bluuebunny/crossref_metadata_2025 huggingface dataset:
CD8 radiomics signature to assess inter-lesion spatial heterogeneity and cold liver lesions in advanced non-small cell lung cancers treated with durvalumab.
Authors: Sun Roger , Emeriau Yanis , Achkar Samir , Mitrea Diana , Laville Adrien , Deny Nicolas , Bockel Sophie , Chaffai Ines , Mrissa Linda , Cifliku Vjona , Talebi Fereshteh , Wu Wenxia , Le Pechoux Cecile , Barlesi Fabrice , Robert Charlotte , Levy Antonin , Deutsch Eric
Published: June 2024

2511

Background: The objective of this study was to assess whether a validated CD8 radiomics signature may help to evaluate patient inter-lesion heterogeneity and to predict the clinical outcome of advanced non-small cell lung cancers (NSCLC) patients treated with durvalumab in Study 1108 phase I/II trial (NCT01693562). Methods: Clinical data and imaging data from patients with naïve and pretreated advanced NSCLC who received durvalumab monotherapy were used. Radiomic features were extracted on contrast-enhanced CT scans and a validated CD8 radiomics signature was applied. A progressive lesion was defined by an increase in lesion longest diameter of 20% at 8 weeks. Dispersion metrics of the radiomics signature were estimated to evaluate the impact of inter-lesion heterogeneity on patient’s response. Results: A total of 188 patients were included in this study, accounting for a total of 1137 lesions (median [IQR] = 4 [3 - 9] lesions per patient) evaluated at baseline using a radiomics approach. A low CD8 radiomics score at baseline was associated with a significantly higher risk of progression at the lesion-level (AUC=0.59, P-value<0.0001), and was especially performant for liver lesions (AUC=0.66, P-value=0.0002). At the patient level, the least infiltrated lesion of a patient according to the radiomics score of CD8 T-cells was positively associated with OS (HR=0.70, P-value=0.029) and PFS (HR=0.68, P-value=0.014), the highest values being associated with the best outcomes. 55 patients had liver lesions, with worse prognosis than patients without liver lesion (HR=2 for OS and PFS, P-value = 0.00012 and 0.00022 respectively). In these patients, the CD8 radiomic score enabled the stratification of patients according to hot and cold liver metastasis (HR=0.6, P-value=0.072 and HR=0.54, P-value=0.038 for OS and PFS respectively). A 4-class stratification of the whole cohort based on the least infiltrated (cold/hot) and liver or non-liver lesion was independently associated with clinical outcomes. These radiomics approaches have shown independent prognostic values when adjusting for PD-L1 status in multivariate analyses (Table). Conclusions: These results confirm the predictive value at a lesion level and the patient level of the biologically inspired CD8 radiomics score for advanced NSCLC patients treated with durvalumab. It has shown interesting results in discriminating outcomes of patients with liver lesions by identifying hot and cold lesions. [Table: see text]
Clinical landscape of precision oncology for rare cancers among diverse Asian populations: Insights from the MASTER KEY registry.
Authors: Mizoguchi Chiharu , Okuma Hitomi Sumiyoshi , Muto Manabu , Kinoshita Ichiro , Baba Eishi , Takahashi Masanobu , Ando Masashi , Soo Hoo Hwoei Fen , Yusak Suhana , Voon Pei Jye , Ramachandran Rangasamy , Thiagarajan Muthukkumaran , Imasa Marcelo Severino Bulauitan , Malik Rozita Abdul , Choi Wonyoung , Dao Tu Van , Chen Tom Wei-Wu , Yonemori Kan , Nakamura Kenichi , Yamamoto Noboru
Published: June 2024

3024

Background: Despite considerable strides in novel cancer treatments, disparities in access and care persist globally. This is particularly pronounced for rare cancers and among Asian patient cohorts, presenting a dual challenge. Methods: We conducted an analysis on clinical and biomarker data from the MASTER KEY Study, a multi-regional, prospective, observational precision oncology initiative encompassing 3,764 rare cancer patients across Asia. Clinical treatment and biomarker data, inclusive of DNA/RNA sequencing, were scrutinized to compare precision oncology adoption across various countries. Results: Within the Japanese cohort (3,268 patients), predominant rare cancer types included soft tissue sarcomas (22.0%), CNS/brain tumors (12.8%), and head and neck tumors (9.2%). The broader Asian cohort (496 patients) included soft tissue sarcomas (14.6%), liver/biliary tract tumors (14.4%), and head and neck tumors (13.8%), drawing patients from Malaysia, Korea, Taiwan, Philippines, Thailand, and Vietnam. Clinical trial participation for these rare cancers was notably higher in Taiwan (8.2%), followed by Japan (6.5%) and Malaysia (2.0%). The utilization of molecular target agents and/or immune checkpoint inhibitors was highest in Japan (20.3%), trailed by Taiwan (18.9%) and Korea (12.8%). DNA/RNA targeted sequencing data was available for 1,852 patients in Japan (56.7%) and 321 patients (64.7%) across the rest of Asia. 19.5% and 7.0% received on-target therapy in Japan and the rest of Asia, respectively. Notably, in Japan, patients harboring detectable targetable genes like BRAF V600E, BRCA1, and BRCA2 received BRAF/MEK inhibitors and PARP inhibitors at rates of 78.3%, 37.8%, and 25.0%, respectively, with varying response rates of 33.3%, 18.2%, and 20.2% each. Intriguingly, TP53 mutation acted as a negative predictor for response to BRAF/MEK inhibitors. Notably, no patients in the Asian cohort received BRAF/MEK inhibitors or PARP inhibitors despite the detection of these genes. Conclusions: The MASTER KEY Study demonstrates the feasibility of a prospective precision oncology platform, spotlighting rare cancers and enabling on-label targeted therapy as well as off-label targeted therapy for a subset of patients through trials. However, the broader Asian population outside Japan encounters heightened limitations in accessing precision oncology. Urgent expansion of clinical trials throughout Asia is crucial to effectively address the disparity that lies within Asian rare cancer patients.
Selpercatinib in non-MTC, RET-mutated tumors: Efficacy in MEN-associated and other tumors.
Authors: Cassier Philippe Alexandre , De Braud Filippo G. , Ryder Mabel M. , Robinson Bruce , Tomasini Pascale , Morise Masahiro , Lakhani Nehal J. , Szymczak Sylwia , Peterson Patrick , Barker Scott , Sukrithan Vineeth
Published: June 2024

3150

Background: Selpercatinib, a first-in-class highly selective and potent RET kinase inhibitor with CNS activity, is approved in multiple countries for the treatment of RET-activated cancers. Current indications for RET mutant disease are limited to MTC. This analysis examined if selpercatinib was effective in non-MTC, RET mutation positive tumors and whether certain RET mutations demonstrated better activity (n=23; data cut-off: 13Jan2023). Methods: The phase 1/2 LIBRETTO-001 trial (NCT03157128) enrolled pts with locally advanced/metastatic RET-altered solid tumors, including pts with RET mutations in tumors other than MTC. Mutations must be known to be activating based on activity in MTC or other published evidence. Primary endpoint was objective response rate (ORR) by independent review committee (IRC). Secondary endpoints included ORR by investigator (INV), duration of response (DoR), progression-free survival (PFS), and safety. Results: Fourteen different tumor types were identified among the 23 pts with non-MTC RET-mutated tumors. This included 8 tumors from the Multiple Endocrine Neoplasia (MEN) syndrome spectrum; adrenal (pheochromocytoma; n=5), paraganglioma (n=2), neuroendocrine (n=1) (Table). Most of the mutations were located in extracellular cysteine-rich domain (CRD) and in the tyrosine kinase domain (TKD) of RET. In 23 efficacy-evaluable pts, confirmed ORR by IRC was 21.7% (5/23, 95% CI: 7.5, 43.7). ORR by IRC for pts with MEN-associated tumors (n=8) was 37.5% while five of these pts (62.5%) had stable disease lasting at least 16 weeks (SD16+). ORR by IRC for the sub-population with pheochromocytoma (n=5) was 40.0% and for pts with tumors manifesting RET extracellular cysteine mutations (n=5) was 60.0%. Of the 15 pts with non-MEN-associated tumors, 2 pts (8.7%; mutation in TKD) had a partial response (both with NSCLC adenocarcinoma, of which one had co-existent MTC). For the overall pts, the median DoR was 12.2 months (95% CI: 3.8, NE) and median PFS was 5.5 months (95% CI: 1.8, 19.4). No new safety signals were identified compared to previous reports. One grade 5 AE, general physical health deterioration, was observed and deemed by INV as not related to selpercatinib. Conclusions: This study suggests that RET-mutated, MEN-associated cancers (adrenal, paraganglioma, neuroendocrine) may benefit from selpercatinib treatment, which could be mediated through mutations in the extracellular CRD. The non-MTC RET-mutated tumor types appear not to derive benefit from selpercatinib. Clinical trial information: NCT03157128 . [Table: see text]
Real-world use of anti-EGFR therapy in metastatic colorectal cancer.
Authors: Robinson Hannah Ruth , Hu Junxiao , Balmaceda Nicole Baranda , Lentz Robert William , Baiyee Toegel Emily , Leal Alexis Diane , Kim Sunnie S. , Messersmith Wells A. , Lieu Christopher Hanyoung , Davis S. Lindsey
Published: June 2024

3552

Background: Anti-EGFR therapies including cetuximab and panitumumab are recommended in frontline or later-line treatment regimens for left-sided metastatic colorectal cancer (mCRC) lacking mutations in RAS or BRAF. Here we report patterns of anti-EGFR therapy use in patients with mCRC diagnosed between 2013 and 2023. Methods: This study used the nationwide Flatiron Health electronic health record (EHR)-derived de-identified database, which contains patient-level data originating from approximately 280 cancer clinics in the United States (~800 sites of care).Adult patients diagnosed with mCRC from January 1, 2013 to April 28, 2023 who received at least 1 line of treatment were included. The percentage of patients who received anti-EGFR agents based on biomarker indication and primary tumor sidedness (PTS) was determined. PTS was assessed by ICD codes, with left-sided disease defined as tumors originating from the splenic flexure to the rectum. Univariate and multivariable analyses were performed to evaluate for factors associated with utilization of biomarker-directed anti-EGFR therapy. Results: A total of 25,937 patients were included in this analysis. Among these, 3,425 (13.2%) had a confirmed indication for anti-EGFR therapy, based on the presence of left-sided disease and documented KRAS, NRAS,and BRAFwildtype status (Cohort 1). In contrast, 15,015 (57.9%) patients had a documented RASor BRAF mutation and/or right-sided disease (Cohort 2). Anti-EGFR therapy was included in frontline treatment for 19.7% of patients in Cohort 1 versus 3.3% of patients in Cohort 2. Anti-EGFR therapy was included in any-line treatment for 56.6% of patients in Cohort 1 versus 12.1% of patients in Cohort 2. Patients in Cohort 1 were less likely to receive anti-EGFR therapy in any treatment line if they were ≥ 75 versus < 45 years old at diagnosis (odds ratio [OR] 0.72, p = 0.027), had a primary rectal versus colon cancer (OR 0.87, p = 0.045), or were diagnosed at a later timepoint. For instance, while 72.4% of Cohort 1 patients diagnosed between 2013-2015 received anti-EGFR therapy, only 63.9% (OR 0.68, p = 0.05), 59.5% (OR 0.57, p < 0.001), and 46.7% (OR 0.34, p < 0.001) of patients diagnosed between 2016-2017, 2018-2019, and 2020-2023 received anti-EGFR therapy, respectively. Patient sex, race, ethnicity, practice setting, socioeconomic index, and performance status were not associated with anti-EGFR therapy use. Conclusions: Based on results from the Flatiron Health database, use of anti-EGFR therapy is enriched among patients with biomarker-based indications for treatment. Notably, anti-EGFR therapy was employed in only 56.6% of patients with RAS and RAF wildtype, left-sided mCRC, with decreased use observed from 2013 to 2023.
Phase Ib/II trial of hepatic arterial infusion chemotherapy in combination with fruquintinib for refractory unresectable colorectal cancer 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

3561

Background: Hepatic arterial infusion chemotherapy (HAIC), a highly efficient local therapy for patients with colorectal liver metastases (CRLM), is supposed to have a synergetic effect when it is in combination with a systemic therapy. The aim of this study was to determine the recommended phase 2 dose (PR2D) of fruquintinib combine with HAIC and evaluate efficacy and safety in expansion cohort of patients with CRLM. Methods: This open-label, single-arm, phase Ib/II study (NCT05406206) enrolled patients with CRLM who had received at least two prior lines of treatment. In the dose-finding phase, based on a standard 3+3 design, patients were treated with HAIC involving oxaliplatin (85 mg/m2) and 5-FU (2000 mg/m2) on day 1 and 2 every 4 weeks, alongside fruquintinib (3mg, 4mg, 5mg, d3-23, q4w, respectively) until unacceptable toxicities, progressive disease, or death occurred. In the dose-expansion phase, patients received HAIC and RP2D of fruquintinib determined in the dose-escalation phase. The primary endpoint was progression-free survival (PFS), and the secondary endpoints included RP2D, objective response rate (ORR; RECIST 1.1), disease control rate (DCR), overall survival (OS) and safety. Results: As of data cutoff date on January 30, 2024, a total of 30 patients were enrolled. 9 (30.0%) patients were female, and the mean age was 56 years, 22 (73.3%) patients were RAS/BRAF mutant. During the dose-escalation phase, 15 patients were enrolled, with 3, 6, and 6 patients receiving doses of 3 mg, 4 mg, and 5 mg, respectively. Only one dose-limiting toxicity occurred in a patient of 4 mg level (G3 hypertension failed to control with antihypertensive treatment within 7 days). RP2D of fruquintinib was established as 5 mg. Fifteen patients were evaluable for efficacy, with best response of pathological complete response in 1 patient, partial response in 5 patients and stable disease in 6 patients, yielding an ORR of 40.0% and DCR of 80.0%. Median hepatic-PFS and median PFS was 6.8 months (95% CI, 5.890-7.710) and 5.9 months (95% CI, 3.576-8.224), respectively. The median OS reached 15.0 months (95% CI, 8.671-21.329). 7 (23.3%) patients experienced G3/4 treatment-related adverse events (TRAEs). The most common TRAEs of all grades were voice alteration, hypertension, abdominal pain and hand-foot syndrome. Conclusions: The combination of HAIC and fruquintinib showed a manageable safety profile and survival benefit of heavily treated CRLM patient. Clinical trial information: NCT05406206 .
Effect of p16 immunohistochemical expression (exp) on irinotecan in metastatic colorectal cancer (mCRC): A translational analysis of the TRIBE and TRIBE2 studies.
Authors: Germani Marco Maria , Moretto Roberto , Conca Veronica , Signorini Francesca , Proietti Agnese , Giordano Mirella , Rossini Daniele , Studiale Vittorio , Murgioni Sabina , Di Paolo Giacomo , Pietrantonio Filippo , Russo Alessandra , Taravella Ada , Passardi Alessandro , Zaniboni Alberto , Latiano Tiziana Pia , Cappetta Alessandro , Ugolini Clara , Cremolini Chiara
Published: June 2024

3562

Background: CDKN2A encodes the inhibitor of the cyclin-dependent kinases p16 and is frequently methylated in colorectal cancer, thus reducing the exp levels of p16 protein. In pre-clinical models of colorectal cancer cells, the demethylation of CDKN2A gene induces topoisomerase I upregulation increasing the sensitivity to irinotecan. In metastatic colorectal cancer (mCRC) pts, the role of p16 expression has been poorly investigated. Methods: Tumour samples of pts randomized in the phase III TRIBE2 study comparing upfront FOLFOXIRI/bevacizumab (bev) versus (vs) FOLFOX/bev were assessed for p16 immunohistochemical exp. A validation analysis in patients treated with FOLFIRI/bev in the TRIBE study was conducted. Results: Out of 679 patients enrolled in the TRIBE2 study, 231 tumours were assessed for p16 exp. Overall, 152 (66%), and 79 (34%) were classified as positive (pos) (IHC 2+ and 3+) and negative (neg) (IHC 0 and 1+), respectively. In the p16 pos group, 69 (45%) and 83 (55%) pts received FOLFOXIRI/bev and FOLFOX/bev, respectively, while in the p16 neg cohort, FOLFOXIRI/bev was administered in 37 (47%) and FOLFOX/bev in 42 (53%) cases. Pts with p16 neg tumours had more frequently an ECOG-PS of 1-2 (16% vs 6%, p=0.0098) and a BRAF mut tumour (26% vs 7%, p=0.0002). No PFS difference was observed between p16 neg and pos patients, while a trend for a longer OS was shown in favour of p16 pos pts (25.5 vs 21.3 months; HR: 0.74, 95%CI: 0.53-1.02, p=0.068) that was not confirmed at the multivariate analysis (p=0.61). Among patients with p16 pos tumours, those treated with FOLFOXIRI/bev reported longer PFS (12.8 vs 9.4 months, HR: 0.55, 95%CI: 0.39-0.78, p=0.0008) and OS (30.0 vs 21.4 months, HR: 0.66, 95%CI: 0.46-0.95, p=0.026) than those receiving FOLFOX/bev. On the other hand, no significant difference was observed among p16 neg patients in terms of both PFS (9.0 vs 9.4 months, HR: 0.91, 95%CI: 0.57-1.46, p=0.69) and OS (21.3 vs 19.5 months, HR: 0.95, 95%CI: 0.58-1.57, p=0.85), thus suggesting a differential treatment effect according to p16 exp (pinteraction for PFS =0.12; pinteraction for OS =0.19). Among patients treated with FOLFIRI/bev in the TRIBE study (N=58) patients with p16 pos tumours reported longer PFS and OS than those with p16 neg. (HR for PFS: 0.45, 95%CI: 0.22-0.92, p=0.026; HR for OS: 0.41, 95%CI: 0.20-0.85, p=0.013). Conclusions: In mCRC, p16 pos exp seems associated with higher benefit from irinotecan. Prospective confirmation in independent randomized series is warranted.
International, open-label phase 2 study of regorafenib plus pembrolizumab in patients with advanced hepatocellular carcinoma (HCC) previously treated with immune checkpoint inhibitors (ICI).
Authors: El-Khoueiry Anthony B. , Kim Tae-You , Blanc Jean-Frédéric , Rosmorduc Olivier , Decaens Thomas , Mathurin Philippe , Merle Philippe , Dayyani Farshid , Masi Gianluca , Pressiani Tiziana , Galle Peter Robert , Hatogai Ken , Ishii Yuko , Seidel Henrik , Mueller Udo , Kalambakas Stacey Anastasia , Bouattour Mohamed
Published: June 2024

4007

Background: The optimal second-line treatment for HCC after ICI is not established. Regorafenib is approved for treatment of advanced HCC after sorafenib. The primary aim of this study was to evaluate the activity of regorafenib plus pembrolizumab in patients with advanced HCC who progressed on only one prior ICI regimen. Methods: Patients aged ≥18 years, CP Class A, BCLC stage B or C, and ECOG PS of 0 or 1 received oral regorafenib 90 mg once daily 3 weeks (wk) on/1 wk off plus i.v. pembrolizumab 400 mg every 6 wk. The daily regorafenib dose could be escalated to 120 mg after the first 4-wk cycle of regorafenib if tolerated. Pembrolizumab dose reductions were not allowed. Cohorts were defined by prior treatment: Cohort 1 = atezolizumab + bevacizumab; Cohort 2 = any other ICI regimen (alone or combination). Primary endpoint was overall response rate (ORR) by independent central review (RECIST 1.1). Results: 95 patients were treated in 8 countries; Cohort 2 appeared to have more favorable disease characteristics (Table). Most common prior ICIs in Cohort 2 were durvalumab (30%), nivolumab (30%), ipilimumab (22%), and pembrolizumab (19%). Overall, median follow up was 7.1 months (mo). Median duration of regorafenib/pembrolizumab treatment (including interruptions, delays) was shorter in Cohort 1 vs Cohort 2 (11.0/9.4 wk vs 21.4/24.1 wk). ORR was 5.9% in Cohort 1 and 11.1% in Cohort 2; stable disease rates were 48.5% and 63.0%, respectively. Median PFS was 2.8 mo in Cohort 1 and 4.2 mo in Cohort 2. Overall, treatment-emergent adverse events (TEAE) were grade 3 in 56% of patients and grade 4 in 5%; drug-related grade 3 and 4 TEAE occurred in 37% and 3%, respectively. One patient (Cohort 1) had a grade 5 drug-related TEAE (cardiac arrest). Most common drug-related TEAE were palmar-plantar erythrodysesthesia syndrome (39%), asthenia (33%), decreased appetite (32%), diarrhea (28%), and hypertension (20%). Biomarkers assessed in paired biopsies (baseline and wk 6/day 1) showed on-treatment reductions in macrophages and angiogenesis RNA signatures. Conclusions: To our knowledge, this is the first prospective evaluation of a kinase inhibitor plus an ICI following first-line ICI therapy for HCC. Regorafenib plus pembrolizumab had modest activity in second line after first-line ICI regimens. The safety profile of the combination was consistent with those of either drug. Optimal treatment for patients with advanced HCC who progress after an ICI regimen remains an unmet need. Biomarker findings will be detailed in presentation. Clinical trial information: NCT04696055 . [Table: see text]
Safety and efficacy of IBI389, an anti-CLDN18.2/CD3 bispecific antibody, in patients with advanced pancreatic ductal adenocarcinoma: Preliminary results from a phase 1 study.
Authors: Hao Jihui , Zheng Li , Ruihong Dai , Jieer Ying , Xu Qi , Wang Li-Wei , Jin Yongdong , Zhao Ying , Pan Yueyin , Liu Lulu , Zhang Jun , Sun Yuping , Niu Zuoxing , Yao Jun , Hua Dong , Zhang Mingjun , Guanghai Dai , Zhang Yulong , Zhou Hui , Bi Feng
Published: June 2024

4011

Background: CLDN18.2 expression has been observed in various solid tumors. In pancreatic ductal adenocarcinoma (PDAC), positive CLDN18.2 expression was reported in nearly 60% patients (pts), indicating its potential as a novel target for anti-tumor therapy. IBI389 is an anti-CLDN18.2/CD3 bispecific antibody that induces immune synapse formations by linking CD3 molecules in T-cell receptor complexes and CLDN18.2 antigens on the membrane of tumor cells. Herein, we report preliminary result from a phase I study to evaluate safety and efficacy of IBI389 in pts with PDAC. Methods: EligibleCLDN18.2-positivepts with locally advanced, refractory or metastaticPDAC who failed or were intolerant to standard treatments were enrolled. IBI389 monotherapy was intravenously administered at 6 dose levels (5-600 µg/kg, Q3W or Q2W) during the 2-stage dose escalation and the dose expansion. In dose levels ≥ 30 µg/kg, the step-up dosing strategy with priming dose of 3 to 10 µg/kg was applied. The primary objective was safety. Secondary objective was efficacy assessed by investigator per RECIST v1.1 including objective response rate (ORR) and disease control rate (DCR). Results: As of January 9, 2024, a total of 64 CLDN18.2-positive PDAC pts were enrolled (males: 64.1%, females:35.9%, median age: 60.0 years, stage IV: 84.4%). All patients received prior therapy with a median of 2 lines (range: 1 to 5). Treatment-related adverse events (TRAEs) occurred in 62 (96.9%) pts including 35 (54.7%) pts had grade ≥3 TRAEs. The most common grade ≥3 TRAEs (≥5%) were gamma-glutamyl transferase increased (20.3%), lymphocyte count decreased (9.4%) and nausea (7.8%). Cytokine release syndrome (CRS) related adverse events occurred in 33 (51.6%) pts with no grade ≥3 CRS occurred. TEAEs leading to dose interruption and treatment discontinuation occurred in 24 (37.5%) and 3 (4.7%) pts. Preliminary efficacy of IBI389 was observed in pts with CLDN18.2 expression ≥10% (immunohistochemistry 2+/3+) at 600 µg/kg. As of January 31, 2024, there were 23 evaluable pts including 7 pts with PR and 9 pts with SD. The ORR was 30.4% (95%CI: 13.2-52.9) and DCR was 69.6% (95%CI: 47.1-86.8). The median duration of response (DoR) and progression-free survival (PFS) was not reached. More updated data on safety and efficacy will be presented at the meeting. Conclusions: IBI389 showed manageable safety profiles in pts with advanced PDAC. Preliminary efficacy was observed, including in pts with relatively low expression of CLDN18.2. Clinical trial information: NCT05164458 .
Global, randomized, phase III study of tislelizumab plus chemotherapy versus placebo plus chemotherapy as first-line treatment for advanced/metastatic esophageal squamous cell carcinoma (RATIONALE-306 update): Minimum 3-year survival follow-up.
Authors: Yoon Harry H. , Kato Ken , Raymond Eric , Hubner Richard , Shu Yongqian , Pan Yueyin , Jiang Yi , Zhang Jingdong , Park Sook Ryun , Kojima Takashi , Lin Chen-Yuan , Wyrwicz Lucjan S. , Tougeron David , Ishihara Ryu , Li Liyun , Wu Hongqian , Peng Yanyan , Yan Shican , Xu Jianming
Published: June 2024

4032

Background: RATIONALE-306 (NCT03783442) is the first global study to investigate anti-programmed cell death protein 1 therapy in combination with different chemotherapy (chemo) options in the first-line (1L) treatment of advanced/metastatic esophageal squamous cell carcinoma (ESCC). At interim analysis (IA), tislelizumab (TIS) plus chemo demonstrated a statistically significant, clinically meaningful improvement in overall survival (OS) versus placebo (PBO) plus chemo, with a manageable safety profile. Here, we report updated efficacy and safety data with minimum 3 years’ follow-up after study unblinding at IA. Methods: Adults with unresectable locally advanced recurrent/metastatic ESCC and no prior systemic treatment for advanced disease were enrolled and randomized (1:1; stratified by region, prior definitive therapy, and investigator [INV]-chosen chemo) to receive TIS 200 mg (Arm A) or PBO (Arm B) IV every 3 weeks plus chemo (platinum plus fluoropyrimidine or platinum plus paclitaxel), until disease progression or intolerable toxicity. The primary endpoint was OS in the intent-to-treat population. Secondary endpoints included progression-free survival (PFS), objective response rate (ORR), and duration of response (DoR), all per INV, and safety. Results: In total, 649 patients (pts) were randomized (Arm A, n=326; Arm B, n=323). At a minimum study follow-up of 36.0 months, improvements in OS, PFS, and DoR in Arm A versus B (Table) were maintained relative to the IA. The hazard ratio (HR) for OS with TIS plus chemo versus PBO plus chemo was 0.70 (95% confidence interval: 0.59, 0.83). Similar to the IA, incidences of any-grade (96.6% vs 96.3%) or grade ≥3 (67.0% vs 64.5%) treatment-related adverse events (TRAEs) were comparable between Arms A and B, respectively; treatment-emergent adverse events leading to treatment discontinuation were higher in Arm A (32.1%) versus B (22.1%). In Arm A versus B, respectively, serious TRAEs occurred in 29.9% vs 19.6% of pts; TRAEs leading to death occurred in 1.9% and 1.2%. Conclusions: After minimum 3 years’ follow-up, 1L TIS plus chemo continued to demonstrate clinically meaningful improvements in OS and PFS and durable antitumor response benefit versus PBO plus chemo in pts with advanced/metastatic ESCC, with no new safety signals. Clinical trial information: NCT03783442 . [Table: see text]
Updated results and biomarker analyses from the phase 2 trial of nab-paclitaxel plus sintilimab as second-line therapy for advanced or metastatic gastric/gastroesophageal junction adenocarcinoma (G/GEJA).
Authors: Jiang Zhichao , Zhang Wen , Yang Lin , SUN Yongkun , Zhao Yun-Bo , Deng Wei , Cui Liang , Zhou Aiping
Published: June 2024

4037

Background: Sintilimab plus Nab-paclitaxel (nab-PTX) has exhibited promising efficacy and safety in the second line (2L) treatment of PD-1/PD-L1 inhibitor naïve advanced G/GEJA (ZC Jiang et al 2022 ASCO GI). This update presents the latest findings on efficacy, survival outcomes and exploration of biological markers. Methods: We collected blood samples from the advanced G/GEJA patients (pts) who were enrolled in our Phase 2 clinical trial and treated with sintilimab plus nab-PTX. Target-capture deep sequencing of 1,021 genes was conducted to identify somatic variants in circulating tumor DNA (ctDNA) from the baseline plasma samples (N=55) and disease progression samples of the pts with PFS >4 months (N=17). And T cell repertoire sequencing was performed on pretreatment samples (N=55) as well as on paired blood samples obtained during the first tumor evaluation (N=45). Results: From Nov 2019 to Sep 2022, 58 pts were enrolled, with a median follow-up of 20.9 months (95% CI 17.04-24.76) until July 10, 2023. The objective response rate (ORR) and disease control rate (DCR) were 44.8% and 79.3%, respectively. The median progression free survival (mPFS) and median overall survival (mOS) were 4.8 months (95%CI 3.06-6.54) and 11.8 months (95%CI 10.43-13.17). Analysis of baseline ctDNA revealed a notably higher prevalence of EPHB1 mutation in non-responders (PD+increased SD) compared to responders (CR+PR+decreased SD) (21.43% vs. 0%, P=0.022). Pts with EPHB1 mutation showed a significantly increased risk of disease progression (HR 3.86, 95% CI 0.43-34.41, p=0.013) and death (HR 4.49, 95% CI 0.43-46.93, p=0.005) compared to wild-type EPHB1 pts. In contrast to high ctDNA level (mean tumor molecules [MTM] per mL of plasma, cutoff value=2999.7), low ctDNA level demonstrated a significantly reduced risk of disease progression (HR 1.88, 95% CI 1.05-3.37, p=0.034). Dynamic T cell receptor (TCR) diversity analysis during baseline and the initial tumor assessment showed a significant post-treatment increase in the Shannon index within the responder group (P=0.045, median Shannon index change: responder 0.43 vs. non-responder -0.49). An increased Shannon index was correlated with significantly prolonged mPFS (HR 0.44, 95% CI 0.22-0.91, P=0.009), while no significant difference was observed in mOS (HR 0.74, 95% CI 0.36-1.54, P=0.399). A negative correlation between the Shannon index and MTM was observed (R=-0.37, P=0.009). Conclusions: 2L-treatment with sintilimab plus nab-PTX maintains favorable efficacy in advanced G/GEJA pts without prior PD-1/PD-L1 inhibitor treatment. EPHB1 mutation and dynamic change of TCR could serve as potential predictive factors. Further investigation is warranted. Clinical trial information: NCT04140318 .
Validation of PD-L1 as a predictive biomarker of response in operable gastroesophageal adenocarcinoma: A meta-analysis and meta-regression of neoadjuvant chemoimmunotherapy trials.
Authors: Cammarota Antonella , Kamarajah Sivesh Kathir , Markar Sheraz , Smyth Elizabeth Catherine
Published: June 2024

4065

Background: Perioperative chemotherapy (ChT) is a standard for operable gastroesophageal adenocarcinoma (GEA). The addition of immune checkpoint inhibitors (ICIs) has improved pathological complete response (pCR) with unclear survival advantages in an unselected population. In the advanced setting, PD-L1 is a validated biomarker of response to ICIs. We aimed to assess its predictive role in the early stages wherein remains unexplored. Methods: We conducted a systematic review of randomised clinical trials (RCTs) of neoadjuvant or peri-operative ChT +/- ICIs in non-metastatic GEA, published between 2006-2024. Biomarker-unselected phase 2/3 or phase 3 RCTs with an active comparator were selected. Odds ratios (ORs) for pathological response (defined as pCR, ypT0, or ypT≤1), the primary outcome of this meta-analysis, were extracted and analysed using a random-effect meta-analysis. Subgroup analysis (ICI-ChT versus ChT) was performed to estimate the pooled effect of peri-operative ICIs on pathological response. Sensitivity analyses were performed to account for between-study heterogeneity. We then extracted pCR data by PD-L1 (cutoffs 1, 5, 10) from phase 2 trials of neoadjuvant ICIs+ChT or chemoradiotherapy (CRT) published between 2006-2024. Weighted Pearson trial-level correlation and a meta-regression model were used to assess the relationship of PD-L1 with pCR. Results: Nine RCTs were eligible for the analysis, one of which had two experimental arms contributing to two comparisons. Of 5359 included patients, 1302 received ICI-ChT and 4057 systemic ChT. ICI-ChT showed a significant improvement in pathological response (pooled OR 2.90, 95% CI 1.81-4.63, p<0.001) with a larger effect compared to ChT-only trials (pooled OR 1.40, 95% CI 1.10-1.79, p=0.007). Results were consistent in sensitivity analyses of pCR-only, non-Asian, and since-FLOT studies. Fourteen studies were included in the phase 2 trials dataset (n=10 ICI+ChT and n=4 ICI+CRT) accounting for 708 patients receiving ICIs. PD-L1 showed a moderate positive correlation with pCR, stronger for higher cut-offs (weighted R for cut-offs 1, 5, and 10: 0.33, 0.51, and 0.65, respectively) and after exclusion of CRT trials (weighted R for cut-offs 5 and 10: 0.67 and 0.99, respectively). In a mixed-effect meta-regression model, PD-L1 ≥5 was a significant predictor of response (effect size [ES]: 0.71, 95% CI, 0.29-1.13, p=0.001), even after accounting for the backbone treatment (ChT versus CRT) (ES: 0.60, 95% CI, 0.20-1.00, p=0.003). Conclusions: Neoadjuvant ICI-ChT consistently improves pathological response in operable GEA, particularly in PD-L1-positive tumours. PD-L1 ≥5 appears a significant biomarker of pCR in non-metastatic GEA, supporting stratification by PD-L1 and biomarker-selected trials for evaluation at the individual patient level.
Neoadjuvant S-1 plus cisplatin-based chemoradiotherapy compared with surgery alone for locally advanced gastric cancer: Randomized, phase II trial.
Authors: Hong Moonki , Yun Kum-Hee , Jung Minkyu , Rha Sun Young , Kim Hyoung-Il , Park Jun Chul , Lee Sang Kil , Choi Seo Hee , Jung Inkyung , Lim Joon Seok , Hyung Woo Jin , Koom Woong Sub , Kim Hyo Song
Published: June 2024

4076

Background: Patients with locally advanced gastric cancer (LAGC), are known to have a high risk of recurrence even after surgery. This study was designed to delineate whether neoadjuvant concurrent chemoradiotherapy (CCRT) using the S-1/Cisplatin (SP) regimen can effectively downstage the T stage in patients with clinically T4 stage compared with surgery alone (OP). Methods: This is a randomized phase II open label trial and gastric cancer patients with initial clinical T4 were enrolled. Patients were randomized into neoadjuvant CCRT or OP. For the CCRT group, S-1 (20 mg/m2 twice daily, 2 weeks on and 1 week off) and cisplatin (30 mg/m2/day, first day of week 1, 2, 4, and 5) were administered concurrent with radiotherapy (day 1-5 for 5 weeks, total 45 Gy/25 fractions,). Surgery was performed within 3 to 6 weeks after the completion of CCRT. For the OP group, curative surgery was performed within 3 weeks after randomization. Post-operative adjuvant chemotherapy was chosen as S-1 monotherapy or combination of Capecitabine, and Oxaliplatin according to the physician’s choice. The primary objective of this study was to compare the downstaging rates between the groups (65% and 40% for the CCRT and OP group). Using a type I error rate of 0.10 and a power of 0.80, the planned sample size was 51 patients per group but the study was closed prematurely. Results: Between November 2016 and August 2021, 49 patients with T4 were enrolled. Of those, 26 (CCRT) and 23 (OP) patients were randomized but diagnostic laparoscopy for preoperative screening revealed peritoneal seeding in some patients. Finally, 23 (CCRT) and 17 (OP) patients were evaluable and clinicopathologic characteristics were well balanced between the two groups in per protocol analysis. For CCRT, 19 out of 23 (82.61%) patients satisfied downstage, while among 8 out of 17 (47.06%) patients in OP group satisfied downstage ( P=0.038). The median disease-free survival (DFS) was 27.91 months in CCRT group, and 45.96 months in OP group ( P=0.985). The median overall survival (OS) was not reached in CCRT group, and 51.2 months in OR group ( P=0.335). There were no statistically significant differences between neoadjuvant CCRT and surgery group in the aspect of both hematologic and non-hematologic adverse events. Conclusions: In this study, neoadjuvant SP based CCRT significantly increased downstaging in T stage compared than OP alone. The prespecified genomic analysis with transcriptomic sequencing will be available at the meeting. Clinical trial information: NCT03814759 .
Extracellular (EC) Mucin5AC (MUC5AC) detection after neoadjuvant therapy (NAT) and the risk of recurrence in resected pancreatic ductal adenocarcinoma (R-PDA).
Authors: Manne Ashish , Esnakula Ashwini K. , Sheel Ankur , Sara Amir , He Kai , Cloyd Jordan M. , Noonan Anne M. , Hays John L. , Roychowdhury Sameek , Mittra Arjun , Malalur Pannaga G. , Jin Ning , Rahman Shafia , Tsai Susan , Dillhoff Mary , Yang Wancai , Yu Lianbo
Published: June 2024

4171

Background: The clinical significance of MUC5AC glycoforms is unclear to date. Our earlier study showed the association of lower mature (MM) and immature (IM) MUC5AC in R-PDA with pathological treatment response and EC detection of MM (EC-MM). Here, we have the significance of EC-MM detection in the tissue of R-PDA post-NAT. Methods: Formalin-fixed paraffin-embedded tissue blocks of R-PDA from January 2010 to June 2021 were obtained from the Ohio State University biorepository. Using monoclonal antibodies for 45M1 (MM) and CLH2 (IM), immunohistochemistry was performed to study the cellular expression of MM and IM, and H-scores were calculated. Also, the presence or absence of EC expression of MM is noted. progression-free survival (PFS) and overall survival (OS) were the primary endpoints. Univariate and multivariate Cox regression models were used to model PFS and OS, and clinical and pathological variables were adjusted in the multivariate models. We performed univariate logistic regression analysis to examine the impact of MUC5AC expression on pathological features in resected specimens. Results: Among 100 R-PDA patients, 43 received NAT and 57 had upfront surgery (UpS)). In NAT-group (36-FOLFIRINOX, 2-FOLFOX, and 5-gemcitabine/nab-paclitaxel), EC-MM detection in the resected specimens was associated with worse PFS on multivariate analysis (MVA) (Hazard Ratio (HR) 0.2, 95 % CI: 0.059-0.766, p = 0.01). In the FOLFIRINOX-treated group, the EC-MM detection had a similar impact (HR 0.2, 95 % CI: 0.052-0.847, p = 0.02) on PFS. Cellular MM and IM expression were significant (p < 0.05) on MVA for OS in both groups, but the HRs were not clinically significant (NAT-group, MM - 0.9 & IM - 1.04, FOLFIRNIOX-group, MM - 0.8 & IM -1.02). Expression levels of cellular MM and IM in FOLFIRINOX group and MM alone in NAT-group significantly (p < 0.05) correlated with incomplete resection (R1/R2 vs R0) and perineural invasion. In the UpS group, MUC5AC glycoforms did not significantly correlate with survival or pathological features. Conclusions: Post NAT EC-MM detection and cellular MUC5AC (MM and IM) expression levels are associated with worse PFS and pathological features. Their role in the treatment of naïve patients is still unclear. MUC5AC can be a clinically useful predictive biomarker. Future research should focus examining its importance in advanced tumors and manipulating it for therapeutic purposes.
Effect of tocotrienol and tocopherol regulation by the microbiome on colitis-associated cancer.
Authors: Stafford Amanda , Lam Jie (James) Min , Basgaran Amedra , Lymberopoulos Eva , Tanweer Mohammad , Hobbs Michael , Arney James , Korovilas Dionisios , Delanoue David , Moore Stephen , Alomari Muhannad , Sharma Nikhil
Published: June 2024

e15512

Background: The association between inflammatory bowel disease (IBD) and a higher risk of colorectal cancer (CRC) has been well established, and is commonly attributed to chronic inflammation and a predisposition to genomic instability ( Feagins et al., 2009 ). Independently, an altered gut microbiome has been evidenced in both IBD ( Halfvarson et al., 2017 ) and CRC ( Marchesi et al., 2011 ). It is unknown whether the altered the IBD-associated microbiome is able to directly influence carcinogenesis via an inflammation-independent mechanisms. Methods: Microbiome analysis was performed using BioCorteX’s industry-leading knowledge graph and integrated proprietary engines v20240126_153156. 2,081 stool samples from adults with IBD and 2,000 stool samples from healthy adults were included. Shannon’s Diversity Index was used to consider within-sample diversity, and PERMANOVA and dimensional scaling based (MDS) on Bray-Curtis diversity was used to consider between-sample diversity. Differential abundance analysis was used to identify species significantly associated with IBD, and a database built on existing literature was used to consider their metabolic products and interactions with known human oncogenes and tumour suppressor genes. Results: Our results show a clearly separation of the IBD microbiome from the healthy population (PERMANOVA p = 0.01), as well as a collapse in Shannon diversity (p < 2.2e-16). Compared to the healthy microbiome, 79 species were significantly (FDR < 0.01) enriched in the IBD stool microbiome, including: Bacteroides fragilis, Bacteroides vulgatus, Bacteroides uniformis, Escherichia coli, Veillonella parvula, Enterococcus faecalis, Fusobacterium mortiferum, and Fusobacterium ulcerans, all of which have previously been evidenced to be enriched in CRC ( Randa et al., 2023 , Bi et al., 2022 , Du et al., 2022 ). Conversely, 115 species were enriched in healthy subjects, including several bacteria with probiotic and anti-tumourigeneic potential such as: Segatella copri, Roseburia inulinivorans, Lactobacillus rogosae, and Coprococcus comes ( Sarah et al., 2022 , Kang et al., 2023 , Campisciano et al., 2020 , Yang et al., 2019 ) Two of the bacteria enriched in the healthy group are producers of both delta-tocotrienol and gamma-tocopherol. These vitamin E isoforms have been implicated in suppression of cancer invasion and proliferation ( Ya et al., 2008 ), in part through NFkB signalling ( Ling et al., 2012 ). Conclusions: This work suggests that that IBD-associated microbiome may contribute to colorectal cancer risk via the suppression of vitamin E isoform signalling, a mechanism that is independent from inflammation. This could present a highly targetable way of mediating CRC-risk in the IBD population.
Exploring young-onset colorectal cancer sex difference incidence rates by race and ethnicity: A SEER database analysis (2000-2020).
Authors: Hechter Sharon , Appiah Jennifer , Kanukuntla Anish Kumar , Alnaser Ibrahim , Eliachevsky Christina , Ji Sophia , Nair Ambica , Greenberg David B.
Published: June 2024

e15529

Background: Since 1994, there has been a 51% increase in young onset colorectal cancer incidence rates, as reported by the National Cancer Institute. Recently, the U.S. Preventative Task Force revised its guidelines, recommending colorectal cancer screening to commence at age 45 rather than 50. This study aimed to explore sex differences in cancer incidence across various race and ethnicities, aiming to discern whether these differences are rooted in biological factors or environmental exposures. Methods: Cancer incidence data from the Surveillance, Epidemiology and End Result (SEER) program (2000-2020) was used to calculate male-to-female incidence rate ratios (MF IRR) for colon and rectal cancer, stratified by race and ethnicity (non-Hispanic White, non-Hispanic Black, non-Hispanic Asian/Pacific Islander, American Indian/Alaskan Native, and Hispanic), and age-standardized to the 2000 U.S. population for individuals under the age of 50 diagnosed with colon or rectal cancer. Results: A total of 82,238 patients with colorectal cancer under the age of 50 were identified in the study period. Of these, 43,255 (52.6%) were males and 38,983 (47.4%) were females. The incidence trends over the years were analyzed, revealing a steady increase, with the highest incidence found in 2019 (4,819, 5.8%) and the lowest in 2000 (3,189, 3.8%). Non-Hispanic Whites comprised 57.2% of the cases, while the second and third largest groups were Non-Hispanic Black (13.2%) and Hispanic (17.9%). Incidence rates were highest among the non-Hispanic American Indian/Alaskan Native population (8.6 per 100,000 cases), followed by the non-Hispanic Black population (8.4 per 100,000 cases), and lowest in the Hispanic population (5.7 per 100,000 cases). Young-onset colorectal cancer incidence rates exhibited a male predominance, with the MF IRR consistently > 1 every year across race and ethnicity. Non-Hispanic Asian/Pacific Islander had the highest MF IRRs (7 per 100,000 cases in males vs. 5.8 per 100,000 cases in females), while Non-Hispanic American Indian/Alaskan Native had the lowest MF IRRs throughout the years, with the lowest being in 2019 (5.1 per 100,000 cases in males vs. 12.6 per 100,000 cases in females). Conclusions: The MF IRR for young onset colorectal cancer showed no significant variation by race, implying a potential influence of biological factors. Notably, disparities in incidence rates were observed among different racial and ethnic groups, with the highest rates among non-Hispanic Black and non-Hispanic American Indian/Alaskan Native populations. Further research is warranted to pinpoint specific factors driving young onset colorectal cancer, facilitating targeted interventions for at-risk populations.
Study of ELU001, a C’Dot drug conjugate (CDC) targeting folate receptor α (FRα) overexpressing solid tumors.
Authors: Ma Wen Wee , Tolcher Anthony W. , Perez Cesar Augusto , Wahner Hendrickson Andrea Elisabeth , Orr Douglas W. , Murciano-Goroff Yonina R. , Anders Carey K. , Hamilton Erika P. , Swisher Elizabeth M. , Mathews Cara Amanda , Bashir Babar , Rojas-Espaillat Luis Alexander , Colon-Otero Gerardo , Adams Gregory Paul , Reddick Catherine W. , Bayever Eliel
Published: June 2024

TPS3173

Background: ELU001, pasifolate exatecan, is an ultra-small nanoparticle drug conjugate, known as a CDC (~6 nm), designed to target and penetrate into solid tumors. Due to its size, ELU001 exhibits rapid renal elimination which is expected to reduce or eliminate the toxicities associated with many antibody drug conjugates. ELU001 has ~13 folic acid targeting moieties and ~21 cathepsin-B cleavable exatecan topoisomerase-1 inhibitor payloads covalently bound to short polyethylene glycol chains surrounding a silica core, the C’Dot. ELU001 binds to cancer cells expressing FRα and is internalized into the lysosome where it releases the exatecan payload. ELU001’s dose escalation study reported at ESMO Congress 2023 (1), examined weekly, bi-weekly (Q2W), and tri-weekly schedules over a range of doses in 42 patients. The study revealed that ELU001 could be administered safely and identified a dose level and schedule for the Expansion Studies described below. 22 of the patients with ovarian or endometrial cancers had >1 post-baseline scan(s), of these 2 had a PR and 19 had SD by RECIST v1.1 criteria. ELU001 demonstrated activity against tumors across a range of FRα expression levels, from low to high, retrospectively assessed using the VENTANA FOLR1 RxDx assay and the PS2+ scoring system. Methods: The current multicenter, Tumor Group Expansion open-label phase 1/2 clinical trial investigates ELU001 in patients with ovarian and endometrial cancers and is enrolling three cohorts; 1) ovarian cancer with high FRα expression, 2) ovarian cancer with moderate and low expression and 3) endometrial cancer with low to high expression with assessments based upon the PS2+ scoring system (high = ≥ 75%, moderate = ≥ 50% to < 75%, low = 25% to < 50%, negative = <25% of tumor cells with 2+ or 3+ staining intensity). An initial exploratory dose of 2.0 mg/m2 Q2W was employed in all three cohorts and a second dose of 1.7 mg/m2 Q2W will be studied in the ovarian cancer cohorts. Patients will ultimately be randomized to one of two or more doses to optimize dosing for registration. Primary endpoint: Objective Response Rate (ORR); secondary endpoints include DOR, PFS, TFST, PFS2, OS, adverse events, PK, and ADA assessments. Approximately 20 patients per tumor group will be recruited in the U.S. 1. Ann. Oncol. (2023) 34 (suppl_2): S458-S497. Clinical trial information: NCT05001282 .