bluuebunny/crossref_metadata_2025 huggingface dataset:
Real-world comparison of triplet- versus doublet-chemotherapy with bevacizumab in patients with newly diagnosed metastatic colorectal cancer (mCRC).
Authors: Chapin William Joseph , Hwang Wei-Ting , Mamtani Ronac , O'Hara Mark H.
Published: June 2023

3574

Background: Meta-analysis of five randomized intensification trials in mCRC demonstrated an overall survival (OS) benefit of triplet chemotherapy (5FU/leucovorin, oxaliplatin, irinotecan) plus bevacizumab (Triplet/Bev) compared to doublet chemotherapy plus bevacizumab (Doublet/Bev) (HR 0.81). Guidelines recommend first-line Triplet/Bev for patients with excellent performance status and normal organ function who can withstand increased toxicity, but such patients are less represented in the real world. In this retrospective cohort study, we examine the real-world effectiveness of Triplet/Bev compared to Doublet/Bev in the U.S. Methods: We used the nationwide Flatiron Health electronic health record-derived database, comprising de-identified patient-level structured and unstructured data curated via technology-enabled abstraction from ~ 280 cancer clinics. Included were mCRC patients treated with first-line Triplet/Bev or Doublet/Bev between 10/23/14 and 10/31/22. OS by treatment was assessed using the Kaplan Meier method and adjustment for confounding variables was performed using Cox proportional hazards modeling with stabilized inverse probability of treatment weighting (IPTW). Pre-specified confounding variables included age, gender, race/ethnicity, year of metastatic diagnosis, health insurance, practice setting, KRAS/NRAS/BRAF mutation status, MMR/MSI status, synchronous/metachronous metastases, primary tumor sidedness, CEA, renal dysfunction, hepatic dysfunction, and ECOG performance status. Missing data were imputed using multiple imputation with chained equations. Results: Among 10,016 patients, 391 (3.9%) received Triplet/Bev and 9,625 (96.1%) received Doublet/Bev. Patients who received Triplet/Bev were younger (median age 52 vs 63 years) and were more likely to be treated at academic practices (27% vs 8%), to have synchronous metastatic disease (83% vs 65%), and to have KRAS/NRAS/BRAF wild-type disease (30% vs 17%). In the univariate analysis, median OS was 30.0 months (95% CI 24.7 – 34.7) in the Triplet/Bev cohort versus 23.4 months (95% CI 22.8 – 24.1) in the Doublet/Bev cohort (HR 0.73; 95% CI 0.62 – 0.85; p < 0.001). In Cox proportional hazards modeling with IPTW, there was no significant difference in hazard of death between Triplet/Bev and Doublet/Bev (HR 0.92; 95% CI 0.75 – 1.12; p = 0.4). Conclusions: In this large, national, real-world population of patients with mCRC, first-line treatment with Triplet/Bev was not associated with improved survival compared to Doublet/Bev after accounting for differences in baseline patient characteristics. The benefit to Triplet/Bev observed in randomized trials does not translate well to a more heterogeneous, real-world population. Sub-group analyses including by age, tumor sidedness, KRAS/NRAS/BRAF status, and baseline CEA level will be performed.
Efficacy and safety of IBI351 (GFH925) monotherapy in metastatic colorectal cancer harboring KRASG12C mutation: Preliminary results from a pooled analysis of two phase I studies.
Authors: Yuan Ying , Deng Yanhong , Jin Yongdong , Pan Yueyin , Wang Cunji , Wang Zhiwu , Zhang Zhiye , Meng Xiangjiao , Hu Yi , Zhao Mingfang , Wang Huijuan , Yang Nong , Wu Dongde , Dong Xiaorong , Huang Dingzhi , Sun Meili , Liu Lian , Hua Dong , Guo Zengqing , Ding Ke-Feng
Published: June 2023

3586

Background: IBI351 (GFH925) is an irreversibly covalent inhibitor of KRASG12C and has demonstrated promising anti-tumor activity with acceptable safety in advanced solid tumors. Here, we report a pooled analysis of two phase I studies (NCT05005234, NCT05497336) evaluating the efficacy and safety of IBI351 (GFH925) monotherapy for metastatic colorectal cancer (CRC) harboring KRASG12C mutation. Methods: Eligible metastatic CRC patients (pts) with KRASG12C mutation were included. Pts received IBI351 (GFH925) orally at dose levels of 700mg once daily (QD), or 450/600/750mg twice daily (BID). The primary endpoint was objective response rate (ORR) assessed by investigator per RECIST v1.1. Data cutoff for the analyses was November 30, 2022 unless otherwise specified. Results: A total of 45 pts were enrolled (median age: 58.0 years; male: 57.8%; ECOG PS 1: 71.1%; pts with ≥2 prior lines of treatment: 66.7%), including 3, 4, 37, and 1 pts in 700mg QD, 450mg BID, 600mg BID, and 750mg BID cohorts, respectively. The median exposure to therapy was 84 days (range, 7-286), and 36 pts (80.0%) were still on treatment including one patient at 450mg BID with treatment exposure for 286 days. As of December 15, 2022, ORR was 47.5% (19/40, 95% CI: 31.5%-63.9%) and disease control rate (DCR) was 85.0% (95% CI: 70.2%-94.3%) for the efficacy-evaluable pts across all dose levels. The median duration of response (DOR) was not reached. For 32 efficacy-evaluable patients at 600mg BID, ORR and DCR were 43.8% (14/32) and 87.5%, respectively. Treatment-related adverse events (TRAEs) occurred in 40 (88.9%) pts, with the most common being anaemia, white blood cell count decreased, alanine aminotransferase increased, and pruritus. Grade ≥ 3 TRAEs occurred in 9 (20.0%) pts. No drug-related adverse events leading to treatment discontinuation or death occurred. Conclusions: IBI351 (GFH925) monotherapy demonstrated promising anti-tumor activity with manageable safety profile in metastatic CRC patients harboring KRASG12C mutation. These two studies are still ongoing and longer follow-up will provide more solid evidence. Updated data will be presented at the meeting. Clinical trial information: NCT05005234 , NCT05497336 .
Phase II study of biweekly TAS-102, irinotecan and bevacizumab in pre-treated metastatic colorectal cancer (TABAsCO).
Authors: Boland Patrick M , Mukherjee Sarbajit , Imanirad Iman , Vijayvergia Namrata , Cohen Seth D. , Gupta Medhavi , Iyer Renuka V. , Chatley Sarah , Cahill Beth , Vadehra Deepak , Attwood Kristopher , Hochster Howard S. , Fountzilas Christos
Published: June 2023

3590

Background: The efficacy of 2nd line FOLFIRI plus VEGF inhibition (VEGFi) is limited for metastatic colorectal cancer (mCRC). TAS-102 is a novel oral anti-metabolite approved for pts with mCRC following standard treatment with FP, oxaliplatin and irinotecan. TAS-102 has a distinct mechanism of action from 5-FU and overcomes 5-FU resistance in preclinical models, and in the clinic. We hypothesized that the combination of TAS-102 with irinotecan (TAS-IRI) and bevacizumab (BEV) would prove superior to FOLFIRI/VEGFi. Methods: Phase II, single-arm study of TAS-IRI and BEV in 2nd-line mCRC. Eligible patients had received prior treatment with a fluoropyrimidine and oxaliplatin in the advanced setting or experienced recurrence within 12 mos of this regimen in the adjuvant setting. Adequate organ function, ECOG PS 0-1, measurable disease (RECIST 1.1), no prior irinotecan or TAS-102 exposure and candidacy for BEV were required. Pts were treated with BEV 5 mg/kg IV, irinotecan 180 mg/m2 IV (day 1 and 15), and TAS-102 25 mg/m2 orally bid (days 2-6 and 16-20) in 4-week cycles (PMID: 31924737). Treatment continued until disease progression or unacceptable toxicity. The primary endpoint was median progression-free survival (PFS). Assuming a median PFS for historic control (FOLFIRI/VEGFi) of 6 mos vs. 9 mos for TAS-IRI plus BEV (HR: 0.67), treatment of 36 evaluable pts would achieve 80.5% power (at α = 0.1) to detect such an effect. Results: Forty-nine patients were enrolled; 42 were eligible and 38 had at least one disease assessment (median age 59 yr, 47% male, 74% colon primary, tumor KRAS/NRAS mutated in 55%/21%). The median PFS was 8.7 mos (range: 6.7-11.8 mos, p = 0.009), meeting the primary endpoint. The most common reason for study treatment discontinuation was progressive disease (53%). The objective response rate was 16% (90% CI: 8.0-27.3%); the median OS was 16.5 mo (range: 11.8-25.3). Twenty-eight pts (67%) had a treatment-related adverse event (TRAE) G3 or higher (Table). The most common TRAEs were gastrointestinal and hematologic. Grade 3/4 neutropenia occurred in 34%, with only 1 episode of febile neutropenia, though G-CSF use was frequently needed to maintain dose density/intensity. Conclusions: TAS-IRI plus BEV is an effective 2nd line therapy for patients with mCRC. The median PFS appears higher compared to historical controls (FOLFIRI/VEGFi). Neutropenia is common and can affect dose density/intensity mandating use of G-CSF. A randomized study versus standard of care therapy is warranted. (Clinical trial registration ClinicalTrials.gov NCT04109924). Clinical trial information: NCT04109924 . [Table: see text]
Preoperative assessment in lung-limited metastatic patients with colorectal cancer: The Meta-Lung Score.
Authors: Ziranu Pina , Ferrari Paolo Albino , Guerrera Francesco , Bertoglio Pietro , Tamburrini Alessandro , Lyberis Paraskevas , Pretta Andrea , Grimaldi Giulia , Lai Eleonora , Santoru Massimiliano , Dubois Marco , Riva Laura , Bardanzellu Fabio , Alzetani Aiman , Luzzi Luca , Solli Piergiorgio , Paladini Piero , Ruffini Enrico , Cherchi Roberto , Scartozzi Mario
Published: June 2023

3598

Background: Due to the inconsistent data on curative resection of isolated lung metastases (LM) from colorectal cancer (CRC) and the lack of specific recommendations, the therapeutic approaches for metastatic liver disease are mostly applied to LM treatment, despite differences in their biological behavior. Like Fong's criteria in CRC liver metastases, our study proposed a score associated with clinical outcomes in patients (pts) undergoing CRC lung metastasectomy, aiming to better pts' selection for surgery and the most appropriate therapeutic strategy. Methods: We retrospectively collected data from 260 pts (aged 18-85) who underwent CRC lung metastasectomy with curative intent from December 2002 to January 2022 at four Italian Centers: the Division of Thoracic Surgery at “A. Businco Cancer Center” in Cagliari, the Division of Thoracic Surgery at “Città della Salute e della Scienza” in Tourin, the Department of Thoracic Surgery at “IRCCS Azienda Ospedaliero-Universitaria” in Boulogne, and the Medical Oncology Unit of the University Hospital of Cagliari. Statistical analysis was performed with MedCalc (survival distribution: Kaplan-Meier; survival comparison: log-rank test; association between categorical variables: Fisher's exact test). Results: We analyzed the impact of different clinicopathological features on overall survival (OS). At the univariate analysis: higher baseline CEA levels (p = 0.0001), disease-free survival less than or equal to 12 months (m) (p = 0.0043), LM size larger than 2 cm (p = 0.0187), multiple resectable nodules (p = 0.0083), and positive nodal status of the primary tumor (p = 0.0011) were associated with poorer prognosis. In a Cox regression model, these five characteristics retained their independent role for OS (p < 0.0001) and were chosen as criteria to be assigned one point each for clinical risk score. The 5-year survival rate in pts with 0 points was 88%, while no pts with a 5-points score survived at 2 years. Based on the 0-2 versus 3-5 score range, we obtained a significant difference in median OS: 101.7 m (95%CI 64.6 - 101.7) vs. 39.5 m (95%CI 27.3 - 87.5) respectively (p < 0.0001) stratifying pts into good and poor prognosis. Conclusions: The Meta-Lung Score appeared to be an exciting prognostic tool in selecting CRC pts’ candidates for radical surgical treatment when LM were diagnosed. Whether early surgery should be considered in pts with a score 0-2, the same choice should be taken with caution in pts with a score 3-5, for whom early chemotherapy would allow better assessment of tumor biology and appropriate selection for surgery.[Table: see text]
Targeting EZH2 to overcome the resistance to immunotherapy in microsatellite stable colorectal cancer: Results from the CAIRE study.
Authors: Palmieri Lola Jade , Cousin Sophie , Spalato Mariella , Guégan Jean Philippe , Bessede Alban , Pernot Simon , Italiano Antoine
Published: June 2023

3599

Background: Profound epigenetic and transcriptomic changes induced by EZH2 in tumor cells and immune cells mobilize the elements of the TME, leading to immune-suppressive activity of solid tumors. Targeting EZH2 can enhance anti-tumor immunity by reshaping the tumor microenvironment (TME). The CAIRE study is first study investigating the impact of EZH2 inhibition in combination with immune checkpoint inhibitor in solid tumors. Methods: This is a single-arm open-label multicentric phase II trial assessing the efficacy and safety of tazemetostat (800 mg BID) combined with durvalumab (1120 mg every 3 weeks) in patients with advanced microsatellite stable colorectal cancer. The primary endpoint was the disease control rate within 24 weeks after treatment onset defined as the proportion of patients with at least a tumor assessment showing connfirmed or unconfirmed complete response, confirmed or unconfirmed partial response or stable disease based on central review according to RECIST 1.1. Secondary endpoints included: 1-year progression free survival (PFS), 1-year overall survival (OS), and safety using NCI-CTCAE v5.0. All patients underwent sequential blood and tissue sampling for translational studies. Results: Between July 2021, and June 2022, 47 pts were enrolled at Institut Bergonié (Bordeaux, Centre). Median age was 67.7 (range 39.6 – 84.0). Median number of previous treatment lines was 4: (range 1 – 6). The most common treatment related adverse events were grade 1/2 asthenia, nausea. No death was related to the treatment. Among the 34 pts for whom blinded central review of imaging was available for at least one imaging tumor assessment, best tumor response was confirmed partial response, stable disease and progressive disease in 1 (2.9%), 11 (32.3%) and 22 (64.7%) patients respectively. The disease control rate was 35.3% (95%CI 19.7 – 53.5). Conclusions: The CAIRE study met its first endpoint for disease control rate in patients with advanced colorectal cancer. Efficacy data on the whole cohort of patients and full biomarkers analyses will be presented at the meeting. Clinical trial information: NCT04705818 .
Cost-effectiveness analysis of later-line therapies for metastatic colorectal cancer (mCRC) based on a novel methodology of network meta-analysis (NMA) of survival curves.
Authors: Obeng-Kusi Mavis , Roe Denise , Erstad Brian L , Abraham Ivo
Published: June 2023

3605

Background: With advances in the management of mCRC, survival outcomes of patients have improved. While some patients still progress after first and second lines of treatment, there remain options for third or later-line treatment. This study aimed to determine the cost-effectiveness of later-line (>3) treatments for patients with mCRC in the US, based on a NMA of survival curves. Unlike conventional NMA using constant hazard ratios, this method is not constrained by the proportional hazard assumption and uses parametric fitting that incorporates the shape and scale parameters to provide time-varying treatment effects. Methods: The NMA compared the efficacy of 6 treatments, atezolizumab+/-cobimetinib (ATE+/-COB), fruquintinib (FRU), regorafenib (REG), TAS-102+/-bevacizumab (TAS+/-BEV), including biosimilar, to placebo (PBO). The study used a 3-state partitioned survival model over a 5-year time horizon incorporating drug acquisition, administration, adverse events, monitoring, and end of life costs, and utilities sourced from literature. Total costs, life-years (LY) and quality-adjusted LYs (QALY) for each treatment were determined. Incremental cost-effectiveness (ICER) and incremental cost-utility ratios (ICUR) were estimated using PBO as a common comparator. Results: Over the 5-year period and across the 6 therapies, survival ranged from 0.62 LYs for PBO to 1.15 LYs for TAS+BEV, translating to QALYs ranging from 0.44 for PBO to 0.85 for TAS+BEV. Total costs of treatment ranged from 278,877 for PBO to 417,495 for TAS+BEV (405,002 with biosimilar). TAS+BEV yielded the lowest ICER of an additional 261,421 (237,860 with biosimilar)/LY gained (g) and ICUR of an additional 343,458 (312,504 with biosimilar)/QALYg; while ATE presented the least favorable ICER and ICUR of an additional $522,602/LYg and $701,381/QALYg, respectively (Table). Conclusions: Among the 6 treatments evaluated, TAS+BEV emerged as the most cost-effective later-line treatment for mCRC while atezolizumab was the least cost-effective. Additionally, replacing BEV with a biosimilar reduces costs and enhances cost-effectiveness, improving access for patients. [Table: see text]
Efficacy and safety of mFOLFOX6 with apatinib as postoperative adjuvant chemotherapy in stage IIIB or IIIC colorectal cancer.
Authors: Gu Xiaodong , Zhou Minwei , Wang Zihao , Li Zhenyang , Yang Yi , Zang Yiwen , Zhou Yiming , Xiang Jianbin , Chen Zongyou
Published: June 2023

3613

Background: Antiangiogenic therapy has shown benefit in metastatic colorectal cancer. However, the role of apatinib in adjuvant treatment of stage IIIB and IIIC colorectal cancer remains unclear. Methods: Patients received modified FOLFOX6 once every 2 weeks for a 6-month period (control group) or modified FOLFOX6 for 6 months plus apatinib (500mg) once a day for a 12-month period (experimental group). Progression free survival (PFS), overal survival (OS) and treatment-related adverse events were evaluated in two groups. Results: 63 patients have been enrolled in this study. This trial reported a 3-year PFS of 74.2% for modified FOLFOX6 plus apatinib vs. 61.5% for modified FOLFOX6 ( P< 0.05). 5-year OS was significantly improved in the experimental group compared with the control group (86.3% vs. 72.5%; P< 0.05). The most common grade 3 adverse events were hypertension and hand–foot syndrome. No treatment-related grade 4 adverse events or treatment-related deaths were observed. Conclusions: Apatinib can prolong PFS and OS when added to adjuvant chemotherapy in resected stage IIIB and IIIC colorectal cancer. The toxicities associated with apatinib were generally acceptable. Clinical trial information: NCT03365765 .
Mismatch Repair system protein deficiency as a factor of resistance to chemo-radiotherapy treatment in patients with locally advanced rectal adenocarcinoma and its influence on disease-free survival.
Authors: Pretta Andrea , Ziranu Pina , Giampieri Riccardo , Donisi Clelia , Pinna Giovanna , Randon Giovanni , Loi Francesco , Deias Giulia , Palmas Enrico , Morano Federica , Solinas Cinzia , Lai Eleonora , Pusceddu Valeria , Puzzoni Marco , Zorcolo Luigi , Barbara Raffaele , Faa Gavino , Berardi Rossana , Pietrantonio Filippo , Scartozzi Mario
Published: June 2023

3615

Background: Available data on Mismatch Repair system deficit and microsatellite instability are conflicting and are generally derived from a small number of patients due to the rarity of this condition in rectal cancer. Our study aimed to evaluate the frequency and therapeutic implications of Mismatch Repair proteins (MMR) status in patients with locally advanced rectal cancer (LARC). Methods: We retrospectively collected data from 318 patients affected by LARC adenocarcinoma (cT3-4 +/- N1-2) treated at the Medical Oncology Unit of the University Hospital of Cagliari, Italy, the Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy and at the Medical Oncology Unit, AOU Ospedali Riuniti, Ancona. Italy. All patients included in the study underwent neoadjuvant concurrent capecitabine and long-course radiotherapy (RT) (total dose of Gy 50.4), afterwards a total mesorectal excision (TME) was performed. MMR expression was evaluated through immunohistochemistry. The primary objective was major TRG (0-1 Ryan’s score) while secondary objectives were pathological complete response, disease-free survival (DFS) and overall survival (OS). Results: 160 patients (148 pMMR and 12 dMMR) were included in exploratory cohort and 158 (146 pMMR and 12 dMMR) were included in validation cohort. A major TRG has been shown in 64/148 (42,6%) and 63/146 (43,1%) patients with pMMR in exploratory cohort and validation cohort, respectively; while no major TRG have been shown in dMMR patients in exploratory cohort nor in validation cohort. Both exploratory and validation cohorts showed a statistically significant higher median DFS in pMMR patients compared to dMMR ones: NR vs 14 months in exploratory cohort ( p = 0,003) and NR vs 17 months in validation cohort ( p = 0,02). Conclusions: Our retrospective study indicated an association between dMMR and poor or no response to preoperative chemoradiotherapy. These results are consistent with the role of MMR as a predictor of poor-response to chemoradiotherapy and represent a hypothesis-generating study for the selection of these patients for immunotherapy in the neoadjuvant setting, in which the available data are immature.
Prophylactic hyperthermic intraperitoneal chemotherapy in T4 colorectal cancer: Can it improve the oncologic prognosis?
Authors: Sun Lifeng , Zheng Yuyan , Chen Chao , Gong Zhiyuan
Published: June 2023

3619

Background: Previous studies have shown that T4 stage was one of the risk factors for peritoneal metastasis (PM) of colorectal cancer (CRC). However, there is paradoxical data to prove that prophylactic hyperthermic intraperitoneal chemotherapy (HIPEC) treatment is beneficial for CRC patients. Methods: In this cohort study, 220 consecutive CRC patients with T4N0-2M0 were enrolled and recorded from November 2014 to November 2018 with a 3-year follow-up following surgery. A propensity score matching (PSM) approach was applied to balance the clinicopathological characteristics. Finally, 180 patients were matched successfully to further analyze. The 3-year disease-free survival (DFS) was set as the primary outcome, and the PM rate between the two groups after PSM was analyzed. Results: Before PSM, of 220 CRC patients enrolled, the 3-year DFS was 83.9% in the HIPEC group, which was better than 67.2% in the control group. The cumulative PM incidence was 2.2% in the HIPEC group and 12.6% in the control group (p = 0.047). After PSM, 180 matched patients were formed for further analysis. The DFS and the cumulative PM rate of the patients in the HIPEC group were also better than that in the control group (p = 0.034 and 0.047, respectively). For laparoscopic surgery subgroup analyses, PM rate of the patients with laparoscopic surgery was 13.8% in the No HIPEC group, and 2.6% in the HIPEC group (p = 0.070). Through multivariable analysis, it was found that prophylactic HIPEC correlated to better DFS [hazard ratio (HR) 0.43, 95% confidence interval (CI) 0.19-0.95; p = 0.037], and N2 stage correlated to worse DFS [HR 1.97, 95% CI 1.09-3.56; p = 0.025]. Besides, no post-operative death occurred, the anastomotic leakage rate was 2.2% in the HIPEC group and 0.7% in the control group (p = 0.439). Conclusions: Prophylactic HIPEC may improve the prognosis in the patients with T4N0-1M0 CRC, but not in the T4N2M0 CRC, and it does not significantly increase the surgery-related complications. Laparoscopic surgery followed by HIPEC for T4 stage CRC is relatively safe, which does not increase the risk of PM.
Molecular profiling and characterization of the tumor immune microenvironment (TME) in appendiceal carcinoma (AC).
Authors: Rehman Muneeb , Baca Yasmine , Xiu Joanne , Walker Phillip , Lou Emil , El-Deiry Wafik S. , Lenz Heinz-Josef , Shields Anthony F. , Marshall John , Johnston Curtis , Oberley Matthew James , Goel Sanjay , Weinberg Benjamin Adam , Holowatyj Andreana Natalie
Published: June 2023

3622

Background: The rarity of AC presents challenges in understanding disease pathogenesis. We previously showed that AC has higher rates of mutations in KRAS and GNAS and lower rates of TP53, APC, and PIK3CA than CRC. The appendix also has many lymphoid clusters and regulates IgA production in the large bowel, suggesting that AC may be subject to more lymphocytic regulation than CRC. We sought to characterize the molecular profile and TME across AC histopathological types. Methods: AC samples were analyzed by DNA sequencing (592 genes, NextSeq, or whole exome sequencing, NovaSeq), whole transcriptome sequencing (WTS, NovaSeq), and immunohistochemistry (IHC) for molecular profiling, including microsatellite instability (MSI), mismatch repair (MMR), PD-L1 (SP142), and tumor mutational burden (TMB). Microenvironment Cell Population-counter Quantiseq was used to quantify tumor immune contexture using WTS. AC histopathology was derived from pathology reports. Mann-Whitney U and ChiSquare tests were applied as appropriate, with P-values adjusted for multiple comparisons using Benjamini-Hochberg. Results: AC (N = 731) were grouped by histology: 5% goblet cell (GC), 6% high-grade adenocarcinoma (HGA), 14% low grade mucinous (LGM), 33% mucinous adenocarcinoma (MA), 1% pseudomyxoma peritonei (PMP), 6% signet ring cell carcinoma (SRC), and 35% adenocarcinoma not otherwise specified (NOS) (see Table). Age at collection and PD-L1+ (0-5.2%) did not differ by histopathology. Seven patients had dMMR (4 NOS and 3 MA). Median TMB was significantly higher in NOS vs. GC (4 mutations/megabase vs 2, q < 0.001), NOS vs. LGM (4 vs 3, q = 0.048), MA vs. GC (4 vs 2, q < 0.001), and MA vs. LGM (4 vs 3, q = 0.037). Distinct TME patterns were observed in NOS vs. MA (median cell fraction: dendritic cells 0.07 vs 0, q < 0.01; M2 macrophages 0.055 vs 0.042, q = 0.030; natural killer cells 0.034 vs 0.031, q = 0.011; CD4 T cells 0.006 vs 0, q = 0.044) and GC vs. MA (M1 macrophages 0.039 vs 0.057, q = 0.021; dendritic cells 0.012 vs 0, q < 0.01; B cells 0.061 vs 0.050, q = 0.013; M2 macrophages 0.074 vs 0.042, q < 0.01; natural killer cells 0.041 vs 0.031, q = 0.01; and neutrophils 0.017 vs 0.038 q = 0.045). T cell inflamed signature (TIS) and immune-oncology (IO) marker gene expression were higher in HGA and lower in LGM and MA. Somatic mutation rates differed by histopathology (see Table). Conclusions: There is significant heterogeneity in TMB, TME, and mutational profiles across AC histologies. MA has a particularly immune-cold TME shown by lower infiltration of lymphocytes, TIS, and IO gene expression. These findings are critical to identify novel biomarkers and develop new therapeutic strategies for AC. [Table: see text]
Health-related quality of life (HRQoL) in the phase 3 KEYNOTE-966 study of pembrolizumab (pembro) plus gemcitabine and cisplatin (gem/cis) versus placebo plus gem/cis for advanced biliary tract cancer (BTC).
Authors: Yoo Changhoon , Finn Richard S. , Klümpen Heinz-Josef , Kelley Robin Kate , Vogel Arndt , Furuse Junji , Ren Zhenggang , Yau Thomas , Chan Stephen Lam , Ozaka Masato , Oh Sang Cheul , Gu Shanzhi , Park Joon Oh , Valle Juan W. , Edeline Julien , Kamble Shital , Norquist Josephine M , Yu Li , Malhotra Usha , Ueno Makoto
Published: June 2023

4003

Background: In the randomized, double-blind, phase 3 KEYNOTE-966 trial (N = 1069; NCT04003636), pembro + gem/cis significantly improved OS versus placebo + gem/cis (HR 0.83; 95% CI 0.72-0.95; P = 0.0034) and had an expected and manageable safety profile as first-line therapy for unresectable locally advanced or metastatic BTC. We present the protocol-specified exploratory patient-reported outcomes (PROs) from KEYNOTE-966. Methods: PROs were assessed using the EORTC QLQ-C30, EORTC QLQ-BIL21, and EQ-5D-5L questionnaires. The analysis population included all treated patients (pts) who completed ≥1 HRQoL assessment for the specific endpoint. A constrained longitudinal analysis model (covariates: treatment, time, treatment by time interaction, and stratification factors) was used to compare least squares mean (LSM) score changes from baseline (BL) to wk 18 (ie, latest timepoint that completion was ≥60% and compliance was ≥80%) in QLQ-C30 global health status (GHS)/QoL, physical functioning (PF), and role functioning (RF), QLQ-BIL21 jaundice and pain, and EQ-5D-5L visual analogue scale (VAS). A stratified Cox proportional hazards model was used to assess the magnitude of the between-arm difference in time to deterioration (TTD) in GHS/QoL, PF, RF, jaundice, and pain (ie, time to first onset of ≥10-point deterioration from BL in each scale/subscale confirmed by ≥10-point deterioration from BL at the next visit; established as clinically relevant). Results: Questionnaire compliance was >87% from BL to wk 18 in both arms. LSM changes from BL to wk 18 in QLQ-C30 GHS/QoL, PF, and RF, QLQ-BIL21 jaundice and pain, and EQ-5D-5L VAS were similar between arms. Time to deterioration was also similar between arms: median not reached (NR) vs 21.2 mo for GHS/QoL (HR 0.86, 95% CI 0.70-1.07), NR vs 12.0 mo for PF (HR 0.95, 95% CI 0.78-1.17), 6.5 mo vs 5.8 mo for RF (HR 0.98, 95% CI 0.81-1.18), NR vs NR for jaundice (HR 1.20, 95% CI 0.94-1.54), and NR vs NR for pain (HR 0.79, 95% CI 0.59-1.05). Conclusions: HRQoL was maintained when pembro was added to gem/cis. Together with the efficacy and safety data, these results support pembro + gem/cis as a new first-line treatment option for advanced BTC. Clinical trial information: NCT04003636 . [Table: see text]
Results from the MORPHEUS-liver study: Phase Ib/II randomized evaluation of tiragolumab (tira) in combination with atezolizumab (atezo) and bevacizumab (bev) in patients with unresectable, locally advanced or metastatic hepatocellular carcinoma (uHCC).
Authors: Finn Richard S. , Ryoo Baek-Yeol , Hsu Chih-Hung , Li Daneng , Burgoyne Adam , Cotter Christopher , Badhrinarayanan Shreya , Wang Yulei , Yin Anqi , Rao Edubilli Tirupathi , Gane Edward
Published: June 2023

4010

Background: Atezo + bev is the current first-line standard of care for uHCC based on the IMbrave150 study, which demonstrated superior overall survival, progression-free survival (PFS), and objective response rate (ORR) vs sorafenib (Finn, et al. New Engl J Med 2020; Cheng, et al. J Hepatol 2022). TIGIT is a novel inhibitory immune checkpoint present on activated T cells and NK cells. Tira (anti-TIGIT) may synergize with other immunotherapies, such as PD-L1/PD-1 inhibitors. The MORPHEUS platform comprises multiple phase Ib/II trials to identify early efficacy signals and safety of treatment combinations across cancers. Here we report data from a cohort of the MORPHEUS-liver study (NCT04524871) evaluating the combination of tira + atezo + bev vs a control arm (atezo + bev) in patients with uHCC. Methods: Patients with previously untreated uHCC were randomized to receive atezo (1200mg IV) + bev (15mg/kg IV) with or without tira (600mg IV) every three weeks. The primary endpoint was investigator-assessed ORR by RECIST V1.1. Secondary endpoints included PFS and safety. Results: A total of 58 patients were randomized (tira + atezo + bev, n=40; atezo + bev, n=18). As of 28 November 2022, median follow up was 14.0 months in the tira + atezo + bev arm and 11.8 months in the control arm. Confirmed ORR was higher in the tira + atezo + bev arm (42.5%) vs the control arm (11.1%). Median PFS was longer with tira + atezo + bev (11.1 months; 95% CI: 8.2–NE) vs control (4.2 months; 95% CI: 1.6–7.4), corresponding to a PFS hazard ratio (HR) of 0.42 (95% CI: 0.22–0.82). A similar pattern of increased ORR and PFS was observed for the treatment arms in both PD-L1+ (n=23) and PD-L1– (n=27) subgroups. For tira + atezo + bev vs control arm, grade 3/4 treatment-related AEs were 27.5% vs 33.3% and AEs leading to any treatment discontinuation were 22.5% vs 22.2%, respectively. Conclusions: The addition of tira to atezo + bev resulted in higher ORR and longer PFS compared with atezo + bev, and no new safety signals were identified. These data suggest that tira + atezo + bev may be a promising novel first-line treatment option for patients with uHCC, and support further study in this setting. Clinical trial information: NCT04524871 . [Table: see text]
Subgroup analysis of double-blind, placebo-controlled Ph. 2 study of nanvuranlat in treatment of pre-treated, advanced, refractory biliary tract cancer (BTC): Patients with high LAT1 expression and response to nanvuranlat.
Authors: Ikeda Masafumi , Ueno Makoto , Furukawa Masayuki , Morizane Chigusa , Takehara Tetsuo , Nishina Tomohiro , Todaka Akiko , Okano Naohiro , Hara Kazuo , Nakai Yousuke , Ohkawa Kazuyoshi , Sasaki Takashi , Sugimori Kazuya , Yokoyama Naoyuki , Yamamoto Kouji , Furuse Junji
Published: June 2023

4011

Background: L-type amino acid transporter 1 (LAT1, SLC7A5) is overexpressed in cancer cells leading to aggressive proliferation and lymphatic metastases. LAT1 sustains energy resources by supplying essential amino acids to the TCA cycle in chemotherapy-resistant cancer cells. LAT1 is a documented marker of poor prognosis. In a placebo-controlled, randomized trial involving patients with pre-treated, advanced, refractory biliary tract cancer (BTC), monotherapy with nanvuranlat (JPH203), a selective LAT1 inhibitor, demonstrated a significant improvement in progression free survival (PFS) compared to placebo. Subgroup analysis was conducted to determine whether the level of expression of LAT1 affects nanvuranlat efficacy. Methods: Patients with four different subtypes of advanced BTC were enrolled: intrahepatic and extrahepatic cholangiocarcinoma, and gallbladder and ampulla of Vater cancers. All were refractory to or intolerant of standard chemotherapy and other investigational medicines. Our analysis compared efficacy and safety in the subgroup with high LAT1 expression and all patients group. LAT1 expression was immunohistochemically evaluated in tumor specimens of BTC patients at baseline, as defined by Yanagisawa N, et al. (Cancer Med 2014). Results: At data cut-off (Feb 28, 2022), 211 BTC patients consented at 14 centers in Japan, and 104 patients were randomized (2:1) to nanvuranlat (n = 69) or placebo (n = 35) as the full analysis set (FAS) population. Among the samples immunohistochemically evaluable for LAT1, 62.5% had high LAT1 expression. There was no significant difference in background demography between all patient group and the high-LAT1 subgroup. Nanvuranlat met its primary endpoint (FAS by the blinded independent central review (BICR)), demonstrating a statistically significant improvement in PFS by BICR in comparison with the placebo group. The hazard ratios were further improved with nanvuranlat versus placebo, on analysis of the high-LAT1 subgroup of patients in both PFS and OS. Safety was comparable between nanvuranlat and placebo, on analysis of the high-LAT1 subgroup. Conclusions: This subgroup analysis indicates that the efficacy of nanvuranlat in PFS and OS is enhanced in BTC patients with high LAT1 expression, when compared with placebo. Safety profiles were similar for nanvuranlat- and placebo-treated patients in this subgroup analysis. Clinical trial information: UMIN000034080 . [Table: see text]
A randomized study of consolidation chemoradiation (CTRT) vs observation after first-line chemotherapy (CT) in advanced gall bladder cancers (GBC): RACE-GB Study.
Authors: Agrawal Sushma , Rahul Rahul , Singh Ashish , Mishra Prabhakar , Saxena Rajan
Published: June 2023

4016

Background: CT (gemcitabine plus cisplatin) is the standard of care for patients presenting with unresectable advanced GBC but their prognosis remains poor. The value of CTRT after CT is uncertain. We therefore conducted a randomised trial evaluating consolidation CTRT versus Observation after four cycles of CT in those patients whose disease did not progress during CT (NCT05493956). Methods: Responders (partial response and stable disease) to 4 cycles of CT were randomised to CTRT vs observation (n=135). CTRT was delivered by 3D-Conformal Radiation Therapy along-with concurrent capecitabine @1250 mg/m2. The dose of RT was 45 Gy in 25 fractions to GBC and lymphatics followed by a boost of 9 Gy in 5 fractions to the GBC. The primary endpoint was overall survival which was calculated from the date of randomisation. The trial is designed to detect an improvement in 2-year OS from 8% in the control arm to 25% in study arm with 80.0% power at a 0.05 significance level. The required sample size was 130 (65 in each arm) over a duration of 4-5 years. CTRT was delivered by 3DCRT along-with concurrent capecitabine @1250 mg/m2. The dose of RT was 45Gy in 25 fractions to GBC and lymphatics followed by a boost of 9 Gy in 5 fractions to the GBC. Toxicities documented during CT and CTRT were recorded using the CTCAE version 3.0. and RTOG criteria respectively. Chi square test and Survival analysis was performed for the data analysis. Demographic data and CTRT Dose volume data were correlated with side effects and survival. Statistical analysis was performed with SPSS version-23. Results: 67 patients were randomized to observation and 68 to CTRT. Their demographic characteristics were well balanced. 63% were women, 58% had T4 tumours, 42% had N2, 27% needed stenting for obstructive jaundice. The median overall survival in the CTRT arm was 10 months versus 4 months in the observation arm (HR 0.47 [95% CI 0.33-0.68] p=0.001). Adverse events (grade 3 or higher) due to CTRT included the following: Nausea 3%, Anemia 9%, GI bleed 6%, hepatotoxicity 13%. Updated survival data and prognostic factors affecting overall survival will be presented in the meeting. Conclusions: CTRT after 4 cycles of CT significantly prolonged overall survival but was also associated with adverse events. Clinical trial information: NCT05493956 .
Not all treated KRAS-mutant pancreatic adenocarcinomas are equal: KRAS G12D and survival outcome.
Authors: Ardalan Bach , Ciner Aaron , Baca Yasmine , Darabi Sourat , Kasi Anup , Lou Emil , Azqueta Jose Ignacio , Xiu Joanne , Nabhan Chadi , Shields Anthony F. , Aguirre Andrew , Singh Harshabad , Shroff Rachna T. , Pishvaian Michael J. , Goel Sanjay
Published: June 2023

4020

Background: KRAS is an oncogenic driver in pancreatic ductal adenocarcinoma (PDAC) with mutations identified in > 90% of cases. G12D is the most frequent variant, followed by G12V and G12R. We recently reported on the prognostic impact of distinct KRAS mutations. The current study utilized a large clinical and genomic database, to further explore and characterize the prognostic and molecular differences between KRAS variants, focusing on KRAS G12D and G12R. Methods: PDAC samples were tested using whole transcriptome sequencing (WTS; Illumina NovaSeq) and NextGen DNA sequencing (NextSeq, 592 Genes and NovaSEQ, WES) at Caris Life Sciences (Phoenix, AZ). Transcriptomic signatures including MPAS (MAPK activation score), T-cell inflamed score and tumor micro environment (TME) characterization were calculated on WTS data. Significance was determined by X2 and Fisher-Exact and p-value was adjusted for multiple comparisons (q). Real-world overall survival (rwOS) obtained from insurance claims data was calculated from tissue collection to last contact (comparison done by Kaplan-Meier test). Results: 5,555 PDAC patients harboring either KRAS G12D (n = 2,671), G12V (n=1,871) G12R (n = 904) or G12C (n = 109) variants were identified. Patients with KRAS G12R mutant tumors had significantly longer OS compared to G12D (396 vs 311 days, HR 0.81, CI 0.74-0.88, p<0.0001). There was no difference among KRAS variants in the rate of TP53, CDKN2A and SMAD4 mutations. ARID1A and KMT2D were more frequently mutated in KRAS G12D vs. G12R. The MPAS gene signature reflecting MAPK pathway activation trended lower in G12R vs. G12D. Expression of multiple genes in this pathway was statistically lower in the G12R cohort. Immune profiling suggested that: PDL1 expression is significantly lower in G12R vs G12D (13% vs 19%), TMB-H and dMMR were comparable in G12D vs G12R and several glucose and glutamine metabolism genes were significantly lower in expression when comparing G12R vs G12D - table. OS was improved within the G12R cohort for those patients on metformin (n=273 patients) (416 vs 388 days, HR 0.84, CI 0.72-0.99, p =0.037) while no difference was seen in those with KRAS G12D based on metformin use. Conclusions: Patients with G12D mutations have significantly lower survival compared to G12R. Significant molecular differences were seen in MAPK pathway gene expression, markers of immune activation, and genes involved in glucose and glutamine metabolism. Intriguingly, metformin use appeared to impact survival in the KRAS G12R subgroup. We aim to further explore distinct vulnerabilities based on MAPK pathway activation and dysregulated metabolism. Based on this data, future studies should address the KRAS mutation status and explore distinct therapeutic vulnerabilities. [Table: see text]
Prospective evaluation of the utility of concurrent 18F-FDG PET/CT and 68Ga-DOTA-TOC imaging in gastroenteropancreatic neuroendocrine neoplasms (GEPNENs): The PETNET study.
Authors: Solar Vasconcelos Joao Paulo , Zhou Marilyn , Ravi Pavithraa , Allan Hayley , Saprunoff Heather , Bloise Ingrid , Harsini Sara , Wilson Don , Benard Francois , Martineau Patrick , Loree Jonathan M.
Published: June 2023

4022

Background: Somatostatin receptor imaging (SRI) is a standard of care for patients with GEPNETs. The additional value of concurrent 18F-FDG PET/CT (FDG PET) remains unclear. We reviewed a prospective functional imaging study to determine the utility of FDG PET in GEPNENs. Methods: PETNET is a prospective study in British Columbia, Canada, which provides all 68Ga-DOTA-TOC (DOTA PET) imaging in the province. Every patient receives a DOTA PET scan and an FDG PET within 30 days. PETNET enrolls all patients with an indication for SRI. Scans are ordered per treating physician discretion at any point in the disease course. This abstract focuses on the WD-GEPNEN population. Only the first dual functional imaging scans were analyzed and FDG was interpreted qualitatively (positive/negative). Results: From 04/2017-01/2023, 375 patients with NEN were enrolled, 165 (44%) with metastatic GEPNENs. Baseline characteristics are described. Median time between scans was 4 days (IQR 1-11). The proportion of patients with positive FDG PET at baseline increased with WHO grade. For patients with well differentiated G1 to G3 GEPNENs (N=161), overall survival was significantly lower with a positive FDG PET (HR: 4.22; 95%CI 1.61-11.02 p=0.001). FDG remained prognostic when G3 tumors were excluded (N=148) (HR 3.52; 95%CI 1.32-9.42 p= 0.007). When analyzing dual tracer PET imaging, patients with DOTA+/FDG- had reduced risk of dying in comparison with DOTA+/FDG+ (HR:0.26; 95%CI 0.09-0.67 p=0.01). After multivariate analysis, FDG positivity remained independently associated with reduced survival (HR 2.87; 95%CI 1.06-7.75 p=0.04) when controlling for grade of tumor and age. Conclusions: In this prospective cohort of metastatic GEPNENs, a positive FDG PET was significantly associated with reduced overall survival. These results provide additional evidence to support dual tracer functional imaging use in metastatic well differentiated GEPNEN’s. [Table: see text]
Nivolumab (NIVO) plus chemotherapy (chemo) vs chemo as first-line (1L) treatment for advanced gastric cancer/gastroesophageal junction cancer/esophageal adenocarcinoma (GC/GEJC/EAC): 3-year follow-up from CheckMate 649.
Authors: Janjigian Yelena Y. , Shitara Kohei , Moehler Markus H. , Garrido Marcelo , Gallardo Carlos , Shen Lin , Yamaguchi Kensei , Wyrwicz Lucjan , Skoczylas Tomasz , Campos Bragagnoli Arinilda Silva , Liu Tianshu , Tehfe Mustapha , Elimova Elena , Bruges Maya Ricardo Elias , Cleary James M. , Karamouzis Michalis , Soleymani Samira , Lei Ming , Amaya-Chanaga Carlos , Ajani Jaffer A.
Published: June 2023

4025

Background: NIVO + chemo demonstrated superior overall survival (OS) and clinically meaningful progression-free survival (PFS) benefit vs chemo and acceptable safety in previously untreated patients (pts) with advanced GC/GEJC/EAC, leading to approvals in multiple countries including the US. NIVO + chemo continued to demonstrate clinically meaningful improvement in efficacy after 2 years of follow-up. We present efficacy and safety analyses from NIVO + chemo vs chemo from the 3-year follow-up of CheckMate 649. Methods: Adults with previously untreated, unresectable advanced, or metastatic GC/GEJC/EAC were enrolled, regardless of programmed death ligand 1 (PD-L1) expression, excluding pts with known HER2-positive status. Pts were randomized to NIVO (360 mg Q3W or 240 mg Q2W) + chemo (XELOX Q3W or FOLFOX Q2W), NIVO + ipilimumab, or chemo. Primary endpoints for NIVO + chemo vs chemo were OS and PFS by blinded independent central review (BICR) in pts with PD-L1 combined positive score (CPS) ≥ 5. Results: 1581 pts were concurrently randomized to NIVO + chemo or chemo. With 36-month (mo) minimum follow-up, NIVO + chemo continued to demonstrate OS and PFS benefit vs chemo in pts with PD-L1 CPS ≥ 5 and all randomized pts. The objective response rate (ORR) per BICR in pts with PD-L1 CPS ≥ 5 who had measurable lesions at baseline was 60% (95% CI 55–65) with NIVO + chemo vs 45% (95% CI 40–50) with chemo; in all randomized pts, ORR per BICR was 58% (95% CI 54–62) with NIVO + chemo vs 46% (95% CI 42–50) with chemo. Responses were more durable with NIVO + chemo vs chemo in pts with PD-L1 CPS ≥ 5 (median [m] duration of response [mDOR] 9.6 mo [95% CI 8.2–12.4] vs 7.0 mo [95% CI 5.6–7.9], respectively) and in all randomized pts (mDOR 8.5 mo [95% CI 7.7–9.9] vs 6.9 mo [95% CI 5.8–7.2], respectively). OS benefit with NIVO + chemo was observed across most prespecified subgroups. No new safety signals were identified. A summary of treatment-related adverse events (TRAEs) is shown in the Table. Additional analyses will be presented. Conclusions: After 3 years of follow-up, NIVO + chemo continued to demonstrate clinically meaningful long-term survival benefit with acceptable safety, further supporting its use as a standard 1L treatment in previously untreated pts with advanced GC/GEJC/EAC. Clinical trial information: NCT02872116 . [Table: see text]