bluuebunny/crossref_metadata_2025 huggingface dataset:
Trifluridine/tipiracil plus capecitabine and bevacizumab as upfront treatment for metastatic colorectal cancer: Results of the phase 1 TriComB study.
Authors: Ciracì Paolo , Conca Veronica , Moretto Roberto , Antoniotti Carlotta , Ambrosini Margherita , Murgioni Sabina , Gori Giovanni , Russo Alessandra , Bergamo Francesca , Randon Giovanni , Studiale Vittorio , Fini Elisabetta , Marmorino Federica , Borelli Beatrice , Germani Marco Maria , Vetere Guglielmo , Carullo Martina , Boccaccio Chiara , Masi Gianluca , Cremolini Chiara
Published: June 2024

3558

Background: Capecitabine (cap) plus Bevacizumab (bev) is a standard option for previously untreated unresectable metastatic colorectal cancer (mCRC) patients (pts) deemed not fit for upfront chemotherapy doublets. A synergistic effect of the sequential administration of cap and Trifluridine/Tipiracil (FTD/TPI) has been shown both in vitro and in vivomodels. Here, we present safety and preliminary activity results of the phase 1 TriComB study, an open-label, multicenter, phase 1/2 trial, evaluating FTD/TPI in combination with cap and bev in mCRC pts. Methods: Patients with previously untreated mCRC, ineligible for oxaliplatin- and/or irinotecan- based regimens, were enrolled. A 3 + 3 dose escalation design was used to identify the recommended dose (RD) of FTD/TPI (days 15-19 and 22-26) in combination with cap (1000 mg/sqm/BID days 1-14) and bev (5 mg/kg day 1,15) in 28-days cycles. Adverse events (AEs) were reported according to CTCAE version 5.0 and tumor response was assessed by RECIST version 1.1. Results: 11 pts (5 men, 6 women; median age: 77, range: 47-84 years) were enrolled. For the first three patients (FTD/TPI: 25mg/sqm BID) no dose limiting toxicities (DLTs) were observed. At 30 mg/sqm BID dose level, 3/5 DLTs were reported: 2 pts experienced a dose delay of >7 days from the scheduled timing and 1 patient was unable to receive ≥ 75% of study drugs’ doses during the first cycle. FTD/TPI was de-escalated and 3 additional patients were treated at 25 mg/sqm BID. Since 1/6 pts experienced a DLT (grade 4 colonic perforation) that was identified as the RD. Grade 3/4 AEs are listed in the Table. As of January 2024, Overall Response Rate is 72.7% (8/11 pts) and 66.7% (4/6 pts) in the overall population and at the RD, respectively. Conclusions: The sequential combination of cap and FTD/TPI with bev is feasible. The phase 2 of the study is ongoing to evaluate antitumor activity of this regimen in the same patients' population. Clinical trial information: NCT04564898 Safety summary Clinical trial information: NCT04564898 . [Table: see text]
Updated survival results of BBCAPX-II: Sintilimab combined with bevacizumab and CapeOx as first-line treatment in patients with RAS-mutant, microsatellite stable, unresectable metastatic colorectal cancer.
Authors: Yuan Ying , Zhu Ning , Fang Xuefeng , Zhong Chenhan , Li Dan , Wang Liu-Hong , Li Jun , Weng Shanshan , Hu Hanguang , Dong Caixia , Song Yongmao , Xu Dong , Wang Jianwei , Sun LIfeng , Wang Jian , Liao Xiujun , Yu Ningjuan , Zhang Suzhan , Ding Ke-Feng
Published: June 2024

3563

Background: Microsatellite stable (MSS) and RAS-mutant metastatic colorectal cancer (mCRC) patients are characterized by an immunosuppressive microenvironment and a low response rate to immunotherapy. Sintilimab plus bevacizumab and CapeOX (BBCAPX) has proved its efficacy and safety in above unresectable mCRC patients (Ying Yuan et al. ASCO 2023 and Xuefeng Fang et al. ASCO 2022). Here, we report updated survival results of this single arm, open-label, phase 2 trial. Methods: Eligible patients were aged 18 to 75 years with histologically confirmed unresectable metastatic colorectal adenocarcinoma by multidisciplinary team, and had RAS gene mutation and confirmed MSS status. All patients received treatment with sintilimab (200 mg, day 1) plus bevacizumab (7.5mg/kg, day 1) and oxaliplatin (135 mg/m2, day 1) and capecitabine (1g/m2, bid, day 1-14) of each 21-day cycle. The primary endpoint included objective response rate (ORR) and adverse events. Secondary endpoint was disease control rate (DCR) and progression-free survival (PFS). Results: From April 2021 to December 2021, 25 patients were enrolled. The ORR was 84% and the DCR was 100%. Six (24%) patients underwent surgical treatment and unexpectedly achieved no evidence of disease status. At the data cut-off day (January 26, 2024), the median PFS in the full analysis set was 17.9 months (95% CI, 8.84-27), and the median PFS in the per-protocol set was 9.79 months (95% CI, 6.44-24.3). Median PFS was 23.7 months (95% CI, 4.8-NA) in the patients with only liver metastasis and 11.5 months (95% CI, 4.83-24.3) in the patients with other metastasis. The PFS rate at 6 months was 84% (95% CI, 70.8-99.7). The PFS rate at 12 months was 56% (95% CI, 39.6-79.3). The most frequent grade 3 or 4 TRAEs were neutropenia (3/25) and increased alanine transaminase (2/25). No grade 5 adverse events occurred during the study. Conclusions: The combination of sintilimab plus bevacizumab and CapeOx showed promising antitumor activity and manageable toxicity in RAS-mutant, MSS, unresectable mCRC. Patients with liver metastases presented better prognosis compared other metastases. Furthermore, we are currently launching a phase III, randomized, open-label, multicentric clinical trial (NCT05171660) to further analyze the effects, safety, and prognostic biomarkers of this regimen. Clinical trial information: NCT04194359 . [Table: see text]
Comparing the efficacy and safety of HepaSphere drug-eluting bead transarterial chemoembolization combined with hepatic arterial infusion chemotherapy versus hepatic arterial infusion chemotherapy alone in unresectable colorectal liver metastases.
Authors: Feng Aiwei , Gao Song , Guo Jianhai , Kou Fuxin , Liu Shaoxing , Zhang Xin , Liu Baojiang , Wang Xiaodong , Chen Hui , Xu Haifeng , Liu Peng , Cao Guang , Gao Qinzong , Zhu Xu
Published: June 2024

3565

Background: Drug-eluting bead transarterial chemoembolization (DEB-TACE) and hepatic arterial infusion chemotherapy (HAIC) are widely employed treatments for unresectable colorectal liver metastases (CRLM). Limited evaluation exists regarding TACE plus HAIC versus HAIC alone. This study aimed to evaluate the efficacy of combining HepaSphere DEB-TACE with HAIC compared to HAIC alone in patients with unresectable CRLM. Methods: A total of 259 CRLM patients aged over 18 years, treated at Peking University Cancer Hospital between March 2015 and November 2022, were included in this retrospective study. Among them, 157 patients received HepaSphere DEB-TACE combined with HAIC (DEB-TACE-HAIC), while 102 patients received HAIC alone. Propensity score matching (PSM) was performed to avoid selection bias and enable comparative analysis of efficacy and safety between the two cohorts. The primary endpoint was progression-free survival (PFS), while secondary endpoints comprised hepatic progression-free survival (hPFS), overall survival (OS), objective response rate (ORR), disease control rate (DCR) and safety. Results: PSM resulted in 83 pairs, achieving comparable baseline between DEB-TACE-HAIC and HAIC cohorts. Of these pairs, 116 were male and 50 were female. Notably, 51.2% of patients harbored mutations in either KRAS, NRAS, or BRAF genes. Prior to enrollment, 94.6% of patients had received systemic treatments. Median hPFS, PFS and OS were all higher in the matched DEB-TACE-HAIC cohort (median hPFS: 7.6 vs. 4.1 months, P=0.023; median PFS: 5.1 vs. 3.5 months, P=0.092; median OS: 15.5 vs. 14.7 months, P=0.513). ORR was 37.3% in the DEB-TACE-HAIC group and 27.7% in the HAIC group, with DCR of 75.9% and 69.9%, respectively. There were no treatment related deaths. Serious adverse events were comparable between the two groups, except for nausea, which occurred more frequently in the HAIC group (39.8% vs. 22.9%, P=0.019). Conclusions: DEB-TACE-HAIC demonstrated superior survival compared to HAIC alone in unresectable CRLM, even in patients refractory to systemic therapy. The combination of HepaSphere DEB-TACE and HAIC appears promising as a regional treatment option with improved outcomes and a comparable safety profile.
Efficacy of fadraciclib (CYC065), a novel dual CDK2/9 inhibitor, on patient-derived models of colorectal cancer.
Authors: Zokaasadi Mohammad , Altunel Erdem , Dayanidhi Divya Lakshmi , Mantyh John B , Watlington Wylie K , McCall Shannon J. , Blake David , Somarelli Jason A. , Hsu David S.
Published: June 2024

3596

Background: Colorectal cancer (CRC) is the third most common type of cancer among adults in the United States. Given the heterogeneous nature of the disease and the limited number of treatments available, there is an unmet need to identify new therapeutic vulnerabilities for advanced CRC. One promising approach is targeting of cyclin dependent kinases (CDKs). In our current study, we sought to understand the potential efficacy of fadraciclib (CYC065), a novel dual CDK 2/9 inhibitor, as a novel treatment for metastatic CRC. Methods: Eighteen CRC patient-derived organoids (PDOs) were generated from patients undergoing biopsy or resection for their primary or metastatic CRC under an IRB approved protocol at Duke University. IHC and H&E staining were first performed on the established PDOs to confirm the diagnosis of CRC. PDOs were treated with standard of care chemotherapy (oxaliplatin, irinotecan (SN38) and 5-Flurouracil), CDK4/6 inhibitor palbociclib, and fadraciclib (CYC065). All drugs were used in doses ranging from 6.4nM to 100µM, and drug sensitivities were determined using Cell-Titer Glo (CTG) 72 hours after treatment. Subsequently, three matching PDXs were generated for in vivo validation and treated with fadraciclib (CYC065) via oral gavage at a dose of 25 mg/kg BID five days a week for two weeks. Target validation for CDK2/9 inhibition was performed via western blotting, cell cycle arrest was determined via flow cytometry, and killing by anaphase catastrophe was determined by immunofluorescence staining. Results: CRC PDOs were more sensitive to fadraciclib (CYC065) than chemotherapy and palbociclib, with IC50 values lower than chemotherapy or palbociclib (2.65±3.92µM for fadraciclib (CYC065) vs. 29.92±41.98µM for chemotherapy (P<0.05) or palbociclib (12.33±9.87µM)). Subsequently, we validated our findings in vivo using 3 matched PDX showing significant tumor growth inhibition (TGI) with fadraciclib (CYC065) compared to control (p<0.05) without serious adverse effects. We showed that fadraciclib (CYC065) induces G2/M cell cycle arrest, resulting in anaphase catastrophe as evident by the presence of multipolar mitosis in fadraciclib (CYC065)-treated cells. CDK2/9 inhibition leads to downregulation of c-Myc levels and upregulation of apoptosis induction as a second mechanism of action for this drug. Conclusions: Our data using both in vitro and in vivo patient-derived models support further exploration of fadraciclib (CYC065) has a potential therapy for advanced CRC. CDK2/9 inhibition impacts multiple critical pathways involved in transcription, mitosis and apoptosis. Further studies will be needed to reveal molecular biomarkers of sensitivity and resistance to this novel agent.
Phase II study of neoadjuvant short-course radiotherapy combined with CAPEOX plus envafolimab in patients with microsatellite stable locally advanced rectal cancer: Updated results of PRECAM study.
Authors: Dai Sheng , Wang Fei , Lv Yiming , Zhang Feixiang , Shi Liming , Wang Yunfei , Shen Yanbin , Xu Lingna , Hu Peng , Tang Wen , Xu Dengyong , Shan Lina , Jia Xiya , Chen Yiyi , Larson David W. , Wang Da , Lao Weifeng , Gu Hongcang , Sun Xiaonan , Huang Xuefeng
Published: June 2024

3614

Background: Conventional neoadjuvant chemoradiotherapy (nCRT) yields a pathologic complete response (pCR) rate of about 15%–- 30% for locally advanced rectal cancer (LARC). This PRECAM study aimed to investigate the efficacy and safety of neoadjuvant short-course radiotherapy combined with CAPEOX plus Envafolimab in Patients with Microsatellite Stable (MSS) LARC, redefining the standard of care (SOC) for LARC. Methods: The study is an open-label, prospective, single-arm, phase II clinical study . Eligible patients with MSS LARC were consecutively enrolled. Participants received short-course radiotherapy (25Gy/5f) with subsequent two cycles of CAPEOX (capecitabine and oxaliplatin) and 6 cycles of Envafolimab (subcutaneous injection, 150 mg, QW ) followed by total mesorectal excision surgery. The primary endpoint was pathological complete response (pCR) rate, and the secondary endpoint was major pathologic (MPR) rate and safety. Results: From April to December 2022, 34 patients were enrolled, of whom 32 completed the study. Remarkably, The pCR rate was62.5% (20/32), and the (MPR) rate was 75% (24/32). Furthermore, 65.6% (21/32) patients achieved a neoadjuvant rectal (NAR) score below 8, suggesting an effective treatment response. Common adverse events included tenesmus (78.1%), diarrhea (62.5%), and leukocyte decrease (40.6%), with two cases of Grade 3 adverse events. Surgical procedures were performed in all 32 cases, with minor complications observed. During the follow-up period of up to 20 months, no recurrence or death were reported. Conclusions: Short-course radiotherapy combined with CAPEOX plus Envafolimab showed favorable pCR rate with manageable adverse effects and surgical complications in LARC, underscoring the potential of the combination therapy for MSS LARC. A Randomized controlled trial is warranted for further exploration and validation. Clinical trial information: NCT05216653 .
An exploratory analysis of the genetic alteration associated with early-onset gastric and colorectal cancer using a large-scale nationwide database of Japan (C-CAT).
Authors: Nakayama Izuma , Miyazaki Naoki , Ueno Risa , Fukada Ippei , Yamaguchi Kensei , Shinozaki Eiji
Published: June 2024

4058

Background: The recent global concern about the early onset cancer (EOC) has been rising in the field of GI cancers. Precision oncology based on comprehensive genome profile (CGP) test is anticipated to attribute the improvement of cancer treatment for EOC. This study explored the genetic alteration of EOC and association with genome matched therapy in colorectal cancer (CRC) and gastric or gastroesophageal junction cancer (G/GEJC). Methods: We retrospectively assessed Japanese nationwide, the Center for Cancer Genomics and Advanced Therapeutics (C-CAT) database. Pts meets following eligibility criteria were enrolled. 1) Pts received the reimbursed CGP tests between June 2019 and May 2023 in Japan, 2) pts registered as CRC or G/GEJC, 3) pts agreed with the utilization of their data. We defined EOC as diagnosed at less than 50 and 40 in EO-CRC and EO-G/GEJC, respectively. We investigated the genomic alterations of EOC and compared the genes with a difference in frequency of 5% or more between earlier and later onset cancer of disease. The transition rate to the subsequent matched therapy was compared between EOC and non-EOC. This study was approved by both the ethics committee of Cancer Institute Hospital of JFCR (No. 2022-GB-121) and C-CAT data utilization review board (No. AP20230309-01N). Results: Among a total of 8,180 eligible pts, 1,289 (19.9%) and 123 (7.2%) EOC were identified in CRC and G/GEJC, respectively. Tissue based assay with Foundation One (n = 6.591, 80.6%) was most frequently employed as CGP test. TP53 (84.1%), APC (77.2%) and KRAS (49.5%) mutation were most frequently occurred in EO CRC. Meanwhile, TP53 (64.2%), CDH1 (36.5%) and ARID1A (17.1%) mutation were the most prevalent in EO G/GEJC. Among the top 30th somatically mutated genes in EO CRC and EO G/GEJC, 31 (96.9%) and 29 (85.3%) genes shared with non-EO in CRC and G/GEJC, respectively. Notably, the proportion of shared genes was significantly decline to 21 (71.9%) and 18 (52.9%) in CRC and G/GEJC when they compared between pts aged <30 and ≥30 years old. The proportion of pts harboring at least one actionable mutation was 42.3% in EO CRC similar to that of non-EO CRC (43.2%) and 19.5% in EO G/GEJC and lower than that of non-EO G/GEJC (32.2%), respectively. The proportions of individuals who received targeted therapy as recommended by CGP test were all approximately 5% (EOC vs. non-EOC: 6.4% vs. 5.6% in CRC and 4.1% vs. 4.4% in G/GEJC). The treatment access rate was not improved in very young pts (aged <30). Conclusions: Genomic alterations were mostly shared between EOC and non-EOC in pts with CRC and G/GEJC. The mutation profile apparently differs between earlier onset (<30) and later onset (≥30) both in CRC and G/GEJC. Very limited proportion of EOC could access the matched therapy after CGP test in the treatment of CRC and G/GEJC as well as non-EOC.
Comparative outcomes of esophageal stent placement in patients with esophageal cancer: A prospective study of 183 cases.
Authors: Chudy-Onwugaje Dilichukwu , Salem Ahmed Elsayed , Roland Bani
Published: June 2024

4061

Background: Esophageal stent placement is vital for alleviating dysphagia, enabling immediate relief and smoother food passage. This minimally invasive procedure reduces hospital stays, enhancing quality of life and offering a safer option for high-risk patients. Effective in both malignant and benign cases, stents are cost-efficient and require skilled professionals for optimal outcomes. This study examines outcomes of various stent types in 183 esophageal cancer patients, evaluating efficacy, safety, and impact on quality of life. Methods: Between January 2022 and December 2022, 183 patients with esophageal cancer were enrolled from three tertiary health care facilities and divided into three groups based on the type of esophageal stent used: self-expanding metallic stents (SEMS, n = 84), self-expanding plastic stents (SEPS, n = 61), and fully covered self-expanding metallic stents (FCSEMS, n = 38). Stent placement was performed under endoscopic guidance. Follow-up with endoscopic assessments were conducted at 1 week, 1 month, 3 months, and 6 months post-stent placement to evaluate stent patency, dysphagia relief, and complications. Results: The technical success rates for stent placement were high across all groups, with SEMS at 96.4%, SEPS at 95.1%, and FCSEMS at 97.4%. Immediate dysphagia relief was achieved in 87.4% of patients across the three stent types. FCSEMS demonstrated a significantly longer median stent patency duration (8.0 months) compared to SEMS (6.3 months) and SEPS (5.6 months). The SEPS group experienced a higher incidence of stent migration (13.1%) compared to SEMS (8.3%) and FCSEMS (6.5%) groups. Post-interventional complications were documented in 18.0% of patients, with tissue overgrowth (8.7%) and stent migration (6.0%) being the most common. Overall survival rates at 6 months were comparable across the three groups. Notably, FCSEMS displayed superior patency (p < 0.05), suggesting its potential preference in specific cases. The study confirms the effectiveness of stent placement in enhancing patient comfort and quality of life. Conclusions: This study underscores the efficacy of esophageal stent placement as a crucial palliative intervention for dysphagia in esophageal cancer patients. Fully covered self-expanding metallic stents (FCSEMS) exhibited notable advantages, demonstrating prolonged stent patency compared to other types. However, careful consideration is warranted for patients in the self-expanding plastic stents (SEPS) group due to a higher incidence of stent migration. The high technical success rates and immediate dysphagia relief affirm the proficiency and immediate positive impact of this procedure. Overall, this research highlights the importance of tailored stent selection and ongoing investigation to optimize outcomes for esophageal cancer patients.
Neoadjuvant dual checkpoint inhibition followed by immune-chemoradiation in patients with resectable gastric adenocarcinoma.
Authors: Pabon Cindy M. , Xiao Lianchun , Badgwell Brian D. , Mansfield Paul F. , Ikoma Naruhiko , Sewastjanow-Silva Matheus , Lee Jeffrey H. , Bhutani Manoop S. , Weston Brian , Coronel Emmanuel , Smith Grace L. , Holliday Emma , Tian Jessie , Das Prajnan , Minsky Bruce D. , Waters Rebecca E , Estrella Jeannelyn , Li Jenny Jing , Ajani Jaffer A. , Blum Murphy Mariela A.
Published: June 2024

4067

Background: Localized gastric cancer is a potentially curable condition and long-term outcomes depend on YP staging. Currently, preferred adjunctive therapy depends on geographic location. Preliminary data from NCT01928394 have shown promising clinical activity of immunotherapy (IO) agents nivolumab (nivo) +/- ipilimumab (ipi) in the metastatic setting. We conducted a single-arm study using IO + chemotherapy followed by immune-chemoradiation prior to surgery, followed by adjuvant IO, in patients with localized gastric adenocarcinoma. Our primary objective was to determine safety and toxicity with this approach. Secondary objectives included efficacy by YP staging and R0 resection rate. Methods: Patients with localized gastric adenocarcinoma were enrolled into NCT03776487 (n=30). Participants received the following: (1) biweekly chemotherapy with 4 doses of 5-Fluorouracil (5-FU)/Oxaliplatin, (2) nivo 240mg q2weeks (x3) and ipi 1mg/kg q6weeks (x1), (3) immune-chemoradiation (biweekly nivo + 5FU Mon-Fri concurrently with a total of 45 Gy given in 25 fractions), and (4) surgical resection. Those with residual disease received adjuvant nivolumab monthly for 6 doses. Correlative studies are planned. To assess preliminary efficacy, the clinical and pathologic complete response rates (pCR) were estimated along with the corresponding exact 95% confidence interval. Adverse events and toxicities were summarized using descriptive statistics. Results: Median follow-up was 27.4 months at the time of data cutoff. Of 30 enrolled, 23 patients completed surgery and seven did not due to progression of disease(n=5) and worsening co-morbidities(n=2). The side effect profile was similar to prior IO studies, with no grade 5 events observed. Three patients (10%) experienced grade 4 events (acute kidney injury, myocarditis, and neutropenia). The most frequent grade 3 toxicity was nausea and vomiting (10%). From the 23 participants that underwent resection, 22 had pathologic data at the time of analysis, with 9 achieving ypT0ypN0 (40.9%, 95% CI: 20.7%, 63.7%). There was an 86% R0 resection rate. Conclusions: Our results are encouraging and support further development of this strategy for localized gastric adenocarcinomas. The regimen is safe and potentially generalizable. Clinical trial information: NCT03776487 .
Neoadjuvant immunotherapy (PD-1) combined with chemotherapy for locally advanced thoracic esophageal carcinoma (EC): A single-arm, open-label, phase II study.
Authors: Wang Qi , Deng Siyou , Shen Qian , Zhang Ni , Zhang Li
Published: June 2024

4075

Background: This study aimed to evaluate the efficacy and safety of PD-1 combined with chemotherapy as neoadjuvant therapy in patients with locally advanced EC and sought to explore biomarkers related to treatment prognosis and efficacy prediction for screening patients who would benefit most from this therapy. Methods: In this phase 2 study, patients (pts) with histopathologically confirmed ESCC, diagnosed as clinical stage cT1-3N1-3M0 and ECOG PS 0-1 were enrolled to receive two cycles of neoadjuvant chemoimmunotherapy with PD-1 blockade (Pembrolizumab/Tislelizumab on d1) plus nab-paclitaxel (260mg/m2 in total on d1 and d8) and cisplatin (60mg/m2 in total on d1-3) of each 21-day cycle, followed by esophagectomy. Biopsied pretreatment tumor tissues along with surgical tumor specimens were collected for RNA sequencing. The primary endpoint was complete pathologic response (pCR) rate. The secondary endpoints were overall response rate (ORR), event-free survival (EFS), overall survival (OS) and safety. Biomarkers associated with clinical prognosis were assessed as exploratory objectives. Results: From Jan 11, 2021 to, Apr 25 2022, 56 pts were enrolled and 42 pts received neoadjuvant therapy and operation. Among them, 66.7% (28/42) had clinical complete response, 50% (21/42) had partial response, and ORR was 78.6% (33/42). 42 pts underwent surgical resection, achieving a 100% (42/42) R0 resection rate and a pCR rate of 33.3% (14/42), tumor regression grade (TRG, Mandard system) 1, 2 and 3 were 14.3% (6/42), 14.3% (6/42) and 71.4% (30/42) respectively. With a median follow-up of 24.4 months (range 14.3-33.4), 12(28.6%) patients had disease recurrence. Within 24 months, 14.3% (2/14) pts who achieved pCR experienced recurrence. 2-year EFS rate was 54.8% (95%CI,43.4, 66.3% ), 2-year OS rate was 81.5% (95%CI,69.4, 90.2% ). Overall, grade ≥3 AEs included leukopenia (11.9% [5/42]), thrombocytopenia (4.8% [2/42]), and no deaths were due to TRAEs. With 34 patients of RNA sequenced, we divided the patients into two groups based on whether they had recurred within 24 months as favorable prognosis and poor prognosis respectively, to analyze gene expression in different treatment effect. The poor outcome patients had significant molecular differences were seen in PI3K−Akt pathway gene expression, markers of immune activation, and genes involved in ECM−receptor interaction and focal adhesion in baseline samples, and the pathway enriched by differential genes expression in samples after treatment validated this result. Conclusions: Combining PD-1 blockade with nab-paclitaxel and cisplatin is feasible and effective in patients with locally advanced resectable ESCC, and might be a promising approach for neoadjuvant treatment. Clinical trial information: NCT05028231 .
Comparing toripalimab combined with chemoradiotherapy versus chemoradiotherapy alone for locally advanced esophageal squamous cell carcinoma: A multicenter, open-label, randomized phase II clinical trial.
Authors: Xu Yujin , Cheng Qi , Wang Yu , Zhu Weiguo , Huang Jing , Du Dexi , Tian Zhifeng , Yang Haihua , Zhou Chao , Zhou Suna , Sun Xiaojiang , Wang Yuezhen , Wang Jin , Wang Zhun , Hu Xiao , Chen Ming
Published: June 2024

4079

Background: Esophageal squamous cell carcinoma (ESCC) is the predominant histological subtype in Asia, representing approximately 90% of all esophageal cancer cases. Despite definitive chemoradiotherapy (CRT) being the standard treatment for unresectable locally advanced ESCC, the prognosis remains poor. The introduction of PD-1 inhibitors has shown significant improvement in survival outcomes for advanced ESCC. This study aims to evaluate the efficacy and safety of combining induction and consolidation toripalimab (a PD-1 inhibitor) with CRT in patients with locally advanced ESCC (Clinical trial information: NCT04084158). Methods: Patients aged 18-75 years with unresectable, locally advanced ESCC and an ECOG performance status of 0-1 were eligible. Participants were randomly assigned (1:1) to either two cycles of toripalimab (3mg/kg q2ws) followed by concurrent CRT with 50.4Gy+weekly paclitaxel and carboplatin (TC), TC consolidation, and toripalimab (study arm), or standard CRT alone (control arm). The primary endpoint was progression-free survival (PFS), with secondary endpoints including overall survival (OS) and objective response rate (ORR). Results: Between September 2019 and July 2020, 46 ESCC patients (40 males) were screened for eligibility across four participating centers in China. Forty-four patients were eligible for survival analysis, all with histopathologically confirmed ESCC. Median ages were 64 years (range 49-75) in the study arm and 61 years (range 47-74) in the control arm, with similar clinical AJCC stages. As of the February 1, 2024 cutoff, the median follow-up was 50.6 months. Median PFS was 10.0 months in the study arm and 17.8 months in the control arm (HR: 1.567, 95% CI: 0.755-3.251, p=0.228). Median OS was 23.7 months and 25.9 months, respectively (HR: 1.140, 95% CI: 0.536-2.427, p=0.733). ORR rates were 64% and 86% (p=0.164), respectively. The incidence of grade 3 or worse treatment-related adverse events was similar between groups, with the most common adverse event being lymphopenia. Conclusions: Our findings indicate no significant benefit in adding induction and consolidation immunotherapy to CRT for treating locally advanced ESCC. However, the combination of radiotherapy and immunotherapy warrants further exploration. Ongoing analyses of biomarker correlates of response and survival will provide additional insights. Clinical trial information: NCT04084158 .
The clinical utility of plasma cell-free DNA (cfDNA) in NET-02: Randomised, phase II trial of liposomal irinotecan (nal-IRI)/5-fluorouracil (5-FU)/folinic acid or docetaxel as second-line (2L) therapy in patients (pts) with progressive poorly differentiated extra-pulmonary neuroendocrine carcinoma (PD-EP-NEC).
Authors: McNamara Mairead Geraldine , Pearce Simon , Swain Jayne , Halford Mollie Anne , Sharma Rohini , Faluyi Olusola Olusesan , Wadsley Jonathan , Morgan Carys , Wall Lucy R. , Chau Ian , Reed Nick , Sarker Debashis , Margetts Jane , Anthoney Alan , Oughton Jamie B. , Lamarca Angela , Hubner Richard , Rothwell Dominic G. , Valle Juan W. , Clipson Alexandra
Published: June 2024

4130

Background: In NET-02, nal-IRI/5-FU, but not docetaxel, met the primary endpoint of 6-month (mo) progression-free survival (PFS) rate in pts with progressive PD-EP-NEC (1). The prognostic potential of cfDNA in progressive PD-EP-NEC has not been explored in a prospective randomised trial. Methods: NET-02 was a multi-centre, randomised (1:1), phase II trial of IV nal-IRI/5-FU/folinic acid, Q14 days (ARM A), or IV docetaxel, Q21 days (ARM B), as 2L therapy in pts with progressive PD-EP-NEC. Plasma samples were taken at baseline (T0), following 6 weeks of treatment (T1) and at progression (T2). Samples were analysed using a multi-omic next-generation sequencing (NGS) approach (T7-MBD-seq) (measures genome-wide methylation and low pass whole genome copy number alterations (CNA)). The tumour fraction (TF) of cfDNA was determined using ichorCNA and correlated with clinical outcomes using Cox proportional hazards model and Logistic regression. Results: Of 56 pts evaluable for efficacy, there were 54 (96%) T0 samples (48 passed quality control), 31 (55%) at T1 and 20 (36%) at T2. At T0, 36/48 (75%) samples had detectable TF by copy number (using 3% TF cut-off). For the entire cohort, T0 TF was negatively prognostic for overall survival (OS) (Hazard Ratio (HR) 1.17, 95% Confidence interval (CI) 1.00-1.37, P=.044), but not for 6 mo PFS rate (Odds ratio (OR) 1.25, 95% CI 0.91-1.73, P=.17), response rate (RR) (OR 1.11, 95% CI 0.67-1.76, P=.65) or PFS (HR 1.04, 95%CI 0.91-1.20, P=.53). In the entire cohort, median OS split by TF (N=16 each) was 10.2 mo (95% CI 4.1-not available (NA)) for low (TF≤8.6%), 6.9 mo (95% CI 3.4-14.8) for medium (8.624.3%). T0 TF was also negatively prognostic for 6 mo PFS rate and OS in ARM A (P=.02, P=.03), but not ARM B (P=.61, P=.48), but was not prognostic for RR or PFS (Table). TF correlated with the presence of liver metastases (Wilcoxon Rank Sum P=.009), but not with ECOG PS (P=.14), sex (P=.10), Ki-67 (P=.39) or age (Spearman rank correlation P=.45). Longitudinal copy number and methylation cfDNA analysis is on-going. Conclusions: These results suggest that it may be possible to stratify prognosis based on amount of baseline TF in patients with progressive PD-EP-NEC, and may also identify patients who would benefit most from the nal-IRI combination. 1. McNamara 2023, EClin Med. Clinical trial information: 03837977. [Table: see text]
Prognostic value of circulating tumor DNA testing in surgically resected pancreatic cancer.
Authors: Miceli Madeline Rose , Littman Dalia , Masri Lena , Becker Daniel Jacob , Oberstein Paul Eliezer
Published: June 2024

4134

Background: The majority of patients with pancreatic cancer who undergo curative intent resection have recurrence, but optimal surveillance is unknown. Circulating tumor DNA (ctDNA) tests, custom-designed multiplex-PCR tumor assays unique to each patient’s tumor, may assist in monitoring for recurrence. Methods: We performed a single center retrospective review of patients with surgically resected pancreatic cancer who had at least 1 ctDNA test performed post-operatively between 8/1/21 and 11/13/23 with Natera Inc.’s Signatera assay. Primary outcomes were documented radiographic progression and death. Results: 74 patients were identified, of whom 36 were positive for ctDNA at any point during the study (median follow up from surgery 19.1 months) while 38 remained negative for ctDNA (15.3 months). There was no difference in age (≥ or < 70), sex, or race. Positive ctDNA at any time point was associated with advanced stage disease (p=0.013), positive resection margins (p=0.008), and having received neoadjuvant therapy (p=0.005). Those with any positive ctDNA were more likely to have radiographic progression (p<0.0001) or death (p=0.0005) by the end of the study. These differences remained when the population was examined in subgroups of first post-operative ctDNA positive, first ctDNA negative but at least one subsequent ctDNA positive, and all ctDNA negative. In Cox proportional hazard models, both any positive ctDNA test and positive first ctDNA test (first ctDNA limited to ≤120 days post-op) were associated with higher risk of radiographic progression and/or death compared to never testing positive for ctDNA and negative first ctDNA test, respectively (HR 12.6 (3.0-51.9), p=0.0005; HR 5.6 (1.4-22.8), p=0.02). Conclusions: Positive ctDNA tests, both in the immediate post-operative and subsequent settings, are associated with higher risk of radiographic progression or death in patients with resected pancreatic cancer. These data suggest that ctDNA testing provides independent, meaningful prognostic information superior to traditional pathologic risk factors and CA19-9 testing alone. These findings have implications for future clinical study design and decisions about surveillance and treatment. [Table: see text]
Effect of ctDNA whole-exome sequencing in pancreatic adenocarcinoma on prognostic value, actionable alterations, and organ tropisms in metastatic disease.
Authors: Huerta Marisol , Martín-Arana Jorge , Gimeno-Valiente Francisco , Carbonell-Asins Juan Antonio , García-Micó Blanca , Martínez-Castedo Belén , Camblor Daniel G. , Fleitas Tania , García Bartolomé Miguel , Alfaro-Cervello Clara , Garcés-Albir Marina , Dorcaratto Dimitri , Muñoz-Forner Elena , Mora-Oliver Isabel , Gambardella Valentina , Roselló-Keränen Susana , Sabater Luis , Roda Desamparados , Cervantes Andres , Tarazona Noelia
Published: June 2024

4149

Background: The dismal prognosis associated with pancreatic ductal adenocarcinoma (PDAC) needs a deeper understanding of progression mechanisms and personalized treatment. While the prognostic value of ctDNA has already been established, this study purposes to apply plasma whole-exome sequencing (WES) to identify molecular alterations beyond KRAS. This approach aims to predict survival, uncover progression mechanisms, and identify therapeutic targets. Methods: Eighty metastatic PDAC patients were prospectively recruited and divided into two consecutive cohorts: discovery (n=37) and validation (n=43). Tumor and plasma obtained at diagnosis were analyzed using WES. The variant allele frequency (VAF) of KRASmutations was quantified by ddPCR in plasma at baseline and at response from all patients (n=80). Results: Plasma WES identified at least one pathogenic variant across all individuals, which can be categorized into four pathways: oncogenic mechanisms, DNA repair, microsatellite instability and TGFb pathway alterations. 7 unique druggable mutations were detected in tissue and 11 in plasma. Other targetable mutations ( CDK12, NF1, BRCA2, and TSC2), were prevalent in plasma but absent in tissue. Patients with survival less than 11 months showed enrichment in cellular organization pathways and exclusive targetable CDK12 mutations. Longer survival cases exhibited exclusive mutations in DNA regulation and repair genes. Patients with liver metastasis displayed unique mutations not just in KRAS but also in the adaptive immune response pathway genes. Baseline plasma KRAS mutations detected by ddPCR was associated with worse progression-free survival. (HR=2.315, CI 95%= 1.027-5.217, p = 0.038; and HR= 3.022, CI 95% = 1.299 - 7.030, p= 0.007 in the discovery and validation cohort, respectively). A significant risk of progression (p = 0.006) was observed if KRAS VAF at response assessment did not decrease, at least, 84.75% in both cohorts. Conclusions: ctDNA WES unveils molecular signatures of rapid progression, potential actionable alterations, and liver metastasis-specific mutations in the adaptive immune response pathway. KRAS detection at baseline and its evolution during treatment emerge as prognostic biomarkers. [Table: see text]
Fragmentomics of cell-free DNA as a sensitive biomarker for early detection of pancreatic cancer.
Authors: Yin Lingdi , Cao Cheng , Lin Jianzhen , Zhang Kai , Peng Yunpeng , Xu Cheng , Yang Ruowei , Zhu Dongqin , Wang Fufeng , Chang Shuang , Bao Hua , Guo Feng , Tu Min , Chen Jianmin , Wei Jishu , Wu Junli , Gao Wentao , Miao Yi , Lu Zipeng , Jiang Kuirong
Published: June 2024

4173

Background: Pancreatic ductal adenocarcinoma (PDAC) is one for the most lethal types of cancer. Nearly 80% of the PDAC patients are diagnosed at advanced unresectable stages. Therefore, an accurate early diagnosis assay is urgently needed for reducing PDAC related mortalities. In this study, we aim to utilize cfDNA fragmentomics and machine learning techniques for sensitively detecting PDAC patients. Methods: Total647 cases were prospectively enrolled in this study. Plasma samples were collected from each participant for shallow WGS (~5X). After quality control process, 166 PDAC patients and 167 healthy controls were enrolled as a training cohort. Additional 112 PDAC patients and 111 healthy controls were included as an independent validation cohort. Additional 67 cases with pancreatic benign cystic tumors were also enrolled for model validation including IPMN (Intraductal papillary mucinous neoplasms), MCN (Mucinous cystic neoplasms) and SCN (Serous cystic neoplasms). Four fragmentomics profiles, including copy number variation, fragment size, mutation signatures, and FRAGmentomics-based Methylation Analysis (FRAGMA) were utilized by a machine learning algorithm for developing a predictive model. Results: The predictive model showed an exceptional performance to distinguish PDAC patients from healthy controls, yielding Area Under the Curve (AUC) of 0.993 in the training cohort (5-fold cross validation) and 0.990 in the validation cohort. In the training cohort, our model was capable of detecting PDAC patients at sensitivity of 95.8% and specificity of 95.2% while using 0.49 as cutoff. The validation cohort achieved 99.1% sensitivity at 91.0% specificity while applying the same cutoff. Conclusions: Our model was able to accurately detect PDAC at early stages, by incorporating fragmentomics features through machine learning. It can potentially be used for PDAC early screening, and therefore reducing PDAC related mortalities.
Durvalumab and stereotactic ablative body radiotherapy (SABR) in locally advanced (LA) and borderline resectable (BR) pancreatic cancer (PDAC): Long-term outcomes and correlative insights.
Authors: Keane Fergus , Tuli Richard , O'Connor Catherine A , Schwartz Carly , Park Wungki , Varghese Anna M. , Perry Maria , Singhal Anupriya , Vardhana Santosha , Hendifar Andrew Eugene , Tarcan Zeynep , Basturk Olca , McDermott Raymond S. , Reyngold Marsha , Crane Christopher H. , O'Reilly Eileen M. , Schoenfeld Joshua David
Published: June 2024

4174

Background: Immune checkpoint blockade (ICB) has limited activity in genomically unselected patients (pts) with PDAC. While anti-tumor activity with combination SABR/ICB has been shown, biomarkers of response are poorly defined. We conducted a phase 1/2 study of PD-L1 inhibitor Durvalumab (D) and SABR after induction chemotherapy in LA and BR PDAC (NCT03245541). We report long-term outcomes and correlative biospecimen analyses. Methods: A multi-institutional, single arm phase 1/2 trial was conducted at Cedars-Sinai and Memorial Sloan Kettering. Initial clinical data reported by Tuli et al, ASCO 2023. Pre-treatment tissue assessed for p40 and GATA3 to determine classical vs basal subtype by immunohistochemistry. Tissue interrogated by immunofluorescence for PD-L1 expression and infiltration of immune cell subsets. Multiparametric immunophenotyping of peripheral blood mononuclear cells (PBMCs) by flow cytometry conducted on baseline and on treatment samples. Wilcoxon rank sum test used to determine difference in biomarkers from each timepoint; p-value <0.05 significant. Results: N= 36 enrolled from 08/2017-05/2022; N=31(86%) LA, N=5 (14%) BR. N= 9 (25%) underwent resection; all R0. At median follow up 36.5 months, 6- and 12-month PFS 69%, 36%. Median PFS 8.7m (95% CI 6.1-14), median OS 16m (95% CI 13-26). N=2 (6%) alive without disease progression. Correlative analyses summarized (table). Key findings; Classical/basal subtyping feasible on N=9 (8 classical, 1 basal). Median PD-L1 score not associated with survival. Peri-tumoral, but not intratumoral CD8+ cells associated with PFS >6 months. Flow cytometry feasible for 70 samples from N=35. Frequency of pre-treatment non-naïve CD4+ FoxP3+ Treg associated with PFS >12. CD103+ CD8+ T Cells significantly expanded on treatment only in patients with PFS>12m (p=0.038) and were significantly enriched relative to PFS<12m on treatment. Conclusions: A proportion of pts with LA PDAC achieve durable control with D and SABR after induction chemotherapy. Baseline peri-tumoral CD8+ cells and peripheral CD103+ CD8 T cells and CD4+ Treg in PBMCs at baseline and on treatment may predict for benefit. Further analyses ongoing and validation in larger cohorts is warranted. Clinical trial information: NCT03245541 . [Table: see text]
Trophoblast cell-surface antigen 2 is a biomarker and potential therapeutic target in human colon cancer.
Authors: Li Qingli , He Wei , Cheng Xin , He Lina , Cheng Xiaojiao , Tu Shuiping
Published: June 2024

e15514

Background: Trophoblast cell-surface antigen 2 (TROP2), a transmembrane glycoprotein in epithelial cells, is implicated in malignant progression, notably in breast cancer therapy. However, the clinicopathologic aspects of TROP2 in colorectal cancer (CRC) are unclear. This study aims to explore the association between TROP2 expression and clinicopathological features in CRC and investigate the inhibitory effects of the anti-TROP2 antibody-SN-38 conjugate (ADC-TROP2) on colon cancer cells. Methods: A retrospective analysis of 1296 CRC patients who underwent colorectomy at Renji Hospital, Shanghai Jiaotong University School of Medicine, was conducted. Immunohistochemistry determined the expressions of TROP2, HER2, and PD-L1 in colon cancer tissues. Statistical analyses, including the chi-square test and Cox proportional hazards model, assessed associations. Sacituzumab Govitecan (ADC-TROP2 drug) cytotoxicity on human cancer cells was determined using the MTT method. Results: TROP2 was predominantly expressed at the cell membrane of cancer tissues, with 50% of cases TROP2-positive. The overexpression of TROP2 (staining extension 2+ or 3+) were found in 356 (27.5%) cases. The clinicopathological features of all 1296 patients based on the TROP2 expression in their cancer cells were summarized in Table 1. Compared to TROP2 negativity expression, the high TROP2 expression was significantly associated with the advantaged tumor stage (III/IV, P = 0.022), high tumor invasion depth (T3/T4, P = 0.002), lymph node metastasis (N1/N2, p = 0.026), HER-2 expression (2+/3+, p = 0.013) ,PD-L1 CPS (CPS≤5,P = 0.007). Sacituzumab Govitecan exhibited stronger inhibition in TROP2-positive human CRC cells in TROP2-negative CRC cells compared to TROP2-negative cells and the control SN-38 agent. Conclusions: TROP2 expression positive in 50% of CRC cases is associated with with advantaged tumor stage, high tumor invasion depth, lymph node metastasis. Sacituzumab Govitecan demonstrates potent targeting of TROP2-positive CRC cells, suggesting TROP2 as a potential biomarker for clinical prognosis and therapeutic targeting in colon cancer. [Table: see text]
177Lu-edotreotide versus everolimus in patients with advanced neuroendocrine tumors of lung or thymic origin: The phase 3 randomized LEVEL, GETNE-T2217 trial.
Authors: Garcia-Alvarez Alejandro , Garcia-Carbonero Rocio , Anton-Pascual Beatriz , Jimenez-Fonseca Paula , Llana Belen , Pubul Virginia , Anido Urbano , Molina-Cerrillo Javier , del Olmo-García Maribel , Teule Alex , Benavent Viñuales Marta , Taieb David , Lepage Come , Beron Amandine , Ansquer Catherine , Deshayes Emmanuel , Baudin Eric , Haissaguerre Magalie , Walter Thomas , Capdevila Jaume
Published: June 2024

TPS3177

Background: Everolimus is the only approved drug for the treatment of patients with neuroendocrine tumors (NETs) of lung and thymic origin, showing a median progression-free survival (PFS) of 11 months. Retrospective data for peptide receptor radionuclide therapy (PRRT) have demonstrated promising activity in somatostatin receptor (SSTR)-positive lung NETs. This study aims to compare the efficacy, safety, and patient-reported outcomes of 177Lu-edotreotide versus the standard of care everolimus in patients with advanced lung and thymic NETs. Methods: The LEVEL trial is a randomized, open-label, phase 3 international trial of 177Lu-edotreotide versus everolimus in patients with progressive, advanced, and well/moderately differentiated NETs of lung (typical/atypical) or thymic origin. Patients could be treatment naïve or have progressed (PD) on somatostatin analogues or ≤2 additional systemic treatments. Prior PRRT or mTOR inhibitors are not permitted. Eligible patients are randomly assigned 3:2 to 6 cycles of 177Lu-edotreotide (7.5±0.7 GBq / cycle) or to oral everolimus 10 mg once daily until PD or unacceptable toxicity. Computed Tomography (CT) or Magnetic Resonance Imaging (MRI) scans are performed every 12 weeks until PD. Blood samples are analyzed at baseline, at 1st tumor assessment, and at PD for pharmacodynamic endpoints. Archival tumor tissue samples will be analyzed for ancillary studies. The primary endpoint is PFS according to RECIST v1.1. Secondary endpoints include overall response rate, duration of response, overall survival, safety, and quality of life (assessed through EORTC QLQ-C30). The expected sample size is 120 patients using a two-sided group sequential Lan-DeMets with O’Brien-Fleming-like boundaries test to demonstrate statistically significant risk reduction of 46.4% (HR= 0.536) in PFS between arms (α=0.05, β=0.2). The study has received institutional review board/ethics committee approval. Recruitment started in Oct 2023. Thirteen patients are already included. Clinical trial information: NCT05918302 .