bluuebunny/crossref_metadata_2025 huggingface dataset:
Gut microbiome composition as predictor of the efficacy of adding atezolizumab to first-line FOLFOXIRI plus bevacizumab in metastatic colorectal cancer: A translational analysis of the AtezoTRIBE study.
Authors: Marmorino Federica , Piccinno Gianmarco , Rossini Daniele , Ghelardi Filippo , Murgioni Sabina , Salvatore Lisa , Nasca Vincenzo , Antoniotti Carlotta , Daniel Francesca , Schietroma Francesco , Conca Veronica , Silva Carolina Alves Costa , Tamburini Emiliano , Tamberi Stefano , Passardi Alessandro , Antonuzzo Lorenzo , D'Onofrio Raffaella , Zitvogel Laurence , Cremolini Chiara , Derosa Lisa
Published: June 2023

3534

Background: Gut microbiome has emerged as a biomarker of clinical benefit to immune-checkpoint inhibitors (ICI) but no data are available in metastatic colorectal cancer (mCRC). The AtezoTRIBE study demonstrated that the addition of atezolizumab (atezo) to FOLFOXIRI plus bevacizumab (bev) prolongs progression-free survival (PFS), but this benefit is limited for patients with proficient mismatch repair (pMMR) tumors. Here, we aimed at investigating the potential predictive role of microbiome in identifying mCRC patients able to achieve benefit from ICI. Methods: AtezoTRIBE was a phase II trial in which 218 mCRC patients, unselected for MMR status, were randomized 1:2 to receive first-line FOLFOXIRI/bev (arm A) or FOLFOXIRI/bev/atezo (arm B). Stools were prospectively collected. Metagenomic (MG) data from whole genome sequencing (WGS) at level of species genome bins (SGBs) were analysed by linear models corrected for clinical and tumor-related parameters and fold-ratios. We defined as responders (R) those patients who experienced a PFS ≥ 12 months. Results: Stool samples were collected at baseline for 171 (78%) patients (55 in arm A and 116 in arm B) but only 163 were available for MG. Patients with deficient MMR (dMMR) tumors (N = 10) showed significantly lower MG diversity than pMMR ones (N = 148) harboring oral bacteria and pathobionts whose intrinsic immunogenicity has not been demonstrated. Regarding pMMR mCRC patients, baseline microbiome composition was not significantly different according to the treatment arm. The microbiome diversity was not significantly different between R and not-R in both arms, but specific immunogenic SGBs (Lachnospiraceae family members) were over-represented in R treated in arm B. Veillonellaceae and pathobionts were associated with poor prognosis and/or differential benefit from the addition of atezo. Fusobacterium nucleatum was associated with a poor prognosis, also in arm B. Conclusions: This is the largest prospective analysis showing that SGBs may be useful as a biomarker of potential benefit or detrimental effect from atezo in pMMR mCRC patients. Our results prompt the design of microbiota-centered diagnostic tests to identify pMMR mCRC patients more likely to benefit from ICI-based therapeutic strategies. Clinical trial information: NCT03721653 .
Evaluation of microsatellite instability status, a definitive predictive biomarker for immune checkpoint inhibitors (ICI), in underrepresented minorities (URM) with gastrointestinal (GI) cancers.
Authors: Balogun Fiyinfolu , Altoe Mirella , O'Connor Catherine , Chowdhury Nobel , Cercek Andrea , Lee Choong-kun , Foote Michael Bonner , Kim Daehee , Maron Steven Brad , Kim Dae Won , Ronski Karyn , Park Joon Oh , Chao Calvin Y. , Janjigian Yelena Y. , Abou-Alfa Ghassan K. , Diaz Luis A. , O'Reilly Eileen Mary , Sanchez-Vega Francisco , Chakravarty Debyani , Park Wungki
Published: June 2023

3538

Background: Mismatch repair deficiency (dMMR) results in MSI-H state and is the first tumor type-agnostic biomarker predictive of ICI response. Among GI cancers, MSI-H is most frequent in colorectal cancer (CRC 15%), gastroesophageal (GEC, 5%) and other (small bowel, hepatopancreatobiliary; 1%). For CRC, MSI-H can be attributed to germline mutation (Lynch syndrome, 3%) or somatic inactivation (sporadic, 12%) of foundational MMR genes. Studies evaluating ICI efficacy in dMMR cancers focus primarily on non-Hispanic White (NHW) patients (pts). We present prevalence, tumor genomic features, and outcomes in pts from a large cohort at Memorial Sloan Kettering (MSK). Methods: Retrospective analysis of MSI-H GI cancers from MSK-IMPACT database. Pts were grouped by self-reported race and ethnicity into 4 study arms: NHW, Asian, non-Hispanic Black (NHB), and Hispanic. Age, tumor type, tumor mutation burden (TMB), and MMR genes were analyzed. Overall survival (OS) estimated with Kaplan-Meier. Results: Of 776 pts with MSI-H GI cancers: 623 (80.3 %) NHW, 60 (7.7 %) Hispanic, 50 Asian (6.5 %), and 43 (5.5 %) NHB. CRC (76%), GEC (14%), other cancers (10%). We present initial evaluation of CRC and GEC: Median age, TMB, and most frequently altered MMR genes (MMR gene FA) are in table. Median OS (mOS) in NHW/URM by receipt of ICI in MSI-H CRC were 38.5m/25.3m (p 0.07) in no-ICI group, 34.2m/28.7m (p 0.64) in +ICI group; MSI-H GEC 43.4m/30m (p 0.44) in no-ICI group, 28.8m/26.7m in +ICI group. Conclusions: Number of URM MSI-H CRC/GEC pts is 7 to 15-fold less than NHW, with no such difference in % MSI-H/MSS between groups; reflecting significant undertesting in URM pts. In MSI-H CRC, median age (m-Age) at sequencing was younger in URM compared to NHW; pronounced in Asian and Hispanic patients, who were 10+ years younger than NHW. No such age difference seen in GEC. No difference in mOS detected between NHW and URM, however a non-significant trend towards worse mOS in URM was observed in the no-ICI group. Next steps include validation of clinico-genomics of MSI-H GI cancers in other large cohorts, including TEMPUS (N = 768) which is ongoing. [Table: see text]
Prognostic and predictive significance of pre- and post-operative plasma tumor markers in patients with appendiceal adenocarcinoma undergoing cytoreductive surgery: Insights from a single-center study.
Authors: Yousef Abdelrahman M.G. , Yousef Mahmoud M.G. , Zeineddine Mohammad A. A. , Ito Ichiaki , Chowdhury Saikat , Gu Yue , Knafl Mark , Jin Jeff , Edelkamp Paul , Uppal Abhineet , Bhutiani Neal , Alfaro-Munoz Kristin , Neus Bota-Rabassedas Neus , Helmink Beth A , White Michael , Taggart Melissa , Raghav Kanwal Pratap Singh , Overman Michael J. , Fournier Keith F. , Shen John Paul Y.C.
Published: June 2023

3539

Background: Appendiceal adenocarcinomas (AA) are both rare and heterogeneous diseases. Cytoreductive (CRS) surgery followed by heated intraperitoneal chemotherapy (HIPEC) remains the best treatment for AA patients with peritoneal metastasis. This study seeks to investigate the clinical utility of pre- and post-operative plasma tumor markers (TM, CEA, CA19-9, CA-125) by association with survival outcomes. Methods: Under an approved IRB protocol the Palantir Foundry software system was used to query MD Anderson internal database to identify patients with AA who underwent CRS between 2016 to 2022. Elevation of TM was defined as above the laboratory upper limit of normal (CEA > 3 ng/mL, CA 19-9 > 37 U/mL, and CA-125 > 37 U/mL). Relationship between normal and elevated serum TM and progression-free survival (PFS) and overall survival (OS) was evaluated using univariate and multivariate Cox-proportional hazards regression analysis, considering multiple clinicopathologic variables. Results: 296 patients were identified; preoperative CEA, CA19-9 and CA125 was elevated in 60%, 29% and 28% of patients, respectively. Preoperative elevation of any TM was associated with higher PCI score (22 vs. 15, p< 0.0001). Moreover, elevated preoperative TM was associated with incompleteness of cytoreduction (OR = 6.5, p< 0.0001). Compared to preoperative measurements, all TM levels dropped after surgery (Mean score 31 vs 11 for CEA, 136 vs 32 for CA19-9 and 36 vs 17 for CA125). Preoperative elevation of any TM (HR = 1.5, p= 0.0288) and post-op elevation of any TM were with poor PFS on univariate analysis, however only post-op elevated TM levels (HR = 2.3, p= 0.0001) were associated with poor PFS on multivariate analysis. Interestingly, elevated TM was not associated with OS. Post-op TM levels were analyzed to evaluate the positive and negative predictive value in prediction of relapse in 6 months from surgery, PPV was 45% and NPV was 84%. Conclusions: Preoperative elevation of TM can identify patients at higher risk for incomplete cytoreduction and relapse after surgery. Postoperative elevation of TM is a risk factor for relapse. [Table: see text]
Artificial intelligence–derived immune phenotypes for prediction of prognosis in patients with stage III colon cancer (NCCTG N0147; Alliance).
Authors: Saberzadeh Ardestani Bahar , Nelson Garth D. , Segovia Diana I , Lim Yoojoo , Yan Dongyao , Shanmugam Kandavel , Alberts Steven R , Park Gahee , Shi Qian , Ock Chan-Young , Sinicrope Frank A.
Published: June 2023

3542

Background: Solid tumors can be characterized by distinct immune phenotypes based on the level of T cell infiltration in the tumor microenvironment (TME) which may provide prognostic information and also inform strategies to restore the anti-tumor immune response. Immune phenotypes were determined using an artificial intelligence (AI) algorithm in digitized whole-slide images (WSI) of tumors with deficient (d) mismatch repair (MMR) vs proficient (p) MMR. Methods: Stage III colon carcinomas (N = 401; 393 met QC) from participants in a phase III trial of FOLFOX-based adjuvant chemotherapy were analyzed including all available tumors with dMMR (n = 196) and a randomly selected cohort of pMMR tumors (n = 195). Using an AI algorithm (Lunit SCOPE) previously trained on solid tumors, digitized tumors were categorized into three immune phenotypes based on epithelial and stromal TIL data-driven cutpoints in dMMR and pMMR (inflamed: TIL high in epithelium (> upper 25%); excluded: TIL high in stroma (>lower 25%), low in epithelium; and desert: TIL low in epithelium and stroma). Phenotypes were then examined in relationship to disease-free survival (DFS) using Kaplan-Meier methodology. Results: Of the 3 immune phenotypes in dMMR tumors, 25% were inflamed, 50% were immune-excluded, and 25% were immune-desert. Based on univariate results, multivariable modeling was performed incorporating immune phenotype in addition to age, histological grade, N stage, T stage, performance status, treatment arm, BRAF and KRAS status and identified immune phenotypes and N stage to be significantly associated with DFS. Among dMMR tumors, immune desert phenotype was associated with the poorest DFS (Desert: HR adj 1.95, 95%CI (1.01, 3.80); Excluded: HR adj 0.89, 95%CI (0.47, 1.69); Inflamed: ref; p:0.01). When compared to immune desert tumors, immune-excluded tumors had significantly better DFS (HR adj 0.49, 95%CI (0.27, 0.88), p:0.01). At a median follow-up of 60 months, 3-year DFS of patients with dMMR was 71.2% with Immune inflamed, 78.5% with Excluded, and 54.5% with Desert phenotypes. In contrast to dMMR, univariate analyses of data-driven cutpoints in pMMR tumors was not prognostic. Using a different data-driven cutpoint (15%), the revised immune phenotypes remained non-significant for DFS within pMMR tumors. Conclusions: Distinct AI-derived immune phenotypes in the TME were identified that were significantly prognostic in patients with dMMR, but not pMMR colon cancers. A data-driven immune-desert phenotype was identified in dMMR tumors that was associated with significantly poorer survival. Further investigation of the potential predictive utility of these phenotypes for immunotherapy are planned. Support: https://acknowledgments.alliancefound.org . ClinicalTrials.gov Identifier: NCT00079274 .
A deep learning model for the prediction of microsatellite instability and pathogenic POLE mutations in colorectal cancer using histopathologic images.
Authors: Xu Ting , Yu Jinze , Tan Luxin , Wang Zhenghang , Li Jian , Dong Siyao , Zhou Haoyi , Shen Lin , Li Zhongwu , Li Jianxin , Wang Xicheng
Published: June 2023

3543

Background: Immunotherapy has brought about a landmark change in anti-tumor treatment in the past years. High microsatellite instability (MSI-H) is now the only clinically approved biomarker predicting response to immunotherapy in CRC. Increasing evidence suggests that POLE mutations in the exonuclease domain could drive an ultra-mutational phenotype and improve the treatment outcomes of ICI in solid tumors. In this study, we set out to apply a deep learning model using H&E-stained, formalin-fixed, paraffin-embedded (FFPE) whole slide images (WSIs) of CRC primary tumors. Methods: The deep learning model is developed and validated through five-fold cross-validation using WSI of primary tumors from 506 CRC patients and externally validated using 52 WSIs from a prospective cohort. The microsatellite status, tumor mutation burden (TMB) and POLE genotype were determined by next-generation sequencing (NGS). Patients with MSS status and a low TMB (＜20Mutations/Mb) were admitted to the MSS group, and CRCs with a POLE mutation which was defined as an oncogenic mutation referring to the POLE functional mutation list at OncoKB( POLE (oncokb.org) were admitted to the POLE mutant group. Clustering-constrained-attention multiple-instance learning (CLAM) model is employed as the base model, and we conduct the model ensemble by performing a large-scale hyper-parameter search, selecting five models with the highest value in one of the performance metrics, including the AURoC, accuracy, precision, recall, and f1 score, and finally averaging the predictions of the five models. Results: The internal dataset included 237 MSS, 142 MSI-H, and 127 POLE mutant CRC. The three groups had significant differences in primary location (p ＜ 0.0001), histology (p ＜ 0.0001), tumor differentiation (p = 0.002), tumor stage (p ＜ 0.0001), Crohn's-like reaction (p ＜ 0.0001) and tumor growth pattern (p = 0.001). The cross-validation performance of the ensemble model (M E) in the internal dataset achieves an AURoC of 0.944 for three-way classification task (POLE vs. MSI-H vs. MSS) and 0.940 for two-way classification task (POLE & MSI-H vs. MSS) which were superior to the performance of each single CLAM model. To demonstrate the generalizability of the deep learning model, a domestic perspective cohort consisting of 20 MSS, 17 MSI-H, and 15 POLE mutant CRC H&E images were used to validate the external performance. And the M E retained robust performance on the external dataset, with an AURoC of 0.904 for three-way classification task and 0.836 for two-way classification task. Conclusions: A CLAM-based deep learning model could directly predict the MSI-H and POLE mutation from histological images that could be used to stratify CRC patients for immunotherapy with faster turnaround time and lower costs compared with traditional sequencing methods.
Plasma arginine as a candidate predictive biomarker for response to immune checkpoint inhibition (ICI) in metastatic colorectal cancer (mCRC): Analysis of the CCTG CO.26 trial.
Authors: Ma Lucy Xiaolu , Loree Jonathan M. , Jonker Derek J. , Kennecke Hagen Fritz , Berry Scott R. , Couture Felix , Ahmad Chaudhary E. , Goffin John R. , Kavan Petr , Harb Mohammed , Colwell Bruce , Samimi Setareh , Samson Benoit , Abbas Tahir , Aucoin Nathalie , Aubin Francine , Koski Sheryl L. , Tu Dongsheng , O'Callaghan Christopher J. , Chen Eric X
Published: June 2023

3545

Background: Nutritional stress is one of the mechanisms used by tumour cells to evade the immune system. Arginine (ARG), an amino acid involved in several cellular functions including immunomodulation, is important in regulating T-lymphocyte cell activity and the anti-tumour response. ARG deficiency in the tumour microenvironment has been shown to impair T-cell response while ARG supplementation may promote anti-tumour immune activity. In this exploratory post-hoc analysis of the Phase II CO.26 trial (NCT02870920), we investigated the role of plasma ARG in predicting response to ICI in patients (pts) with refractory mCRC. Methods: CO.26 was a phase II trial which randomized pts with refractory mCRC to durvalumab plus tremelimumab (D+T) versus best supportive care (BSC). Plasma ARG concentrations were determined from blood samples pre-treatment using HPLC-tandem mass spectrometry. The median plasma ARG value was used as a cut-off stratifying pts into ARG-high (≥10650 ng/ml) versus ARG-low ( < 10650 ng/ml) groups. Progression-free (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method and compared between groups using the log-rank test. Cox proportional hazard models were used to analyze prognostic and predictive impacts of ARG on PFS and OS. Results: Of 180 pts enrolled in CO.26, 162 pts (N = 115 treated with D+T and 47 BSC) had pre-treatment blood samples for baseline ARG analysis. There were no significant differences in baseline characteristics between pts included in this analysis and the total study pts, or between ARG-high and ARG-low pts. In pts treated with D+T, ARG-high was associated with more favourable prognosis (ARG-high median OS 7.62 months vs. ARG-low 5.49 months, multivariable hazard ratio [HR] 0.60, 95% confidence interval [CI] 0.40-0.91, p = 0.016). In ARG-high pts, D+T significantly improved OS (median OS 7.62 months with D+T vs 3.61 months BSC; HR 0.61, 95% CI 0.37-0.99, p = 0.04). In ARG-low pts there was no OS benefit with D+T (median OS 5.49 months D+T vs 4.27 months BSC; HR 0.84, 95% CI 0.50-1.41, p = 0.51. Interaction p = 0.037). Baseline ARG values had no association with PFS or disease control rate. Conclusions: Baseline plasma ARG was prognostic in pts with mCRC treated with D+T, and high ARG was predictive of improved OS with ICI. Prospective studies should be done to validate ARG as a biomarker identifying mCRC pts likely to derive benefit from ICI. Therapeutic approaches targeting the ARG pathway should be investigated in future studies.
A prospective study of FOLFIRI plus aflibercept as second-line treatment after failure of FOLFOXIRI plus bevacizumab in patients with unresectable/metastatic colorectal cancer (CRC): EFFORT study.
Authors: Satake Hironaga , Ando Koji , Yasui Hisateru , Negoro Yuji , Kinjo Tatsuya , Yuge Koutarou , Baba Kenji , Orita Hiroyuki , Hirata Keiji , Shimokawa Mototsugu , Makiyama Akitaka , Saeki Hiroshi , Oki Eiji , Baba Hideo
Published: June 2023

3549

Background: FOLFOXIRI plus bevacizumab (BEV) is a first-line treatment option for patients with unresectable or metastatic CRC. However, there are no clear recommendations for second-line therapy after failure of FOLFOXIRI plus BEV. The EFFORT study investigated whether FOLFIRI plus aflibercept is active following FOLFOXIRI plus BEV in unresectable/metastatic CRC. Methods: EFFORT was an open-label, multicenter, single arm phase II study. Patients with unresectable/metastatic CRC who failed FOLFOXIRI plus BEV as a first-line therapy received aflibercept plus FOLFIRI (aflibercept 4 mg/kg, irinotecan 150 mg/m2 IV over 90 min, with levofolinate 200 mg/m2 IV over 2 hours, followed by fluorouracil 400 mg/m2 bolus and fluorouracil 2400 mg/m2 continuous infusion over 46 hours) every 2 weeks on day 1 of each cycle. The primary endpoint was progression-free survival (PFS) in the full analysis set (FAS). To achieve 80% power to show a significant benefit with a one-sided alpha level of 0.10, assuming a threshold PFS of 3 months and an expected value of at least 5.4 months, 32 patients needed to be enrolled. Major secondary endpoints included overall survival (OS), overall response rate (ORR) and safety. Results: From April 2019 to May 2021, 35 patients were enrolled and FAS included 34 patients (one patient who did not met eligibility criteria was excluded). Of them, 18 were males, median age was 63 years (range: 32-78) and ECOG Performance Status was either 0 (n = 28) or 1 (n = 6). The primary tumor was left-sided in most patients (23/34) and 27 patients had liver metastases. And 23 patients had RAS mutation. The primary endpoint was met with a median PFS of 4.3 months [80% CI: 3.7-5.1]. The median OS was 15.2 months [95% CI: 8.9-22.7]. Objective tumor responses were CR (n = 1), PR (n = 4), SD (n = 21) or PD (n = 8). ORR was 14.7% (5/34) [95% CI: 5.0-31.1], and disease control rate was 76.5% (26/34) [95% CI: 58.8–89.3]. Main grade 3 or 4 adverse events were neutropenia (7/35, 20.0%), thrombopenia (3/35, 8.6%), leucopenia (2/35, 5.7%), and hypertension (3/35, 8.6%). No severe proteinuria and no treatment-related death were reported. Conclusions: Aflibercept plus FOLFIRI given after failure of FOLFOXIRI plus BEV is active and shows a manageable safety profile. This regimen maybe a useful as second-line treatment option in such patients. Clinical trial information: jRCTs071190003 .
First-line (1L) nivolumab (NIVO) + ipilimumab (IPI) in patients (pts) with microsatellite instability-high/mismatch repair deficient (MSI-H/dMMR) metastatic colorectal cancer (mCRC): 64-month (mo) follow-up from CheckMate 142.
Authors: Lenz Heinz-Josef , Overman Michael J. , Van Cutsem Eric , Limon M. Luisa , Wong Mark Ka , Hendlisz Alain , Aglietta Massimo , Garcia-Alfonso Pilar , Neyns Bart , Gelsomino Fabio , Cardin Dana Backlund , Dragovich Tomislav , Shah Usman , McCraith Stephen M. , Wang Abigail , Lei Ming , Yao Jin , Jin Lixian , Lonardi Sara
Published: June 2023

3550

Background: NIVO + IPI demonstrated robust, durable clinical benefit, and was well tolerated as a 1L therapy in pts with MSI-H/dMMR mCRC in the phase 2 CheckMate 142 study (NCT02060188), leading to the inclusion of NIVO + IPI in the NCCN guidelines as an initial therapy option for these pts. At 52-mo median follow-up, 1L NIVO + IPI continued to demonstrate durable clinical benefit, and no new safety signals were identified. Here we report longer follow-up results. Methods: Pts with MSI-H/dMMR mCRC and no prior treatment for metastatic disease received NIVO 3 mg/kg Q2W + IPI 1 mg/kg Q6W until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR) by investigator assessment (INV) per RECIST v1.1. Other key endpoints were disease control rate (DCR), duration of response (DOR), progression-free survival (PFS), all by INV; overall survival (OS); and safety. Results: In total, 45 pts received 1L NIVO + IPI. With median follow-up of 64.2 mo (range, 59.4–68.9 mo), ORR by INV was 71% (95% CI, 56–84%). The proportion of pts with a best overall response of complete response (CR) was 20%, partial response (PR) was 51%, stable disease (SD) was 13%, and progressive disease was 16%. Median DOR (mDOR) was not reached, and the 60-mo DOR rate was 72%. Median PFS (mPFS) by INV and median OS (mOS) were not reached, with 60-mo PFS and OS rates of 55% and 67%, respectively (Table). Among pts alive at the data cutoff (n = 31), 30 remained treatment-free after initial study treatment without receiving any subsequent systemic therapy, with a median treatment-free interval of 34.7 mo (range, 1.6–61.4 mo). Exploratory analysis by tumor mutational burden status will be presented. Safety data are shown in the Table. Conclusions: At 64-mo follow-up, NIVO + IPI continued to demonstrate clinically meaningful survival and durable responses, with mPFS, mOS, and mDOR still not reached, suggesting the potential for long-term clinical benefit. Safety remained consistent with previous data. These findings further support current recommendations for NIVO + IPI as a 1L treatment for pts with MSI-H/dMMR mCRC. Clinical trial information: NCT02060188 . [Table: see text]
Prognostic value of liver metastases in colorectal cancer treated by systemic therapy: An ARCAD pooled analysis.
Authors: Cohen Romain , Raeisi Morteza , Shi Qian , Chibaudel Benoist , Yoshino Takayuki , Zalcberg John Raymond , Adams Richard , Cremolini Chiara , Van Cutsem Eric , Heinemann Volker , Tabernero Josep , Punt Cornelis J. A. , Arnold Dirk , Hurwitz Herbert I. , Douillard Jean-Yves , Venook Alan P. , Saltz Leonard B. , Maughan Timothy S. , Andre Thierry , De Gramont Aimery
Published: June 2023

3554

Background: Approximately 30% of patients (pts) diagnosed with colorectal cancer (CRC) develop liver metastases (LM). Liver is the most common organ of metastasis of CRC. The ARCAD database contains individual patient data of randomized trials that included CRC pts with initially unresectable metastases treated with systemic therapy. The aim of this study was to assess the response and survival outcomes in non-LM (NLM) vs LM across different lines of treatment. Methods: We analyzed survival outcomes of mCRC pts with either single site (SS) or multiple sites (MS) according to LM status in the following treatment groups: A: chemotherapy (CT) alone, B: CT + VEGF-antibodies, C: CT + EGFR-antibodies in KRAS wild-type tumors, within first-line (1L) and second line (2L) of therapy and D: pts enrolled on third line (≥3L) trials treated with trifluridine/tipiracil or regorafenib and placebo. The primary and secondary endpoints were overall survival (OS) and progression-free survival (PFS) which were assessed using Kaplan-Meier estimates and adjusted Cox models on ECOG PS, age, and gender. Results: We included 26 trials with 17924 pts. 14066 pts had LM. Pts with LM had a higher rate of colon vs rectum as primary tumor (72 vs 62%; P < .001) and less SS (31 vs 47%; P < .001) than those with NLM. OS and PFS results in subgroups are reported in the table. In groups A and B, we found better OS and PFS outcomes in NLM pts as either SS or MS in 1L and 2L. In group C from 1L, we found better survival outcomes in pts with SS LM. In pts with MS, NLM superiority was observed in OS but not in PFS. However, these results were influenced by primary tumor sidedness. In group D, better OS and PFS was observed in pts without LM than those with LM whether in pts with SS or MS. Response rates were higher in LM than in NLM in most 1L and 2L subgroups. Conclusions: LM is a poor prognostic factor for mCRC increasing from the 1L to ≥3L. Survival with CT alone and CT + anti-VEGF according to LM and NLM differs significantly in 1L and 2L but not with CT + anti-EGFR. This data justifies using LM as a stratification factor at least in ≥3L trials. [Table: see text]
A phase Ib/II study to evaluate surufatinib combined with camrelizumab and chemotherapy in the second-line treatment of advanced colorectal cancer: Phase Ib results.
Authors: Li Sheng , Zhu Liangjun , Li Xiaoyou , Huang Jiayuan , Bao Jun
Published: June 2023

3555

Background: Surufatinib is a novel small-molecule kinase inhibitor targeting VEGFR1-3, FGFR and CSF-1R with confirmed efficacy in epNET and pNET. Preclinical studies have demonstrated that surufatinib combined with immune checkpoint inhibitors (ICIs) have synergistic antitumor effects by modulating tumor immune microenvironment. Additionally, surufatinib plus toripalimab (anti-PD-1) has showed preliminary anti-tumor activity in multiple solid tumors, including colorectal cancer (CRC). This study aimed to evaluate the efficacy and safety of surufatinib plus camrelizumab (anti-PD-1), irinotecan and GM-CSF as second-line treatment in advanced CRC. Here we reported the results of the phase Ib study. Methods: This ongoing phase Ib/II, open-label trial (NCT04929652) enrolled patients (pts) aged 18-75 years old with pathologically confirmed locally advanced or metastatic CRC who have progressed on/been intolerant to the standard first-line therapy. In the Ib dose escalation/de-escalation phase, pts received surufatinib at 250mg once daily (QD) as starting dose, in combination with fixed dose of camrelizumab (200 mg, d1), irinotecan (200 mg/m2, d1) and GM-CSF (5ug/kg, d2-d7), every 3 weeks (Q3W). Based on DLTs, the dose of surufatinib should escalate to 300 mg or de-escalate to 200 mg. The primary objective of the phase Ib study was to determine the safety and DLT in first treatment cycle defining the recommended phase 2 dose (PR2D). Additional 36 pts were enrolled in the phase II dose expansion stage using RP2D. Primary endpoint of phase II was ORR as per RECIST 1.1. Secondary endpoints included PFS, DCR, OS and safety. Results: Enrollment opened in Nov 2021 and data cutoff in Dec 2022. 12 pts (median age 54) were treated in Phase Ib study (surufatinib 250 mg: N = 6; surufatinib 300 mg: N = 6). 75% were male and 17% had ECOG PS 1. 11/12 (92%) pts were positive for KRAS, NRAS or BRAF mutations. No DLT was observed in the starting dose cohort (surufatinib 250 mg), and one patient in the surufatinib 300 mg cohort experienced DLT (Grade [G] 3 vomiting). Surufatinib 300 mg QD was defined as the RP2D. Other G3 treatment related adverse events (TRAEs) were hypertension (1/12; 8.3%) and diarrhea (1/12; 8.3%). All other TRAEs were grade 1-2, and the most common (≥40%) were diarrhea (75%), fatigue (58%), vomiting (58%), nausea (50%), hypertension (42%), proteinuria (42%) and alopecia (42%). Of the 12 pts evaluable for tumor response, 3 pts achieved PR, 9 pts achieved SD. The ORR was 25% (3/12), the DCR was 100% (12/12) and median PFS was 7.2 months (95%CI 3.7-10.7). Conclusions: Surufatinib plus camrelizumab, irinotecan and GM-CSF was well tolerated, with a manageable safety profile, and showed preliminary anti-tumor activity in patients with advanced CRC. The dose-expansion phase is ongoing. Clinical trial information: NCT04929652 .
Novel GUCY2C targeting CAR-T therapy: Efficacy in advanced colorectal cancer.
Authors: Zhang Qianyu , Lin Lin , Wang Lin , Wang Wei , Qian Liting , Pan Yueyin , Liu Hu
Published: June 2023

3559

Background: Chimeric antigen receptor (CAR) T cells have shown remarkable success in treating patients with hematologic malignancies. However, the majority of CAR-T cell clinical trials in solid tumors have limited success which is partially attributed to the detrimental tumor microenvironment and the lack of ideal target. Recently, GUCY2C emerges as an ideal therapeutic target which is highly expressed in colorectal cancer (CRC). Here, a novel nanobody-based GUCY2C targeting CAR-T cell developed by us is applied to treat advanced colorectal cancer patients who failed third-line therapy. Methods: In this open-label, single-arm, investigator-initiated exploratory trial (ChiCTR2100044831), we primarily explore the safety and the low-dose efficacy of the autologous anti-GUCY2C CAR-T cells. All patients screened by IHC met our criteria for GUCY2C positivity. All enrolled patients had received at least 3 prior lines of therapy and had multiple metastases at baseline. Totally, 13 advanced CRC patients aged 18 to 65 years were infused with the anti-GUCY2C CAR-T cells at a dose range of 0.5-3 x10e6/kg after standard Cy-Flu lymphodepletion. Adverse events (AE) were graded according to CTCAE 5.0, and objective tumor responses were assessed per RECIST 1.1 criteria. Results: Between November 2021 and December 2022, 13 subjects with refractory metastatic CRC (mCRC) were treated with the anti-GUCY2C-CAR-T cells infusions at a dose range of 0.5-3 x10e6/kg. There were no dose-limiting toxicities, treatment-related death or any form of neurotoxicity occurred in this study. The most common TEAEs were diarrhea in 9/13 (69%) subjects (Grade 1: 2/13 (15.38%) Grade 2: 3/13 (23.07%) Grade 3: 4/13 (30.77%)). 8/13 (62%) mCRC subjects experienced grade1 or grade 2 mouth ulcer generally appear as a single lesion lasting for a few days. All cytokine release syndromes (CRS) observed were grade 1. Totally 9 pts (69%) experienced grade 1 CRS and all resolved by supportive care without the need of tocilizumab. No grade 4 AEs except for decreased lymphocytes in 12/13 pts (92%), decreased white blood cells in 1/13 pts (7.7%) and decreased platelet in 1/13 pts (7.7%). Among 10 evaluable patients, 6 partial responses, 2 stable disease and 2 progressive disease were achieved. At all dose levels ORR and DCR were 60% and 80% respectively. Notably, all 3 patients infused at the dose level above 2x10e6/kg reached partial responses. Among the 3 non-evaluable patients, 1 patient lost follow-up, 1 patient died of bone marrow failure and 1 patient died of COVID-19 related complications before the first efficacy evaluation. Additional data will be presented at the meeting. Conclusions: This clinical study indicated that the anti-GUCY2C CAR-T cell therapy was well tolerated and had promising efficacy in heavily pretreated mCRC patients. Clinical trial information: ChiCTR2100044831 .
Matching-adjusted indirect treatment comparisons (MAIC) of sotorasib vs trifluridine/tipiracil (T/T) and regorafenib as monotherapy in chemorefractory KRAS G12C-mutated metastatic colorectal cancer (mCRC).
Authors: Price Timothy Jay , Kopetz Scott , Kuboki Yasutoshi , Prenen Hans , Majer Istvan Matyas , Rehn Marko , Chan Emily , Fakih Marwan
Published: June 2023

3560

Background: In the single-arm phase 1/2 CodeBreaK 100 study (NCT03600883) evaluating sotorasib monotherapy in KRAS G12C-mutated mCRC patients whose disease progressed on or after fluoropyrimidine, oxaliplatin, and irinotecan treatment, the overall response rate was 12%, and the median progression-free survival (PFS) and overall survival (OS) was 4.2 and 13.4 months, respectively (data cutoff March 2021, n = 91). To compare the efficacy and safety of sotorasib with standard of care (SOC) T/T and regorafenib as monotherapy treatments, MAICs were performed. Methods: Clinical outcomes and adverse events (AEs) were compared from representative studies in mCRC patients who received sotorasib 960 mg once daily in CodeBreaK 100, T/T in the phase 3 RECOURSE study (NCT01607957, n = 534), and regorafenib in the phase 3 CORRECT study (NCT01103323, n = 505). By weighting individual patient-level data from CodeBreak 100, differences in available baseline characteristics considered to be prognostic factors, including age, race, sex, type of cancer (colon vs. rectum), ECOG performance status, time from diagnosis of metastatic disease, number of metastatic sites, number of prior lines of therapy, and prior bevacizumab treatment, were adjusted with the MAIC. MAICs compared sotorasib with T/T and regorafenib separately. Odds ratios (ORs) were estimated for objective response rates, hazard ratios (HRs) were used for PFS and OS. AEs were compared descriptively. Results: The effective sample size of sotorasib with matched characteristics consisted of 29 and 56 patients in the T/T and regorafenib comparison, respectively. The MAIC results showed that treatment with sotorasib increases the likelihood of response to treatment, with an adjusted OR of 8.5 vs T/T and 16.1 vs regorafenib. Sotorasib decreased the risk of progression or death by 41% vs T/T and 45% vs regorafenib (Table). Grade 3+ treatment-emergent AEs occurred in 37%, 69%, and 78% of sotorasib-, T/T-, and regorafenib-treated patients, respectively. Conclusions: The analyses suggest that sotorasib monotherapy is associated with a statistically significant and clinically meaningful improvement in response rates, PFS and OS vs. T/T and regorafenib in heavily pretreated chemorefractory KRAS G12C-mutated mCRC patients. The analyses are limited by the decreased sample size for sotorasib, the lack of KRAS G12C-specific data in SOC studies, and the impact of differences in post-progression treatments on OS across studies. [Table: see text]
Determinants of permanent liver limited disease (pLLD) in metastatic colorectal cancer (mCRC).
Authors: Salva Francesc , Dopazo Cristina , Adam René , Marques Hugo Pinto , Mirza Darius , Ferrero Alessandro , Giuliante Felice , Kaiser Gernot , Lapointe Real , Krawczyk Marek , Laurent Christophe , Gelli Maximiliano , Tralhao Jose Guilherme , Lopez Ben Santiago , Popescu Irinel , Isoniemi Helena , Hubert Catherine , Zagainov Vladimir Evgenievich , Andres Axel , Elez Elena
Published: June 2023

3561

Background: CRC is a complex and heterogeneous disease, with the liver being the most frequent site of metastasis. Around 20% of patients will always progress exclusively in the liver. These patients may be candidates for more aggressive therapeutic procedures that will impact in their outcome. LIVERMET SURVEY Database (LMSD) is a prospective international database, focused on patients operated for CRC liver metastasis, whether resected or not, which purpose is to evaluate patient outcomes and prognostic factors for these resected patients. We propose to analyse all patients enrolled in the (LMSD) to better characterised those determinants that are associated with pLLD. Methods: We analyzed all patients included in the LMSD. Patients with relapse of their disease after the first liver surgery were selected. In order to test associations between hepatic only and extrahepatic metastasis, a univariate and multivariate logistic model was performed with the variables considered clinically more relevant. Imputation of missing data using the mice method (Multivariate Imputation via Chained Equations) was performed. All analyses were performed with R 4.1.1 software. Results: A total of 8715 patients out of 33581 (26%) included in the LMSD presented disease recurrence after a first liver surgery. During their oncological history, pLLD occurred in 1392 patients (16%), and extrahepatic relapse was presented in 7323 patients (84%). The characteristics of patients with pLLD were as follows: 58.4% patients presented synchronic disease, 20.2% had right sided primary tumor, 58.6% presented unilateral disease at time of first hepatic surgery and 20.4% of patients presented R1 surgery. In multivariant analysis, right sided and rectum (HR 0.82. p = 0.001), unilateral liver involvement (HR 0.74, p < 0.001) and > 3cm of diameter in greatest lesion with maximum of 3 lesions (HR 0.85, p = 0.02) were predictive determinants of extrahepatic disease. Only synchronic metastases (HR 1.29, p < 0.001) and male sex (HR 1.15, p = 0.028) were associated with pLLD. Molecular information according to RAS, BRAF and MSI status was not evaluable in a majority of patients since this item has been recently implemented in the questionnaire. Conclusions: This study confirms that about 16% of patients with LLD mCRC will be pLLD mCRC. Despite clinical determinants like synchronic metastatic disease, which is associated with pLLD, further analyses including molecular determinants are needed. Identifying those determinants of pLLD in a scenario where more extreme surgeries and liver transplantations are being considered is a great challenge that needs to be addressed.
A phase II study of regorafenib plus sintilimab as salvage-line treatments in non–MSI-H metastatic colorectal cancer (mCRC).
Authors: Liu Rui , Ji Zhi , Wang Xia , Zhang Le , Yang Yuchong , Ning Tao , Ge Shaohua , Li Hongli , Bai Ming , Deng Ting , Ba Yi
Published: June 2023

3562

Background: PD-1 blockade is particularly ineffective in patients with microsatellite stable (MSS) or mismatch repair (MMR)-proficient colorectal cancer (CRC). Regorafenib (R) has been shown to modulate anti-tumor immunity by different mechanisms including reduction of tumor-associated macrophages (TAMs) and the immunosuppressive cells. Synergy between Regorafenib and anti–PD-1/PD-L1 antibodies has been shown in pre-clinical models, as well as in several clinical studies, compared with either treatment alone. The purpose of this study was to evaluate the activity of regorafenib in combination with immune checkpoint inhibitors. Methods: This is a single-arm, open-label, phase II trial assessing the efficacy and safety of Regorafenib (80mg QD 3weeks/4) + Sintilimab (S) (200mg every 3 weeks) combination in non MSI-H mCRC patients (pts). The primary endpoint was the overall survival (OS). Secondary endpoints included progression free survival (PFS), objective response rate (ORR), disease control rate (DCR) and Safety. Results: As of February 1, 2023, a total of 103 patients with mCRC were enrolled and received R+S. Median age was 57 (range, 28-75). Male 59.2%, ECOG PS 0/1/2 20.4%/66.0%/13.6%, left-sided colon/right-sided colon/rectum 39.8%/15.5%/44.7%, RAS mutant 42.7%. The ORR was 21.4% and DCR was 63.1%, with complete response (cCR) in 1 (1.0%), partial response (PR) in 21 (20.4%) and stable disease (SD) in 43 (41.7%) patients. With a median follow up of 19.9 months (range, 0.1-41.4), the median PFS was 4.0 months (95% CI, 3.1-4.4 months) and median OS was 13.0 months (95% CI, 12.0-16.5 months). The patients who achieved ORR have significantly longer PFS (20.8 vs. 3.2 months, p＜0.001) and OS (not reach vs. 12.0 months, p＜0.001) than the non-ORR patients. The median PFS were similar regardless the KRAS mutation status, primary sidedness, or liver metastases. Multivariate analysis revealed that male, ECOG PS2, the number of metastatic sites ≥2, and RAS mutant were significantly associated with worse OS. The most common grade 3/4 adverse events were hand-foot syndrome (1.9%), stomatitis (1.9%), rash (1.0%), hypertension (1.0%), allergic reaction (1.0%), fatigue (1.0%) and fever (1.0%). 8(7.8%) patients experienced at least 1 dose modification or treatment interruption. No death was related to the treatment. Conclusions: In this study the R+S combination as salvage-line treatments in non-MSI-H mCRC achieved a promising clinical benefit, with a manageable safety profile. Female, ECOG PS0/1, single metastases, RAS wild type mCRC were associated with better OS. Clinical trial information: NCT04745130 .
Reversion of RAS mutations in metastatic colorectal cancer in the CCTG CO.26 clinical trial.
Authors: Wu Florence T.H. , Topham James T. , O'Callaghan Christopher J. , Feilotter Harriet , Kennecke Hagen Fritz , Banks Kimberly , Renouf Daniel John , Jonker Derek J. , Tu Dongsheng , Chen Eric Xueyu , Loree Jonathan M.
Published: June 2023

3567

Background: RAS mutations in metastatic colorectal cancer (mCRC) drive resistance to anti-EGFR antibodies. It is unclear if RAS mutations are ever clonally lost, potentially uncovering a new therapeutic option for patients over time. Methods: We examined the temporal evolution of RAS mutation status among patients enrolled in CO.26 [ NCT02870920 ] – a phase II clinical trial that assessed durvalumab + tremelimumab in patients with heavily pretreated mCRC – using whole exome sequencing (WES) of archival primary tumor tissue and circulating tumor DNA (ctDNA) sequencing of serial plasma samples that were taken at baseline, week 8 and on progression. Results: Six out of 95 (6.3%) patients diagnosed with KRAS/ NRAS-mutated mCRC showed ‘neo- RAS-wildtype’ reversions at the time of baseline or week-8 ctDNA collection for the CO.26 trial. The majority (4/6) had falling tumor mutation burden (TMB) but stable or rising maximum mutation allele frequency (MAF) when reversions occurred. These were unlikely false negatives from non-secreting cancers as there were continued strong presence of other somatic clonal mutations (e.g., TP53, ATM). The majority (4/6) of reversions were transient, with mutations reappearing with progressive disease. ‘Neo- RAS-wildtype’ revertors had numerically longer median overall survival (OS) from date of cancer diagnosis to death compared those with persistent RAS mutations (7.7 vs. 4.2 yrs, HR = 0.65, 95% CI 0.31 to 1.36, log-rank P= 0.26). However, ‘neo- RAS-wildtype’ revertors were earlier-stage at diagnosis compared to those with persistent RAS mutations (33% vs. 63% had synchronous metastases, χ2 P= 0.15), and had lower disease burden upon enrollment (50% vs. 68.5% had liver metastases, P= 0.17; 33% vs. 75% had > 4 lesions, P= 0.03*). Survival from stage IV diagnosis to death did not differ between those with reverted vs. persistent RAS mutations (median 3.8 vs. 3.2 yrs, HR = 0.77, 95% CI 0.35 to 1.72, P= 0.52). ‘Neo- RAS-wildtype’ reversions were not associated with side of primary tumors ( P= 0.41), archival BRAF/MEK/ERK-mutant status ( P= 0.16, 1.00, 0.09), baseline HER2 amplifications ( P= 1.00), or baseline TMB ( P= 0.21). Conclusions: We identified a 6.3% prevalence of ‘neo- RAS-wildtype’ reversions in the CO.26 trial, however only 2.1% of patients had persistent loss when serial time points were considered. Further research is needed to understand if ‘neo- RAS-wildtype’ revertors may benefit from anti-EGFR therapy. Clinical trial information: NCT02870920 .
Transcriptomic signatures of MSI-high metastatic colorectal cancer to predict efficacy of immune checkpoint inhibitors.
Authors: Gallois Claire , Landi Matteo , Taieb Julien , Lonardi Sara , Bergamo Francesca , Intini Rossana , Maddalena Giulia , Pietrantonio Filippo , Corti Francesca , Ambrosini Margherita , Martinetti Antonia , Germani Marco Maria , Boccaccio Chiara , Vetere Guglielmo , Mouillet-Richard Sophie , de Reynies Aurélien , Laurent Puig Pierre , Cremolini Chiara
Published: June 2023

3570

Background: Microsatellite instability (MSI) is currently the only predictive biomarker of efficacy of immune checkpoint inhibitors (ICI) in metastatic colorectal cancers (mCRC). However, 10-40% of patients with MSI mCRC will experience a primary resistance to ICI. Methods: In a cohort of 103 patients with MSI mCRC treated with ICI, 3’RNAseq was performed from primary tumors resected before the beginning of ICI. Previously described single-cell transcriptomic signatures of tumor microenvironment (TME) were analysed. Results: The unsupervised clustering of this cohort allowed the identification of three clusters of tumors with distinct transcriptional profiles: cluster A (“stromalHIGH-proliferationLOW”), cluster B (“stromalHIGH-proliferationMED”), and cluster C (“stromalLOW-proliferationHIGH”), with an enrichment of patients progressing at first disease assessment under ICI in the cluster A (30% vs 12% in cluster B and 8.1% in cluster C, p = 0.074). Progression-free survival (PFS) was also significantly shorter in patients belonging to cluster A, compared to clusters B or C (p < 0.001) with 2-year PFS rates of 33.5%, 80.5% and 78.3%, respectively. Similar results were observed for overall survival (OS).In multivariate analysis, PFS was still significantly longer in patients belonging to cluster B (HR: 0.26 95%CI 0.11-0.58, p = 0.001) and cluster C (HR: 0.35 95%CI 0.16-0.78, p = 0.01), compared to patients belonging to cluster A (Table). No association of identified clusters with PFS during non-ICI-based regimens was identified. Conclusions: This unsupervised transcriptomic classification identified three groups of MSI mCRCs with different compositions of TME cells and proliferative capacities of TME/tumor cells. The “stromalHIGH-proliferationLOW” cluster is associated with a lower efficacy of ICI. [Table: see text]