bluuebunny/crossref_metadata_2025 huggingface dataset:
A large-scale, multi-center molecular characterization of MET fusions in a real-world Chinese population.
Authors: Liu Yutao , Xia Hui , Zhang Junhua , Si Tongguo
Published: June 2022

3064

Background: MET is a driver gene notable in its diversity of clinically relevant aberrations, including exon 14 skipping, copy number gain, point mutations, and gene fusions. Compared with the former two, MET fusions are severely under-reported, leaving unanswered a series of fundamental questions. In this study, we addressed this knowledge gap by screening for and characterizing MET fusions in a real-world, multi-center population of Chinese cancer patients. Methods: We retrospectively included patients with solid tumors and available genome profiles acquired between August 2015 to May 2021. MET fusion-positive ( MET+) patients were subsequently selected for clinical and molecular characterization. Results: A total of 79816 patients across 27 tumor types were screened. We detected 155 putative MET fusions from 122 patients, resulting in an overall prevalence of 0.15%. Lung cancer comprised the majority of MET+ patients (92, 75.4%). Prevalence was markedly higher in liver, biliary tract cancer, and renal cancer (range 0.52%-0.60%) and lower in ovarian cancer (0.06%). A substantial proportion (48/58, 82.8%) of unique partners were reported for the first time. The fusion partners also turned out to be highly heterogeneous, with ST7, HLA-DRB1, and KIF5B as the three most common partners. Mutational landscape analysis of lung adenocarcinoma patients (n = 32) revealed high prevalence of aberrant TP53 in MET+ patients as well as EGFR L858R, L861Q and MET amplification as concurrent alterations. Conclusions: This study is, to our knowledge, currently the largest in characterizing MET fusions. Our findings warrant further clinical validation and mechanistic study that may translate into therapeutic avenues for MET fusion-positive cancer patients.
Real-world utilization of ctDNA in the management of colorectal cancer.
Authors: Savill Kristin M. Zimmerman , Gentile Danielle , Jeune-Smith Yolaine , Klink Andrew J. , Feinberg Bruce A.
Published: June 2022

3075

Background: The utilization of circulating tumor DNA (ctDNA) as a non-invasive biomarker for the detection of minimal residual disease, prediction of recurrence in the post-operative setting, and real-time monitoring of treatment efficacy has the potential to vastly improve the care and outcomes of patients with colorectal cancer (CRC). In August of 2020, ctDNA testing first gained approval for use in solid tumors and its prognostic benefit after curative intent surgery has been demonstrated to exceed that of prior standard of care clinicopathological criteria in CRC patients. The comprehensive integration of validated ctDNA approaches into the routine clinical care of patients with CRC would not only fundamentally change how risk of recurrence is assessed but could also reduce treatment with unneeded/unwarranted toxic therapies and allow for earlier recognition and treatment in cases with a high risk of relapse. This survey-based study aimed to evaluate the utilization of ctDNA testing in the management of CRC among practicing community oncologists in the U.S. Methods: Questions related to ctDNA utilization for patients with CRC were presented to community oncologists during a virtual meeting held in July 2021. Descriptive statistics were used to analyze the results. Results: Of 55 participating oncologists geographically distributed across the U.S., 49% indicated not using ctDNA to make treatment decisions in CRC. A proportion of physicians reported using ctDNA to detect recurrence (27% of physicians); make decisions around post-resection adjuvant therapy (25%); monitor disease progression/relapse (18%); and track tumor resistance during treatment (9%). The most frequently cited barriers to ordering ctDNA testing for patients with metastatic CRC were reimbursement issues (reported by 56% of oncologists), insufficient clinical evidence (46%), and limited familiarity with ctDNA use (28%). Oncologists reported that the following would increase their utilization of ctDNA testing: more clinical evidence of the utility of ctDNA (reported by 66% of physicians), increased education on methodology (60%), more education on the use of ctDNA (57%), more financial aid and reimbursement support for patients (49%), more decision support tools (47%), and better communication between physicians and vendors (26%). Conclusions: These findings demonstrate limited adoption of ctDNA testing by community oncologists in the care of CRC patients. Insufficient demonstration of clinical utility, limited familiarity with methodology, and reimbursement issues were cited as barriers to uptake. Education for community oncology providers about ctDNA testing and its demonstrated clinical utility, and increased financial support for patients may improve its utilization and adoption in CRC to improve patient outcomes and care.
Updated analysis of the efficacy and safety of entrectinib in patients (pts) with locally advanced/metastatic NTRK fusion-positive (NTRK-fp) solid tumors.
Authors: Krzakowski Maciej Jerzy , Lu Shun , Cousin Sophie , Smit Egbert F. , Springfeld Christoph , Goto Koichi , Garrido Pilar , Chung Christine H. , Lin Jessica Jiyeong , Bray Victoria J. , Pitcher Bethany , Zeuner Harald , Patel Siddhartha , Bordogna Walter , Gelderblom Hans
Published: June 2022

3099

Background: NTRK gene fusions, coding for chimeric TRK proteins, are oncogenic drivers in many solid tumors. In an integrated analysis of three phase 1/2 trials (ALKA-372-001 [EudraCT 2012-000148-88]; STARTRK-1 [NCT02097810]; STARTRK-2 [NCT02568267]), entrectinib, a potent CNS-active TRK inhibitor, showed durable systemic and intracranial responses in pts with NTRK-fp solid tumors. We report updated data from a larger cohort with longer follow-up (clinical cutoff 2 Aug 2021). Methods: Pts with locally advanced/metastatic NTRK-fp solid tumors and ≥12 months’ follow-up from first tumor assessment were efficacy evaluable. The safety cohort also included pts from TAPISTRY (NCT04589845). Tumor responses were assessed by blinded independent central review (BICR) per RECIST v1.1 at Week 4 and every 8 weeks thereafter. Primary endpoints: objective response rate (ORR) and duration of response (DoR). Progression-free survival (PFS), overall survival (OS), intracranial (IC)-ORR and safety were also assessed. Results: The efficacy-evaluable cohort comprised 150 adults (vs 121 previously) with 17 different solid tumor types. Median age was 58.5 years; 91% of pts had ECOG PS 0–1 and 37% had received ≥2 prior lines of therapy. Median survival follow-up was 30.6 months. ORR was 61.3% (n = 92/150; 95% CI: 53.1–69.2), including 25 complete responses. Responses were observed in all tumor types with n>1 (Table). Median DoR, PFS and OS were 20.0 months (95% CI 13.2–31.1), 13.8 months (95% CI 10.1–20.0), and 37.1 months (95% CI 27.2–not estimable [NE]), respectively. In pts with and without investigator-assessed baseline CNS metastases (n = 31 / n = 119), ORR was 61.3% (95% CI 42.2–78.2) and 61.3% (95% CI 52.0–70.1) respectively. IC-ORR was 69.2% (n = 9/13) in pts with BICR-assessed measurable CNS metastases; median IC-DoR was 17.2 months (7.4–NE). In the safety population (N = 235: all treated pts), most treatment-related adverse events (TRAEs) were grade 1/2 and not serious; the most frequent were dysgeusia (36.6%), diarrhea (29.8%) and weight increase (28.5%). TRAEs led to dose interruption, reduction and discontinuation in 32.8%, 24.3% and 7.2% of pts, respectively. Conclusions: In this updated analysis, entrectinib continued to demonstrate deep and durable responses and was well tolerated in pts with NTRK-fp solid tumors with or without baseline CNS metastases. Clinical trial information: STARTRK-2 [NCT02568267]. [Table: see text]
The distribution of genetic mutations correlated with resistance to KRASG12C inhibitors in Chinese patients with lung cancer.
Authors: Lin Shengcheng , Ma Kai , Xu Yafei , Liu Xinyi , Huang Xiaochun , Huang Mengli
Published: June 2022

3141

Background: In lung cancer, p.G12C is the most frequent variant in Kirsten rat sarcoma viral oncogene homologue (KRAS) gene. KRASG12C inhibitors have shown promising efficacy in lung cancer in recent clinical trials, acquired resistance, however, eventually occurred in most patients. Preliminary studies revealed that a number of genetic mutations were correlated with resistance to this type of drugs, including KRAS secondary mutations, KRAS activating mutations, mutations in RTK-RAS-MAPK signaling pathways members, oncogene rearrangements and copy number gain. To clarify the potential clinical application of KRASG12C inhibitors, herein we analyzed the distribution of reported resistance gene alterations in a large and natural group of Chinese lung cancer, as well as the gene mutation landscape of the subset of patients with suspected resistant mutations. Methods: A total of 32878 Chinese lung cancer including early-stage, late-stage without treatment or late-stage with previously treated were analyzed in this study. Wide NGS panel testing was used to detected single nucleotide variants (SNV), copy number variants (CNV) and oncogenic gene rearrangements. Results: KRAS mutations were detected in 2767 (8.4%) cases, of which KRAS G12C was the most common variant (30.86%). Among 854 patients (2.6%) harbored KRAS G12C, 75 (10%) carried the above resistance mutations, such as G12D/R/V (n = 7). Fusions (20%) which previously observed only in coloretal cancer were unexpectedly detected in this corhort, including EML4-ALK (n = 1), FGFR1-MECOM (n = 1), EWSR1-CHEK2 (n = 2), SPEN-KAZN (n = 2), MET-KCNB2 (n = 1), NOTCH2-NOTCH2NLA (n = 5), SMARCA4-DNAH8 (n = 1), and LIPM-FAS (n = 1). Furthermore, KRAS (46.7%), MYC (25.3%) and MET (10.7%) were amplified. Among this subset of patients with resistant mutations, TP53 (66%), LRP1B (25%), and STK11 (22%) were the most frequently mutated genes. It is noteworthy that STK11/KEAP1 /NFE2L2 gene mutation was detected in nearly 30% in this group of patients. Conclusions: The results of our analysis suggested that about 10% KRAS G12C-mutated Chinese lung cancer patients would be resistant to KRAS G12C inhibitors. Moreover, a small number patients have co-mutated genes which were negatively related to immunotherapy in NSCLC, indicating they were also inappropriate for immunotherapy.
Updated survival follow-up for phase I study of abexinostat with pazopanib in patients with solid tumor malignancies.
Authors: Tsang Erica S , Aggarwal Rahul Raj , Thomas Scott , Dhawan Mallika Sachdev , Pawlowska Nela , Bartelink Imke Heleen , Grabowsky Jennifer A. , Jahan Thierry Marie , Truong Thach-Giao , Ryan Charles J. , Munster Pamela N.
Published: June 2022

3150

Background: Histone deacetylase (HDAC) inhibition downregulates HIF-1a, which may be effective in overcoming resistance to VEGF-targeting tyrosine kinase inhibitors. We report the updated survival follow-up for patients treated with abexinostat and pazopanib in a phase Ib trial. Methods: Patients with solid tumor malignancies were enrolled in this phase Ib, open-label trial (NCT01543763) of abexinostat in combination with pazopanib (3+3 design), with a dose expansion restricted to renal cell carcinoma (RCC). Patients received a 1-week run-in period with abexinostat alone, and then combination abexinostat with pazopanib during a 28-day treatment cycle until disease progression, unacceptable toxicity or study withdrawal. Plasma samples from 29 patients were sent for metabolomics analysis. Results: 51 patients were enrolled: N = 36 patients in dose escalation, N = 15 in dose expansion. At the time of last report in 2017, 5 patients remained on study treatment: N = 4 with RCC, and N = 1 with thymic neuroendocrine carcinoma. 4 of these patients have now had disease progression. Median duration of therapy measured 44.9 months (range 39.8-102.2). One patient with metastatic RCC (patient 1) remains on study treatment, after progression on 5 prior lines of systemic therapy. With updated survival follow-up, median OS measured 12.4 months in the dose escalation arm and 27.65 months in the RCC dose expansion cohort. Overall median duration of therapy in all 51 patients measured 5.6 months (range 1-103 months). Progression-free survival among patients with high PBMC HDAC2 expression (> 0.4) remains longer compared to those with low expression (median 6.3 vs. 3.7 months, p = 0.0041). Metabolomics analysis demonstrated a negative correlation between HDAC2 and N6-acetyllysine, suggesting that baseline HDAC2 may impact efficacy of HDAC inhibition. Conclusions: The combination of abexinostat with pazopanib appears promising, with the potential for long-term responses particularly in patients with metastatic RCC. This has led to an ongoing phase III trial examining this combination in RCC. Clinical trial information: NCT01543763. [Table: see text]
Cell-free DNA (cfDNA) fragmentomes predict tumor burden in metastatic colorectal cancer (mCRC).
Authors: Leal Alessandro , van 't Erve Iris , Lumbard Keith , Keefer Laurel , Carey Jacob , Wu Tony , Jakubowski Debbie , Butler Denise , Rongione Michael , Chesnick Bryan , Punt Cornelis J. A. , Meijer Gerrit A. , Dracopoli Nicholas C , Maddala Tara , Scharpf Robert , Bach Peter Brian , Velculescu Victor E. , Fijneman Remond
Published: June 2022

3541

Background: Measurement of plasma mutant allele fraction (MAF) in patients with cancer provides prognostic information, but this approach typically relies on prior tumor tissue analyses or knowledge of specific mutations. There is a clinical need to develop rapid and accurate noninvasive plasma-only approaches to estimate disease burden dynamics. Comprehensive genome-wide analyses of cfDNA fragmentomes has become a useful tool for noninvasive cancer characterization. Here we present a novel application to predict MAF from genome-wide fragmentation-related profiles (fMAF) as a prognostic marker in mCRC patients with initially unresectable liver-only metastases enrolled in the phase III CAIRO5 study (NCT02162563). Methods: 693 longitudinal plasma cfDNA samples were obtained from patients with RAS/BRAF-mutant mCRC (training arm, N = 78) and patients with RAS/BRAF wild-type mCRC (validation arm, N = 75) treated with first-line fluoropyrimidine-based chemotherapy were collected. MAFs as measured by digital droplet PCR (ddPCR) were obtained for patients in the training arm. We trained an initial regression model to predict MAFs with genome-wide fragmentation features using subject-level random intercepts. Out of sample predictions for participants in the RAS/BRAF-mutant mCRC arm were obtained through cross-validation. Cox proportional hazards models were used to evaluate the association between fMAF and PFS and overall survival (OS) at pre- and first post-treatment blood draws. Standardized hazard ratios (sHR) and 95% confidence intervals (CI) are reported. Results: There were 68 and 61 evaluable participants with median (range) age of 62 y (41-79 y) and 58 y (27-76 y), and 38% and 36% female in the training and testing arms, respectively. Median time between pre- and post-treatment blood draw was 8 weeks. In the training cohort, median fMAFs dropped from pre- to post-treatment initiation (17.8% to 1.8%). Median PFS was 9 months. For both fMAFs and RAS/BRAF MAFs, the association with PFS was stronger for the pre-treatment than the post-treatment timepoint (Table). Post-treatment fMAFs were not associated with PFS in the training cohort and similar trends were observed for OS. Conclusions: Initial modeling demonstrates the ability of cfDNA fragmentomes to estimate cell-free DNA tumor burden with performance comparable to standard approaches. Ongoing modeling efforts will result in evaluation of a final model in the testing arm. The development of a noninvasive tissue-independent diagnostic approach that does not rely on mutation detection in the circulation has the potential to expand the use of liquid biopsies for advanced disease monitoring. Clinical trial information: NCT02162563. [Table: see text]
Association between environmental quality index and young onset colorectal cancer.
Authors: Goksu Suleyman Yasin , Khatib Jude , Reddy Sarah , Ozer Muhammet , Maxwell Mary Claire , Khosama Leticia , Kainthla Radhika , Sanford Nina Niu , Pogacnik Javier Salgado , Chilakamarry Sitaram , Huang Emina , Beg Shaalan Shaalan , Kazmi Syed Mohammad Ali
Published: June 2022

3548

Background: The factors associated with the rise of young-onset colorectal cancer (YOCRC) remain unclear. However, environmental exposures are believed to be associated with YOCRC in addition to hereditary factors. Therefore, we evaluated the association between the national level Environmental Quality Index (EQI) and YOCRC in the US. Methods: We queried the SEER database to identify adult colorectal cancer patients diagnosed between 2010-2016. YOCRC was defined as age at diagnosis < 50 years. EQI (2005-2010) is a measure of county-level cumulative environmental exposures that includes 5 domains: sociodemographic, built, air, land, and water. A higher value represents a lower environmental quality. We distributed the total EQI and each EQI domain into five quintiles. Multivariable logistic regression analysis was used to assess the relationship between YOCRC and quintiles (upper-most vs. lowest) of EQI after adjusting by race (White, Black, and Others), gender, and stage at diagnosis. The age-adjusted incidence rate was also calculated using the SEER*Stat, and correlation efficiency was estimated between EQI domains and incidence rate. Results: A total of 261,417 CRC patients were included; 11% were YOCRC. In the adjusted multivariable analysis, poor built EQI (OR 1.15 [1.11-1.20]) and water EQI (OR 1.08 [1.03-1.12]) were more likely to be associated with YOCRC. Poor built EQI was more strongly associated with Black YOCRC (OR 1.21 [1.09-1.35]) as compared to White YOCRC (OR 1.14 [1.09-1.19]). Poor sociodemographic EQI was more strongly associated with Others (OR 1.47 [1.25-1.72]) compared to Black YOCRC (OR 1.14 [1.03-1.25]). In addition, poor built EQI (OR 1.19 [1.12-1.27]) and water EQI (OR 1.12 [1.05-1.19]) were more strongly associated with the metastatic disease among YOCRC patients. However, the total poor EQI was not associated with YOCRC (OR 0.99 [0.95-1.03]). On incidence analysis, there was a positive correlation between the incidence rate of YOCRC and sociodemographic EQI (rho = 0.49, p < 0.001), air EQI (rho = 0.30, p < 0.001), and land EQI (rho = 0.18, p < 0.001). Conclusions: This study evaluated a population-based ecological approach and showed that YOCRC was associated with lower environmental quality, including built and water domains. EQI domains were also associated with different racial groups among YOCRC. Instead of studying single environmental exposures, the impact of the cumulative environmental index should be recognized and studied further to understand the mechanism of cancer development.
Early detection of colorectal adenocarcinoma by decoding epigenetic and DNA fragmentation fingerprints of plasma cell-free DNA.
Authors: Suxing Li , Han Tiancheng , Yang Shunli , Liu Dan , Nie Peiyao , Lv Fang , He Shuying , Yang Ying , LI Yulong , Yu Jianing , Hong Yuanyuan , Huang Yu S. , Chen Weizhi , Wen Zhengqi
Published: June 2022

3550

Background: Cell-free DNA (cfDNA) methylation, fragmentation patterns, chromosome instability, and chromatin accessiblity have been previously shown to be valid plasma biomarkers for non-invasive cancer detection. However, conventional whole-genome bisulfite sequencing (WGBS) is unable to simultaneously profile all these biomarkers due to bisulfite-induced DNA damages. Here we developed a machine learning approach to comprehensively integrate multiple types of cancer genomic markers from enzyme-conversion-based low-pass whole-methylome sequencing (WMS) of plasma cfDNA to non-invasively detect colorectal adenocarcinoma. Methods: Plasma cfDNA sampels from 215 colorectal adenocarcinoma patients and 568 healthy individuals were collected and were split into the discovery and independent testing cohort. The discovery cohort includes 150 cancer patients and 398 healthy individuals and the independent testing cohort includes 65 cancer patients and 170 healthy individuals. Whole methylome sequencing (WMS) libraries were generated from enzymatically converted cfDNA and were subsequently paired-end sequenced at ̃2X coverage. The genome-wide methylation density, fragmentation fingerprints, chromosome instability, and chromatin accessibility were extracted from the WMS data and individually modelled via machine learning methods such as SVM, LR, GBDT, random forest. The final predictive model is an ensemble model integrating all uni-modal models. All models were trained and fitted on the discovery cohort. Results: Data of different modalities provide complementary information in separating the cancer patients from the healthy individuals. Unsupervised clustering of the individuals showed clear separation between cancer patients and healthy individuals. The final predictive model achieved AUC =0.982 in the discovery cohort and AUC =0.9664 in the independent testing cohort. Under a specificity of 94.71% (CI: 90% - 98.82%), sensitivity was 78.46% (CI: 60% - 92.31%) in the independent testing cohort. Separating the cancer patients into different stages, we found that the detection power is usuaul lower for early-stage cancer patients. Conclusions: These results demonstrate the first proof of principle on the feasibility of integrating multiple genomic cancer markers to non-invasively detect colorectal adenocarcinoma from WMS plasma cell-free DNA. A large prospective cohort study is planned to further validate its clinical performance.
CPGJ602 plus mFOLFOX6 as first-line treatment for patients with KRAS/NRAS/BRAF wild-type metastatic colorectal cancer: A randomized phase II study.
Authors: Xu Jianming , Cao Bangwei , Gu Kangsheng , Bai Yuxian , Li Wei , Zhang Jingdong , Liu Caigang , Niu Zuoxing , Zhang Liangming , Zhong Haijun , Luo SuXia , Zhou Jian-Wei , Liu Tianshu , Gu Yanhong , Lin Jingguan , Deng Yanhong , Chen Chuangqi , Li Yunfeng , Yang Xiuli , Li Bihui
Published: June 2022

3574

Background: CPGJ602 is a recombinant anti-EGFR human-mouse chimeric monoclonal antibody. CPGJ602 plus modified fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) may have efficacy in KRAS/NRAS/BRAF wild-type metastatic colorectal cancer. Methods: In this open-label, randomized trial, patients who had received no previous treatment were randomly assigned (2:2:1) to receive CPGJ60（325mg/m2, q2w) plus mFOLFOX6 (biweekly group), CPGJ602 (400 mg/m 2 initial dose followed by 250 mg/m2 /week thereafter) plus mFOLFOX6 (weekly group) or cetuximab (400 mg/m2 initial dose followed by 250 mg/m2 /week thereafter) plus mFOLFOX6 (cetuximab group). All subjects received treatment up to 16 weeks. The primary endpoint was the best overall response (BOR) at 16 weeks. The second endpoints were DCR, DOR, PFS, safety. Results: As of Dec 30, 2021, 76 patients were enrolled (30 in biweekly group, 32 in weekly group and 14 in control group). The best overall response achieved at 16 weeks was 76.7% (23/30, 95% CI 60.3% - 92.0%),78.1% (25/32, 95% CI 62.5% - 92.5%) and 78.6% (11/14, 95% CI 49.2% - 95.3%) in the biweekly group, weekly group and cetuximab group, respectively. The confirmed overall response rate at 16 weeks was 60%(18/30), 71.9%(23/32) and 57.1%(8/14) in the biweekly group, weekly group and cetuximab group, respectively. The PFS rates at 16 weeks were 81.5% (95% CI 57.7% -92.6%), 96.8% (95% CI 79.2%-99.5%), 81.3% (95% CI 41.5%- 95.2%) in the biweekly group, weekly group and cetuximab group, respectively. The most common adverse events were a decreased neutrophil count (60%，78.1% and 71.4% in the biweekly group, weekly group and cetuximab group respectively), decreased white-cell count (53.3%, 78.1% and 71.4% respectively), decreased platelet count (40.0%, 40.6% and 42.9% respectively), and elevated serum aspartate aminotransferase (43.3%, 37.5% and 35.7% respectively). Conclusions: CPGJ602 plus mFOLFOX6 could be an option for KRAS/NRAS/BRAF wild-type metastatic colorectal cancer. Clinical trial information: NCT04466254.
Codon-specific KRAS mutations predict overall survival benefit of trifluridine/tipiracil in metastatic colorectal cancer.
Authors: van de Haar Joris , Ma Xuhui , Ooft Salo N. , van der Helm Pim W. , Hoes Louisa Rose , Mainardi Sara , Wessels Lodewyk F.A. , Voest Emile E.
Published: June 2022

3593

Background: Genomics-based precision medicine has greatly improved how patients with cancer are being treated with targeted agents, but clinical-grade genomic biomarkers for chemotherapies are currently lacking. The chemotherapeutic trifluridine/tipiracil (FTD/TPI) is approved for the treatment of late-stage metastatic colorectal cancer (mCRC). We aimed to find genomic biomarkers to improve patient selection for FTD/TPI treatment in mCRC. Methods: In a discovery cohort of FTD/TPI-treated mCRC patients (n = 37), genome-wide somatic variants were tested for association with treatment duration and overall survival (OS). In vitro drug testing on isogenic cell lines and patient-derived mCRC organoids, as well as a re-analysis of the double-blind, placebo-controlled, phase 3 RECOURSE trial (n = 800) were performed to support our findings. Results: In the discovery cohort, KRAS codon G12 (KRASG12) mutation status was the only significant genomic determinant of poor outcome of FTD/TPI treatment, which could be replicated in vitro by drug testing on isogenic cell lines and PDOs. In these models, KRASG12 mutations were associated with increased resistance to FTD-induced (geno)toxicity in vitro. KRASG12-based resistance was absent for the closely related chemotherapeutic 5-FU. In the RECOURSE study, KRASG12 mutations were predictive biomarkers for reduced OS benefit of FTD/TPI vs placebo (unadjusted interaction P= 0.0017, adjusted interaction P= 0.017). For patients with KRASG12 mutations, OS was not significantly prolonged with FTD/TPI vs placebo (n = 279; HR, 0.97; 95% CI, 0.73−1.20; P= 0.85). An exploratory analysis showed that the KRASG13 mutant subgroup demonstrated clearly prolonged OS with FTD/TPI vs placebo (n = 60; unadjusted HR, 0.29; 95% CI, 0.15−0.55; P< 0.001; adjusted HR, 0.20; 95% CI, 0.092−0.45; P< 0.001), which was significantly more pronounced as compared to the KRASG12 mutant and KRASWT populations (adjusted interaction P< 0.001 and P= 0.036, respectively). Conclusions: Together, KRASG12 mutations were associated with reduced OS benefit of FTD/TPI treatment, with potential implications for ̃28% of patients with metastatic colorectal cancer now considered for treatment with FTD/TPI. Furthermore, our data show that genomics-based precision medicine may be possible for a subset of chemotherapies.
Effectiveness of nationwide insurance coverage for next-generation sequencing in advanced colorectal cancer: A real-world data study.
Authors: Park Sun-Kyeong , Kang Dong-Won , Yu Ye Lee , Cha Yongjun , Kang Sokbom
Published: June 2022

3602

Background: Next-generation sequencing (NGS) has been covered by Korean national health insurance since March 2017 for patients with advanced colorectal cancer (CRC). We explored the clinical and socioeconomic impact of NGS compared with that of a single gene test (SGT) alone. Methods: From the nationwide database, we identified patients who 1) are diagnosed with advanced CRC classified as a distant disease using Summary Stage between March 1, 2017, and December 31, 2018; 2) had NGS or SGT within 2 months after diagnosis of advanced CRC. Multivariate logistic regression with covariates including age, sex, Charlson comorbidity index, insurance type, year of diagnosis, and region and type of hospital with the initial diagnosis was conducted to identify factors affecting the performance of NGS. We conducted 1:3 propensity score matching to minimize the impact of confounding factors. The median overall survival and the adjusted hazard ratio (aHR) were estimated using the Kaplan-Meier method and the Cox proportional hazard model, respectively. We calculated the total medical cost, and per patient per year (PPPY) cost adjusted for the survival period. Results: Among 5,029 patients with advanced CRC, 655 patients were identified as NGS group and 1,995 as SGT group after matching. Old age, low household income, rural location, and non-tertiary hospital were all characteristics that reduced the likelihood of obtaining an NGS test. The NGS group showed significantly favorable survival compared to the SGT group (median survival 29.2 vs. 24.9 months, P =.031; adjusted hazard ratio [HR] 0.86, P =.034). The total medical cost was lower in the NGS group ($55,445) than the SGT group ($57,989), and the PPPY cost was also lower in the NGS group ($44,879 and $49,734, respectively). Conclusions: We found that some socioeconomic factors such as age, insurance type, region, and hospital type may hamper the implementation of NGS. Also, lowering the barrier of NGS tests by reimbursing NGS in a specific clinical setting may have survival and cost-benefit in patients with advanced CRC.
Preservation of liver function with local radiation therapy in patients with metastatic intrahepatic cholangiocarcinoma with extrahepatic disease.
Authors: Upadhyay Rituraj , Ludmir Ethan B. , De Brian , Holliday Emma , Smith Grace L. , Taniguchi Cullen M. , Das Prajnan , Minsky Bruce D. , Koong Albert C. , Javle Milind M. , Lee Sunyoung S. , Vauthey Jean-Nicolas , Tzeng Ching-Wei D. , Tran Cao Hop , Koay Eugene Jon
Published: June 2022

4080

Background: Tumor related liver failure (TRLF) is the most common cause of death in patients with metastatic intrahepatic cholangiocarcinoma (mICC) accounting for up to 72% deaths in patients treated with systemic therapy alone. We present our institutional experience of treating mICC patients with local liver-directed radiation therapy (RT). Methods: ICC patients with extrahepatic metastatic disease who received radiation therapy at our center with a biologically equivalent dose (BED) of at least 50 Gy from January 1, 2011 to March 31, 2021 were included in our study. Patient, tumor and treatment characteristics as well as the survival outcomes were recorded. TRLF was considered the cause of death if the patient died due to liver failure; and freedom from TRLF (FFTRLF) at 1 year and 2 years after RT was calculated. Results: Sixty-seven patients were included in the study. The median age was 63 years (range 29-83 years) and median RT dose was 60 Gy (range, 40-100 Gy). 73.1% patients received a BED > 80.5 Gy. All except 1 patient were treated with upfront induction chemotherapy, followed by RT to the primary lesion in liver with (71.6%) or without (28.4%) concurrent chemotherapy. The most common induction chemotherapy regimen used was gemcitabine and cisplatin (65.7%) followed by gemcitabine, cisplatin and paclitaxel (22.4%), while the most common concurrent systemic therapy was capecitabine. Out of 43 patients with satellitosis, 29 were treated with RT to the dominant liver lesion while 14 received RT to the primary as well as one or more satellites. Overall, 15 patients (22.4%) had local progression of the radiated lesion, 42 patients (62.7%) progressed elsewhere in liver, and 52 patients (77.6%) had a distant progression. TRLF was the cause of death in 28.4% of patients. Median OS from diagnosis was 25 months while median OS after RT was 11.9 months. The 1- and 2-year rates of FFTRLF were 73.1% and 58.2% respectively, which were significantly higher than 1- and 2-year OS after RT (47.1% and 24.7% respectively, p < 0.005). Univariate analysis did not identify significant association of FFTRLF or OS with age, sex, performance status, size of liver lesions, T or N stage, satellitosis, vascular thrombosis, TRLF, timing of metastasis, site of metastasis, RT technique and dose and chemotherapy. Conclusions: Liver directed radiation therapy in patients with mICC with extrahepatic disease appears to have favorable rates of TRLF and survival times, compared to historical data. Future prospective studies are warranted to define the survival benefit in these patients attributable to radiation therapy.
Clinical impact of MAPK pathway alterations in advanced biliary tract cancer (BTC): SCRUM-Japan GOZILA and COLOMATE international collaboration.
Authors: Takahashi Hideaki , Caughey Bennett Adam , Umemoto Kumiko , Green Michelle , Nakamura Yoshiaki , Datto Michael , Ueno Makoto , Walden Daniel , Esaki Taito , Oliver Thomas , Komatsu Yoshito , Mizuno Nobumasa , Oki Eiji , Taniguchi Hiroya , Bando Hideaki , Morizane Chigusa , Yoshino Takayuki , Strickler John H , Ikeda Masafumi , Bekaii-Saab Tanios S.
Published: June 2022

4086

Background: Abnormalities in the MAPK pathway are potential therapeutic targets in various cancers. However, the clinical impact of alterations in the MAPK pathway in BTC have not been elucidated, especially outside of canonical mutations in KRAS and BRAF. We investigated the clinical outcomes of advanced BTC with MAPK pathway alterations treated with chemotherapy in Japan and the United States. Methods: Patients with advanced BTC who received gemcitabine plus cisplatin as first-line therapy were included from the GOZILA study in Japan and Duke Molecular Registry of Tumors in the US. Genetic abnormalities were detected by Guardant360, a cell-free DNA assay, in Japan and by blood or tissue-based next-generation sequencing (NGS) at Duke University. Two hundred and seven patients with BTC from Japan were included in an exploratory cohort to evaluate the association of MAPK alterations with overall survival (OS) according to MAPK alteration status. One hundred and ten patients with BTC from both Japan and the US harboring oncogenic alterations in the MAPK pathway were included in a biomarker selected cohort to assess the association of specific MAPK alterations with OS. Multivariate analysis was performed using a Cox regression model based on a univariate p-value < 0.2. Results: MAPK pathway-related oncogenic alterations detected in each cohort are shown in the table below. In the exploratory cohort, median OS was shorter for patients with MAPK alterations vs. no MAPK alteration (15.9 m vs. 24.9 m, log-rank p = 0.001). Based on univariate analysis, the following covariates were selected for multivariate analyses: age, prior resection, and MAPK pathway alteration in the exploratory cohort; country, the timing of NGS, distant metastasis, KRAS amplification, and BRAF class 2 mutation in the biomarker selected cohort. In the exploratory cohort, multivariate analysis identified MAPK pathway alterations as an independent predictor of shorter OS with a HR of 1.92 (95% CI = 1.28-2.87, p = 0.001). In the biomarker selected cohort, multivariate analysis identified BRAF class 2 mutations and KRAS amplification as independent predictors of shorter OS with a HR of 16.2 (95% CI = 3.26-80.8, p = 0.001) and 5.97 (95% CI = 1.74-19.3, p = 0.002) respectively. Conclusions: MAPK pathway alterations, especially BRAF class 2 mutation and KRAS amplification, had a significant negative impact on clinical outcomes in BTC receiving first-line chemotherapy. These results are newly confirmed in BTC. [Table: see text]
Resectable pancreatic adenocarcinoma neo-adjuvant FOLF(IRIN)OX-based chemotherapy: A multicenter, non-comparative, randomized, phase II trial (PANACHE01-PRODIGE48 study).
Authors: Schwarz Lilian , Bachet Jean-Baptiste , Meurisse Aurelia , Bouché Olivier , Assenat Eric , Piessen Guillaume , Terrebonne Eric , Hammel Pascal , Regenet Nicolas , Turco Célia , Taieb Julien , Mabrut Jean-Yves , Turrini Olivier , Portales Fabienne , Paye Francois , Barbier Louise , Truant Stephanie , Sa Cunha Antonio ,   PANACHE01-PRODIGE48 Authors' Group
Published: June 2022

4134

Background: Despite the limited number of published RCTs, patients with resectable pancreatic adenocarcinoma (rPAC; NCCN criteria) seem to benefit from neoadjuvant (NAT) with regards to R0 resection rate, downstaging and survivals (PREOPANC-1; Preop-02/JSAP-05; NEONAX, SWOG05-15). Few prospective results are currently available concerning the completion of the full therapeutic sequence and oncological results. Methods: In the PANACHE01-PRODIGE48 prospective multicenter controlled non-comparative Phase II trial, 153 patients with rPDAC were randomized 2:2:1 to 4 cycles of NAT chemotherapy (mFOLFIRINOX; Arm1 or FOLFOX; Arm2) or upfront surgery (Ctrl_Arm) in 28 French centers from 02/2017 to 07/2020. Primary objective was to evaluate the safety and efficacy of two regimens of NAT chemotherapy. The main co-primary endpoints were 1y-OS rate after randomization and the rate of patients undergoing the full therapeutic sequence. Event-free survival (EFS) was used to evaluate the time to recurrence between groups. An event being defined as progression before surgery, unresectable or metastatic disease at surgical exploration, recurrence after surgery or death. Results: Of the 153 randomized patients, 146 were available for analysis (Arm1,n=70; Arm2,n=50; Ctrl_arm,n=26). In the Arm1 and 2, completion of the 4 planed cycles was 88.6 and 84%, respectively, with a dose reduction in 52% and 24%. The cumulative rates of grade 3/4/5 toxicity were 56.7 and 57.4%, respectively. The resection rates (RR) were 74, 68 and 81% respectively in Arm1, Arm2 and Ctrl_Arm. Respectively, 88.4, 91 and 85.7% of patients started adjuvant chemo. 1y-OS rates were respectively of 84.1, 71.8 and 80.8% in Arm1, Arm2 and Ctrl_Arm with a median follow-up in each group of 25.6, 33, 30.9 months. Following the intermediate analysis, the Arm2 was stopped for lack of efficacy (rejection of the H0 hypothesis for 1yOS). 1y-Event free survival (EFS) rates were 51.4% in Arm1, 43.1% in Arm2 and 41.7% in Ctrl_Arm, with corresponding median EFS of 12.4, 11 and 9.2 months. Conclusions: The feasibility and efficacy of the mFOLFIRINOX neoadjuvant chemotherapy is confirmed regarding completion of therapeutic sequence and oncological outcomes. These results confirm the rationale for ongoing clinical trials, PREOPANC3 and Alliance AO21806. Clinical trial information: NCT02959879.
Impact of subsequent therapies in patients (pts) with advanced renal cell carcinoma (aRCC) receiving lenvatinib plus pembrolizumab (LEN + PEMBRO) or sunitinib (SUN) in the CLEAR study.
Authors: Voss Martin H , Powles Thomas , McGregor Bradley Alexander , Porta Camillo , Grünwald Viktor , Merchan Jaime R. , Rolland Frederic , Maroto-Rey Pablo , Goh Jeffrey C. , Xing Dongyuan , Perini Rodolfo F. , McKenzie Jodi , Mody Kalgi , Motzer Robert J.
Published: June 2022

4514

Background: In the open-label, randomized, phase 3 CLEAR study, LEN + PEMBRO had significant PFS (primary endpoint) and OS (key secondary endpoint) benefits over SUN among pts with aRCC in the 1L setting (Motzer 2021, NEJM). We evaluated PFS on next-line therapy (“PFS2”) and explored the effect of subsequent anticancer therapy on OS in the LEN + PEMBRO and SUN treatment arms of CLEAR. Methods: PFS2 was defined as time from randomization to disease progression (as assessed by investigator) on next-line treatment or death from any cause (whichever occurred first). PFS2 was evaluated in all pts randomly assigned to LEN 20 mg orally QD + PEMBRO 200 mg IV Q3W (n=355) or SUN 50 mg orally QD (4 wks on/2 wks off) (n=357) using Kaplan-Meier estimates, and compared between treatment arms via a log-rank test stratified by geographic region and MSKCC prognostic groups. The HR and corresponding CI were estimated using the Cox regression model with Efron’s method for ties, using the same stratification factors. A post hoc analysis accounting for the effect of subsequent anticancer therapy on OS (time from randomization to death from any cause) in the LEN + PEMBRO and SUN arms using 2-stage estimation was conducted. Results: Among pts who received subsequent anticancer therapy in the LEN + PEMBRO (n=117 pts) and SUN (n=206 pts) arms (Table), median time to next-line therapy was 12.2 mos (range 1.45–37.36) and 6.4 mos (range 0.39–28.52), respectively. Median duration of first subsequent anticancer therapy was 5.2 mos (range 0.10–30.23) in the LEN + PEMBRO arm and 6.8 mos (range 0.03–30.72) in the SUN arm. Among all pts, PFS2 was longer with LEN + PEMBRO than with SUN (median not reached vs 28.7 mos; HR, 0.50; 95% CI 0.39–0.65; nominal P<0.0001); PFS2 rates at 24 and 36 mos are in the Table. The unadjusted OS HR for LEN + PEMBRO vs SUN (from the primary analysis [Motzer 2021, NEJM]) was 0.66 (95% CI 0.49–0.88); the HR for OS adjusted for subsequent therapy was 0.54 (bootstrap 95% CI 0.39–0.72). Conclusions: LEN + PEMBRO had a statistically significant and clinically meaningful benefit over SUN in the CLEAR study. These findings remained consistent after accounting for subsequent therapies, as evidenced by prolonged PFS2 and adjusted OS. Results further support LEN + PEMBRO as a standard of care in 1L aRCC. Clinical trial information: NCT02811861. [Table: see text]
Preliminary results of a phase Ib/II combination study of RC48-ADC, a novel humanized anti-HER2 antibody-drug conjugate (ADC) with toripalimab, a humanized IgG4 mAb against programmed death-1 (PD-1) in patients with locally advanced or metastatic urothelial carcinoma.
Authors: Sheng Xinan , Zhou Li , He Zhisong , Guo Hongqian , Yan Xieqiao , Li Siming , Xu Huayan , Li Juan , Chi Zhihong , Si Lu , Cui Chuanliang , Mao Lili , Lian Bin , Tang Bixia , Wang Xuan , Bai Xue , Guo Jun
Published: June 2022

4518

Background: RC48-ADC has shown promising data in HER2-positive and even negative patients with metastatic urothelial carcinoma (mUC) who failed with platinum-based chemotherapy. RC48-ADC combined with anti-PD-1 antibody may have a synergistic antitumor effect. Methods: This is an open-label, multicenter, phase 1b/II trial to evaluate the safety and activity of RC48 combined with toripalimab in mUC. Patients received RC48-ADC at 1.5 or 2 mg/kg, in combination with 3mg/kg toripalimab every two weeks in a dose-escalation and expansion cohort until confirmed disease progression, unacceptable toxicity, or voluntary withdrawal. The key primary endpoint was safety; secondary endpoints included efficacy and tumor tissue biomarkers. Results: As of 17 Jan 2022 (data cutoff), 41 la/mUC pts (19 males; median age 66 y [42-76]) were enrolled since 20 Aug 2020. 61% patients were systemic treatment naïve, and 54% had visceral metastases (mets), including 24% with liver mets. The primary site was in upper tract UC in 54%. HER2 expression was positive (IHC 2+ or 3+) in 59% patients, and PD-L1 positive (CPS ≥ 10) in 32%. No dose-limiting toxicity was observed. The recommended dose was RC48-ADC 2mg/kg + toripalimab 3mg/kg every 2 weeks. With a median follow-up of 8.0 mos, 36 patients had at least one tumor assessment, the best ORR was 83.3%, and the confirmed ORR was 76.7% (95%CI: 57.7, 90.1), including 10% CR. The cORR was 82.4% for 1L previously untreated mUC patients, 100% for patients with HER2 IHC (2+ or 3+) & PD-L1 (+), 92.3% for HER2 (2+ or 3+) & PD-L1 (-), 50% for HER2 (0 or 1+) & PD-L1 (+), and 50% HER2 (0 or 1+) & PD-L1 (-). DCR was 96.7% (95%CI: 82.8, 99.9). The median PFS was immature and 9.2 mos (95%CI: 5.49, 10.32) by the time and the median OS was not reached. The most common treatment-related AEs were ALT/AST increase (65.9%), peripheral sensory neuropathy (58.5%), appetite decrease (56.1%), asthenia (56.1%), hypertriglyceridemia (48.8%). Grade ≥3 TRAEs included γ-glutamyl transferase increase (12.2%), ALT/AST increase (7.3%), asthenia (7.3%), hypertriglyceridemia (4.9%), and neutropenia (4.9%). 9 pts had irAEs (22.0%, 7.3% ≥ G3), including immune-related pneumonitis, hepatitis, and myositis. Conclusions: RC48-ADC in combination with toripalimab demonstrated promising efficacy in patients with mUC and a manageable safety profile. A randomized study of RC48-ADC and toripalimab vs. platinum-based chemotherapy in previously untreated la/mUC patients is ongoing. Clinical trial information: NCT04264936. [Table: see text]
Molecular profile and clinical outcomes of renal cell carcinoma brain metastases treated with stereotactic radiosurgery.
Authors: Ma Jennifer , del Balzo Luke , Khaleel Sari Safaa , Flynn Jessica , Zhang Zhigang , Voss Martin H , Freeman Benjamin , Hakimi A. Ari , Lee Chung-Han , Eichholz Jordan , Kelly Daniel W. , Yang Jonathan T. , Mueller Boris , Carlo Maria Isabel , Motzer Robert J. , Imber Brandon S. , Beal Kathryn , Moss Nelson S. , Kotecha Ritesh , Pike Luke Roy George
Published: June 2022

4526

Background: Molecular profiles of renal cell carcinoma (RCC) tumors are associated with systemic treatment (ST) responses and clinical outcomes. However, the molecular profiles of RCC brain metastases (BM) and their correlation with ST response and clinical outcomes are not well characterized. Effective management of BM with locoregional therapies including stereotactic radiosurgery (SRS) is critical as ST advances have improved overall survival (OS). Therefore, we sought to identify the clinical and genomic features of RCC BM in a large cohort of patients treated with SRS. Methods: We performed an institutional retrospective analysis of RCC BM patients treated with SRS and evaluated corresponding genomic next generation sequencing (NGS) data via a targeted sequencing panel (MSK-IMPACT). A comparison cohort of all institutional patients with available NGS data was utilized to investigate genes enriched in our BM cohort using Fisher exact testing. Kaplan Meier analyses were performed for OS and intracranial progression-free survival (iPFS). Clinical factors and genes mutated in ≥ 10% of samples were assessed per patient using Cox proportional hazards models, and per individual BMs using clustered competing risks regression with a competing risk of death. Results: From 2010-2021, 91 RCC BM patients underwent SRS for 212 BMs, including 86% clear cell and 14% non-clear cell RCC. NGS data was available for 76 patients (84%), including 18 resected BMs, 26 extra-cranial metastatic lesions (EM), and 32 primary kidney tumors (Table 1). Median follow-up was 3.2 years with median OS of 21 months (m) and median iPFS of 7.8m. Karnofsky performance status ≥80 and extracranial disease control were significantly associated with improved OS on multivariable analyses (MVA; p=0.049 and 0.01, respectively). No clinical variables were significantly associated with iPFS on MVA. At the BM level, SETD2 alterations approached significance for improved iPFS (HR=0.35; 95%CI 0.11, 1.05; p=0.06). Enrichment in SMARCA4 alterations was seen in the BM cohort as compared to primary kidney and EM samples from patients without BM (17% vs 1% vs 2%, p<0.05). Conclusions: To our knowledge, this is the largest study investigating mutational profiles of RCC BM. SMARCA4 alterations were enriched in BM samples and a trend towards improved iPFS was seen in SETD2 variant BMs, warranting further investigation.[Table: see text]