bluuebunny/crossref_metadata_2025 huggingface dataset:
Clinical efficacy and biomarker analysis of pucotenlimab (HX008) in patients with previously treated advanced mismatch repair-deficient or microsatellite instability-high solid tumors: A single-arm, multicenter, phase 2 study.
Authors: Zhang Bo , Song Yan , Luo Suxia , Yin Xianli , Li Enxiao , Wang Hui , He Yifu , Liu Zhihui , Fan Qingxia , Liang Xinjun , Shu Yongqian , Liu Yunpeng , Xu Nong , Zhang Shu , Zhuang Zhixiang , Zhang Jingdong , Kou Xiaoge , Wang Fen , Zhu Xiaodong , Huang Jing
Published: January 2023

799

Background: Pucotenlimab is a humanized IgG4 anti-PD-1 monoclonal antibody with an engineered Fc domain. We aim to assess the efficacy and safety of pucotenlimab, and potential predictive biomarkers of response in patients with previously treated advanced microsatellite instability-high (MSI-H) or mismatch repair-deficient (dMMR) solid tumors. Methods: In this single-arm, multi-center, phase 2 study, eligible patients had locally advanced or metastatic, centrally confirmed MSI-H or dMMR solid tumors treated with at least one prior systemic therapy. Patients received pucotenlimab 200mg every 3 weeks until disease progression or unacceptable toxicity. The primary endpoint was overall response rate (ORR) assessed by the independent review committee (IRC) per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Besides, patients’ PD-L1 expression, blood neutrophil to lymphocyte ratio (NLR), germline HLA-I genotyping, loss of heterozygosity (LOH) of HLA-I genes, tumor mutational burden (TMB), and genetic alterations in the tumor revealed by next-generation sequencing were investigated to identify potential predictors of efficacy. Results: 100 patients with MSI-H or dMMR solid tumors were enrolled. Colorectal cancer (n=71) and gastric cancer (n=10) were the most common cancer types. The median follow-up duration was 22.5 months (range: 0.3-37.4) at data cutoff (December 4, 2021). The ORR was 49.0% (95% CI 38.86%-59.20%), and the 12-month progression-free survival (PFS) rate was 56.1% (95% CI 45.63%-65.24%) based on IRC’s assessment. Both the median PFS and median duration of response were not reached. Pucotenlimab was well tolerated. Grade ≥3 treatment-related adverse events (TRAEs) were reported in 18 patients, most commonly anemia, leukocytopenia, and hypertension. For the biomarker analysis, patients with NLR <4 at the second treatment cycle, TMB≥32.5 muts/Mb (the lower 35th TMB-percentile), or mutations in the KMT2D gene showed significantly higher ORR. Conclusions: Pucotenlimab demonstrated durable antitumor activity and manageable safety for previously treated patients with advanced MSI-H/dMMR solid tumors. KMT2D gene mutation, along with NLR and TMB, warrants further investigation as predictive biomarkers. Clinical trial information: NCT03704246 .
Association of lifestyle-related risk factors with incidence and mortality rates of colorectal cancer among adolescents and young adults (AYA) in the United States.
Authors: Grewal Udhayvir Singh , Aggarwal Manik , Kumar Prabhat , Fei Naomi , Monga Varun , Chandrasekharan Chandrikha
Published: January 2023

80

Background: Incidence of colorectal cancer (CRC) among adolescents and young adults (AYA) is increasing. A significant proportion of adolescents and young adults (AYA) with colorectal cancer (CRC) lack traceable genetic risk factors. We sought to study the impact of lifestyle-related risk factors on the incidence and mortality of CRC in these patients. Methods: We extracted data on crude incidence and mortality rates of CRC (reported per 100,000 population) for ages 15-39 years in all 50 U.S. states and District of Columbia from the Center for Disease Control (CDC) WONDER database (1999-2018). Data on risk factors such as obesity, physical activity, alcohol and tobacco abuse and nutrition were obtained from the Behavioral Risk Factor Surveillance System (BRFSS, 2020). Correlations were analyzed using Pearson’s co-efficient. p < 0.05 was considered statistically significant. Statistical analysis was performed using VassarStats. Results: Median crude incidence and mortality rates of CRC in AYA in the US from 1999-2018 were 3.8 (IQR 3.2, 4.4) and 0.7 (IQR 0.5,0.9) per 100,000 population respectively. States with higher age-adjusted prevalence of obesity per 100,000 had higher incidence (r = 0.36, p = 0.01) and mortality rates (r = 0.49, p = 0.0002) of CRC in AYA population. States with a higher age-adjusted prevalence of adherence to recommended weekly aerobic activity had lower incidence (r = -0.4515, p = 0.001) and mortality (r = -0.569, p < 0.0001) rates. While states with higher age-adjusted prevalence of tobacco abuse had higher incidence rate of CRC (r = 0.33, p = 0.02), there was no correlation with mortality rates (r = 0.24, p = 0.09). Higher prevalence of alcohol consumption was associated with decreased mortality rate (r = -0.44, p = 0.001), with no impact on incidence rate (r = -0.16, p = 0.26). States with lower daily consumption of fruits had higher incidence (r = 0.37, p = 0.01) and mortality rates (r = 0.59, p < 0.0001). No correlation of daily consumption of vegetables with incidence (r = -0.1516, p = 0.29) and mortality (r = 0.18, p = 0.22) rates was noted. Conclusions: In the current analysis, higher prevalence of obesity, lower rates of aerobic activity and lower daily consumption of fruits were strongly associated with increased incidence and mortality rates. The impact of tobacco abuse and alcohol consumption was more variable. Apart from improving access to genetic testing and counseling, efforts aimed at mitigating the rise of CRC incidence among AYA should also focus on traditional lifestyle-related risk factors.
Prognostic impact of immune-related adverse events on survival outcomes in metastatic gastrointestinal cancer: A single-institutional experience.
Authors: Ogbue Olisaemeka , Unlu Serhan , Sorathia Sharmeen , Nanah Abdel Rahman , Haddad Abdo S. , Daw Hamed
Published: January 2023

801

Background: Immune checkpoint inhibitors (ICIs) have several approved indications in the treatment of gastrointestinal (GI) malignancies including metastatic disease. The adverse events related to ICI use or Immune related adverse events (irAEs) are now being more readily recognized. The association between the occurrence of irAEs and survival outcomes is not well understood. Whereas complete tolerability of ICIs with minimal irAEs may be indicative of a lack of response, the development of moderate to severe irAEs could result in significant morbidity and mortality especially in already advanced disease. This dilemma has provided an impetus to present our 5-year single institutional experience wherein we aim to determine the impact of irAEs on survival outcomes in metastatic GI malignancies. Methods: We retrospectively reviewed a cohort of adult patients who received ICIs for metastatic GI malignancies at the Cleveland Clinic foundation between 2017-2022 by utilizing an outpatient oncology pharmacy database. ICIs of interest included atezolizumab, ipilimumab, nivolumab and pembrolizumab. The occurrence of irAEs was as determined by primary oncologist. The primary and secondary outcomes were overall survival (OS) and progression free survival (PFS) in patients based on irAE presence, respectively. Results: There was a total of 151 patients who received ICIs for various metastatic GI malignancies. Among these, 38 unique irAEs were identified constituting 25% of the entire cohort. The table shows their distribution by organ system and type of GI malignancy. We observed hyper progressive disease in 3% of irAE cohort. Grade 3-4 irAEs requiring hospitalization occurred in 32% of all irAEs, median hospital length of stay of 5 (range:1-15) days with 11% resulting in death. 26 % discontinued treatment due to irAEs while 44% had palliative care consultations/hospice transition soon after. The median OS rates in patients who had irAEs vs those who didn’t, respectively, were 10 months [95% confidence interval (CI, 5-NA)] vs. 9 months [95% confidence interval (CI, 6-12)], p=0.85. There was also no statistically significant difference in median PFS between both groups (p=0.76). Conclusions: In our single institution cohort of metastatic gastrointestinal cancer patients, despite significant morbidity from irAEs, the prognosis was similar as previous studies suggesting a better outcome in patients with irAEs compared to those who did not experience irAEs.[Table: see text]
Frequency and outcomes of BRAF alterations identified by liquid biopsy in metastatic non-colorectal gastrointestinal cancers.
Authors: Mahipal Amit , Bucheit Leslie , Zhang Nicole , Jiang Jing , Kiedrowski Lesli A. , Chakrabarti Sakti
Published: January 2023

808

Background: The impact of BRAF V600E, a known poor prognostic factor in metastatic colorectal cancer (CRC), has not been assessed broadly in non-CRC gastrointestinal (GI) cancers including pancreatic (PC), gastric/gastroesophageal (GC), hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA). In view of recent tumor-agnostic approval of a BRAF V600E inhibitor, it is important to determine the prevalence and impact of BRAF alterations on non-CRC GI cancer patients (pts). Methods: Genomic results from pts with PC, GC, HCC, or CCA tested with Guardant360 (G360, Guardant Health) as part of clinical care from June 2019 – June 2022 were retrospectively queried. Prevalence of characterized nonsynonymous BRAF genomic alterations (GA) was analyzed; differences between cancer types was assessed using the Chi-squared test. The GuardantINFORM database with aggregated commercial payer health claims and de-identified records from over 243,000 individuals with G360 results was used to derive real-world overall survival (rwOS), reported in months, calculated from diagnosis of metastatic cancer; differences between cancer types were compared using log-rank tests. Results: 23,069 patients were included: PC:49%; GC:24%; CCA:20%; HCC:6%. Pts were more likely to be male (p<0.01). PC/HCC pts were tested more often at new diagnosis (vs at disease progression) than GC/CCA (p=0.02, p<0.01, respectively). BRAF GAs were identified in 2.9%, comparable to tissue-based datasets (MSK-IMPACT: 2.4%); 21% of BRAF GAs were V600E (0.6% prevalence overall). PC/CCA pts were more likely to have BRAF GAs than the overall cohort (p<0.01); they also had more BRAF V600E GAs (p<0.01). rwOS differed by cancer type and BRAF status (Table). Notably, CCA pts with BRAF V600E had superior rwOS compared to CCA pts without BRAF findings (p=0.02). rwOS is not reported for HCC due to small n. Conclusions: Identification of BRAF GAs and V600E in the non-CRC GI population by liquid biopsy is similar to rates observed in tissue-based testing and may be reliably used to assess BRAF status. BRAF GAs and subtypes have mixed prognostic implications on survival for PC/CCA/GC patients that warrants further exploration. [Table: see text]
Diagnostics and treatment for HER2+ mG&CRC: Learning outcomes of GetSMART.
Authors: Lou Emil , Marshall John , Jacobs Ginny , Fleming Matthew , Coutinho Anelisa Kruschewsky , Yoshino Takayuki , Augustyniak Monica , McFadden Pam
Published: January 2023

82

Background: Gastric/colorectal cancer (G&CRC) are among the most prevalent cancers. Efforts are ongoing to better assess their clinical/genomic factors. HER2 (human epidermal growth factor receptor 2) testing is strongly recommended in clinical practice to guide treatment. An accredited education program (GetSMART) was launched online (January 2021–April 2022) to equip healthcare providers (HCPs) with knowledge, skills, and confidence to accurately assess/apply molecular testing and therapy options for metastatic G&CRC patients. Methods: A knowledge/confidence-based assessment was embedded in four modules to measure learners’ knowledge mastery (% answering correctly with confidence) pre/post-activity. Self-reported confidence and anticipated performance in clinical practice were measured before/after each module. At the end of program, HCPs were asked about their commitment to change. McNemar’s test was applied to assess statistical significance in pre-post for paired items, and descriptive analysis for non-paired items. Results: Overall, 925 unique HCPs engaged in GetSMART, 31% (n=284) completed all modules, of which 57% (n=163) consented analysis of their data. A statistically significant increase (p<0.05) was measured in percentage of HCPs demonstrating knowledge mastery, confidence, and commitment to change their practice from pre to post across four competencies, except for percentage of HCPs “often”/“always” engaging patients in shared decision-making (SDM) (3, Performance). Largest gains in knowledge mastery/confidence were noted for HCPs’ ability to anticipate/manage adverse events (AE) ( 4A); and for anticipated performance, in HCPs considering appropriate treatment. Post-activity, 66% (98/149) of HCPs intended to change practice based on module content, 83% (70/84) of whom were “highly”/“somewhat” confident to make changes. The activity’s anticipated impact on patients was rated “major”/“moderate” by 69% (103/149) of HCPs. Conclusions: Identification of HER2 aberrations in mG&CRC and its appropriate treatment selection remains challenging in oncology care. This evaluation demonstrated that GetSMART positively impacted HCPs’ knowledge, confidence, and anticipated performance in clinical practice to enhance health outcomes of HER2+ mG&CRC patients. [Table: see text]
Costs of adverse event management associated with first-line cetuximab or panitumumab in patients with metastatic colorectal cancer in Spain.
Authors: Suárez Begoña Graña , Tarazona Noelia , Duran Moran Olga , Fernandez Gonzalez Ana , De los Santos Real Heidi , Pescott Chris P.
Published: January 2023

83

Background: Patients with RAS wild-type metastatic colorectal cancer (mCRC) in Spain may be treated with an epidermal growth factor receptor inhibitor: cetuximab (cet) or panitumumab (pan), in combination with chemotherapy (CT). Several factors may influence the choice of treatment regimen, including adverse event (AE) management, as cet- and pan-based therapies have distinct individual safety profiles. Patients may experience multiple adverse events during treatment. This study aimed to estimate the associated financial impact on Spain’s National Health System (SNHS). Methods: An economic model was developed to project the mean number of AEs per patient (p-p) and to estimate p-p and population-level costs of AE management (cAEm) associated with first-line cet+CT and pan+CT treatment regimens. Data on common and very common AEs and their severity were sourced from the summaries of product characteristics and a meta-analysis by Petrelli, et al. Categorical values were converted into numerical values using the mean values of the frequencies for each AE. Applicable resource costs were obtained from a Spanish database with health unit costs from official records, and from literature on oncology treatment-related costs. The eligible patient population was determined from published and grey literature, and market research. AEs of grade 1-2 were assumed to be treated in an outpatient setting, and those of grade 3-4 treated in an inpatient setting. The model inputs were validated by clinical oncologists in Spain. Results: An estimated 3,794 (cet+CT) and 2,325 (pan+CT) eligible patients received first-line treatment for mCRC. For patients receiving cet+CT or pan+CT, the average frequency of AEs p-p was estimated to be 7.2 (cet+CT) and 17.2 (pan+CT), with estimated p-p cAEms of €5,655 and €13,571, respectively. Conclusions: The lower rates of AEs for cet+CT may result in a reduced AE burden for eligible patients with mCRC, with estimated savings of €7,917 p-p on average. Although overall costs and clinical outcomes should be considered, treatment with cet+CT could yield annual cAEm savings for the SNHS of 35%. Future studies should consider the impact of AE management in a real-world setting.
Reflex testing for RAS and BRAF mutations in metastatic colorectal cancer: A single Canadian academic oncology center experience.
Authors: Cvetkovic Lena , Said Lauren , Ayoub Jean-Pierre M. , Tehfe Mustapha , Florescu Marie , Nguyen Bich Ngoc , Tran-Thanh Danh , Soucy Geneviève , Letourneau Richard , Loungnarath Rasmy , Aubin Francine
Published: January 2023

86

Background: Patients with left-sided metastatic colorectal cancer (mCRC) without mutations in RAS or BRAF V600E are eligible to a combination treatment of an anti-EGFR monoclonal antibody in association with chemotherapy. This combination is associated with a survival benefit and is recommended by oncology guidelines as first line therapy for RAS/BRAF wild type left-sided mCRC patients. The CHUM (University of Montreal Hospital Center) has implemented reflex testing of RAS/BRAF mutations for mCRC since October 22nd 2019, and was one of the only hospitals in Canada to do so. With this study, we want to demonstrate that reflex testing of these mutations improves the quality of care received by patients. Methods: In this retrospective study, we reviewed pathological and clinical data of 101 patients with newly diagnosed mCRC that had their pathological diagnosis done at the CHUM. Patients diagnosed between July 1st 2017 and October 21st 2019, before implementation of reflex testing, (“Before reflex testing” group, n = 62 patients) were compared to patients diagnosed between October 22nd 2019 and December 31st 2021 (“After reflex testing” group, n = 39 patients). Results: The average delay between the mCRC biopsy and the result of the RAS/BRAF mutations was reduced to 25 days (CI95% 22.6 – 28.1) in the “After reflex testing” group, compared to 154 days (CI95% 111.2 – 202.5) in the “Before reflex testing” group. Respectively 66% (41/62) of patients in the “Before reflex testing” group and 69% (27/39) of patients in the “After reflex testing” received a systemic treatment. At initiation of systemic therapy, results of RAS/ BRAF mutations were available for 85% (35/41) of patients in the “After reflex testing” group, versus only 17% (7/41) of patients in the “Before reflex testing” group. Among patients eligible for an anti-EGFR monoclonal antibody and who received it, 100% of them (6/6) received it in the first line setting in the “After reflex testing” group, compared to 33% (3/9) in the “Before reflex testing” group. Conclusions: Our study shows that with reflex testing of RAS/ BRAF mutations, oncologists have quicker access to all relevant information to make the best treatment decision for their patients. It allows eligible patients to receive an anti-EGFR therapy in the first line setting, as recommended by oncology guidelines.
Symptom burden over time among early-onset young adult colorectal cancer survivors.
Authors: Cheng Justin , Nadim Bahram , Stal Julia , Cohen-Cutler Sally , Gallagher Phuong , Kaslander Jonathan N , Marin Priscilla , Barzi Afsaneh , Lenz Heinz-Josef , Freyer David R. , Miller Kimberly Ann
Published: January 2023

88

Background: From 1995-2016, rates of colorectal cancer (CRC) have increased among young adults (YA) under 50 years by 2% annually, despite overall rates of CRC among adults over age 65 decreasing. Unfortunately, this population is disproportionately affected by diagnosis at later stage of disease due to systematic and healthcare factors. Such late diagnoses are associated with higher symptom burden among survivors; however, symptom burden among YA early-onset CRC (EOCRC) survivors is poorly understood. The present study aims to characterize symptom burden among YA EOCRC survivors. Methods: A cross sectional survey was administered online in collaboration with a national organization for YA CRC survivors. Respondents (18-49 years) were EOCRC survivors who were 6-36 months from diagnosis/relapse. Survivors endorsed symptoms they experienced among 23 common CRC late effects. Responses were stratified by symptom duration (6-18 versus 19-36 months) to examine differences in endorsement rates among respondents. Results: Respondents (n=235) were colon (n=86) and rectal (n=149) cancer survivors, primarily male 63%, diagnosed at 32.4 years (SD=6.65), with an average of 5.1 (SD=2.57) symptoms. Overall, the most highly reported symptoms were fatigue, perceived change in appearance after treatment, and nail color changes. Comparisons of 6-18 and 19-36 months-from-diagnosis groups revealed similar symptom endorsement rates, with those 19-36 months from diagnosis endorsing constipation/diarrhea, anal bleeding, and incisional discomfort at higher rates than those 6-18 months from diagnosis. The 6-18 and 19-36 months-from-diagnosis groups carried similar symptom burdens of 4.9 (SD=2.57) and 5.1 (SD=2.58), respectively. Conclusions: YA EOCRC survivors endorse numerous symptoms that may interfere with their daily living and quality of life. Similarities in endorsement between 6-18 month and 19-36-month groups suggest symptoms may become chronic and persist beyond cancer treatment. Fortunately, many symptoms can be mitigated or prevented with proper medical and/or psychosocial intervention, patient education, and resource availability. Providers can leverage these findings in their evaluation of YA EOCRC patients during treatment and follow-up care to ensure the delivery of optimal symptom management. [Table: see text]
One-week versus two-week chemoradiotherapy followed by curative surgery in rectal cancer: Long-term comparative pooled analysis of two prospective multicenter phase II trials.
Authors: Lee Jong Hoon , Sung Soo-Yoon , Kim Sung Hwan
Published: January 2023

96

Background: The optimal short-course chemotherapeutic regimen for rectal cancer has not been clearly defined until now. KROG 10-01 and KROG 11-02 prospective trials investigated the efficacy and safety of one- and two-week chemoradiotherapy (CRT), respectively. We compare and report long-term outcomes by pooling data from two prospective trials for one- and two-week schedules of preoperative CRT and curative surgery in rectal cancer. Methods: Patients eligible for KROG 10-01 and KROG 11-02 involved those with clinical T3-4N0-2M0 rectal cancers. They received preoperative CRT and total mesorectal excision. Patients in KROG 10-01 received radiation of 25 Gy in 5 fractions during one week with 5-fluorouracil/leucovorin. Patients in KROG 11-02 received radiation of 33 Gy in 10 fractions during two weeks with oral capecitabine. Results: A total of 150 patients consisting of 70 patients from KROG 10-01 and 80 patients from KROG 11-02 were collectively analyzed. With a median follow-up time of 89.2 months, the 5-year overall survival (OS) rate was 86.5% in one-week CRT and 85.3% in two-week CRT ( P = 0.84). The 5-year recurrence-free survival (RFS) rate was 83.5% in one-week CRT and 77.1% in two-week CRT ( P = 0.45). One patient (1.4%) in one-week CRT and eleven patients (13.8%) in two-week CRT exhibited pathologic complete regression (ypT0N0M0) after radiotherapy ( P = 0.01). Downstaging (ypT0-2N0M0) occurred in 20 patients (28.2%) in one-week CRT and 27 patients (33.8%) in two-week CRT ( P = 0.50 ). One-week CRT arm had significantly higher acute hematologic (12.8% vs. 3.8%, P = 0.040) and non-hematologic (38.6% vs. 16.3%, P = 0.002) toxicities than two-week CRT arm. Conclusions: Both one- and two-week schedules of CRT showed favorable survival outcomes after seven years of follow-up. But, two-week course achieved more increased tumor response and decreased acute toxicity rather than one-week course. Clinical trial information: KROG 10-01 is registered at ClinicalTrials.gov (number, NCT01129700 ) and KROG 11-02 is registered at ClinicalTrials.gov (number, NCT01431599 ).
Phase 2 randomized, active-controlled, multicenter trial to assess the safety and efficacy of RRx-001 + irinotecan vs. regorafenib + irinotecan in third/fourth-line colorectal cancer.
Authors: Reid Tony R. , Abrouk Nacer , Oronsky Bryan , Caroen Scott , Fisher George A.
Published: January 2023

97

Background: RRx-001 is a novel cysteine-targeted alkylating agent that, upon binding, under severe hypoxia, which is primarily present in tumors, releases nitric oxide (NO) and other cytotoxic metabolites. The primary biological activities of this hybrid molecule include macrophage repolarization, CD47 downregulation, and vascular normalization. The purpose of this clinical trial (ROCKET) (NCT02096354) was to compare the safety and efficacy of the combination therapy RRx-001 + irinotecan vs. regorafenib + irinotecan in 3rd/4th line colorectal cancer that previously received treatment with irinotecan. Methods: A total of 34 patients were randomized (24 to RRx-001 + irinotecan (RxI) and 10 to regorafenib + irinotecan (RegI)) and were the basis for the intention-to-treat analysis (ITT, comprising all 34 patients). RRx-001 treatment was administered as an up-to-2-month induction therapy or “primer” followed by irinotecan for patients randomized to the RRx-001 arm (24). The efficacy and safety data are presented for the 34 patients in the ITT efficacy analysis. Therapy consisted of intravenous administration of RRx-001 at 4 mg once weekly for up to 2 months followed by intravenous infusion of irinotecan at 180 mg/m2 on day 1 in a 21-day cycle vs. 160 mg oral regorafenib daily for 3/4 weeks followed at progression, if applicable, by irinotecan 180 mg/m2 on day 1 in a 21-day cycle. Results: Median patient follow-up was approximately 14.5 months (SD 4.5 months). Median overall survival was 8.6 months for RxI and 4.7 months for RegI. Median progression free survival was 6.1 months for RxI vs. 1.7 months for RegI (a statistically significant result, two-sided log-rank test, p = 0.0030). Overall response rate was 20.8% for RxI vs. 0% for RegI. Moreover, the toxicity profile of RxI was substantially improved compared with RegI. Conclusions: The results of this trial demonstrate improved efficacy of RxI compared with RegI in patients with metastatic colorectal cancer after previous treatment with irinotecan, and late-stage clinical development in this indication is planned on the strength of the observed “signal” accompanied by a sufficient safety profile. Clinical trial information: NCT02096354 .
Effect of Tabernero's prognostic subgroups or development of neutropenia on survival outcomes of patients with refractory metastatic colorectal cancer (mCRC) treated with trifluridine/tipiracil plus bevacizumab (TASBEV) in real-world practice.
Authors: Martinez-Lago Nieves P. , Alonso de Castro Beatriz , Reboredo Rendo Cristina , Calleja Teresa , Gómez-Randulfe Rodríguez Martín Igor , Silva Diaz Sofia , Parajó Vázquez Iria , Mateos Salvador Maria , Busto Fernandez Fernando , Grana Suarez Begona , De la camara Juan , Reboredo Lopez Margarita
Published: January 2023

99

Background: TASBEV, compared with TAS-102, was associated with an improvement in progression-free survival (PFS) with tolerable toxicity in a randomized, open-label phase 2 trial. However, the subgroups of patients who may benefit from long-term TASBEV treatment are unknown. Methods: We conducted a retrospective, observational study of patients (pts) with mCRC refractory or intolerant to standard therapies treated with TAS-102 30-35 mg/m2 twice daily on days 1–5 and 8–12 every 28 days plus BEV 5 mg/kg on days 1 and 15 at University Hospital a Coruña (Spain). Results: We recorded 47 pts treated between July 2019 to June 2022. Median age was 65 years (range 41 – 82 years), 78.7% ECOG PS0-1, 51.1% RASmt, 78.7% of pts had liver and 23.4%, peritoneal metastases; 29.8% time since diagnosis of 1st metastases <18 months and 57.4% poor prognostic Tabernero Subgroup. Previous treatment included 94.3% previous antiVEGF treatment and 74.5% received TAS-102 BEV as 3rd line of treatment. Median of cycles received was 4 (range 1-15 cycles). ORR and DCR were 2.4% and 48.8%, respectively. With a median follow up of 15.7 months, median PFS was 4.3 months (95% CI, 3.4-5.1 months) and median OS was 9.8 months (95% CI, 7.3-12.3 months). Univariate analysis of prognostic factors for progression-free and overall survival are listed in the table. Conclusions: In our series identified that Tabernero's prognostic subgroups or the development of grade 3-4 neutropenia during treatment, among others; identify patients who may benefit from long-term TASBEV treatment. [Table: see text]
Penpulimab plus chemotherapy with or without anlotinib as first-line treatment for patients with advanced esophageal squamous cell carcinoma (ANSWER): A randomized, two-arm, clinical trial in progress.
Authors: Wang Wei , Lin Shuimiao , Wang Rong , Wu Dehua
Published: January 2023

TPS482

Background: For patients with advanced esophageal squamous cell carcinoma (ESCC), the combination of immune checkpoint inhibitors with chemotherapy has demonstrated synergistic antitumor activity and manageable safety profile. Anti-angiogenic targeted drugs for ESCC patients are still being explored. Penpulimab is a humanized high-affinity IgG1 anti-programmed cell death 1 (PD-1) monoclonal antibody engineered to completely eliminate Fcγ receptor binding and Fc-mediated effector functions that can compromise antitumor activity. Anlotinib, an oral small molecule tyrosine kinases inhibitor, targeting VEGFR 1/2/3, FGFR 1-4, PDGFR α/β and c-kit, have been recommended by the guidelines for advanced ESCC in China because of its good efficacy and tolerance. The purpose of the study was to investigate the efficacy and safety of penpulimab plus chemotherapy with or without anlotinib as first-line treatment for patients with advanced ESCC. Methods: This is a multi-center, two-arm, phase II study which enrolled patients with advanced ESCC. Eligible patients are aged 18-75 years, ECOG performance status 0~1. Approximately 100 patients will be randomly assigned 1:1 to induction with penpulimab (200mg, iv, d1, q3w) plus chemotherapy (TP: cisplatin [60-75mg/m2, iv, d1-d3, q3w] plus paclitaxel [135-175mg/m2, iv, d1, q3w] or albumin-bound paclitaxel [200-260mg/m2, iv, d1, q3w]) for 4-6 cycles followed by consolidation with penpulimab (200mg, iv, d1, q3w) (arm 1) or induction with penpulimab (200mg, iv, d1, q3w) plus anlotinib (10mg/d [<60kg] / 12mg/d [≥60kg], p.o., d1~14, q3w) plus chemotherapy (TP: cisplatin [60-75mg/m2, iv, d1-d3, q3w] plus paclitaxel [135-175mg/m2, iv, d1, q3w] or albumin-bound paclitaxel [200-260mg/m2, iv, d1, q3w]) for 4-6 cycles followed by consolidation with penpulimab (200mg, iv, d1, q3w) and anlotinib (10mg/d [<60kg)/12mg/d [≥60kg], p.o., d1~14, q3w) (arm 2). Randomization will be stratified by gender (male or female), age (<65, >65), PD-L1 combined positive score (CPS; <1, ≥1, ≥5, ≥10), metastatic site, history of surgery and disease. Patients in arm 1 were treated with second-line anlotinib combined with penpulimab after progression until further disease progression. Patients in arm 2 will continue treated with first-line anlotinib combined with penpulimab until disease progression. Tumor imaging assessment will be performed q6w for 1-6 cycle and q9w thereafter. The primary endpoint was objective response rate (per RECIST v1.1 assessed by investigator). Secondary endpoints included disease control rate, progression-free survival (per RECIST v1.1 assessed by investigator), overall survival, safety and quality of life score. Enrollment in this trial is ongoing. Clinical trial information: NCT05214222 .
Perioperative penpulimab plus anlotinib combined with chemotherapy for locally advanced gastric cancer: A single arm, multicenter, phase II clinical trial.
Authors: Wang Mian , Zhou Wei , Miao Yan , Tan Zhaobang , Li Yiding , Hong Liu
Published: January 2023

TPS485

Background: Perioperative therapy, especially whether preoperative neoadjuvant therapy (NAT) can improve R0 resection rate and prolong overall survival of patients with locally advanced gastric cancer, has been paid more and more attention. NAT is mainly defined as a preoperative chemotherapy or chemoradiotherapy, aiming at increasing radical resection rate by downstaging tumor and eliminating micrometastases. Anlotinib is an oral multi-targeted tyrosine kinase inhibitor targeting VEGFR1/2/3, FGFR1-4 and PDGFRα/β, which effectively blocks tumor neovascularization and growth. Previous phase I/II clinical trials suggested that penpulimab monotherapy as second-line therapy was well tolerated and showed clinical anti-tumor activity in gastric or gastroesophageal junction carcinoma (GC/GEJ) (NCT03352531, NCT04172506). It was demonstrated an objective response rate (ORR) of 26.3%, a disease control rate (DCR) of 42.1% in GC/GEJ patients (pts) using penpulimab monotherapy. This trial was designed to assess the feasibility and efficacy of penpulimab plus anlotinib combined with chemotherapy in perioperative treatment of pts with locally advanced gastric cancer. Methods: This is a multi-center, prospective, single-arm, phase II study. Resectable GC pts with TNM stage T3~4N+M0 per AJCC8th, ECOG PS 0-1, were enrolled and treated with 3 cycles of preoperative penpulimab (200mg, iv, d1, q3w) + anlotinib (12mg, qd, d1-d14, q3w)+ SOX (oxaliplatin 130mg/m2, iv, d1 and S-1 40-60mg, po, bid, d1-14, q3w), and 12 months of postoperative adjuvant therapy formulated by investigators according to the individual situation of the pts. Primary endpoint was pathological complete response (pCR) rate. Secondary endpoints included major pathologic response (MPR) rate, disease free survival (DFS), objective response rate (ORR), R0 resection rate and safety. Based on a two-sided test for one proportion with 5.0% type I error, 80% power to detect an improvement in the rate of pCR from 13% to 29%, there will be 57 pts enrolled considering 10% of pts dropping out. Clinical trial information: NCT05385900 .
A prospective clinical trial to evaluate the performance of a multi-analyte blood test for early detection of hepatocellular carcinoma among at-risk patients with liver cirrhosis: The CLiMB study.
Authors: Roy Dhruvajyoti , Xu Jianfeng , Taggart David J. , Gallant Max A. , Bush Kisha , Reed Octavia , Akhtar Arshia , Yang Ju Dong , Nguyen Mindie , Li Wei , Van Etten Richard A.
Published: January 2023

TPS617

Background: Hepatocellular carcinoma (HCC) is the leading cause of cancer-related death in patients with cirrhosis in the U.S. HCC surveillance is associated with significant improvements in early tumor detection, receipt of curative therapy and overall survival in patients with cirrhosis. However, current surveillance strategies suffer from poor adherence and suboptimal sensitivity. The multi-analyte HelioLiver test is a novel blood test for the early detection of HCC. The test provides a qualitative result based on a multiparametric algorithm that incorporates information from cell-free DNA (cfDNA) methylation markers, protein tumor markers (AFP, AFP-L3%, DCP) and patient demographic characteristics (sex, and age). Here, we describe the protocol for a prospective, multicenter clinical trial designed to investigate the performance of this multi-analyte blood test in cirrhosis patients at risk for HCC. Methods: The Prospective Clinical Trial to Detect Liver Cancer through Quantification of cfDNA Methylation in Blood Samples (CLiMB) is a longitudinal, multicenter, prospective study with a targeted enrollment of 1,600 participants. The main inclusion and exclusion criteria are described in the table. Within the Initial Surveillance Visit (t=0 months), all enrolled subjects will provide blood specimens for the multi-analyte blood test and undergo conventional ultrasound to examine the liver. Every subject will then undergo diagnostic imaging by multiphasic MRI to determine the clinical truth. The results of diagnostic imaging will be scored by a Liver Reporting and Data System (LI-RADS) score and the number and size of any malignant lesions identified will be recorded. After the Initial Surveillance Visit (t=0 months), subjects with an indeterminant HCC finding by MRI (LI-RADS 3) will be recommended to have up to three Follow-Up Visits (t=6 months, t=12 months, and t=18 months) to attempt to resolve the clinical truth for these subjects. The primary endpoints of the trial are to demonstrate the superiority for sensitivity and non-inferiority for specificity of the multi-analyte blood test over ultrasound for the detection of HCC. The data of all diagnostic imaging by MRI will be saved and uploaded for evaluation by a blinded, centralized team of radiologists, which will be used as the basis of the clinical truth for all subjects. All participants are currently enrolled across the U.S. from over 40 clinical sites. Clinical trial information: NCT03694600 . [Table: see text]
A phase II trial of hyperthermic intraperitoneal chemotherapy combined with tislelizumab and targeted therapy in high-risk hepatocellular carcinoma after R0 resection.
Authors: Liu Sulai , Zhang Zhihua , Song Yinghui , Li Yuhang , Yi Weimin , Jiang Bo , Peng Chuang
Published: January 2023

TPS635

Background: Hepatocellular carcinoma (HCC) is the predominant form of liver cancer, accounting for 75%–85% of cases, for which surgical resection represents the most effective treatment, with curative potential. However, the high incidence of tumor relapse (50%–70% 5 years after surgery) has hindered improved survival. Furthermore, early recurrence within 2 years after surgery accounts for 70% of relapsed HCC cases, is rarely treatable, and has been associated with poor survival. With the development of novel tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors for advanced HCC, the management of patients has been greatly improved. However, no guidelines for novel systematic therapy to treat high risk of relapse HCC have been established. Targeted therapy combined with immunotherapy as systemic treatment has become a new approach in high risk of relapse HCC. Hyperthermic intraperitoneal chemotherapy (HIPEC), as an adjuvant treatment of abdominal malignant tumors, has achieved unique effects in the treatment of many cancers. The aim of this study was to assess the activity and feasibility of a combination of HIPEC with Tislelizumab and TKIs for the treatment of high risk of relapse HCC. Methods: The single-center, open-label, one-armed, Phase 2 study (NCT05546619) will enroll ~30 adults who meet the diagnostic criteria of high risk of relapse HCC (multiple tumors or satellite lesions; tumor diameter > 5cm; HCC rupture and bleeding; combined with vascular invasion; AFP > 32ng/ml). Patients will receive the following treatments as noted in the table. The primary and secondary endpoints are listed in the table. Tumor response will be evaluated once every 6 weeks for the first 48 weeks of treatment, and once every 12 weeks thereafter according to RECIST v1.1; safety will be assessed through monitoring the incidence and severity of adverse events graded according to CTCAE 5.0, vital signs and clinical laboratory results. Clinical trial information: NCT05546619 . [Table: see text]
Randomized, phase II selection study of ramucirumab and paclitaxel versus FOLFIRI in refractory small bowel adenocarcinoma: SWOG S1922.
Authors: Overman Michael J. , Guthrie Katherine A , Salem Mohamed E. , Pedersen Katrina Sophia , Kalyan Aparna , Colby Sarah , Fakih Marwan , Gholami Sepideh , Gold Philip Jordan , Chiorean E. Gabriela , Hochster Howard S. , Philip Philip Agop
Published: January 2023

TPS784

Background: Small bowel adenocarcinoma is a rare malignancy with limited evidence to support the choice of systemic chemotherapy beyond the frontline setting. Though second-line therapy has historically been extrapolated from colorectal cancers, recent molecular data has demonstrated small bowel adenocarcinoma to be genomically unique when compared to either colon or gastric cancer. Retrospective analyses of irinotecan- and taxane-based therapies and one prospective phase II clinical trial of nab-paclitaxel have demonstrated clinical activity in this cancer. Ramucirumab/paclitaxel represents an active combination in the management of gastric cancer. SWOG 1922 evaluates the use of FOLFIRI or ramucirumab/paclitaxel in the second- and later-line setting for small bowel adenocarcinoma. Methods: This is randomized, phase II, selection design clinical trial of FOLFIRI (5-fluorouracil, leucovorin and irinotecan) every two weeks or ramucirumab D1,15 and paclitaxel D1,8,15 every 4 weeks with the primary endpoint of progression-free survival (PFS). Secondary endpoints include response rate, overall survival, and safety. Archived paraffin tumor tissue collection and serial blood collections are included for correlative analyses. Key eligibility criteria include having mismatch repair proficient/microsatellite stable small bowel adenocarcinoma (ampullary location excluded); metastatic or locally advanced unresectable disease; prior fluoropyrimidine and/or oxaliplatin therapy; no prior treatment with irinotecan, ramucirumab, or taxanes; no recent bleeding, blood clots, or bowel perforation/fistula; and Zubrod performance status of 0/1. Measurable disease is not required. The null hypothesis is median PFS of 2.5 months. If a median PFS of at least 3.5 months is observed in one or both arms, the goal is to choose the better regimen with respect to this endpoint. The design provides a 90% probability of selecting the more active arm, assuming a hazard ratio of 1.4, if both arms meet this threshold. This trial is open and, as of September 1, 2021, 21 of 94 planned patients have been enrolled. NCT04205968 Funding: NIH/NCI/NCTN grants U10CA180888, U10CA180819, U10CA180820, U10CA180821, U10CA180868; and in part by Eli Lilly and Company. Clinical trial information: NCT04205968 .
A prospective translational study investigating the association of gut microbiome (GM) diversity with pathological complete response (pCR) after neoadjuvant treatment in early stage rectal and esophageal cancers.
Authors: Mc Laughlin Ronan Andrew , Devoy Ciaran , moloney carolyn , Bennett Kathleen , Mcmahon David , Conroy Michael R , Fitzpatrick Orla , Egan Keith , Grogan William , Breathnach Oscar S. , Morris Patrick G. , Murphy Adrian Gerard , Naidoo Jarushka , Tangney Mark , Hennessy Bryan T.
Published: January 2023

TPS819

Background: The gut microbiome (GM) is thought to influence host immunity by modulating multiple immunologic pathways. Studies have suggested that dysbiosis of the GM confers a predisposition to certain malignancies and influences response to immune checkpoint inhibitors. However, little is known about how the GM diversity influences complete pathological response to neoadjuvant therapy in gastrointestinal (GI) tumours. We hypothesize that a more diverse GM constitution at baseline will lead to improved pathological response at the time of definitive surgery. Methods: We designed a cross-institutional multi-center translational study investigating the impact of the GM diversity on the efficacy of neoadjuvant therapy in GI cancers by assessing its association with pathological response. The study population will consist of patients with an early-stage rectal or esophageal cancer due to commence neoadjuvant therapy (including chemotherapy and chemoradiation) and planned for definitive surgery. Patients who received prior chemotherapy/monoclonal antibodies/immune checkpoint inhibitors or radiation will be excluded. The study assessments will include fecal sampling of the GM prior to neoadjuvant therapy, upon completion and again six months post completion of therapy. Fecal samples will be analysed by 16S RNA sequencing. Pathological response will be examined at time of surgery and patients will be classified as responders (complete pathological response) or non-responders. The primary endpoint of the study is to examine the association between the GM diversity and pathological response. 120 patients will be recruited over 18 months. Results: Species richness (Alpha Diversity) will be analysed using the Shannon diversity index and Jaccard similarity index to calculate beta diversity. Classification and clustering analysis will be performed with Principal Component Analysis (PCA) and Random Forest analysis. Comparison of taxa or functions between clinical cohorts will be performed using the two tailed Z test and corrected using the false discovery rate to determine Q-values. The association between GM and complete pathological response will be examined using logistic regression analysis adjusting for potential confounding factors. Adjusted odds ratios (OR) and 95% confidence intervals will be presented. Conclusions: This study will show preliminary insights into the role of GM as a potential biomarker for neoadjuvant therapy efficacy in patients with GI cancers. Recruitment is on-going.
Late Health Outcomes Among Survivors of Wilms Tumor Diagnosed Over Three Decades: A Report From the Childhood Cancer Survivor Study
Authors: Weil Brent R. , Murphy Andrew J. , Liu Qi , Howell Rebecca M. , Smith Susan A. , Weldon Christopher B. , Mullen Elizabeth A. , Madenci Arin L. , Leisenring Wendy M. , Neglia Joseph P. , Turcotte Lucie M. , Oeffinger Kevin C. , Termuhlen Amanda M. , Mostoufi-Moab Sogol , Levine Jennifer M. , Krull Kevin R. , Yasui Yutaka , Robison Leslie L. , Armstrong Gregory T. , Chow Eric J. , Armenian Saro H.
Published: January 2023

PURPOSE

To evaluate long-term morbidity and mortality among unilateral, nonsyndromic Wilms tumor (WT) survivors according to conventional treatment regimens.

METHODS

Cumulative incidence of late mortality (≥ 5 years from diagnosis) and chronic health conditions (CHCs) were evaluated in WT survivors from the Childhood Cancer Survivor Study. Outcomes were evaluated by treatment, including nephrectomy combined with vincristine and actinomycin D (VA), VA + doxorubicin + abdominal radiotherapy (VAD + ART), VAD + ART + whole lung radiotherapy, or receipt of ≥ 4 chemotherapy agents.

RESULTS

Among 2,008 unilateral WT survivors, 142 deaths occurred (standardized mortality ratio, 2.9, 95% CI, 2.5 to 3.5; 35-year cumulative incidence of death, 7.8%, 95% CI, 6.3 to 9.2). The 35-year cumulative incidence of any grade 3-5 CHC was 34.1% (95% CI, 30.7 to 37.5; rate ratio [RR] compared with siblings 3.0, 95% CI, 2.6 to 3.5). Survivors treated with VA alone had comparable risk for all-cause late mortality relative to the general population (standardized mortality ratio, 1.0; 95% CI, 0.5 to 1.7) and modestly increased risk for grade 3-5 CHCs compared with siblings (RR, 1.5; 95% CI, 1.1 to 2.0), but remained at increased risk for intestinal obstruction (RR, 9.4; 95% CI, 3.9 to 22.2) and kidney failure (RR, 11.9; 95% CI, 4.2 to 33.6). Magnitudes of risk for grade 3-5 CHCs, including intestinal obstruction, kidney failure, premature ovarian insufficiency, and heart failure, increased by treatment group intensity.

CONCLUSION

With approximately 40% of patients with newly diagnosed WT currently treated with VA alone, the burden of late mortality/morbidity in future decades is projected to be lower than that for survivors from earlier eras. Nevertheless, the risk of late effects such as intestinal obstruction and kidney failure was elevated across all treatment groups, and there was a dose-dependent increase in risk for all grade 3-5 CHCs by treatment group intensity.