. However, some patients still experience treatment refractoriness or short-term clinical benefit. Methods: We analyzed data of 163 patients with MSI-high mCRC treated with anti-PD-1 +/- anti-CTLA-4 agents. The endpoint was progression-free survival (PFS); multivariable analyses were performed using a cure model (Othus et al, CCR 2012), which allows to test which factors, including ICI type, could identify patients achieving long-term disease control. To account for biases consistent with non-random ICI assignment, we estimated a propensity score (covariates: ECOG PS, age, sex, primary tumor location, its resection, adjuvant treatment, synchronous presentation of mets, mucinous histotype, RAS/BRAF status, n. prior treatment lines, previous chemo, n. metastatic sites, presence of peritoneal, lung, liver, bone, brain, nodal mets), and then in the cure model we applied an inverse-probability-of-treatment-weight (IPTW) based on propensity score. A beforehand variable selection was operated using a random survival forest (RSF) model (RSF covariates: all the propensity score covariates plus ICI line and ICI type, platelets count (PLT), NLR, LDH), where we introduced a weight system in order to adjust variable selection net of ICI type. Results: RFS selected 5 variables: ICI type, ECOG PS, NLR, PLT and N. prior lines, the combination of which allowed to estimate the cure probability: the higher the probability the greater the chance of achieving long-term disease control. The Table shows the odds ratio estimates, defining the chance of being “cured” according to the values of the selected variables. ICI type was significantly associated with long-term disease control: patients treated with anti CTLA-4-combo achieved the highest chance of being cured, 3.41 times greater than the chance of patients treated with anti PD-1 mono. The median cure probability was as higher as 70.1% (IQR: 51.9-81.0%) with CTLA-4-combo vs 34.8% (IQR: 18.4-51.9%) with anti-PD-1 mono; the probability within treatment groups was varying according to ECOG PS, NLR, PLT and n. prior lines. Conclusions: Based on 5 variables including the ICI treatment type, a nomogram was built in order to estimate the cure probability in patients with MSI-high mCRC and potentially assist clinicians in their clinical practice. [Table: see text]
Implementation of hepatic artery infusion (HAI) chemotherapy for unresectable colorectal liver metastases (CRLM): The University of Miami experience.
Authors: Pimentel Agustin , Kronenfeld Joshua , Dudeja Vikas , Merchant Nipun B. , Gallegos Lauren Nicole , Kelly Kristin , McGhee Vivian , Naveda Alissette , Ng-Chen Hoyan , Lockhart A. Craig , Hosein Peter Joel , Ezenwajiaku Nkiruka , Ardalan Bach , Datta Jashodeep
Published: January 2021

96

Background: In patients with unresectable liver-confined CRLM, regional chemotherapy via HAI in combination with modern systemic chemotherapy (CT) can achieve hepatic disease control and expand surgical resectability. We describe patient selection and early outcomes following implementation of a HAI program at our tertiary referral academic center. Methods: We analyzed demographics, previous systemic treatment, primary tumor location, molecular profiling, extent of hepatic/extrahepatic disease, perioperative HAI outcomes (toxicity, conversion to resection/ablation, radiographic response), and overall survival (OS) in CRLM patients selected for HAI treatment (01/2018—06/2020) after multidisciplinary review. Results: Of 35 patients with unresectable CRLM (primary: colon, n = 24; rectum, n = 11) selected for HAI, 57% were heavily pre-treated (with at least 2 lines of pre-HAI systemic chemotherapy), 71% had a Fong clinical risk score ≥3, 86% presented with synchronous disease, 80% had bilobar metastasis, and 86% had > 5 tumors. All tumors were microsatellite stable, with 20% harboring KRAS/NRAS mutations and none had class I/II BRAF mutations. HAI was initiated at a median 14 (IQR 3, 64) months after CRLM diagnosis, and administered for a median of 7 (range 2, 16) cycles; 91% of patients (31/34) received concurrent HAI and systemic chemotherapy. Although most (69%) patients experienced some degree of hepatic toxicity during HAI therapy resulting in FUDR dose reduction and steroid administration, biliary sclerosis requiring intervention was observed in only 3 (9%) of patients. The overall perioperative morbidity was 17%, and there were no surgical-related 90-day mortalities following HAI pump placement. Excluding patients who initiated HAI treatment within the last 3 months of the study period (n = 3), 13 of 32 patients (41%) were rendered disease-free in the liver following complete resection and/or ablation in combination with HAI/systemic chemotherapy; in the remaining 19 patients (59%), hepatic progression-free survival was 7.3 months (IQR 4, 12). At a median follow-up of 11.2 months, post-HAI median OS for the overall cohort was 12.3 (IQR 7, 20) months. Patients undergoing complete resection/ablation demonstrated improved survival compared with those with progressive disease (median 20 vs 12 months, respectively). Conclusions: Implementation of a HAI program for multimodality liver-directed management of unresectable CRLM is feasible and is associated with meaningful clinical outcomes unlikely to be achieved with systemic therapy alone in heavily pre-treated patients.
Phase II study of pembrolizumab after chemoradiotherapy (CRT) as adjuvant therapy for locally advanced esophageal squamous cell carcinoma (LA-ESCC) patients at high risk of recurrence following preoperative CRT plus surgery.
Authors: Hsu Chih-Hung , Guo Jhe-Cyuan , Huang Ta-Chen , Kuo Hung-Yang , Lin Chia-Chi , Hsu Feng-Ming , Cheng Jason C. , Huang Pei-Ming , Lee Jang-Ming
Published: January 2021

TPS259

Background: LA-ESCC is a potentially curable disease, for which preoperative CRT followed by esophagectomy is a standard-of-care. Previous studies have identified that close/involved margin and lymph node metastasis with extranodal invasion (ENI) in post-CRT surgical specimens are associated with increased risk of recurrence. In CheckMate-577 trial, adjuvant nivolumab significantly improved disease-free survival (DFS) in patients with esophageal cancer treated with preoperative CRT and surgery; in another trial (the “PACIFIC” trial), adjuvant durvalumab has significantly improved overall survival (OS) in stage III non-small cell lung cancer treated with definitive CRT. We hypothesize that adding pembrolizumab to CRT as an adjuvant therapy would improve the outcomes of LA-ESCC patients who are treated with preoperative CRT plus esophagectomy and with high-risk of recurrence. Methods: This single institution single-arm phase II study include patients with histologically confirmed LA-ESCC (AJCC 7th staging system:cT3-4aN0M0 or T1-4aN1-3M0) harboring at least one risk factor (closed/involved margin, ENI, or ypN2-3) in post-CRT surgical specimens. Patients with adenocarcinoma of esophagus or gastroesophageal junction or synchronously diagnosed with a squamous cell carcinoma of aero-digestive way other than ESCC are excluded. Patients enrolled will receive adjuvant weekly cisplatin–CRT (cisplatin, 30mg/m2 for 2 cycles every week; radiotherapy, 180-200 cGy/fraction for 10-13 times) followed by pembrolizumab (200 mg, every 3 weeks, for 18 cycles). The primary endpoint of this study is 1-year relapse-free survival (RFS) rate; and the key secondary endpoints include RFS, 3-year RFS rate, OS, 3-yr OS rate, toxicity and safety. The study, registered with clinical trial ID of NCT03322267, started patient enrollment in Aug 2018. As of Aug of 2020, 11 of 46 planned patients have been enrolled. Clinical trial information: NCT03322267.
A phase Ib/II, multicenter, open-label, dose-escalation, and dose-expansion study evaluating trastuzumab deruxtecan (T-DXd, DS-8201) monotherapy and combinations in patients with HER2-overexpressing gastric cancer (DESTINY-Gastric03).
Authors: Janjigian Yelena Y. , Viglianti Natasha , Liu Feng , Mendoza-Naranjo Ariadna , Croydon Liz
Published: January 2021

TPS261

Background: For patients (pts) with HER2-overexpressing metastatic gastric cancer, trastuzumab + chemotherapy is a standard first-line option but provides only a modest overall survival (OS) benefit vs chemotherapy. T-DXd is an antibody-drug conjugate consisting of an anti-HER2 antibody, cleavable tetrapeptide-based linker, and a membrane-permeable topoisomerase I inhibitor payload. Results from a phase 1 trial showed promising antitumor activity (confirmed objective response rate [ORR], 43.2%) in pts with heavily pretreated HER2+ metastatic gastric cancer who received T-DXd (5.4 or 6.4 mg/kg; Shitara K, et al. Lancet Oncol. 2019;20:827-836). Here we describe the phase 1b/2 DESTINY-Gastric03 trial (NCT04379596) evaluating T-DXd monotherapy and combinations in pts with HER2-overexpressing gastric cancer. Methods: This is an open-label, multicenter, 2-part, phase 1b/2 study in pts with HER2-overexpressing (immunohistochemistry [IHC] 3+ or IHC 2+/in situ hybridization positive) locally advanced, unresectable or metastatic gastric or gastroesophageal junction cancer. In part 1 (dose escalation), pts who had received prior trastuzumab-containing therapy will be assigned to 1 of 5 arms: (1) T-DXd + 5-fluorouracil (5-FU); (2) T-DXd + capecitabine (C); (3) T-DXd + durvalumab; (4) T-DXd + 5-FU or C + oxaliplatin (Ox); or (5) T-DXd + 5-FU or C + durvalumab. In part 2 (dose expansion), pts with no prior treatment for metastatic disease will be randomized across 4 arms: (1) T-DXd; (2) trastuzumab + 5-FU or C + Ox or cisplatin; (3) T-DXd + 5-FU or C ± Ox; or (4) T-DXd + 5-FU or C + durvalumab. In part 2, pts will be stratified by HER2 status. Primary endpoints are safety, determination of recommended phase 2 doses (part 1), and investigator-assessed confirmed ORR per RECIST v1.1 (part 2). Secondary endpoints include confirmed ORR (part 1), disease control rate, duration of response, progression-free survival (all per investigator), OS, safety (part 2), pharmacokinetics, and immunogenicity. Clinical trial information: NCT04379596.
Margetuximab (M) combined with anti-PD-1 (retifanlimab) or anti-PD-1/LAG-3 (tebotelimab) +/- chemotherapy (CTX) in first-line therapy of advanced/metastatic HER2+ gastroesophageal junction (GEJ) or gastric cancer (GC).
Authors: Catenacci Daniel V.T. , Rosales Minori Koshiji , Chung Hyun Cheol , Yoon Harry H. , Shen Lin , Moehler Markus H. , Kang Yoon-Koo
Published: January 2021

TPS264

Background: Trastuzumab (T), a monoclonal antibody (mAb) targeting HER2, is standard of care 1st-line therapy for advanced HER2+ GEJ/GC patients. M, an investigational Fc-engineered anti-HER2 mAb, targets the same HER2 epitope but with higher affinity for both 158V (high binding) and 158F (low binding) alleles of activating Fc receptor CD16A. Data suggest margetuximab coordinately enhances both innate and adaptive immunity, including antigen-specific T-cell responses to HER2. PD-1 and LAG-3 are T-cell checkpoint molecules that suppress T-cell function. Retifanlimab (also known as MGA012 or INCMGA00012) is a humanized, hinge-stabilized, IgG4 Κ anti-PD-1 mAb blocking binding of PD-L1 or PD-L2 to PD-1. Tebotelimab (also known as MGD013) is a humanized Fc-bearing bispecific tetravalent DART® protein that binds to both PD-1 and LAG-3, inhibiting their respective ligand binding. We previously reported that a CTX-free regimen of M+PD-1 blockade was well tolerated in GEJ/GC patients, and induced a 44% objective response rate (ORR) in a double-positive biomarker population. This was 2- to 3-fold greater than in historical controls with checkpoint inhibitors alone. This registration-directed trial assesses efficacy, safety, and tolerability of M+checkpoint inhibition ± CTX in metastatic/locally advanced, treatment-naïve, HER2+ GEJ/GC patients. Methods: This is a 2-cohort, adaptive open-label phase 2/3 study (NCT04082364). The first single arm, CTX-free cohort A, evaluates M+retifanlimab in HER2+ (immunohistochemistry [IHC] 3+) and PD-L1+ (excluding microsatellite instability high) patients. After 40 patients are evaluated for response/safety, additional patients will be enrolled if the threshold for continuation is met. In randomized cohort B, HER2+ (IHC 3+ or 2+/fluorescent in situ hybridization+) patients are enrolled irrespective of PD-L1 status. Part 1 of cohort B randomizes patients to 1 of 4 arms (50 patients each): control arm (T+CTX) or 1 of 3 experimental arms (M+CTX; M+CTX+retifanlimab; M+CTX+tebotelimab). CTX is investigator’s choice XELOX or mFOLFOX-6. Part 2 of cohort B consists of control (T+CTX) vs 1 experimental arm (M+CTX) + either retifanlimab or tebotelimab, depending on results from part 1; with 250 patients each. The primary efficacy endpoint for cohort A (both parts) is ORR per RECIST 1.1; for cohort B part 2 it is overall survival. Clinical trial information: NCT04082364.
Trial in progress: A feasibility study of multi-platform profiling using biospecimens from patients with resected biliary tract cancer.
Authors: Diehl Adam , Harris William Proctor , King Gentry Teng
Published: January 2021

TPS359

Background: Biliary tract cancers (BTC) are rare malignancies with a high recurrence rate after resection of localized disease. FDA-approved systemic therapies for advanced disease are limited to combination chemotherapy and FGFR inhibitors for FGFR2-altered BTC. The tools of personalized medicine may guide management and expand treatment options for this disease. In multiple tumor types, circulating tumor DNA (ctDNA) has shown significant predictive power for recurrence after resection, but its utility has not yet been established in BTC. Organoid drug sensitivity screening may also inform and expand treatment options, particularly for patients without targetable mutations on next generation sequencing (NGS). Prospective concordance between organoid drug sensitivity and in vivo clinical responses to a given drug is needed to establish the value of this testing in BTC. We designed a clinical trial to determine the feasibility and physician-assessed utility of multi-platform profiling of resected BTC. Methods: This is an observational, non-randomized feasibility study to assess the ability to obtain NGS, ctDNA monitoring, and organoid drug sensitivity screening on patients with resected localized BTC. Secondary endpoints include physician-adjudicated utility of the profiling results for patient management, prospective concordance of organoid drug sensitivity with in vivo drug activity, and value of ctDNA in prediction of recurrence or response to therapy. Key eligibility criteria include a biopsy or clinical presentation consistent with BTC (excluding mixed HCC-cholangiocarcinoma), surgical candidacy for resection of measurable disease, and no prior targeted or investigational therapies. ctDNA is collected pre- and post-operatively, during adjuvant chemotherapy, during surveillance for up to 5 years and during systemic therapy for recurrent disease. Physician surveys are conducted before and after receipt of profiling results and then at time points where a change in management would be considered. Enrollment began in July 2020 with 5 of a planned 20 patients enrolled at the time of submission. Clinical trial information: NCT04561453.
A phase I study of safety and immunogenicity of survivin long peptide vaccine (SurVaxM) in patients (pts) with metastatic neuroendocrine tumors (NETs).
Authors: Gupta Medhavi , Fenstermaker Robert Alan , Qiu Jing-Xin , Iyer Renuka V.
Published: January 2021

TPS375

Background: Metastatic neuroendocrine tumors (NETs) have a poor prognosis and there are limited options after first-line treatment with somatostatin analogues (SSA)/chemotherapy. Therefore, new therapies are urgently needed. Survivin is an intracellular protein that alters cell division, function of cell death proteases and inhibits apoptosis. It is undetectable in adult cells and expressed in many tumors, making it an ideal target. SurVaxM is a 15 amino acid synthetic peptide vaccine. It stimulates antigen presentation via intracellular cell-surface target recognition and induces CD8+ & CD4+ T cells and IgG production. It was well tolerated in a phase I trial in recurrent glioma pts (Fenstermaker et al., Neurooncol; 2014). Prelim analysis from a phase II study in glioma patients (pts) showed its efficacy (Ahluwalia et al., Neurooncol; 2018). Targeting survivin in NETs is based on our work with tissue microarrays from gastroenteropancreatic (GEP) and lung NETs that showed that its expression correlated with a worse overall survival (Hanif et al., Oncotarget; 2020). We have an ongoing single-arm phase I trial evaluating the safety and immunogenicity of SurVaxM in metastatic NETs. Methods: Ten eligible pts with any grade metastatic GEP/lung origin NETs that are survivin positive by immunohistochemistry and have progression on SSA within the last 6 months on two CT scans >4 weeks apart per RECIST v1.1 are being enrolled. Pts receive a fixed dose of 500 mcg of SurVaxM in Montanide ISA 51 subcutaneously along with 100 mcg of GM-CSF q2 weeks X 4 doses. SSA is continued at the same dose as before. Pts free of progression and toxicity at 6 months get extra doses of SurVaxM q12 weeks, up to 1 year. Subjects are assessed continuously for safety per NCI CTCAEv5.0. Response assessment via CT scans per RECIST v1.1 q12 weeks. Primary objective is to assess safety of SurVaxM +/- SSA. Secondary objectives are to assess overall response rate, progression free survival, duration of response and vaccine immunological response (anti-survivin antibody titers and survivin-specific CD8 T-cell responses). Safety analysis is per Pocock stopping boundary with the assumption of true toxicity of 0.2 and unacceptable toxicity of 0.3 at a significance level of 0.05.To this date, eight patients were screened out of which five patients were enrolled. One patient did not meet the eligibility criterion due to negative survivin staining and the other two did not meet the RECIST v1.1 progression criterion. Of the five pts enrolled, two were of lung origin, two of GEP, and the remainder one of thymic origin. Three pts had high grade neuroendocrine carcinoma, one patient had atypical bronchial tumor and one with low-grade NET. Currently, two pts remain on the study. The enrollment is ongoing. The trial is funded by The Neuroendocrine Tumor Research Foundation.
A phase I dose escalation study of eryaspase in combination with modified FOLFIRINOX in locally advanced and metastatic pancreatic ductal adenocarcinoma.
Authors: Noel Marcus Smith , Philip Philip Agop , Tejani Mohamedtaki Abdulaziz , Marshall John , He Aiwu Ruth , Weinberg Benjamin Adam , Weiner Louis M. , Biswas-Baldwin Nigel , Hoke Frank , Youssoufian Hagop , El-Hariry Iman
Published: January 2021

TPS453

Background: FOLFIRINOX remains the standard of care for the first line treatment of patients with locally advanced and metastatic pancreatic adenocarcinoma, however the prognosis remains poor, thus novel treatment options are indicated. Eryaspase, asparaginase (ASNase) encapsulated in red blood cells (RBCs) is an investigational product under development. Following infusion, asparagine and glutamine are actively transported into RBCs where they are hydrolyzed by the encapsulated ASNase. A randomized phase IIb study in patients with advanced pancreatic cancer whose disease progressed following first-line treatment (NCT02195180) was previously conducted. Eryaspase in combination with gemcitabine monotherapy or FOLFOX combination therapy improved overall survival (OS) and progression free survival (PFS). The safety profile of eryaspase was acceptable. A second line pivotal randomized phase III trial (Trybeca-1) is currently enrolling (NCT03665441). We design this phase I study to determine the safety of mFOLFIRINOX combined with Eryaspase in the first line of treatment. Methods: Patients with locally or metastatic biopsy proven pancreatic adenocarcinoma will be treated with the combination of mFOLFIRINOX plus Eryaspase. This will be a standard 3+3 design with 4 possible doing levels. mFOLFIRINOX dosing will include 5-Fluorouracil 2400 mg/m2 over 46 hours, Oxaliplatin 85 mg/m2, Irinotecan 150 mg/m2 plus Eryaspase 75 Units/kg at dose level 0. Eryaspase will be dose escalated up to 100 Units/kg. The study will enroll at three academic centers. Key eligibility criteria include performance status 0 or 1; locally advanced or metastatic tumor disease; adequate organ function. The primary objective is to determine the maximum tolerated dose and safety of this novel combination. Key secondary objectives include objective response rate, progression-free survival, overall survival, pharmacokinetics, pharmacodynamics, and biomarker research. A data safety monitoring committee will review data every 3 months. Clinical trial information: 04292743.