bluuebunny/crossref_metadata_2025 huggingface dataset:
DNA methylation profiling to determine the primary sites of metastatic cancers using formalin-fixed paraffin-embedded tissues.
Authors: Gu Hongcang , Zhang Shirong , He Shutao , Zhu Xin , Wang Yunfei , Xie Qionghuan , Wang Wenxian , Ma Shenglin , Shi Jiantao
Published: June 2022

3079

Background: Metastatic cancers with uncertain primary sites account for a significant portion of new cases. Among them, 3-9% are eventually assigned to cancer of unknown primary (CUP) site after a comprehensive diagnostic workup. Accurate identification of the primary site is the starting point for cancer diagnosis worldwide, and it is critical to guide the subsequent treatments of metastatic cancers. Here we presented a new DNA methylation sequencing-based method to predict the tissues of origin for metastatic cancers, including CUP. Methods: Cancer diagnosis relies substantially on histological and immunohistochemical analyses of formalin-fixed paraffin-embedded (FFPE) tissues. To take advantage of sample accessibility, we developed an optimized and streamlined method that was particularly used to generate reduced represent bisulfite sequencing (RRBS) libraries for genome-wide DNA methylation profiling with degraded DNA fragments. After confirming that data quality generated using the new FFPE-RRBS method was comparable with regular RRBS, we created an RRBS database using 541 fresh frozen samples across ten most common cancer types and 58 tumor-adjacent normal tissues. By incorporating four distinct methylation summary scores and seven machine learning approaches, 28 models were trained and compared for multi-class classification using our database. Lastly, we selected the best classifier to predict the tissues of origin utilizing 249 FFPE samples across ten metastatic cancer types and 12 FFPE samples from CUP patients. Meanwhile, the classifier was also cross-validated using a DNA methylation microarray data set of 4702 patients diagnosed with corresponding primary cancers in the TCGA project. Results: FFPE-RRBS allowed to construct decent libraries with heavily degraded genomic DNA within 20 hours. Comparable DNA methylation metrics were obtained for the RRBS libraries of paired primary cancer tissues (fresh frozen vs. FFPE) and the libraries of paired FFPE samples derived from primary and metastatic tissues. Among the 28 methylation-based classifiers, the mean methylation-based LinearSVC model performed the best, achieving an overall accuracy of 81% with an AUC of 0.95 in determining the primary sites of 10 metastatic cancers. In a cross-validation assay using the TCGA data set of 4702 cancer patients, the overall prediction accuracy and AUC were 92% and 0.99, respectively. Lastly, our model successfully identified the tissues of origin in 10 of 12 CUP patients in a prospective study. Conclusions: The FFPE-RRBS is a novel method for efficient profiling of heavily degraded FFPE samples and the mean methylation-based LinearSVC model can predict the tissues of origin for metastatic cancers and CUP with high accuracy.
Mechanisms of acquired resistance to TRK inhibitors.
Authors: Harada Guilherme , Choudhury Noura J. , Schram Alison M. , Rosen Ezra , Murciano-Goroff Yonina R. , Falcon Christina J. , Wilhelm Clare , Kaplanis Lauren A. , Liu Dazhi , Chang Jason C. , Yang Soo-Ryum , Dhawan Aradhika , Evans Patrick , Savin Casey , Grimaldi Grace , Shah Ronak H. , Cocco Emiliano , Drilon Alexander E.
Published: June 2022

3104

Background: First-generation TRK tyrosine kinase inhibitors (TKIs) are approved in a tumor-agnostic fashion in more than 40 countries for patients with NTRK fusion-positive adult and pediatric cancers. While resistance to these agents has previously been described, the exact frequency with which major mechanisms of resistance emerges is not clearly understood. Methods: Patients with an NTRK-fusion-positive tumor who received a first-generation TRK TKI were eligible. We retrospectively identified those patients that had post-progression tumor tissue analyzed by next-generation sequencing (NGS). The pattern of serial resistance to a second-generation TKI was analyzed when available. Results: Eighteen patients were identified. The median age was 46 years (range 2-67). Nine unique fusions were detected in ten different tumor types. NTRK1, NTRK2, and NTRK3 fusions were found in eight (44%), one (6%), and nine (50%) patients, respectively. Thirteen patients (72%) were treated with larotrectinib and five patients (28%) received entrectinib. NGS (MSK-IMPACT n = 17, Foundation One n = 1) carried out on post-progression tissue revealed the following profile of acquired resistance: on-target resistance (83%, n = 15/18), off-target resistance (11%, n = 2/18), and no identifiable mechanism (6%, n = 1/18). Among patients with on-target resistance, the most common mutation involved the solvent front (87%, n = 13/15: n = 7 NTRK3 G623R, n = 4 NTRK1 G595R, n = 1 NTRK2 G639L, n = 1 NTRK3 G623E) followed by the gatekeeper region (13%, n = 2/15: n = 1 NTRK1 F589L, n = 1 NTRK3 F617I). Two patients developed off-target alterations. One acquired BRAF V600E mutation and the other MET amplification. Interestingly, solvent front mutation loss was observed in two patients who transitioned to and progressed on a second-generation TRK TKI. One patient with a baseline NTRK1 G595R mutation developed polyclonal resistance with acquisition of KRAS G12A and NTRK1 G667A alterations as well as NTRK1 G595R loss. The other patient with NTRK3 G623R developed an NTRK3 F617I gatekeeper mutation with NTRK3 G623R loss. Conclusions: In NTRK fusion-positive cancers, on-target resistance preferentially involving the solvent front is more frequent than off-target resistance to first-generation TKI therapy. Furthermore, the sequential use of second-generation therapy appears to alter the evolutionary kinetics of mutation retention and acquisition.
Phase I dose-escalation study of IBI351 (GFH925) monotherapy in patients with advanced solid tumors.
Authors: Zhou Qing , Yang Nong , Zhao Jun , Dong Xiaorong , Wang Huijuan , Yuan Ying , Yu Yan , Zhang Meijiang , Zhang Sujie , Huang Mengna , Shen Yuping , Wu Yi-Long
Published: June 2022

3110

Background: IBI351(GFH925) is an irreversibly covalent inhibitor of KRASG12C. In this first-in-human dose-escalation study, we report the preliminary safety and anti-tumor activity of IBI351 (GFH925) in patients (pts) with advanced solid tumors harboring the KRAS p.G12C mutation. Methods: Pts with locally advanced, recurrent or metastatic solid tumors with KRASG12C mutation for whom standard therapy had failed were enrolled. Phase I dose escalation had an accelerated titration design for dose level 250mg QD and a BOIN design with 450/700/900mg QD. The primary end points were safety and tolerabilityThe secondary end points were pharmacokinetics (PK) and anti-tumor activity of IBI351(GFH925) monotherapy per RECIST v1.1. Results: As of Feb 07 2022, 15 pts (13 men, 2 women; median age: 62 yrs, range: 48–74 yrs) were enrolled, among whom 12 had non-small cell lung cancer (NSCLC), and 3 had colorectal cancer (CRC). 4 pts had ≥3 prior lines of treatment (tx). Median tx duration was 66.5 ds (range: 21–98 ds). No dose-limiting toxicity (DLT) or any ≥grade 3 treatment-related adverse events were observed in any dose cohorts. A total of 12 patients (80.0%) had treatment-related adverse events (grade 1, n = 6; grade 2, n = 6). By investigator-assessment, tumor response was evaluated in 9 pts (4 with ≥2 assessments); 6 pts had not reached their first assessment. 2 pts had PR (1 NSCLC at wks 12, 450mg, tx ongoing; 1 CRC at wks 6, 700mg, tx ongoing), 4 pts (NSCLC) had SD, and 3 pts had PD (1 NSCLC at wks 12, 2 CRC at wks 6). As data cut-off date, 11 pts were continuing to receive IBI351 (GFH925). Conclusions: IBI351(GFH925) was well-tolerated without unanticipated adverse events across all doses explored in pts with advanced solid tumors harboring the KRAS p.G12C mutation. The data also demonstrated the preliminary efficacy signal of IBI351 (GFH925) in previously treated advanced NSCLC and CRC. Clinical trial information: NCT05005234.
Perioperative chemotherapy with mFOLFOX6 or CAPOX for patients with locally advanced colon cancer (OPTICAL): A multicenter, randomized, phase 3 trial.
Authors: Hu Huabin , Huang Meijin , Li Yunfeng , Wang Ziqiang , Wang Xiaozhong , Liu Ping , Zhang Ruyi , Zhang Hao , Huang Zhongcheng , Pei Haiping , Zeng Yongming , Lai Jiajun , Chen Wenbin , Chen Jiansi , Ding Zhijie , Wei Hongbo , Xu Qingwen , Chen Jigui , Wang Jianping , Deng Yanhong ,   Chinese Southwest Oncology Group (CSWOG)
Published: June 2022

3500

Background: Adjuvant chemotherapy is the recommended standard treatment for resected stage III and high-risk stage II colon cancer, but disease recurrence remain common. Perioperative chemotherapy has proved effective in several tumors, but not in colon cancer. We aimed to assess whether perioperative chemotherapy could improve outcomes in patients with locally advanced colon cancer. Methods: In this multicenter, randomized, phase 3 trial, participants were recruited from 28 hospitals in China. Eligible patients were aged 18-75 years, had a colon adenocarcinoma, with radiologically staged locally advanced (T3 with ≥5 mm invasion beyond the muscularis propria or T4 assessed by CT). Patients were randomly assigned (1:1) to either the experimental group or standard of care group, stratified by center, cT stage, and cN stage. The experimental group received 3 months of neoadjuvant chemotherapy with mFOLFOX6 or CAPOX, then surgery, then 3 months of adjuvant chemotherapy. The standard of care group received immediate surgery, and optional adjuvant chemotherapy (per physician’s discretion according to pathological stage ). The primary endpoint was disease-free survival assessed in the intention-to-treat population at 3 years. Results: Between January 6, 2016, and April 3, 2021, 752 patients were enrolled and randomly assigned to a treatment, of whom 744 were eligible (371 in the experimental group; 373 in the standard of care group). At a median follow-up of 32.5 months (IQR 19.2-45.7), 3-year disease-free survival rates were 78.7% (95%CI 73.8-83.5) in the experimental group and 76.6% (95%CI 71.8-81.4) in the standard of care group (stratified HR 0.83, 95%CI 0.60-1.15; p = 0.138). A pathological complete response was achieved in 26 (7%) of 371 patients in the experimental group. 69 (19%) patients in the experimental group had low pathological disease stage (pT0-2N0) compared with 16 (4%) of 373 in the standard of care group (p < 0.0001). 3-year overall survival rates were 94.9% (95%CI 92.1-97.7) in the experimental group and 88.6% (95%CI 84.6-92.5) in the standard of care group (stratified HR 0.47, 95%CI 0.25-0.87; p = 0.012). The post hoc subgroup analyses revealed perioperative chemotherapy induced an increase in disease-free survival in female patients (HR 0.54, 95%CI 0.31-0.83; p = 0.025). Conclusions: In patients with locally advanced colon cancer, perioperative chemotherapy with mFOLFOX6/CAPOX increased chance of pathological downstaging, but did not improve disease-free survival compared with standard of care. Clinical trial information: NCT02572141. [Table: see text]
Real-world outcomes of biosimilar bevacizumab-awwb versus reference bevacizumab in patients with metastatic colorectal cancer.
Authors: Pham Catherine , Niu Fang , Delate Thomas , Buchschacher Gary L , Li Yan , Ekinci Ekim , Le Kim , Hui Rita L.
Published: June 2022

3552

Background: Bevacizumab-awwb was the first biosimilar approved by the U.S. Food and Drug Administration (FDA) for treatment of cancer and became available for use in July 2019. Clinical comparative efficacy and safety of bevacizumab-awwb to bevacizumab was established in a single study of adult patients with advanced non-squamous non-small cell lung cancer. Approval based on extrapolation was granted by the FDA for all other indications, including metastatic colorectal cancer (mCRC). The objective of this study was to evaluate the real-world effectiveness and safety outcomes of patients with mCRC initiated on bevacizumab-awwb versus bevacizumab in an integrated healthcare delivery system. Methods: This was an observational cohort study of patients with mCRC in Kaiser Permanente California, Colorado, and Mid-Atlantic States who were initiated on bevacizumab-awwb between July 2019 and March 2020 or reference bevacizumab between July 2015 and June 2018. Patients with history of bevacizumab use in the 6 months prior to the index treatment date were excluded. Patients were followed until 12 months after treatment initiation, end of plan membership, or death, whichever occurred first. The primary outcome of overall survival (OS) was analyzed using a non-inferiority test with lower margin of 10% and Cox proportional-hazards modeling. Secondary outcomes included count of doses received, treatment duration, all-cause hospitalizations, and incidence of serious adverse events. Results: A total of 1,445 patients initiated on either bevacizumab-awwb (n=239) or bevacizumab (n=1,206) were included in the analysis. The mean overall age was 60 ± 13 years and 54% of patients were male. The OS rate was 72.8% and 73.1% for patients receiving bevacizumab-awwb and bevacizumab, respectively ( p<0.01 for non-inferiority). The adjusted hazard ratio for mortality was 1.01 (0.77-1.33, p=0.93). There were no statistically significant differences in secondary outcomes between the 2 study groups (Table). Conclusions: Bevacizumab-awwb is a safe and effective option when compared to the reference bevacizumab in the treatment of mCRC. Future studies should evaluate outcomes after longer follow-up time and in different cancer types. [Table: see text]
Alternative biweekly dosing schedule of trifluridine-tipiracil (TAS-102) reduces rates of myelosuppression while maintaining therapeutic efficacy in patients (pts) with previously treated metastatic colorectal cancer (mCRC).
Authors: Cann Christopher G , Cimino Sarah , Grieb Brian , Ciombor Kristen Keon , Agarwal Rajiv , Das Satya , Goff Laura Williams , Cardin Dana Backlund , Davis Shemeka , Fletcher Casey , Berlin Jordan , Eng Cathy
Published: June 2022

3559

Background: Colorectal cancer remains a significant source of morbidity and mortality within the United States, causing nearly 53,000 deaths in 2021. For unresectable pts, the estimated 5-year survival rate is 14%. Given recent advances in treatment, 50% of pts with mCRC will receive third-line therapy or greater, making optimization of therapy in these settings pivotal. Trifluridine-tipiracil (TAS-102) is FDA approved for third-line or greater in mCRC per the RECOURSE Trial. Standard dosing is 35 mg/m2 twice daily (maximum = 80 mg/day) on Days 1-5 and Days 8-12 of 28-day cycles. This dosing schedule is associated with Grade 3-4 neutropenia (38%), requiring treatment delays (53%), dose reductions (14%) and G-CSF support (9%). To reduce this toxicity while maintaining efficacy, we studied an alternative biweekly dosing (Days 1-5 and Days 15-19 of 28-day cycles). Methods: A retrospective analysis was completed (2019-2021) at Vanderbilt-Ingram Cancer Center in pts with refractory mCRC and appendiceal cancer (CA) who completed > 12 days of TAS-102 therapy. Diagnostic imaging was completed every 8-12 weeks. Patient data was evaluated for lines of prior therapy, ECOG performance status (PS), the addition of bevacizumab, and CTCAE grade of treatment-related myelotoxicity. Evaluation of progression-free survival (PFS) was performed only in mCRC pts. Results: 24 pts met the criteria, with a mCRC:appendiceal CA ratio of 20:4 and Male:Female 13:11. Median age 61.5 yrs (range 31-80); median number of prior therapies 3; median ECOG PS of 1; and median duration of therapy 73.5 days. Hematologic toxicities: Neutropenia 30% [Grade 3 (13%), Grade 4 (0%)]; anemia 17.4% [Grade 3 (8.7%), Grade 4 (0%)]; thrombocytopenia 4.3% [Grade 3/4 (0%)]. No pts required G-CSF. One patient required a treatment-related dose delay (neutropenia), and 2 pts required dose reductions (fatigue). In mCRC pts, the median PFS was 2.3 months. To date, 7 mCRC pts remain on treatment (range: 38-385). Conclusions: In our retrospective cohort analysis, TAS-102 biweekly dosing schedule (35 mg/m2 twice daily; Days 1-5 and Days 15-19 of 28-day cycles) for pts with refractory mCRC and appendiceal CA reduced Grade 3 myelotoxicity without Grade 4 toxicities, while preserving PFS in pts with mCRC. With an improved toxicity profile, this alternative TAS -102 dosing schedule may be a more favorable option for future combination studies. Additional prospective data are needed to validate these findings. To our knowledge, this is the first analysis of biweekly TAS-102 in a US patient population.
Efficacy and safety of tislelizumab plus cetuximab and irinotecan in patients with previously treated RAS wild-type advanced colorectal cancer: Preliminary findings of a phase II, single-arm study.
Authors: Xu Xiaojing , Yu Yiyi , Wang Yan , Cui Yuehong , Li Wei , Liang Li , Li Qian , Yu Shan , Feng Yi , Liu Qing , Zhang Pengfei , Lv Minzhi , Liu Tianshu
Published: June 2022

3566

Background: For adequately treated patients (pts) with advanced colorectal cancer, the current third-line treatment standard of TKIs or TAS-102 administration has a low clinical objective response rate and its effectiveness seems to be limited. Preclinical studies have suggested that EGFR pathway blockage and immune checkpoint inhibition have synergistic therapeutic effects in these pts. The purpose of this study was to examine the efficacy and safety of tislelizumab (anti-PD-1 antibody) plus cetuximab and irinotecan in pts with previously treated RAS wild-type advanced colorectal cancer. Methods: This is an open-label, single-arm, phase II study. RAS wild-type advanced colorectal cancer pts with at least two previous lines of therapy were included in this study and administered with tislelizumab plus cetuximab and irinotecan until disease progression or intolerable toxicity. The primary endpoint was objective response rate (ORR) (RESCIT 1.1). Secondary endpoints included DCR, PFS, OS and safety. Results: In total, 35 eligible RAS wild-type advanced colorectal cancer pts were enrolled from March 2021 to September 2021. The median age was 58 years. All 35 pts were identified as BRAF/RAS wild-type, and 33 (94%) had left-sided colon cancer. The percentages of pts with second-line, third-line and ≥fourth-line previous treatments were 37%, 49%, and 14%, respectively. Thirty-four pts (97%) had received targeted therapies previously, including 29 (83%) with anti-EGFR therapy. By December 31, 2021, 2 pts had withdrawn from the study for personal reasons, and the remaining 33 were evaluated for efficacy. Twelve of the 33 (36.4%) pts achieved clinical partial remission and 14 (42.4%) achieved stable disease; disease progression occurred in 6 pts and 1 patient died. The ORR was 36.4% and the DCR was 78.8%. Until December 31, 2021, 23 pts continued treatments, and the median PFS was not reached. Among the 33 treated pts, 32 (97.0%) had treatment-related adverse events (AEs). Common AEs included rash (n = 32), fatigue (n = 29), decreased appetite (n = 24), nausea (n = 24), diarrhea (n = 13), liver dysfunction (n = 10), vomiting (n = 7), leukopenia (n = 7), anemia (n = 6), paronychia (n = 5), oral mucositis (n = 4), and neutropenia (n = 4). Four (12%) of the 33 pts reported grade ≥3 AEs, including rash (n = 1), neutropenia (n = 2) and vomiting (n = 1). Conclusions: Tislelizumab plus cetuximab and irinotecan shows an encouraging clinical efficacy and tolerable safety in previously treated pts with RAS wide-type advanced colorectal cancer. Clinical trial information: NCT05143099.
Clinical and radiological predictors of organ preservation in patients with rectal cancer treated with total neoadjuvant therapy.
Authors: Yuval Jonathan B , Verheij Floris S , Lin Sabrina T. , Thompson Hannah M , Omer Dana M , Kim Jin K , Smith Jesse Joshua , Gollub Marc J , Qin Li-Xuan , Garcia-Aguilar Julio ,   On behalf of the OPRA consortium
Published: June 2022

3619

Background: Baseline rectal MRI is routinely used for tumor staging, selecting the initial treatment and prognostication of patients with rectal adenocarcinoma. However, associations of baseline clinical and MRI variables with organ preservation (OP) in a prospective randomized trial have not been reported. Methods: Patients with MRI staged clinical stage II or III rectal adenocarcinoma treated in a prospective phase II clinical trial were randomized to either induction chemotherapy (FOLFOX or CAPEOX) followed by chemoradiation or chemoradiation followed by consolidation chemotherapy (FOLFOX or CAPEOX) and recommended total mesorectal excision (TME) or watch-and-wait (WW) based on clinical response. The primary outcome was OP, defined as the time from randomization to the clinical decision of TME or last follow-up, whichever occurred first. Clinical variables included: age, sex, race, tumor grade, radiation dose and treatment arm. Radiological variables (evaluated by baseline MRI prior to randomization) included: distance from the anal verge, tumor length, clinical T stage, clinical N stage, relationship to the mesorectal fascia, presence of extramural vascular invasion (EMVI) and mucinous radiographic findings (>50%). Associations of OP with clinical and radiological variables were assessed utilizing the Cox regression model in univariate and multivariate settings. The final multivariate model was chosen using backward selection. Results were analyzed by intention to treat. Results: Case report forms (CRFs) from baseline MRI were available for 289 of 324 randomized patients (89%). Patients with CRFs differed from those without CRFs in race, distance of the tumor from the anal verge and clinical T stage. Median follow-up was 3.4 years. A total of 156 of 324 patients were recommended TME during the study period. The 3-year OP rate was 47%. Independent predictors of OP in the multivariate analysis can be seen in the table. Conclusions: Although the patients included in this analysis may not be fully representative of the entire cohort, our data shows that several radiological variables associated with unfavorable tumor biology – tumor involvement of the mesorectal fascia, presence of EMVI and involved mesorectal nodes – were negatively associated with organ preservation. This information will be useful in selecting rectal cancer patients for WW and should be used for patient stratification in future clinical trials. Clinical trial information: NCT02008656. [Table: see text]
Validation of a multi-modal blood-based test for the detection of colorectal cancer with sub single molecule sensitivity.
Authors: D'Auria Kevin , Chang Yunpei , Multhaup Michael , Axelrod Haley , Zheng Lu , Burke Jordan , Young Greenwald William , He Yupeng , Pendleton Kathryn , McDonald Nathan , Raymond Victoria M. , Hartwig Anna , Duenwald Sven , Chudova Darya , Talasaz AmirAli
Published: June 2022

3627

Background: Blood-based colorectal cancer (CRC) screening tests can improve adherence to screening guidelines. Yet, current commercially available options have poor sensitivity and specificity inhibiting incorporation into routine clinical care. Here we report the validation of a blood-based test for the detection of colorectal cancer and advanced neoplasia. Methods: This blood-based test aims to detect colorectal neoplasia by identifying tumor-associated biomarkers including genomic or epigenomic (methylation and fragmentomics) signatures in cell-free DNA (cfDNA). cfDNA is partitioned based on methylation level, enriched for informative genomic regions, and sequenced. This novel workflow enables high-fidelity analysis of multi-modal information in majority of extracted cfDNA molecules. Results are integrated into a binary “detected” versus “not-detected” result using a proprietary bioinformatic pipeline (Guardant Health, USA). The assay was trained on samples obtained from >6,000 unique individuals (2,685 cancer-free and 1,698 with advanced colorectal neoplasia (ACN) for training, 1,072 cancer-free and 551 with ACN for threshold setting). The thresholds were frozen prior to validation targeting a specificity of > 91.5%. Each aspect of the validation study followed Nex-StoCT CLIA working group and CLSI guidelines. Results: Limit of detection (LoD) was established across six dilutions. Even for low cfDNA mass inputs of less than 4ng, the 95% LoD was determined to be less than 1 tumor-derived genomic equivalent (0.5), indicating over at least 10-fold increase in assay sensitivity compared to best-in-class assays for somatic mutation detection. Precision studies in 60 positive and negative replicates from clinical samples yielded >90% average positive and negative percent agreement both within and between batches. Endogenous interference studies yielded > 90% positive and negative percent agreement between reference control and common endogenous substances, including albumin, bilirubin, hemoglobin, triglycerides, and genomic DNA, in clinical positive and negative samples and minimally manipulated samples. The clinical validation of the test was conducted in > 300 cases (biobanked pre-operative cohort for CRC cases and screening cohort for advanced adenoma and negative cases). Conclusions: Here we present the validation of a multi-modal blood-based test for the detection of colorectal cancer. This test is currently being evaluated in a registrational study (ECLIPSE: NCT04136002).
Sequential nab-paclitaxel/gemcitabine followed by modified FOLFOX for first-line metastatic pancreatic cancer: The SEQUENCE trial.
Authors: Carrato Alfredo , Pazo-Cid Roberto , Macarulla Teresa , Gallego Javier , Jiménez-Fonseca Paula , Rivera Fernando , Cano Maria Teresa , Rodríguez Garrote Mercedes , Pericay Carles , Diaz Inmaculada , Layos Laura , Graña Begoña , Iranzo Vega , Gallego-Jimenez Inmaculada , Garcia-Carbonero Rocio , Alvarez Alejandro Maria , Ruiz de Mena Inmaculada , GUILLEN PONCE CARMEN , Aranda Enrique
Published: June 2022

4022

Background: Sequential treatment with nab-paclitaxel, gemcitabine followed by oxaliplatin, leucovorin and 5-fluorouracil ( nab-P/Gem-mFOLFOX) have shown a good safety profile and clinical activity in metastatic pancreatic ductal adenocarcinoma (mPDAC) in a previously published phase I SEQUENCE trial. Methods: We have compared nab-P/Gem-mFOLFOX to the standard nab-P/Gem in first-line treatment, in an open-label multi-institutional prospective randomised phase II trial in patients with untreated mPDAC from 14 Spanish hospitals. Patients were allocated 1:1 to nab-paclitaxel (125 mg/m2) plus gemcitabine (1000 mg/m2) on days 1, 8 and 15, followed by modified FOLFOX-6 (oxaliplatin [85 mg/m2], L-leucovorin [200 mg/m2] or racemic leucovorin [400 mg/m2], 5-fluorouracil bolus [400 mg/m2], and 5-fluorouracil 48-hour continuous infusion [2400 mg/m2]) on day 29 of a 6-week cycle or nab-paclitaxel (125 mg/m2) plus gemcitabine (1000 mg/m2) on days 1, 8 and 15 of a 4-week cycle. The primary endpoint was the 12-month overall survival rate (OS) in randomised patients. EudraCT number 2014-005350-19; ClinicalTrial.gov identifier NCT02504333. Results: Between July 27, 2017, and April 16, 2019, 182 patients were screened and 157 randomised: 78 to nab-P/Gem-mFOLFOX and 79 to nab-P/Gem. Patients receiving nab-P/Gem-mFOLFOX showed a significantly higher 12-month, and 24-month OS (95% CI): 55.3% (44.2-66.5%) versus 35.4% (24.9-46.0%) (p = 0.016), and 22.4% (13.0-31.8%) versus 7.6% (1.8-13.4%) (p = 0.012), respectively. The median OS (95% CI) reached 13.2 (10.1-16.2) months with nab-P/Gem-mFOLFOX and 9.7 (7.5-12.0) months with nab-P/Gem (HR = 0.676, 95% CI 0.483-0.947, p = 0.023). 39.7% patients in the nab-P/Gem-mFOLFOX group and 54.4% in nab-P/Gem group received subsequent anticancer treatments. Safety was comparable except for grade ≥3 neutropenia (46.1% versus 24.1%, p = 0.004) and grade ≥3 thrombocytopenia (23.7% versus 7.6%, p = 0.007) that were higher in the nab-P/Gem-mFOLFOX regimen. Two (2.6%) patients died due to adverse events in the nab-P/Gem-mFOLFOX arm. Conclusions: Nab-P/Gem-mFOLFOX showed significantly higher clinical activity than the standard nab-P/Gem treatment, with a manageable safety profile. This regimen represents a feasible and efficient new option for first-line treatment of mPDAC. Clinical trial information: NCT02504333.
Phase 3, multicenter, randomized study of CPI-613 with modified FOLFIRINOX (mFFX) versus FOLFIRINOX (FFX) as first-line therapy for patients with metastatic adenocarcinoma of the pancreas (AVENGER500).
Authors: Philip Philip Agop , Bahary Nathan , Mahipal Amit , Kasi Anup , Rocha Lima Caio Max Sao Pedro , Alistar Angela Tatiana , Oberstein Paul Eliezer , Golan Talia , Sahai Vaibhav , Metges Jean Philippe , Lacy Jill , Fountzilas Christos , Lopez Charles D. , Ducreux Michel , Hammel Pascal , Salem Mohamed E. , Bajor David Lawrence , Benson Al Bowen , Buyse Marc E. , Van Cutsem Eric
Published: June 2022

4023

Background: Metastatic pancreatic cancer (mPC) remains a deadly disease with very limited treatment options. FFX is a standard first-line therapy for mPC with a median overall survival (mOS) of 11.1 months. CPI-613 is a stable intermediate of a lipoate analog that inhibits pyruvate dehydrogenase and α-ketoglutarate dehydrogenase enzymes of the tricarboxylic cycle preferentially within the mitochondria of cancer cells. In a phase I study, CPI-613+mFFX was safe and exhibited promising signal of efficacy. Methods: A global, randomized phase 3 trial was conducted across 73 sites to investigate the efficacy and safety of CPI-613 in combination with mFFX compared to standard dose FFX in treatment-naïve patients with mPC. Treatment was administered in 2-weekly cycles until progression or intolerable toxicity. In the experimental arm, CPI-613 at 500 mg/m2 was given intravenously on days 1 and 3. The doses of irinotecan, oxaliplatin, and 5-fluorouracil in the experimental arm were 65 mg/m2, 140 mg/m2, and 2,400 mg/2, respectively. Primary endpoint was OS. Secondary endpoints were progression-free survival (PFS), overall response rate (ORR), duration of response, pharmacokinetics, patient reported outcomes and safety. Results: 528 patients were randomly assigned (266 in test and 262 in control arm). There were 362 deaths, with a mOS of 11.1 months for CPI-613+mFFX vs. 11.7 months for FFX [hazard ratio (HR), 0.95; 95% CI, 0.77 to 1.18; P = 0.655]; mPFS was 7.8 months vs. 8.0 months respectively [HR, 0.99; 95% CI, 0.76 to 1.29; P = 0.94]; ORR was 39% in the test arm vs. 34% in the control arm [ORR ratio, 1.23 (95% CI, 0.86 to 1.75)]. Grade ≥ 3 treatment-emergent adverse events with ≥ 10% frequency in CPI-613 plus mFFX vs. FFX arm were diarrhea (11.2% vs. 19.6%), hypokalemia (13.1% vs. 14.9%), anemia (13.9% vs. 13.6%), neutropenia (11.2% vs. 14.0%), thrombocytopenia (11.6% vs. 13.6%) and fatigue (10.8% vs. 11.5%). Conclusions: The addition of CPI-613 to mFFX failed to show significant improvements of ORR, PFS or OS. The mFFX in the test arm that had the lowest prospectively tested doses of FFX was without compromise on PFS or OS and may be considered as a reference for future FFX administration. Clinical trial information: NCT03504423.
Combination of oligo-fractionated irradiation with nivolumab can induce immune modulation and replacement of T cell clones in patients with gastric cancer (phase I/II clinical study).
Authors: Kono Koji , Mimura Kousaku , Ogata Takashi , Yoshimoto Yuya , Yoshida Daisaku , Nakajima Shotaro , Sato Hisashi , Machida Nozomu , Yamada Takanobu , Watanabe Yohei , Tamaki Tomoaki , Fujikawa Hirohito , Inokuchi Yasuhiro , Hayase Suguru , Hanayama Hiroyuki , Saze Zenichiro , Katoh Hiroyuki , Oshima Takashi , Suzuki Yoshiyuki , Nardin Alessandra
Published: June 2022

4027

Background: Although basic, translational and clinical research suggest a possibility of synergistic effect of radiation-induced immunogenic cell death with immune checkpoint inhibitors, the effectiveness of the combination therapy is not fully established. Therefore, we conducted a single-arm, phase 1/2 trial (ClinicalTrials.gov, NCT03453164) in gastric cancer (GC) patients treated with a combination of nivolumab and oligo-fractionated irradiation (22.5 Gy/5 fractions/5 days). Methods: Eligible patients (n = 40) had un-resectable advanced or recurrent GC which progressed after primary and secondary chemotherapy with more than one lesion assessable in diagnostic imaging (one lesion must be ≥2cm). PBMCs from enrolled patients underwent high-dimensional flow cytometry-based, multiplexed MHC multimer analysis using a total of 46 tumor-associated antigens (TAA) and 10 virus epitopes and next-generation sequencing-based repertoire analysis of TCR β-chain. Results: The disease control rate (DCR) for the non-irradiated target as abscopal effect as the primary endpoint was 22.5%, and the DCR for the irradiated lesion was 40.0%. The median survival time was 230 days (157-330 days, 95%CI) and probability of 1-year survival rate was 28.6%. Although most TAA-specific T cells could be tracked longitudinally pre- and post-treatment, some several novel TAA-specific CD8 T cells were detected de novo after irradiation, indicating that potential irradiation-driven antigen spreading. Moreover, irradiation was associated with phenotypical changes of TAA-specific CD8 T cells towards higher expressions of KLRG1, HLA-DR, TIGIT and CD160 and lower expression of CD27 and CD127. Furthermore, the T cell clonality evaluated by the inverted Pielou’s evenness indicated that longer survival patients had more diverse TCR beta repertoire during treatment in comparison to shorter survivors. Also, we confirmed several new sequence-reads after radiation and nivolumab treatment in the top 30 most frequent clonotypes. Conclusions: Taken together, our results suggest that irradiation may induce, through immunogenic cell death, an immune-modulating effect with potential antigen spreading and a more diverse TCR repertoire, ultimately resulting in better survival during combination therapy of radiation with nivolumab. Clinical trial information: NCT03453164.
SOURCE beyond first-line: A survival prediction model for patients with metastatic esophagogastric adenocarcinoma after failure of first-line palliative systemic therapy.
Authors: Kuijper Steven C. , Pape Marieke , Haj Mohammad Nadia , Van Voorthuizen Thymen , Zwinderman Aeilko H. , Verhoeven Rob , Van Laarhoven Hanneke W.M.
Published: June 2022

4037

Background: Prediction models for survival may aid shared decision making between physicians and patients. Prior models have been developed that predict survival for patients with potentially curable esophagogastric cancer and patients with metastatic esophageal cancer who start first-line therapy (the SOURCE models). The aim of this study was to develop and internally validate a registry-based clinical prediction model, called SOURCE beyond first-line, for survival of patients with metastatic esophagogastric cancer after failure of first-line palliative systemic therapy. Methods: Patients with unresectable or metastatic (synchronous or metachronous) esophageal or gastric cancer who received first-line systemic therapy (N = 1067) between 2015-2017 were selected from the Netherlands Cancer Registry. Follow-up data were retrieved in 2019. Patient, tumor and treatment characteristics at primary diagnosis and at progression of disease, were used to develop the prediction model. A Cox proportional hazards regression prediction model was developed through forward and backward selection using Akaike’s Information Criterion. The model was internally validated through 10-fold cross-validations to assess performance on unseen data. Model discrimination (C-index) and calibration (slope and intercept) were used to evaluate performance of the complete and cross-validated models. Results: The final model consisted of 10 patient, tumor and treatment characteristics. The C-index was 0.75 (0.74-0.77), the calibration slope 0.99 (0.98-0.99) and the calibration intercept 0.02 (0.01-0.02). Internal cross-validation of the model showed that the model performed adequately on unseen data: C-index 0.79 (0.76-0.80), calibration slope 1.02 (1.00-1.04) and calibration intercept -0.01 (-0.01-0.02). Conclusions: The SOURCE beyond first-line model predicted survival with fair discriminatory ability and good calibration, and is a valuable addition to the existing SOURCE prediction models. In the future this model will be integrated in an online decision support tool that can be used in clinical practice to aid personalized treatment.
A 107-gene Nanostring assay effectively characterizes complex multiomic gastric cancer molecular classification in a translational patient-derived organoid model.
Authors: Skubleny Daniel , Purich Kieran , Williams Thomas , Wickware Jim , Ghosh Sunita , Spratlin Jennifer L. , Schiller Dan E. , Rayat Gina
Published: June 2022

4049

Background: Multi-omics profiling of gastric cancer (GC) has produced numerous molecular classification systems. However, widespread clinical implementation and testing of molecular subtypes are currently limited. Here, we develop, validate and implement a custom Nanostring assay capable of allocating GC molecular subtypes to clinical specimens in a translational patient-derived organoid model. Methods: Using publicly available whole-transcriptome data, machine learning models were developed to predict GC molecular subtypes from 376 Cancer Genome Atlas (TCGA) and 1797 Tumour Microenvironment Score (TME) patients. Models were generated using feature selection with 10-fold nested cross-validation. GC biopsies from 10 local patients were preserved in paraffin (tumour) and established as an organoid culture (organoid). Gene expression was measured using Nanostring. The allocation of molecular subtypes was internally and externally validated using gold-standard reference features in public databases comprising 2202 GC patients and 10 tumour-organoid pairs, respectively. We evaluated the concordance of tumour-organoid molecular subtypes and explored the correlation between subtype scores and in-vitro chemotherapy response. Results: Classification models for TCGA (57 genes) and TME (50 genes) predicted subtypes with an accuracy ± standard deviation of 89.46% ± 0.04 and 89.33% ± 0.02, respectively. Subtype assignment of microsatellite instability (MSI) in reference to capillary electrophoresis was found to have 99.3% [95% CI 97.4-99.9, n = 277] internal and 100% [95% CI 83.2-100, n = 20] external accuracy. In reference to Epstein-Barr Virus (EBV) in-situ hybridization, EBV type internal and external accuracy was 98.7% [95% CI 97.4-99.5, n = 552] and 100% [95% CI 83.2-100, n = 20], respectively. TCGA Genomically Stable (GS) scores followed a previously characterized enrichment of diffuse-type histology compared to intestinal-type in internal and external cohorts (Dunn’s Test, p < 0.0001 and p < 0.05, n = 1471 and n = 15, respectively). Statistically similar subtype scores (Paired Wilcoxon, p > 0.05) were found for tumour-organoid pairs. Discordance occurred in three tumour-organoid pairs. In-vitro Drug Sensitivity Score was not statistically efficacious in any molecular subtype, but Pearson correlation identified increasing efficacy with increasing EBV and MSI scores. Conclusions: Patient-derived organoids generally recapitulate the molecular subtype of parent tumours; however, in specific cases, subtype discordance occurs. Although additional external validation is required, our 107 gene assay effectively captures multi-omics classification systems in GC and allows future inquiry into the prognostic and therapeutic implications of these molecular subtypes.
A phase I study of TST001, a high affinity humanized anti-CLDN18.2 monoclonal antibody, in combination with capecitabine and oxaliplatin (CAPOX) as a first-line treatment of advanced G/GEJ cancer.
Authors: Gong Jifang , Li Ning , Guo Weijian , Zhang Jian , Li Hongli , Zhao Fuyou , Li Wei , Sun Meili , Xia Zhenzhong , Shen Yu , Wang Jianming , Lu Lingmin , Qi Chuan , Qian Xueming , Shi Michael , Shen Lin
Published: June 2022

4062

Background: TST001 is a recombinant humanized IgG1 antibody specifically against human Claudin 18.2 (CLDN18.2) with high affinity and enhanced FcR engaging of NK cells, which can induce strong antibody-dependent cellular cytotoxicity (ADCC) activities. TST001 monotherapy dose-escalation study has been completed (IGCC2022-ABS-1152) and promising anti-tumor activities were observed in advanced gastric cancer patients with CLDN18.2 overexpression who had failed multiple lines of prior therapies. The current study is an open-label, multi-center, multiple cohorts, phase I clinical trial of TST001 monotherapy or in combination with standard treatments in Chinese patients with advanced or metastatic solid tumors (NCT04495296). Methods: This cohort is aimed to determine the recommended phase II dose, evaluate safety, tolerability and preliminary efficacy of TST001 in combination with CAPOX as a 1st line treatment of advanced G/GEJ cancer. A 3+3 design was utilized in the dose escalation phase with treatment naïve advanced G/GEJ cancer patients regardless of Claudin18.2 expression. Claudin 18.2 positive G/GEJ cancer patients were planned to be enrolled in the dose expansion phase in selected dose cohorts. Results: The TST001/CAPOX combination cohort was initiated in August 2021 and is ongoing in multiple sites in China with a data cutoff date of January 27, 2022. 12 subjects were dosed with TST001 with a dose range from 1 to 8mg/kg Q3W in combination with the standard dose of CAPOX in the dose escalation phase and one subject with central lab tested Claudin 18.2 overexpression was dosed in the expansion phase of TST001 at 6mg/kg Q3W with CAPOX. There was no subject experienced dose-limiting toxicity. Treatment-emergent adverse events (TEAEs) were mostly grade 1-2, including nausea (76.9%), anemia (69.2%), vomiting, AST increased (63.8% respectively), hypoalbuminemia, ALT increased (46.2%, respectively). Treatment related grade 3 AEs were hypertension （15.4%）, anemia, hypoproteinemia, WBC count decreased, hypocalcemia aggravated (7.7%, respectively). Among the eight patients from the dose escalation part (with no CLDN18.2 expression selection yet with measurable disease ) with at least one post-treatment tumor assessment, four had achieved partial response, three had achieved stable disease and one had progressive disease as the best tumor response per RECIST1.1. Conclusions: Conclusion: TST001 in combination with CAPOX in first line gastric cancer patients is safe and encouraging anti-tumor activities have been observed. Additional data from the 6 mg/kg dose expansion cohort will be updated at the meeting. Clinical trial information: NCT04495296.
Patient-reported outcomes for the phase 3 TOPAZ-1 study of durvalumab plus gemcitabine and cisplatin in advanced biliary tract cancer.
Authors: Burris III Howard A. , Okusaka Takuji , Vogel Arndt , Lee Myung Ah , Takahashi Hidenori , Breder Valeriy Vladimirovich , Blanc Jean-Frédéric , Li Junhe , Watras Magdalena , Xiong Julia , Abraham Jayne , Patel Nikunj , Wang Julie , Rokutanda Nana , Cohen Gordon , Oh Do-Youn
Published: June 2022

4070

Background: TOPAZ-1 (NCT03875235) is a randomized, double-blind, global, Phase 3 study evaluating the efficacy and safety of durvalumab (D) in combination with (+) gemcitabine and cisplatin (GC) as first-line treatment for patients (pts) with advanced biliary tract cancer (BTC).1 D + GC significantly improved overall survival (OS) versus placebo (PBO) + GC and represents a new treatment option. Methods: A pre-planned secondary objective of TOPAZ-1 was to assess pt-reported outcomes (PROs) for pts receiving D + GC versus PBO + GC. Pts with BTC were randomized 1:1 to D (1500 mg) or PBO, + G (1000 mg/m2) and C (25 mg/m2), for up to 8 cycles, followed by D or PBO monotherapy until disease progression, unacceptable toxicity, or other discontinuation criteria were met. PROs were assessed with the European Organisation for Research and Treatment of Cancer 30-item Quality of Life (QoL) Questionnaire, EORTC QLQ-C30 (C30), and the BTC 21-item module, EORTC QLQ-BIL21 (BIL21). Time to deterioration (TTD) was the primary assessment of PROs; defined as the time from randomization to the date of the first pre-specified, clinically meaningful deterioration (e.g. disease progression). The PRO analysis set included all pts from the full analysis set who completed a questionnaire. Results: Compliance rates for PROs were high at baseline (>81%) and remained high (majority >70% over 28 cycles) for both treatment groups. Baseline scores were comparable between treatment groups. Addition of D was well tolerated, with no significant difference in TTD in D + GC versus PBO + GC for pt-reported symptoms or functioning using either C30 or BIL21 (Table), or Global Health Status/QoL (hazard ratio [HR], 0.87; 95% confidence interval [CI], 0.69–1.12; p=0.279). Conclusions: Addition of D to GC improved OS (Oh D-Y, et al. J Clin Oncol 2022;40(suppl 4). Abs 378) and was well tolerated with no difference in TTD of QoL for pts, supporting D + GC as a new treatment option for pts with BTC. Clinical trial information: NCT03875235. [Table: see text]
Antibiotic therapy and association with oncological outcomes from targeted and immune-based therapy in hepatocellular carcinoma (HCC).
Authors: Pinato David J. James , Li Xiaoxue , Mishra-Kalyani Pallavi Shruti , D'Alessio Antonio , Fulgenzi Claudia A.M. , Wei Guo , Schneider Julie A. , Rivera Donna , Pazdur Richard , Theoret Marc Robert , Casak Sandra J. , Lemery Steven , Fashoyin Ibilola , Cortellini Alessio , Pelosof Lorraine Cheryl
Published: June 2022

4089

Background: Immune checkpoint inhibitors (ICI) alone or in combination with tyrosine kinase (TKI) or VEGF pathway inhibitors (VEGFi) are therapeutic options in unresectable HCC (uHCC). Whether exposure to antibiotics (ATB), a consolidated adverse prognostic factor in ICI recipients, affects outcome in HCC remains unclear. Methods: FDA analysed patient-level data of 4098 patients receiving ICI (n = 842) either as monotherapy (n = 258) or combinations (n = 584), TKI (N = 1968), VEGFi (n = 480) or placebo (n = 808) as part of 9 international clinical trials submitted to the US Food and Drug Administration in support of marketing applications. Associations for ATB exposure within 30 days before or after initiation of anti-cancer treatment (ATB) with overall (OS) and progression-free survival (PFS) were examined across therapeutic modality. Estimates were weighted by propensity score (PSW) using clinically relevant covariates. Results: Out of 4098 patients with uHCC mostly secondary to Hepatitis B (39%) or C (21%) infection, the majority were males (83%) with a median age of 64 (range 18-88), ECOG performance status of 0 (60%) and Child-Pugh A class (98%). Most patients had metastases (68%) but did not have macrovascular invasion (71%). Overall, 620 patients (15%) were ATB+, with comparable rates across placebo (12%), TKI (16%), VEGFi (15%), and ICI (16%). In the overall population, ATB was associated with shorter PFS (2.8 vs 3.9 months [m], HR 1.29, 95%CI 1.22-1.36) and OS (6.4 vs. 8.8 m; HR 1.36, 95%CI 1.29-1.43). In PSW analyses, ATB was associated with shorter PFS in patients treated with ICI (HR 1.52, 95%CI 1.34-1.73), TKI (HR 1.29, 95%CI 1.19-1.39) and placebo (HR 1.23, 95%CI 1.11-1.37). Similar results were observed in PSW analyses of OS in patients treated with ICI (HR 1.22, 95%CI 1.08-1.38), TKI HR 1.40, 95%CI 1.30-1.52), and placebo (HR 1.40, 95%CI 1.25-1.57). Consistent outcomes were observed for ATB+ patients within ICI treatment subgroups, including patients treated with anti-PD-1 monotherapy (PFS HR 1.49, 95%CI 1.22-1.80; OS HR 1.31 1.02-1.68) and ICI combinations (PFS HR 1.50, 95%CI 1.26-1.77; OS HR 1.14 0.99-1.32). Conclusions: Unlike other oncological indications where the detrimental effect of ATB may be more prominent in ICI recipients, ATB is associated with inferior outcomes across a broad range of anti-cancer therapies for HCC and placebo. Whether ATB is causally linked to worse outcomes through disruption of the gut liver axis remains to be demonstrated in translational studies.