bluuebunny/crossref_metadata_2025_split huggingface dataset:
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 .